Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30](C(OCC4C=CC=CC=4)=O)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[CH3:13][N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cccc(-c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cccc(-c2ccc(N3CCNCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
Benzyl 4-[3′-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)biphenyl-4-yl]piperazine-1-carboxylate (1.5 g) was dissolved in a mixed solution of MeOH (15 ml) and THF (15 ml). 10% Pd—C (150 mg) was added thereto, followed by stirring at room temperature for 1 day under a hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration assistant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl (2-{methyl [(4′-piperazin-1-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (860 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13]3[NH:14][CH2:15][CH2:16][N:17]=3)=[CH:10][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24]Br>>[BrH:24].[Br:24][C:10]1[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]=1[NH:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1
Reactant: c1ccc(-c2cc(NC3=NCCN3)n(-c3ccccc3)n2)cc1
Reactant: BrBr
Product: Br
Product: Brc1c(-c2ccccc2)nn(-c2ccccc2)c1NC1=NCCN1

Procedure:
2(1,3-diphenyl-5-pyrazolyl) amino-2-imidazoline (6.0 g.) was treated with 3.2 g. bromine as described in Example III to give 8.85 g. of the product, mp 273° C., decomposed.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9](B3OCCCO3)[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][CH:28]=[CH:27]4)[CH:8]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2n1-c1cccc(B2OCCCO2)c1
Reactant: Brc1ccc2[nH]ccc2c1
Product: Nc1nc2ccccc2n1-c1cccc(-c2ccc3[nH]ccc3c2)c1

Procedure:
2-Amino-1-[3-(5-indolyl)phenyl]benzimidazole was prepared from 3-(2-amino-1-benzimidazolyl)-phenyl-1,3,2-dioxaborinane and 5-bromoindole according to method A. mp 120°-123° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:26][OH:27])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@@H:30]([NH2:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22]([NH:32][C@@H:30]([CH3:31])[C:29]([F:34])([F:33])[F:28])=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:26][OH:27])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1c1ccn2ncc(C(=O)O)c2n1
Product: C[C@H](NC(=O)c1cnn2ccc(N3[C@@H](c4cncc(F)c4)CC[C@@]3(C)CO)nc12)C(F)(F)F

Procedure:
Prepared according to the method of Example 212, Step F, using 54(2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 219, Step F) and (S)-1,1,1-trifluoropropan-2-amine. The title compound was obtained as a white solid (5.4 mg, 31% yield). MS (apci) m/z=467.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[C:15](OCC)(=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].Cl>C(O)C.C(Cl)Cl.O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]2[C:1](=[O:3])[CH:2]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:14][C:5]=2[CH:6]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccc(N)cc2o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.3 %

Procedure:
A mixture of N-[4-acetyl-3-hydroxyphenyl)acetamide (24.1 g, 0.125 mol) and diethyl oxalate (47.5 g, 0.33 mol) in absolute ethanol (200 mL) was added to a solution of sodium ethoxide (14 g sodium in 300 mL absolute ethanol). The reaction was heated to reflux for 2 hours and allowed to cool to room temperature then poured into water (500 mL) and methylene chloride (1500 mL). The aqueous layer was made slightly acidic using 6N hydrochloric acid. The organic layer separated and the aqueous layer washed again using methylene chloride (500 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. The solid material (35.8 g) was dissolved in ethanol (350 mL) and concentrated hydrochloric acid (6 mL) was added. The solution was heated to reflux for 1 day, removed from heat and allowed to stand for 2 days. The orange solid was filtered to afford 17 g of ethyl 7-amino-4-oxo-4H-1-benzopyran-2-carboxylate. The mother liquor was concentrated to afford another 4.94 g of desired product. Yield 75.6%, 1H NMR (DMSO-d6) δ 1.32 (3H, t, J=7.25 Hz, CH2CH3,), 4.34 (2H, q, J=7.03 Hz, CH2CH3), 6.50 (2H, bs, NH2), 6.53 (1H, d, J=1.98 Hz, =CH), 6.69 (1H, dd, J=8.78, 1.98 Hz, ArH), 6.71 (1H, s, ArH), 7.68 (1H, d, J=8.78 Hz, ArH); MS (EI) m/z, 233 (M+).
Reaction SMILES: C(N=C(NC(OCC1C=CC=CC=1)=O)NCCCCC(O)=O)(OCC1C=CC=CC=1)=O.[C:32]([O:35][CH:36]1[N:39]([C:40](=[O:42])[CH3:41])[C:38](=[O:43])[CH:37]1[CH2:44][CH2:45][CH2:46][NH:47][C:48]([NH:60]C(OCC1C=CC=CC=1)=O)=[N:49]C(OCC1C=CC=CC=1)=O)(=[O:34])[CH3:33].[ClH:71].[H][H]>[Pd]>[ClH:71].[C:32]([O:35][CH:36]1[N:39]([C:40](=[O:42])[CH3:41])[C:38](=[O:43])[CH:37]1[CH2:44][CH2:45][CH2:46][NH:47][C:48]([NH2:60])=[NH:49])(=[O:34])[CH3:33]
Reactant: [H][H]
Reactant: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Agent: O=C(O)CCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Product: CC(=O)OC1C(CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 71 %

Procedure:
A methanol/ethyl acetate (1:1/5 mL:5 mL) solution of compound 40 (420 mg, 0.78 mmol) and 1N HCl (0.76 mL), containing 10% palladium on carbon, was shaken in a Parr hydrogenator at 45 psi hydrogen pressure for 2 h. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 170 mg (71%) of the title product as a mixture of trans and cis (2:1) isomers.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(O)C.O.CC(C)=O>[ClH:1].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: C1CNCC(CCCN2CCOCC2)C1
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: Cl
Product: O=C1Nc2cccnc2N(C(=O)N2CCCC(CCCN3CCOCC3)C2)c2ccccc21
Yield: 61 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[3-(4-morpholinyl)propyl]piperidine in a yield of 61% of theory. Colourless crystals, m.p. >260° C. (from ethanol/water/acetone).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[OH:15])=[O:4].Cl.C[NH:18]OC.Cl.C(=O)(O)[O-].[Na+].[O:27]1[CH2:31]CC[CH2:28]1>>[CH3:28][O:27][CH2:31][NH:18][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[OH:15])=[O:4]
Reactant: CNOC
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2ncnc(O)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCNC(=O)c1ccc2ncnc(O)c2c1
Reaction time: 0.5 h

Procedure:
4-Hydroxyquinazoline-6-carboxylic acid methyl ester (XII-1, 4.0 g) was dissolved in tetrahydrofuran (120 ml), N,O-dimethylhydroxylamine hydrochloride (5.7 g) was added, and 2 mol/L iPrMgCl tetrahydrofuran solution (59 ml) was added dropwise over 30 minutes. After completion of addition, the mixture was stirred for 30 minutes under ice cooling and, after completion of the reaction, 40 ml of 2 mol/L hydrochloric acid was added dropwise. The mixture was neutralized with aqueous saturated sodium bicarbonate solution, and extracted with chloroform, and the organic layer was washed with aqueous sodium chloride solution, and dried over sodium sulfate. After concentration, the crystalline residue was purified by silica gel column chromatography (eluting ethyl acetate: methanol=9:1) to obtain 4-hydroxyquinazoline-6-carboxylic acid methoxymethylamide (XIII-1, 2.9 g) as a white solid.
Reaction SMILES: [CH:1]1([N:4]([CH:25]2[CH2:27][CH2:26]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([N:19]=[C:20]=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl.[C:29]([NH2:32])(=[NH:31])[CH3:30].CCN(C(C)C)C(C)C.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[CH:25]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:22]([CH2:23][CH3:24])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][N:32]=[C:29]([CH3:30])[N:31]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:26][CH2:27]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N=C=S)nc21
Reactant: CC(=N)N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)ns3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
A mixture of N,N-dicyclopropyl-6-ethyl-4-isothiocyanato-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 121B, 0.042 g, 0.111 mmol), acetamidine hydrochloride (10.49 mg, 0.111 mmol), and Hünig's Base (0.058 mL, 0.333 mmol) in DMF (0.617 mL) was stirred at rt ON. Diethyl azodicarboxylate (0.088 mL, 0.222 mmol) was added and stirring continued at room temperature for 16 h. The reaction mixture was concentrated. The residue was taken up in MeOH and purified by preparative HPLC. N,N-Dicyclopropyl-6-ethyl-1-methyl-4-(3-methyl-1,2,4-thiadiazol-5-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (4.32 mg, 9% yield) was isolated as a pale yellow solid.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)=[CH:10][C:9]=1[F:19])(=[O:5])=[O:4])[CH3:2].[C:20]1([CH3:38])[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=[C:28]([C:34]([F:37])([F:36])[F:35])[N:27]=2)[CH:21]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([NH:33][CH2:32][C:31]2[C:26]([C:22]3[CH:21]=[C:20]([CH3:38])[CH:25]=[CH:24][CH:23]=3)=[N:27][C:28]([C:34]([F:37])([F:35])[F:36])=[CH:29][CH:30]=2)=[O:17])=[CH:10][C:9]=1[F:19])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)cc1F
Reaction time: 8 h

Procedure:
2-(4-(Ethylsulfonamidomethyl)-3-fluorophenyl)propanoic acid (60 mg, 0.207 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (61 mg, 0.228 mmol) was dissolved and mixed in 1,4-dioxane, followed by addition of N-hydroxybenzotriazole (42 mg, 0.311 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (60 mg, 0.311 mmol) and triethylamine (0.07 mL, 0.518 mmol). The reaction mixture was stirred for overnight and then quenched by water and extracted with ethyl acetate. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 83) in pure form (52 mg, 47%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>CC#N>[CH3:33][O:34][CH2:35][CH2:36][NH:37][C:19]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=1)=[O:20]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: COCCN
Solvent: CC#N
Product: COCCNC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (170 mg, 384 μmol, example 88) in MeCN (0.2 mL) was added 2-methoxyethylamine (36.7 μL, 423 μmol). The resulting mixture was then subjected to a microwave irradiation at 180° C. for 15 min. Then, 2-methoxy-ethylamine (0.02 mL) was added and the mixture was subjected to a microwave irradiation at 180° C. for an additional 15 min. Then, the solvent was removed and the residue was dissolved in a solution of DMSO and MeOH (1:1, 1.0 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (2.0 mL). The solution was washed through PL-HCO3 MP resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 379 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:13])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:14](OC)(OC)OC.[CH3:21][O:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.CO>C(O)(=O)C>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH:14]=[C:3]1[C:2]([CH3:1])=[N:6][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]1=[O:13]
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: COc1ccccc1N
Reactant: COC(OC)OC
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1NC=C1C(=O)N(c2ccccc2)N=C1C

Procedure:
2 g of 5-methyl-2-phenyl-2,4-dihydro-3-pyrazolone, 188 ml of trimethyl orthoformate and 1.29 ml of o-anisidine are heated with stirring in 5 ml of glacial acetic acid at 70° C. for 2 h. The reaction mixture is cooled and 10 ml of methanol are added. The precipitate which has separated out is filtered off with suction and recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:10]3[C:15]([N:16]=2)=[C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:13]=[C:12]([C:23]2[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=2)[N:11]=3)[CH2:3]1.[CH3:35]N(CCS(O)(=O)=O)C.[OH-:44].[Na+]>O1CCCC1>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:12]2[N:11]=[C:10]3[C:15]([N:16]=[C:8]([N:4]4[CH2:5][CH2:6][N:7]([CH:35]=[O:44])[C@@H:2]([CH3:1])[CH2:3]4)[N:9]3[CH2:30][C:31]([F:34])([F:32])[F:33])=[C:14]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:13]=2)=[CH:24][N:25]=1
Reactant: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: CN(C)CCS(=O)(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C=O
Reaction time: 0.75 h
Yield: 88 %

Procedure:
5-{8-[(3S)-3-Methylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (107.1 mg, 0.22 mmol) was added to a tetrahydrofuran solution (5.0 ml) of 1H-benzotriazole-1-carboxyaldehyde (36.6 mg, 0.22 mmol) at room temperature and the resulting mixture was stirred for 45 minutes. The reaction mixture was poured into a 2 N aqueous sodium hydroxide solution and the resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (100.2 mg, 88%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.O.C(O)(=O)C.N([O-])=O.[Na+].[BrH:21]>[Cu](Br)Br>[Br:21][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[F:1]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-fluoro-5-nitroaniline (25.90 g), 47% aqueous hydrogen bromide (100 ml), water (200 ml) and acetic acid (200 ml) was added dropwise an aqueous sodium nitrite (11.56 g) solution (100 ml), and the mixture was stirred at 0° C. for 1 h. This mixture was added at 0° C. to a solution of copper bromide (CuBr: 27.30 g) dissolved in 47% aqueous hydrogen bromide (100 ml) and the mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chomatography (eluent: hexane). Crystallization from hexane gave the title compound (4.01 g) as colorless needle crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH:17]S(C(C)(C)C)=O)[CH2:8][O:9][Si](C(C)(C)C)(C)C)[S:5][CH:6]=1.[ClH:24]>CO.O1CCOCC1>[Cl-:24].[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([NH3+:17])[CH2:8][OH:9])[S:5][CH:6]=1
Reactant: CC(C)(C)S(=O)NC(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1
Reactant: Cl
Solvent: C1COCCO1
Solvent: CO
Product: [Cl-]
Product: [NH3+]C(CO)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-[1-(4-bromothiophen-2-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-2-methylpropane-2-sulfinamide (660 mg, 1.5 mmol) was dissolved in MeOH (15 mL) and the solution was cooled to 0° C., after which HCl (1.87 mL of a 4M solution in dioxane, 7.49 mmol) was added and the mixture was stirred for 120 minutes. The solvents were removed by coevaporation with toluene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14]([OH:17])(=[O:16])[CH3:15].C(OC)(=O)C=O.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>CO>[OH2:11].[NH2:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH:15]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][CH:25]=2)[C:14]([OH:17])=[O:16])=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: CC(=O)O
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: COC(=O)C=O
Solvent: CO
Product: NS(=O)(=O)c1ccc(CCNC(C(=O)O)c2c[nH]c3ccccc23)cc1
Product: O
Reaction time: 96 h
Yield: 63355.6 %

Procedure:
To a stirred solution of 6.01 g (0.03 mmole) of 4-(2-aminoethyl)benzenesulfonamide and 2.5 mL (2.62 g 0.044 mole) of acetic acid in 150 mL of MeOH was added a solution of 2.64 g (0.03 mole) of methyl glyoxylate in 50 mL of MeOH followed by 2.93 g (0.025 mole) of indole. Initially a solution was obtained. Soon solid began separating. The resulting mixture was allowed to stand for four days. The solid was collected by filtration, washed with ether and dried give 3.72 g (38%) of the title compound as a buff solid, m.p. 226° C. (dec). The solid insoluble in CH2Cl2, MeOH, DMSO, DMF and acetic acid.
Reaction SMILES: [NH2:1][C:2]([C:27]1[CH:28]=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=1)([C:21]1[N:22]([CH3:26])[CH:23]=[N:24][CH:25]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.[OH-].N.C(OCC)(=O)C>C(O)(=O)C>[Cl:20][C:16]1[CH:15]=[C:14]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:27]4[CH:28]=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([N:1]=[CH:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[C:21]4[N:22]([CH3:26])[CH:23]=[N:24][CH:25]=4)[CH:4]=3)[NH:9][C:8](=[O:13])[CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: N
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3[nH]c(=O)cc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a solution of the title compound of example 42 (11.89 g, 25.03 mmol) in acetic acid (75 ml) was added p-anisaldehyde (6.09 ml, 50.06 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 4 hours after which time it was cooled to 0° C. 10 ml of ammonia hydroxide was added followed by addition of ethyl acetate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to yield the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1:99:0.1 to 5:95:0.1) as eluents to afford the title compound of Example 43A as a white solid (11.58 g, 78% yield).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)=[CH:21][CH:22]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)cc2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 4-fluorobenzonitrile (303 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was used in the next step without further purification. Isolated 642 mg (2.13 mmol, 85% yield).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccn3)nc12

Procedure:
From 2-pyridylacetic acid hydrochloride, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+26.8° (c=0.51, CHCl3), ES-MS m/e (%): 386 (M+H+, 100).