Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])=[CH:10][CH:9]=2)=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CS(=O)(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(Cc1ccc(C(O)c2ccc(Cl)cc2)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 75.9 %

Procedure:
4-chloro-4'-trifluoromethylsulfonylmethylbenzophenone (5.5 g) was dispersed in methanol (200 ml). Sodium borohydride was gradually added thereto at room temperature with stirring, and the mixture was further stirred overnight at room temperature. After completion of the reaction, methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate (250 ml). The extract was washed with water and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product as a white powder (4.2 g, melting point: 113° to 115° C., yield: 77%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C1CCCCC1)C.Cl.[CH3:25][CH:26]([NH2:30])[CH:27]([CH3:29])[CH3:28].[Cl:31][C:32]1[S:40][C:39]2[S:38](=[O:42])(=[O:41])[NH:37][C:36](=O)[NH:35][C:34]=2[CH:33]=1>O>[Cl:31][C:32]1[S:40][C:39]2[S:38](=[O:42])(=[O:41])[N:37]=[C:36]([NH:30][CH:26]([CH3:25])[CH:27]([CH3:29])[CH3:28])[NH:35][C:34]=2[CH:33]=1
Reactant: CC(C)C(C)N
Reactant: O=C1Nc2cc(Cl)sc2S(=O)(=O)N1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C1CCCCC1
Solvent: O
Product: CC(C)C(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 200 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
Phosphorus pentoxide (2.84 g; 20 mmol), N,N-dimethylcyclohexylamine (5 ml, 33 mmol) and 1,2-dimethylpropylamine hydrochloride (2.47 g; 20 mmol) were carefully mixed in a three necked flask equipped with mechanical stirring and condenser with drying tube. The mixture was heated on an oil bath at 200° C. until a homogeneous mass was obtained. Then 6-chloro-2,3-dihydro-3-oxo-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.2 g; 5 mmol) was added and the mixture was stirred at 240° C. for 45 min. The mixture was allowed to cool to about 100° C., 150 ml of water was added and stirring was continued at ambient temperature for approximately 1 h. The hydrolysed mixture was filtered and the dark precipitate was washed with water and dissolved in boiling ethanol, treated with charcoal, filtered and finally evaporated to dryness. Flash chromatography (ethyl acetate/silica gel) afforded 105 mg (7%) of the pure title compound; m.p. 216°-218° C.; 1H-NMR (DMSO-d6): δ 0.90 (d, 6H, CH(CH3)2), 1.08 (d, 3H, NCHCH3), 1.75 (m, 1H, CH(CH3)2), 3.65 (m, 1H, NHCH), 7.11 (br. s, 2H, 5-H+NH), 10.68 (s, 1H, NH); MS m/e: 307/309 (M+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:24].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C1COCC1>[C:32]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:24])(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 1.15 g (3.39 mmol) 2-(hydroxymethyl)-4-methoxy-6-(5-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-2-yl)phenol in 50 ml anhydrous THF containing BHT inhibitor (Aldrich). Triethylamine (1.4 ml, 11 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (0.436 g, 4.17 mmol) was added dropwise and the mixture was stirred for 1 hr at −10° C. followed by 20 hours at ambient temperature. The solid was filtered and rinsed with 100 ml diethyl ether. The filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and then concentrated via rotary evaporation to give the desired product as a dark yellow oil which was recrystallized in methanol to give 0.35 g product (25%). [M+H+]=408.1. 1H NMR (CDCl3) delta: 10.97 (s, 1H, Ar—OH), 8.30 (s, 1H, Ar—H benzotriazole), 8.07 (d, 1H, Ar—H benzotriazole), 7.91 (s, 1H, Ar—H phenol), 7.69 (d, 1H, Ar—H benzotriazole), 7.10 (s, 1H, Ar—H phenol), 6.21 (s, 1H, C═C—H trans), 5.62 (s, 1H, C═C—H cis), 5.40 (s, 2H, Ar—CH2), 3.90 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3). Elemental analysis: calculated % C (56.02), % H (3.96), % N (10.32), % F (13.99). found % C (56.11), % H (3.96), % N (10.24), % F (14.37).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])[CH3:2].[H-].[Na+].IC.[CH2:28](OCC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[N:8]([CH3:28])[C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1N(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethoxycarbonyl-N-(4-nitrobenzoyl)aniline (3.15 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 442 mg) and the solution was stirred at ambient temperature for 30 minutes. Iodomethane (1.56 g) was added to the solution and the mixture was stirred at ambient temperature for 4 hours. The solution was diluted with ethyl acetate and the solution was washed with successively with 1N hydrochloric acid, water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was solidified with diethyl ether to give 2-ethoxycarbonyl-N-methyl-N-(4-nitrobenzoyl)aniline (3.28 g) as a pale yellow powder.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[F:24][C:10]([CH:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:11]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Boc-L-Proline (4.5 g, 0.02 mmol) and pyridine (8.45 mL, 0.104 mmol) in DCM (20 mL) cooled in an ice bath was added dropwise cyanuric fluoride (5.35 mL, 0.0627 mmol). After the addition the reaction became milky. The solution was stirred at 0° C. for 10 min then warmed to RT and stirred for 4 h. The reaction was quenched with water, and thrice extracted with DCM. The combined organic extracts were washed with brine, dried, and concentrated in vacuo to afford tert-butyl 2-(fluorocarbonyl)pyrrolidine-1-carboxylate. The crude acid fluoride was used in next coupling reaction immediately.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1.[NH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15]>CCOCC.C1C=CC=CC=1.C(O)(C)(C)C>[NH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][O:15][C:7]1[N:6]=[N:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(N)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: CC(C)(N)CCOc1ccc(Cl)nn1
Yield: 84.8 %

Procedure:
A mixture of 0.62 g of 60% sodium hydride, 1.91 g of 3,6-dichloropyridazine and 10 ml of benzene was stirred while being cooled with ice, and a solution consisting of 1.32 g of 3-amino-3-methylbutanol, 3 ml of t-butanol and 5 ml of benzene was added dropwise. After stirring at room temperature for 30 minutes, ether was added to the reaction mixture, and the solid was removed by filtration with Hyflo Super-Cel. The filtrate was concentrated under reduced pressure. n-Hexane was added to the resulting oily product, and the mixture was allowed to stand to give 2.34 g of 3-(3-amino-3-methylbutoxy)-6-chloropyridazine as colorless crystals having a melting point of 63.5° to 65.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[CH:29]=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=[O:24])=[C:18]([O:25][CH3:26])[CH:17]=4)=[O:15])[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:32]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[CH:29]=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:9][CH2:10][N:11]([C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[C:18]([O:25][CH3:26])[CH:17]=4)=[O:15])[CH2:12][CH2:13]3)[O:7][C:6]=2[CH:32]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
To 2-(4-(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbon-yl)-2-methoxyphenyl)acetaldehyde (from Step 1) was added MeOH (1 mL) followed by NaBH4 (95 mg, 2.5 mmol) and the reaction was stirred for 30 minutes at ambient temperature. After 30 minutes, the mixture was filtered and the filtrate was purified by prep-HPLC (1-99% MeOH:H2O) to give (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]-oxazine-4,4′-piperidine]-1′-yl)(4-(2-hydroxyethyl)-3-methoxyphenyl)methanone (16 mg, 7%). ESI-MS m/z calc. 452.2. found 453.2 (M+1)+. Retention time: 2.91 minutes (4.5 min run). (7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(3-fluoro-4-(1-hydroxy-2-methylpropan-2-yl)phenyl)methanone [ESI-MS m/z calc. 468.2. found 469.4 (M+1)+. Retention time: 3.06 minutes (4.5 min run)] and (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)methanone [ESI-MS m/z calc. 450.2. found 451.2 (M+1)+. Retention time: 9.72 minutes (15 min run)] were prepared using the procedures described above.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]([S:48](F)(=[O:50])=[O:49])[CH:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:43]=[C:42]([CH3:41])[CH:47]=[CH:46][N:45]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccnc(S(=O)(=O)F)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 69.7 %

Procedure:
To a suspension (3 mL) of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg), 15-crown-5 (330 mg) and 4-methylpyridine-2-sulfonyl fluoride (343 mg) at room temperature, and the mixture was stirred at room temperature for 41 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow oil (yield 333 mg, 70%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H][H]>CO.[Pd]>[NH2:1][C@@H:2]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCNC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Yield: 99.8 %

Procedure:
The compound obtained in (1) (650 mg) was dissolved in methanol (10 ml) and 10% Pd-C (118 mg) was added. The resulting mixture was vigorously stirred at room temperature under atmospheric pressure of hydrogen overnight. The catalyst was filtered off through Celite and the filtrate was concentrated under reduced pressure to give the product (450 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH:17]2[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:19][CH:11]1[CH2:12]3)[CH2:16]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:8][CH2:9][CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][CH:11]2[CH2:12]4)[CH2:16]3)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: C=CCCCCCOCC1C2CC3CC(C2)CC1C3
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(CCCCCCCOCC2C3CC4CC(C3)CC2C4)cc1
Yield: 46.9 %

Procedure:
General procedure M was used to convert 2.77 mmol of 11d and 3.05 mmol of 1-bromo-4-nitrobenzene to 1.30 mmol (47%) of the title compound.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([CH:20]([OH:21])[C:19]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:18]=2[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])[CH2:3][CH2:4]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Sc1ccccc1F
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C(O)c2cc(C(F)(F)F)ccc2Sc2ccccc2F)CC1
Yield: 100.2 %

Procedure:
A solution of the Grignard reagent is prepared by a reaction of 12.0 g 4-chloro-1-methylpiperidine with 2.3 g of magnesium in 70 ml of tetrahydrofuran and is treated for 10 minutes with a solution of 17.4 g 2-(2-fluorophenylthio)-5-trifluoromethylbenzaldehyde in 40 ml of tetrahydrofuran added dropwise. The mixture is refluxed for 4 hours and after cooling, decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is dried with potassium carbonate and evaporated. There are obtained 23.2 g (100%) crude oily α-(1-methyl-4-piperidyl)-2-(2-fluorophenylthio)-5-trifluoromethylbenzyl alcohol which is used in this state for the final reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[N:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH2:17]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:5]([NH:8][C:21]2[N:16]=[CH:17][C:18]([C:22]#[N:23])=[N:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: N#CC1=NC=CN(Br)C1
Reactant: Nc1cc(N2CCOCC2)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc(N3CCOCC3)c(Cl)cn2)cn1
Temperature: 140 °C
Yield: 31.6 %

Procedure:
5-Chloro-4-morpholinopyridin-2-amine (68 mg, 0.31 mmol), 4-bromo-cyanopyrazine (30 mg, 0.20 mmol), sodium tert-butoxide (45 mg, 0.47 mmol), Pd(OAc)2 (3 mg, 0.01 mmol) and BINAP (0.030 g, 0.05 mmol) were mixed under argon atmosphere before addition of mixture of DMF in toluene (2:1, 0.7 mL). The reaction mixture was heated to 140° C. by microwave irradiation for 20 minutes. The reaction mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Flash chromatography on silica, eluting with ethyl acetate-hexane (1:1) gave 5-(5-chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile as a yellow solid (20 mg, 20%).
Reaction SMILES: C([NH:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:20][C:19]=2[N+:32]([O-:34])=[O:33])[CH2:14][CH2:13]1)=[S:11])(=O)C1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:20][C:19]=2[N+:32]([O-:34])=[O:33])[CH2:14][CH2:13]1)=[S:11]
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCN(C(=S)NC(=O)c3ccccc3)CC2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(C(N)=S)CC2)c([N+](=O)[O-])c1

Procedure:
66.6 g (0.139 mol) of the compound synthesized as described under (a) are boiled under reflux in 1200 ml of methanol and 150 ml of water in the presence of 21.6 g (0.156 mol) of potassium carbonate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:4].[Li+].[OH-].Cl>O1CCOCC1.C(OCC)(=O)C>[F:24][C:22]([F:23])([F:25])[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:13]2[C:9]3[S:10][CH:11]=[CH:12][C:8]=3[CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
323 mg 7-(4-Trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carboxylic acid methyl ester was dissolved in 10 ml of 1,4-dioxane. To this was added 4.4 ml of 1 M LiOH (aq), and the reaction was stirred for 7 h at 60° C. and overnight at room temperature. The reaction mixture was diluted with 5 ml of ethyl acetate, acidified to pH 3 with 2N HCl (aq) and extracted with 10 ml ethyl acetate 4 times. The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo to give 271 mg of 7-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carboxylic acid.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[C:12]=[S:13]>>[OH:4][CH2:3][CH:2]([NH:1][C:12]([NH:11][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[S:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(CO)c1ccccc1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccccc1

Procedure:
The title compound was prepared with 2-amino-2-phenylethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.36 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.38 (d, J=4.6 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 6.88-6.61 (m, 8H), 6.43 (d, J=7.9 Hz, 1H), 5.22-4.90 (m, 1H), 3.46-3.28 (m, 2H); ESIMS m/z 484 ([M+H]+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[OH:14][CH2:13][CH2:15][NH:16][C:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: NCCO
Reactant: O=C(O)c1cc2ccccc2s1
Product: O=C(NCCO)c1cc2ccccc2s1
Yield: 73 %

Procedure:
2-Benzothiophenecarboxylic acid (3.0 g, 16.8 mmol) and ethanolamine (1.21 ml, 20 mmol) were coupled according to the procedure of Example 17 to 2.7 g (73% yield) of an off-white solid. 1H NMR (DMSO-d6): δ 3.3 (m, CH2), 3.5 (q, CH2), 4.79 (t, NH), 7.1-7.4 (m, 2 Ar H), 7.90 (m, 1 Ar H), 7.95 (m, 1 Ar H), 8.09 (s, 1 Ar H), 8.89 (t, NH) Electrospray Mass Spec: m/z 222.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=O.[NH2:16][CH:17]1[CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18]1>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([NH:16][CH:17]1[CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18]1)=[O:9]
Reactant: NC1CCNC(=O)C1
Reactant: COc1cccc(C=CC(=O)O)c1OC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cccc(C=CC(=O)NC2CCNC(=O)C2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
To a solution of 2,3-dimethoxycinnamic acid (5.0 g) in tetrahydrofuran (50 ml) was added N,N'-carbonyldiimidazole (4.28 g) and the mixture was stirred at room temperature for 30 minutes. To this was added 3-amino-δ-valerolactam (3.02 g), followed by stirring overnight. The reaction solution was diluted with chloroform and washed with a saturated soldium bicarbonate solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column to obtain the titled compound (2.91 g, 39.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]([O:26]C)=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:28])[CH:16]=2)[CH3:13])=[O:11])=[CH:4][CH:3]=1.O1CCCC1.[Li+].[OH-]>CO.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:12]([CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:28])[CH:16]=2)[CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c(CN(C)C(=O)/C=C/c3ccc(N)nc3)cn(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cn(C)c2c(C(=O)O)cccc12)C(=O)C=Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.3 %

Procedure:
A solution of (E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (76 mg, 0.2 mmole) in methanol (4 mL), water (2 mL), and tetrahydrofuran (2 mL) was treated with LiOH (39 mg, 1.6 mmole), and the reaction was stirred at ambient temperature for 48 h. The mixture was filtered, and the filtrate was acidified to pH 4.0-4.5 with 1.0 N HCl. The precipitate was collected, washed with water and dried giving the title compound (25 mg, 35%) as a white solid: MS (ES) m/e 365.2 (M+H)+. Anal. Calcd for C20H20N4O3.0.25H2O: C, 65.11: H, 5.60; N, 15.18. Found: C, 64.83; H, 5.52; N, 15.07.