Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[O:25][CH:26]1[CH2:27][CH2:28][N:29]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[O:14][N:13]=3)[CH:7]=2)[CH2:30][CH2:31]1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Reactant: Clc1cccc(OC2CCNCC2)c1
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCC(Oc2cccc(Cl)c2)CC1
Yield: 49.7 %

Procedure:
Dilute a 0.370 M solution (in dimethylformamide) of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine (140 mg, 0.522 mmol) with ethanol (3.0 mL) and add solution of 4-(3-chlorophenoxy)-piperidine (121.5 mg, 0.574 mmol, 1.1 equivalents) (Table No.1, SM 7) dissolved in ethanol (0.200 M solution). Under a vented argon atmosphere, reflux the reaction mixture overnight. Concentrate the reaction mixture and purify with a Waters Sep-Pak 5 g silica gel cartridge and elute with a graded solvent mixture from 1% methanol in dichloromethane to 5% methanol in dichloromethane to give the title compound (124.6 mg, 50% Yield). Purity by LC/MS=100%, [M+H]+=480
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9](O)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.Cl.[CH:33]1([N:36]2[CH2:41][C:40]3([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[O:39][CH2:38][C:37]2=[O:47])[CH2:35][CH2:34]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:44]2[CH2:45][CH2:46][C:40]3([O:39][CH2:38][C:37](=[O:47])[N:36]([CH:33]4[CH2:34][CH2:35]4)[CH2:41]3)[CH2:42][CH2:43]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1
Reactant: NC(=O)C(O)c1c(F)cc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)C(c1c(F)cc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 40 °C
Reaction time: 3 h
Yield: 16.1 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-hydroxyacetamide (4.56 g, 17.1 mmol) and triethylamine (7.17 mL, 51.4 mmol) in anhydrous acetonitrile (25 mL) was added neat methanesulfonyl chloride (1.7 mL, 22.3 mmol). The reaction mixture was stirred vigorously at 40° C. for 3 h, at which point the reaction had proceeded to completion. To the mesylate intermediate was added more triethylamine (7.2 mL, 51.4 mmol) followed by 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (4.23 g, 17.1 mmol). The reaction was heated at 90° C. for 3 h until starting material was consumed. The reaction was diluted with water (25 mL) then the phases were separated and the aqueous phase was extracted with ether (3×25 mL). The combined ether phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (65-100% of 10% methanol in dichloromethane:dichloromethane) provided the title product (1.26 g, 16% yield). MS(ES)+ m/e 458 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.59-0.69 (m, 2 H) 0.75-0.86 (m, 2 H) 1.61-1.74 (m, 2 H) 1.85-1.95 (m, 2 H) 2.21 (s, 1 H) 2.53-2.64 (m, 2 H) 2.66-2.76 (m, 3 H) 2.79 (br. s., 1 H) 3.96 (s, 2 H) 4.68 (s, 1 H) 5.64 (br. s., 1 H) 7.16-7.26 (m, 2 H) 7.35 (br. s., 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1([C:19](N2C=CN=C2)=[O:20])C=CN=C1>O1CCCC1>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:19](=[O:20])[NH:1][C:2]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Into a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-amino-4-nitrobenzoic acid (54.6 g, 300.00 mmol, 1.00 equiv) in tetrahydrofuran (500 mL), di(1H-imidazol-1-yl)methanone (58.32 g, 360.00 mmol). The resulting solution was stirred for 2 h at 10° C. The solids were collected by filtration to yield 7-nitro-1H-benzo[d][1,3]oxazine-2,4-dione as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:36][C:37]([CH3:42])([CH3:41])[C@@H:38]([NH2:40])[CH3:39].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:39][C@H:38]([NH:40][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[C:37]([CH3:42])([CH3:41])[CH3:36]
Reactant: C[C@H](N)C(C)(C)C
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
A round-bottomed flask was charged with 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.40 mmol), HOBT (68 mg, 0.44 mmol) and EDC (85 mg, 0.44 mmol). DMF (1.8 ml) was added followed by (S)-3,3-dimethylbutan-2-amine (0.10 ml, 0.73 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 97 mg (50%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as a light brown oil.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.S(Cl)([Cl:18])=O>>[Cl:18][CH2:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2c(cn1)[nH]c1ccccc12
Product: ClCc1cc2c(cn1)[nH]c1ccccc12

Procedure:
The 3-(hydroxymethyl)-β-carboline was added to an excess (3 grams) of thionyl chloride and the mixture was refluxed for 1 hour. The excess thionyl chloride was then evaporated and the obtained residue was crystallized from hexane. 2.5 grams of 3-(chloromethyl)-β-carboline was obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1>CC#N>[Br-:23].[C:30]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)[CH:29]=1
Reactant: BrCCCOc1cccc(-c2ccccc2)c1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3cccc(-c4ccccc4)c3)(CC1)CC2
Product: [Br-]
Yield: 70.5 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0433 g, 0.148 mmol) and 3-biphenylyl 3-bromopropyl ether (0.0568 g, 0.196 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0610 g, 70.6%). EI-MS m/z 504(M+) Rt (2.37 min).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:32])[C:30]=1[OH:31])[CH:26]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:31][C:30]1[C:29]([CH3:32])=[CH:28][C:25]([C:26]2[NH:10][C:8](=[O:9])[C:7]3[C:2](=[CH:3][C:4]([O:20][CH3:21])=[C:5]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:6]=3[O:11][CH3:12])[N:1]=2)=[CH:24][C:23]=1[CH3:22]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1CN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2nc(-c3cc(C)c(O)c(C)c3)[nH]c(=O)c2c(OC)c1CN1CCOCC1
Temperature: 115 °C
Reaction time: 6 h
Yield: 6.5 %

Procedure:
A solution of 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (1.8 g, 4.54 mmol), EDCl.HCl (1.31 g, 6.82 mmol), HOBt (1.23 g, 9.09 mmol), and triethylamine (3.3 mL, 23.7 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Ammonium hydroxide (50% aqueous, 10 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=2:1:4) to provide 0.9 g of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (50%). A solution of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (0.9 g, 2.74 mmol) in HOAc (20 mL) and 12 N HCl aqueous (20 mL) was stirred at 50° C. for 1 h and then concentrated to dryness using a rotary evaporator. The residue was mixed with saturated sodium bicarbonate aqueous (40 mL), extracted with DCM (3×100 mL), and concentrated. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=3:2:3) to provide 0.6 g of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (89%). A mixture of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (0.6 g, 2.03 mmol), 3,5-dimethyl-4-hydroxy benzaldehyde (0.61 g, 4.06 mmol), sodium hydrogensulfite (1.24 g, 7.0 mmol) and p-toluenesulfonic acid (1.14 g, 6 mmol) in N,N-dimethyl acetamide (20 mL) was stirred at 115° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc, and concentrated. Purification by column chromatography afforded a solid residue, which was made into slurry in a mixed solvent of DCM-hexanes (3 mL-20 mL). The slurry was filtered and washed with hexanes to provide 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one (56 mg, 6.6%) as a light yellow solid. Selected data: MS (ES) m/z: 426.0; MP 237.0-239.1° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([C:35]5[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=5[F:42])[CH:26]=4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1.CO>[ClH:41].[ClH:41].[Cl:41][C:39]1[CH:38]=[CH:37][C:36]([F:42])=[C:35]([C:27]2[CH:26]=[C:25]([C:23]3[CH:22]=[N:21][CH:20]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:24]=3)[C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(-c4cc(-c5cc(Cl)ccc5F)nc5ncccc45)c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)c2cccnc2n1
Reaction time: 3 h

Procedure:
A slurry of 155 mg (0.265 mmol) 4-(4-{5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl-ester in 1.5 ml 4 N HCl in dioxane was treated with 1 drop of methanol. The solution thus formed was left for 3 hours at room temperature and subsequently evaporated. The residue was treated with tert-butyl-methyl-ether and the solid was filtered off. The residue was dissolved in water and lyophilized yielding 2-(5-chloro-2-fluoro-phenyl)-4-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-3-yl]-[1,8]naphthyridine dihydrochloride als colourless lyophilisate; HPLC-MS: 1.65 min, [M+H] 485.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].C(N(C(C)C)CC)(C)C.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52][NH2:53]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:53][CH2:52][CH2:51][N:50]([CH3:54])[CH3:49])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 42.1 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (300 mg, 0.54 mmol) in CH2Cl2 (30 mL) were added diisopropyl ethyl amine (0.2 mL, 1.14 mmol), N,N-dimethyl-ethylenediamine (0.3 mL, 2.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (131 mg, 42%). LC-MS m/z 576 (M+H)+; 1H-NMR (MeOD) δ 2.19 (s, 6H), 2.35 (s, 3H), 2.42 (m, br, 2H), 3.24 (m, br, 2H), 4.16 (s, 2H), 7.12 (m, 4H), 7.52 (m, 2H), 7.72 (m, 2H), 7.83 (s, 1H), 7.99 (d, 1H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:23][CH3:24])(OCC)OCC>C(O)C>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:1]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:24]3[CH:23]=[CH:2][CH:3]=[CH:4][CH:5]=3)=[CH:10][CH:9]=2)=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: C(=Nc1ccc(Nc2ccccc2)cc1)Nc1ccc(Nc2ccccc2)cc1
Yield: 72.4 %

Procedure:
The procedure of Example 1 is repeated using 10.0 g (0.054 mol) of N-phenyl-1,4-phenylenediamine and 3.3 g (0.22 mol) of triethyl orthoformate. The residue is slurried with ethanol to give 7.4 g (83%) of a brown solid, mp. 173°-175° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:39])[CH:36]([CH3:38])[CH3:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 101.6 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by isobutyric acid (27 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-(cis-4-isobutyrylamino-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (110 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([O:17]C)[CH:3]=1.Cl.N1C=CC=CC=1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([OH:17])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1O
Temperature: 170 °C

Procedure:
A mixture of (4-bromo-2-methoxyphenyl)(4-fluorophenyl)methanone (1.60 g, 5.18 mmol) and pyridine hydrochloride (15.0 g, 130 mmol) was heated at 170° C. for 4.5 h and allowed to cool to rt. The resulting mixture was diluted with Et2O and washed with a 2N HCl solution. The ether layer was extracted twice with a 1N NaOH solution. The combined aqueous layers were acidified and extracted with Et2O, and the combined organics dried (MgSO4), filtered and concentrated. The title compound was obtained as a yellow solid, slightly contaminated with an impurity. It was used as such in the following step.
Reaction SMILES: CC([BH-](C(C)C(C)C)C(C)C(C)C)C(C)C.[Li+].[CH3:18][C:19]([O:22][C:23](=[O:31])[NH:24][C@H:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26]1)([CH3:21])[CH3:20]>O1CCCC1.O.C(OCC)(=O)C>[CH3:21][C:19]([O:22][C:23](=[O:31])[NH:24][C@H:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1)([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(=O)C1
Agent: CC(C)C(C)[BH-](C(C)C(C)C)C(C)C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Temperature: -78 °C
Yield: 47.9 %

Procedure:
A 1M solution of lithium tris(1,2-dimethylpropyl)borohydride in tetrahydrofuran (1.99 ml) was diluted with tetrahydrofuran (3 ml), cooled to -78° C. and treated dropwise with a solution of (S)-(3-oxocyclopentyl)carbamic acid 1,1-dimethylethyl ester (0.38 g,1.66 mmol) in dry tetrahydrofuran (2 ml) at 0° C. The reaction was stirred for 2h at -78° C. then allowed to warm to room temperature over 1h. Water (2 ml) was added dropwise then the mixture was diluted with water (20 ml) and ethyl acetate (30 ml). The organic phase was washed with water (20 ml), dried (MgSO4) and evaporated to give impure product which was purified by chromatography on flash silica eluting initially with 15% ethyl acetate in cyclohexane and progressing to neat ethyl acetate. Early fractions gave (1S-cis)-(3-hydroxycyclopentyl)carbamic acid 1,1-dimethylethyl ester (0.16 g) as an oil, nmr (d,CDCl3) 1.43(s,9H), 1.50-2.10(m,6H), 3.97-4.10(m,1H), 4.32-4.40(m,1~H), 5.00-5.12(m,1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:16]=[N:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:13]=1[NH2:25].B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl.O>[NH2:25][C:13]1[N:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:15]=[N:16][C:12]=1[C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[F:1]
Reactant: COc1ccc(-n2nnc(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1c(-c2ccc(C(F)(F)F)cc2F)nnn1-c1ccc(O)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of 5-(2-fluoro-4-trifluoromethyl-phenyl)-3-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-ylamine (16) (0.450 g, 1.2774 mmol) in anhydrous dichloromethane (15 ml), cooled to −78° C. and under a nitrogen flow, a solution of boron tribromide (2.240 g, ˜0.84 ml, 8.9418 mmol) in 5 ml of anhydrous dichloromethane is added drop-wise. The mixture is allowed to reach room temperature spontaneously overnight and it is then cooled again in an ice-salt bath and the excess of the reagent is decomposed upon drop-wise addition of 10 ml of methanol and 10 ml of water. After 10 min stirring, 10% sodium hydroxide solution (15 ml) is added and the aqueous layer, once separated, is acidified with 10% hydrochloric acid solution and extracted with chloroform (3×50 ml). The combined organic layers are dried over MgSO4, filtered and evaporated to afford a solid residue (0.380 g, 88% yield, 99.71% pure at HPLC). M.p. 176.2-177.5° C. LC-ESI-HRMS of [M+H]+ shows 339.0854 Da. Calc. 339.086898 Da, dev. −4.4 ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: OC1CCNCC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC(O)CC5)c34)cc2Cl)cn1
Yield: 36 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 36% yield; NMR Spectrum: 1.32-1.38 (m, 2H), 1.67-1.69 (m, 2H), 2.16 (t, 2H), 2.45 (s, 3H), 2.79 (m, 4H), 3.40-3.44 (m, 1H), 4.43 (t, 2H), 4.52 (br s, 1H), 7.20 (d, 1H), 7.26 (br s, 2H), 7.71 (d, 1H), 8.12 (s, 1H), 8.21 (s, 1H), 8.35 (s, 1H), 8.61 (br s, 1H); Mass Spectrum: 496 (MH+).
Reaction SMILES: [F:1][C:2]1[C:34]([NH:35][S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:32]=[C:31]([F:42])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=3)[N:13]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:10]2=[N:11][CH:12]=1)=[O:5].[CH2:43](Cl)Cl.CO.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CC(O)=O>[F:1][C:2]1[C:34]([NH:35][S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:32]=[C:31]([F:42])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]3[CH2:17][CH2:18][N:19]([CH3:43])[CH2:20][CH:21]=3)[N:13]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:23])=[O:24])[C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C2=CCNCC2)n3S(=O)(=O)c2ccccc2)c1F
Reactant: ClCCl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C2=CCN(C)CC2)n3S(=O)(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 2,6-difluoro-N-(1-(phenylsulfonyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (15 mg, 0.024 mmol) in 5:1 CH2Cl2/MeOH (6 mL) was treated with 37% aqueous formaldehyde (100 μL) and a drop of AcOH. After 5 minutes, the mixture was treated with sodium triacetoxyborohydride (26 mg, 5 eq.), and the reaction mixture was stirred for 16 hours at ambient temperature. The mixture was treated with MeOH (1 mL), concentrated under reduced pressure, and purified by silica gel chromatography (eluting with 10% MeOH/CH2Cl2) to afford 2,6-difluoro-N-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide.