Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:5]=12.C1COCC1>CO>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][OH:31])=[CH:32][CH:33]=3)[N:11]=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[C:5]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(CO)cc1
Reaction time: 16 h
Yield: 35.9 %

Procedure:
Sodium borohydride (19 mg, 0.491 mmol) was added to a solution of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde (100 mg, 0.245 mmol) in methanol (2 mL). After 16 hours, THF (1 mL) and more sodium borohydride (19 mg, 0.491 mmol) was added. 5 hours later, the solvent was removed and water was added. The aqueous layer was extracted with dichloromathane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using ethyl acetate/dichloromethane (80:20 to 100:0) as mobile phase to give {4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]phenyl}methanol (36 mg, 36%).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH:18]=[CH:19][C:20]3[C:25]([C:16]=2[S:15][C:14]=1SC)=[CH:24][CH:23]=[CH:22][CH:21]=3.[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[CH2:41][S:40][C:39]1=[S:44].C(#N)C>C(N(CC)CC)C>[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41](=[C:14]2[N:13]([CH3:12])[C:17]3[CH:18]=[CH:19][C:20]4[C:25]([C:16]=3[S:15]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:40][C:39]1=[S:44]
Reactant: COCCOCCOCCN1C(=O)CSC1=S
Reactant: CSc1sc2c3ccccc3ccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCOCCOCCN1C(=O)C(=C2Sc3c(ccc4ccccc34)N2C)SC1=S
Temperature: 5 °C
Reaction time: 4 h

Procedure:
2.5 g of 3-methyl-2-methylthionaphtho[2,1-d]thiazolium p-toluenesulfonate (synthesized from 2-methylthionaphtho[2,1-d]thiazole and methyl p-toluenesulfonate), 1.7 g of 3-methoxyethoxyethoxyethylthiazolidine-4-on-2-thion and 30 ml of acetonitrile were fed into a 100 ml three-necked flask, and cooled to 5° C. 1.2 g of triethylamine was added to the resultant mixture. After stirring at 10° C. for 4 hours, yellow precipitates thus formed were suction-filtered, washed with 10 ml of acetonitrile twice and dried to obtain the intended compound.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[CH:17][C:18]([Br:20])=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[CH:17][C:18]([Br:20])=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(Br)cc2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc2c(c1)OCCN(Cc1ccccc1)C2
Temperature: 65 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of 4-benzyl-8-bromo-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (4.50 g, 13.5 mmol) in tetrahydrofuran (45 ml) was added 1M borane-tetrahydrofuran solution (54 ml, 54.0 mmol), and the mixture was stirred at 65° C. for 4 hr. Under ice-cooling, methanol (135 ml) and sodium hydroxide (11.7 g, 294 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The residue was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product (4.30 g, 100%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[N:45][CH:46]=1>O1CCOCC1.C(Cl)(Cl)Cl>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:6]1[N:5]=[C:4]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=2)[N:3]=[C:2]([NH:39][CH2:40][C:41]2[CH:46]=[N:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[N:7]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Fc1cccc(Cl)c1-c1nc(Cl)nc(NN=Cc2ccc(OC(F)(F)F)cc2)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1cccc(Cl)c1-c1nc(NCc2ccc(Cl)nc2)nc(NN=Cc2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of 2-chloro-4-(2-chloro-6-fluorophenyl)-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)-1,3,5-triazine (XVII) (250 mg, 0.56 mmol) in 1,4-dioxane (2 mL) was treated with a solution of iPr2NEt (144.8 mg, 1.12 mmol) in 1,4-dioxane (1 mL). The mixture was treated with a solution of 5-aminomethyl-2-chloropyridine (80.37 mg, 0.564 mmol) in 1,4-dioxane (1 mL). The reaction was stirred overnight at room temperature. The reaction was concentrated on a rotary evaporator and the residue was taken up in ethyl acetate and washed with brine. The aqueous layer was extracted twice with ethyl acetate. The combined organics was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield a white solid. The solid was taken up in chloroform and loaded onto 100 g of silica gel. The silica gel was eluted with ethyl acetate/hexanes (30%, 40%, 50%, 70%). The appropriate fractions were concentrated on a rotary evaporator to yield 4-(2-chloro-6-fluorophenyl)-N-((6-chloropyridin-3-yl)methyl)-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)-1,3,5-triazin-2-amine (Example 22) as a white solid (305 mg). ESI/MS 552.3, 554.2 (M+H), 550.4, 552.4 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:20]=3)(=[O:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(Cl)cc2)c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccc(Cl)cc2)c1
Yield: 92 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with [3-(4-chlorophenyl)phenyl]sulfonyl chloride (15.8 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 92% yield (18.9 mg). MS (ESI+) calcd mass for C19H14ClN5O2S 411.055673, found 411.055743.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:26]1[CH2:27][CH2:28][C:23]([F:22])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][CH2:25]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: FC1(c2ccccc2)CCNCC1
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(F)(c2ccccc2)CC1
Yield: 86.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.500 g, 1.44 mmol) obtained in Example 22, step 3 and 4-fluoro-4-phenylpiperidine (WO2002/13824, 0.340 g, 1.73 mmol), the title compound (0.630 g, 86%) was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:21][C:20]1[CH:19]=[CH:18][C:17]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[CH:16][C:15]=1[NH:14][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Reactant: O=C(O)c1ccc2ncccc2c1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(NC(=O)c3ccc4ncccc4c3)c2)cc1
Yield: 18 %

Procedure:
Using an analogous procedure to that described in Example 3, quinoline-6-carboxylic acid was reacted with N-(3-amino-4-chlorophenyl)-4-cyanobenzamide. The crude reaction product was purified by column chromatography on silica using a 97:3 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound in 18% yield; NMR Spectrum: (DMSOd6) 7.58 (d, 1H), 7.62 (m, 1H), 7.77 (m, 1H), 8.01 (d, 2H), 8.12 (t, 4H), 8.28 (d, 2H), 8.56 (d, 1H), 8.67 (s, 1H), 9.01 (d, 1H), 10.34 (s, 1H), 10.67 (s, 1H); Mass Spectrum: M−H− 425.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.[CH2:19]=O.[BH4-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: C=O
Reactant: COc1ccc(C2CCCNC2)c2c1NC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2CCCN(C)C2)c2c1NC(=O)C2
Temperature: 5 °C

Procedure:
4.5 g of the product of Example 1 were dissolved in 100 ml of methanol with stirring under an inert atmosphere and after cooling to about 5° C., 3.4 ml of 40% formic aldehyde were added dropwise. After stirring for 1 hour, 1.8 g of 95% sodium borohydride were added in small fractions and the mixture was stirred for 1 hour. The temperature was allowed to return to ambient and after diluting with iced water, extracting with methylene chloride, drying and evaporating to dryness under reduced pressure, filtering, washing with ether and drying, 4 g of 1,3-dihydro-7-methoxy-4-(1-methyl-3-piperidinyl)-2H-indol-2-one were obtained in the form of a base melting at ≃170° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:13][NH:12][CH2:11]1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][N:40]([C:43](Cl)=[O:44])[CH2:39][CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:13][N:12]([C:43]([N:40]2[CH2:39][CH2:38][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:42][CH2:41]2)=[O:44])[CH2:11]1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.6 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid tert-butyl ester (0.25 g, 0.69 mmol) in CH2Cl2 (5 ml) was added ethyl-diisopropyl-amine (0.20 ml, 1.1 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (189 mg, 0.83 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc) afforded 0.37 g (97%) of the title compound as a white solid. ES-MS m/e: 549.3 (M+H+).
Reaction SMILES: [NH:1]1[C:7](=[O:8])[CH2:6][CH2:5][NH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[O:8]=[C:7]1[N:1]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[NH:4][CH2:5][CH2:6]1
Reactant: COC(=O)CBr
Reactant: O=C1CCNc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCNc2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one (5.0 g, 30.8 mmol) in DMF (30 ml), at −10° C., was added sodium hydride (1.35 g, 60% dispersion, 33.9 mmol). The mixture was stirred at −10° C. for 15 min, then methyl bromoacetate (2.92 ml, 30.8 mmol) was added. The mixture was stirred at −10° C. for a further 1 h and then concentrated in vacuo. The residue was taken up in EtOAc and washed with brine (3 times), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 7.08 g (98%).
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.N1C2C(=CC=CC=2)C(=O)C1=O.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=O)C2=O>>[F:25][C:26]1[CH:34]=[C:33]2[C:32](=[CH:28][CH:27]=1)[N:31]=[C:30]1[C:7](=[O:9])[C:6]3[C:5]([N:11]1[C:10]2=[O:12])=[CH:4][CH:3]=[CH:2][CH:13]=3
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1c2ccccc2-n2c1nc1ccc(F)cc1c2=O
Yield: 57 %

Procedure:
Using the procedure in Example 12, and substituting 5-fluoroisatoic anhydride for 5-chloroisatoic anhydride and isatin for 5-fluoroisatin gave 650 mg (57%) of the title compound: mp 295° C. (dec); 1H NMR (DMSO-d6) δ 7.48-7.54 (m, 1H), 7.82-7.94 (m, 3H), 8.02-8.08 (m, 2H), 8.46-8.51 (m, 1H); MS (M+H)+ 267.1.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH:9]([NH:12][C:13]3[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]4[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=4)[N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C.O>[Cl:19][C:18]1[C:13]([NH:12][CH:9]2[CH2:10][CH2:11][C:6]3([CH2:5][CH2:4][N:3]([C:32](=[O:33])[CH2:31][C:29]#[N:30])[CH2:2][CH2:1]3)[CH2:7][CH2:8]2)=[N:14][C:15]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=2)=[N:16][CH:17]=1
Reactant: N#CCC(=O)O
Reactant: OCCn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
To a solution of 2-[4-[[4-(3-azaspiro[5.5]undecan-9-ylamino)-5-chloropyrimidin-2-yl]amino]-1H-pyrazol-1-yl]ethanol (200.5 mg, 0.4940 mmol) in a mixture of dichloromethane (40 mL) and DMF (10 mL) were added 2-cyanoacetic acid (46.5 mg, 0.547 mmol), HATU (375.2 mg, 0.9868 mmol) and TEA (100.5 mg, 0.9932 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL), and extracted with DCM/MeOH (10/1, 50 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the product as a yellow solid (105 mg, 44.94%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:25][CH2:26][C@@H:27]([C:43]([O:45]C(C)(C)C)=[O:44])[NH:28][C:29]([O:31][CH2:32][C:33]23[CH2:42][CH:37]4[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]4)[CH2:34]2)[CH2:40]3)=[O:30])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH3:2].FC(F)(F)C(O)=O.ClCCl.CO.O.C(O)(=O)C.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[C:4]([NH:25][CH2:26][C@@H:27]([C:43]([OH:45])=[O:44])[NH:28][C:29]([O:31][CH2:32][C:33]23[CH2:34][CH:35]4[CH2:41][CH:39]([CH2:38][CH:37]([CH2:36]4)[CH2:42]2)[CH2:40]3)=[O:30])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[CH3:2]
Reactant: CCc1c(NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1c(NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 61 %

Procedure:
130 mg (0.19 mmoles) of (1,1-dimethylethyl) 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(adamantylmethoxy)carbonyl]alaninate in 20 ml of dichloromethane with 2 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH—H2O—AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 368 mg (Yield=61% expressed as ditrifluoroacetate) of expected product is obtained in the form of an amorphous solid.
Reaction SMILES: [C:1]([CH2:3][C:4]12[CH:20]=[CH:19][CH:18]=[CH:17][CH:5]1C(N(C1C=CC=CC=1)C2=O)=O)#[N:2].C(C[NH2:24])O>>[NH2:24][C:5]1[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: NCCO
Reactant: N#CCC12C=CC=CC1C(=O)N(c1ccccc1)C2=O
Product: N#CCc1ccccc1N
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
100 g of 2-cyanomethyl-N-phenylphthalimide were introduced, a little at a time, into 100 g of monoethanolamine at 80° C. After 10 minutes, the mixture was cooled to 20° C., and 400 g of ice water were added dropwise. The precipitated product was filtered off under suction and washed neutral with ice water.
Reaction SMILES: Br.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:14][C:11]2[S:12][CH:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][CH:7]=3)[N:10]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A mixture of 0.5 g 4-(4-methyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.39 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted twice with 50 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.46 g of 4-methyl-N-[4-(4-methyl-phenyl)-thiazol-2-yl]-benzenesulfonamide was obtained as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)cc4F)c3c2s1
Yield: 68 %

Procedure:
Prepared from VII and 2,4-difluoroaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 68%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2228, 1645, 1611, 1583, 1557, 1488, 1460, 1378, 1357, 1311, 1276, 1260, 1172, 1138, 1091, 962, 854, 831, 818; 19F NMR (282 MHz, DMSO-d6) δ −117.6, −118.7; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.22 (s, 1H), 7.78 (d, 1H, J=9.0 Hz), 7.35-7.24 (m, 2H), 7.06 (t, 1H, J=7.8 Hz); HRMS calcd for C16H8N5SF2 (M+H+): 340.0468, found 340.0458.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:25])=[C:8]([C:16]([C:18]3[CH:19]=[N:20][N:21]([CH3:24])[C:22]=3[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])=[N:2]1.C(N(CC)CC)C.[CH3:33][CH2:34][S:35][C:36](Cl)=[O:37].C(OCC)(=O)C>O1CCCC1>[CH3:25][C:7]1[C:6]([C:3]2[CH2:4][CH2:5][O:1][N:2]=2)=[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:9][C:8]=1[C:16]([C:18]1[CH:19]=[N:20][N:21]([CH3:24])[C:22]=1[O:23][C:36]([S:35][CH2:34][CH3:33])=[O:37])=[O:17]
Reactant: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1C1=NOCC1
Reactant: CCSC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2C)cnn1C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 5-hydroxy-1-methylpyrazol-4-yl 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylsulfonyl)phenyl ketone (100 mg, 2.75×10−4 mol) in anhydrous tetrahydrofuran (5 mL) were added triethylamine (55 mg) and 96% S-ethyl chlorothiolformate (45 mg) at room temperature. After the reaction solution was stirred for 1 hour, 150 mL of ethyl acetate was added, and the solution was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:4) to obtain the desired product (82 mg) as an oil.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9]([O:10][C:11]3[N:44](COCC[Si](C)(C)C)[C:14]4=[N:15][C:16]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6[CH:31]=[CH:30][C:29]([S:32]([N:41]([CH3:43])[CH3:42])(=[O:40])=[N:33]C(=O)C(F)(F)F)=[CH:28][CH:27]=6)=[CH:22][CH:21]=5)=[C:17]([Cl:19])[CH:18]=[C:13]4[N:12]=3)[C@H:5]2[O:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9]([O:10][C:11]3[NH:44][C:14]4=[N:15][C:16]([C:20]5[CH:21]=[CH:22][C:23]([C:26]6[CH:27]=[CH:28][C:29]([S:32](=[NH:33])([N:41]([CH3:42])[CH3:43])=[O:40])=[CH:30][CH:31]=6)=[CH:24][CH:25]=5)=[C:17]([Cl:19])[CH:18]=[C:13]4[N:12]=3)[C@H:5]2[O:4][CH2:3]1
Reactant: CN(C)S(=O)(=NC(=O)C(F)(F)F)c1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)S(=N)(=O)c1ccc(-c2ccc(-c3nc4[nH]c(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)nc4cc3Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of N-({4-[4-(2-{[(3R,3aR,6R,6aR)-6-hydroxy-hexahydrofuro[3,2-b]furan-3-yl]oxy}-6-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}imidazo[4,5-b]pyridin-5-yl)phenyl]-phenyl}(dimethylamino)oxo-λ6-sulfanylidene)-2,2,2-trifluoroacetamide (22 mg) and trifluoroacetic acid (0.30 mL) in dichloromethane (1.00 mL) is stirred over night at room temperature. The reaction mixture is concentrated in vacuo and the residue is dissolved in methanol. Aqueous Na2CO3 solution (2 N; 60 μL) is added and the mixture is stirred for 1 h. The reaction mixture is filtered and the crude product is purified by preparative HPLC to give the title compound. LC (method 1): tR=0.86 min; Mass spectrum (ESI+): m/z=556 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11](O)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][N:16]1CCOCC1.C(OC(Cl)=O)C(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([NH:16][CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
N-(tert-butoxycarbonyl)-2-methylalanine (2.87 g, 14.13 mmol) was dissolved in THF (20 ml) and cooled to −10° C. (acetone/ice). N-methylmorpholine (2.14 g, 21.2 mmol) was added followed by iso-butylchloroformate (2.12 g, 15.5 mmol, 1.1 equivalents) over a period of 3 minutes. The reaction mixture was allowed to stir for 10 minutes, split in two equal halves (approximately 12 ml each). One sample was treated with methylamine in THF (5 ml of 2.0M solution) and the resulting mixture was evaporated to dryness. The residues were re-dissolved in dichloromethane (30 ml), washed with water, saturated aqueous sodium hydrogen carbonate, water, dried over magnesium sulfate and evaporated to dryness to give N2-(tert-butoxycarbonyl)-N1,2-dimethylalaninamide (0.67 g, 42.6%), which was used without further purification, 1H NMR Spectrum: (DMSO-d6) 1.29 (s, 6H), 1.37 (s, 9H), 2.50 (s, 3H), 6.57 (br s, 1H), 6.93 (br s, 1H)