Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C@H:16]2[C@H:11]([CH2:12][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([C:33]5[CH:41]=[C:40]([F:42])[CH:39]=[C:38]6[C:34]=5[CH:35]=[CH:36][NH:37]6)=[N:21][C:20]=4[CH:19]=3)[CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:42][C:40]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[C:33]([C:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:25]3[S:26][C:18]([CH2:17][N:13]4[CH2:14][CH2:15][C@H:16]5[NH:8][CH2:9][CH2:10][C@H:11]5[CH2:12]4)=[CH:19][C:20]=3[N:21]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CN(Cc3cc4nc(-c5cc(F)cc6[nH]ccc56)nc(N5CCOCC5)c4s3)CC[C@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC[C@H]5NCC[C@H]5C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared by BOC-deprotection of (3aS,7aR)-5-[2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-octahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester using TFA:DCM (1:6). The title compound was obtained as a beige solid.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)[CH3:2].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[C:7]=1[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:19])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc2ccccc2o1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1oc2ccccc2c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A stirring solution of 2-ethyl benzofuran (43.8 g; 0.3 mol) in methylene chloride (300 mL) was cooled in an ice bath. Benzoyl chloride (42.2 g; 0.3 mol) was added. Tin (IV) chloride (85 g; 0.33 mol) was then added dropwise. The mixture was stirred at room temperature for 30 minutes then at reflux for one hour. The mixture was then cooled to room temperature, poured over ice, and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous magnesium sulfate, and solvent evaporated. The residue was purified by flash chromatography on silica gel using 1% ethyl acetate in hexane as an eluent. The product was obtained as an oil (26 g). Mass spectrum (ESI, [M+] m/z 250. 1HNMR (400 MHz, DMSO-d6): δ 1.21 (t, 3H, J=7.47 Hz), 2.76 (q, 2H, J=7.47 Hz), 7.21 (dt, 1H, J=7.25, 1.1 Hz), 7.3-7.38 (m, 2H), 7.52-7.56 (m, 2H), 7.61-7.69 (m, 2H), 7.73-7.76 (m, 2H). Elemental Analysis for C17H14O2: Calculated: C, 81.58; H, 5.64. Found: C, 81.73; H, 5.56.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]2[CH2:7][N:8]([CH2:10][C:11]3[CH:26]=[CH:25][C:14]([O:15][C:16]4[S:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:13][CH:12]=3)[CH2:9][CH:3]12.CCN(CC)CC.C([NH:41][CH2:42][C:43](O)=[O:44])(OC(C)(C)C)=O.Cl.CN(C)CCCN=C=NCC.FC(F)(F)C(O)=O>C(Cl)Cl.CO.CS(C)=O>[NH2:41][CH2:42][C:43]([N:2]1[CH2:6][CH2:5][CH:4]2[CH2:7][N:8]([CH2:10][C:11]3[CH:26]=[CH:25][C:14]([O:15][C:16]4[S:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:13][CH:12]=3)[CH2:9][CH:3]12)=[O:44]
Reactant: c1ccc2sc(Oc3ccc(CN4CC5CCNC5C4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)N1CCC2CN(Cc3ccc(Oc4nc5ccccc5s4)cc3)CC21
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
To a stirred solution of 2-[4-(hexahydro-pyrrolo[3,4-b]pyrrol-5-ylmethyl)-phenoxy]-benzothiazole hydrochloride (100 mg, 0.26 mmol) and Et3N (215 μL, 1.6 mmol) in CH2Cl2 (2 mL) was added N-Boc-glycine (95 mg, 0.5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mg, 0.5 mmol). The resulting solution was then stirred at rt for 16 h. The resulting mixture was then treated with trifluoroacetic acid (1 mL) at rt for 3 h. The crude solid was dissolved in CH3OH/DMSO (2:1) and purified via reverse phase preparative HPLC to yield the title compound as a fluffy white solid (37 mg, 35%). MS (ESI): mass calcd. for C22H24N4O2S, 408.5; m/z found, 409.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.74 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.43-7.33 (m, 3H), 7.33-7.26 (m, 3H), 4.51-4.42 (m, 1H), 4.27-4.19 (m, 0.5H), 4.02-3.92 (m, 0.5H), 3.66 (d, J=13.2 Hz, 1H), 3.58 (d, J=5.0 Hz, 0.5H), 3.51-3.37 (m, 3H), 3.28 (d, J=16.7 Hz, 0.5H), 2.91-2.76 (m, 2H), 2.70-2.60 (m, 1H), 2.58-2.50 (m, 1H), 2.50-2.37 (m, 1H), 2.14-1.96 (m, 1H), 1.97-1.80 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23](B(O)O)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1.Br[C:28]1[S:32][C:31]([CH3:33])=[N:30][C:29]=1[CH3:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][C:31]1[S:32][C:28]([C:23]2[C:14]([O:13][CH2:12][C@H:10]3[CH2:11][C@@H:9]3[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)=[N:15][C:16]3[C:21]([CH:22]=2)=[N:20][CH:19]=[CH:18][CH:17]=3)=[C:29]([CH3:34])[N:30]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2B(O)O)nc1
Reactant: Cc1nc(C)c(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2-c2sc(C)nc2C)nc1
Temperature: 100 °C

Procedure:
A mixture of (2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)boronic acid (PP1) (25 mg, 0.050 mmol), 5-bromo-2,4-dimethyl-1,3-thiazole (9.6 mg, 0.050 mmol), K3PO4 (21.2 mg, 0.10 mmol), S-Phos (2.0 mg, 0.005 mmol), and Pd(OAc)2 (0.6 mg, 0.002 mmol) in THF (0.3 mL) and water (0.05 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.83 (dd, J=4.2, 1.6 Hz, 1 H), 8.29 (s, 1 H), 8.20 (d, J=8.5 Hz, 1 H), 8.12 (d, J=2.9 Hz, 1 H), 7.71 (dd, J=8.4, 4.2 Hz, 1 H), 7.30-7.23 (m, 2 H), 4.61 (dd, J=11.3, 6.7 Hz, 1 H), 4.39 (dd, J=11.3, 7.8 Hz, 1 H), 3.78 (s, 3 H), 2.61 (s, 3 H), 2.36 (s, 3 H), 2.20 (dt, J=8.5, 4.6 Hz, 1 H), 1.79 (s, 1 H), 1.24 (s, 1 H), 1.09-1.04 (m, 1 H); HRMS m/z (M+H) 418.1534 found, 418.1536 required.
Reaction SMILES: [CH:1]1([C:4]([C:8]2[C:13]([CH3:14])=[C:12]([Cl:15])[CH:11]=[CH:10][N:9]=2)=[CH:5][O:6]C)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH3:14][C:13]1[C:8]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=[O:6])=[N:9][CH:10]=[CH:11][C:12]=1[Cl:15]
Reactant: COC=C(c1nccc(Cl)c1C)C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(Cl)ccnc1C(C=O)C1CC1
Yield: 80.3 %

Procedure:
A solution of 2-(1-cyclopropyl-2-methoxy-vinyl)-3-methyl-4-chloro-pyridine (6.41 g, 28.7 mmol) in acetic acid (50 mL) was treated with sulfuric acid (6.52 mL, 143 mmol) at room temperature overnight. The reaction mixture was neutralized with 2N NaOH to pH 8-9 extracted with ethyl acetate (2×100 mL). The organic phases were combined, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane/ethyl acetate=2:1) to afford the title compound as a yellow solid (4.83 g, 80%). ESI-MS m/z: 210 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ ppm: 9.89 (d, J=2.4 Hz, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.26 (d, J=5.4 Hz, 1H), 3.26-3.28 (m, 1H), 2.35 (s, 3H), 1.53-1.59 (m, 1H), 0.55-0.79 (m, 2H), 0.25-0.39 (m, 2H).
Reaction SMILES: C([O:8][P:9]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([CH3:87])([CH3:86])[C:28]([O:30][C:31]1[C:35]([O:36][C:37](=[O:67])[C:38]([CH3:66])([CH3:65])[CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][P:47]([O:57]CC2C=CC=CC=2)([O:49]CC2C=CC=CC=2)=[O:48])=[C:34]([C:68](=[O:72])[N:69]([CH3:71])[CH3:70])[N:33]([C:73]2[CH:78]=[CH:77][C:76]([O:79][CH3:80])=[CH:75][CH:74]=2)[C:32]=1[C:81](=[O:85])[N:82]([CH3:84])[CH3:83])=[O:29])([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH3:86][C:27]([CH3:87])([CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][P:9]([OH:10])([OH:11])=[O:8])[C:28]([O:30][C:31]1[C:35]([O:36][C:37](=[O:67])[C:38]([CH3:65])([CH3:66])[CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][P:47]([OH:49])([OH:57])=[O:48])=[C:34]([C:68](=[O:72])[N:69]([CH3:71])[CH3:70])[N:33]([C:73]2[CH:74]=[CH:75][C:76]([O:79][CH3:80])=[CH:77][CH:78]=2)[C:32]=1[C:81](=[O:85])[N:82]([CH3:83])[CH3:84])=[O:29]
Reactant: COc1ccc(-n2c(C(=O)N(C)C)c(OC(=O)C(C)(C)COCCOCCOP(=O)(OCc3ccccc3)OCc3ccccc3)c(OC(=O)C(C)(C)COCCOCCOP(=O)(OCc3ccccc3)OCc3ccccc3)c2C(=O)N(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-n2c(C(=O)N(C)C)c(OC(=O)C(C)(C)COCCOCCOP(=O)(O)O)c(OC(=O)C(C)(C)COCCOCCOP(=O)(O)O)c2C(=O)N(C)C)cc1
Yield: 90 %

Procedure:
A solution of 2,5-bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl bis(3-(2-(2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)ethoxy)-2,2-dimethylpropanoate) (62) (278 mg, 0.22 mmol) in MeOH (112 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 45° C. under H2 (10 bar). The output was concentrated in vacuo to afford 2,5-bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl bis(2,2-dimethyl-3-(2-(2-(phosphonooxy)ethoxy)ethoxy)propanoate) (UL1-121) (175 mg, 88%) as a light yellow oil: m/z 884 (M+H)+ (ES+); 882 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 7.11-7.09 (m, 2H), 6.97-6.95 (m, 2H), 3.91-3.87 (m, 4H), 3.78 (s, 3H), 3.58-3.50 (m, 16H), 2.89 (s, 6H), 2.76 (s, 6H), 1.19 (s, 12H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([NH2:14])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=2)=[CH:19][CH:18]=1.Cl>CN(C)C=O>[CH2:3]([O:10][N:11]([CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:12]([NH2:14])=[O:13])=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)[C:12]([NH2:14])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccc(OCCCCOc2ccc(CCl)cc2)cc1
Reactant: NC(=O)NOCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)N(Cc1ccc(OCCCCOc2ccc(CN(OCc3ccccc3)C(N)=O)cc2)cc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 63.2 %

Procedure:
60% Sodium hydride (0.41 g) and 1.71 g of benzyloxyurea were added to 20 ml of dimethylformamide and the mixture was stirred at 80° C. for 7.5 hours. 1,4-Bis(4-chloromethylphenoxy)butane (1.74 g) was added to the reaction mixture at room temperature and the mixture was stirred at 95° C. for 0.5 hour. The reaction product was cooled to room temperature, poured into ice water, mixed with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution in that order and dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting crude product was washed with ethyl acetate to obtain 1.94 g of 1,4-bis[4-[(1-benzyloxyureido)methyl]phenoxy]butane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](O)=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.B>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: O=C(O)c1cc(Cl)c2cn[nH]c2c1
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(Cl)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of 4-chloro-1H-indazole-6-carboxylic acid (100 mg, 0.5 mmol) in THF (1 mL) was cooled to 0° C. under argon. Borane (1.4 mL, 1.4 mmol) was added dropwise and the solution was stirred overnight at rt. The reaction was quenched with ice cold sat. sodium bicarbonate, extracted with ethyl acetate (3×10 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (60 mg, 66%). MS ESI [M+H]+, calcd for [C8H7ClN2O+H]+ 183.0; found m/z 183.0.
Reaction SMILES: B.CSC.[C:5]([O:9][C:10]([N:12]([CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].OS([O-])(=O)=O.[K+].[OH-].[Na+]>C1COCC1.CO>[C:5]([O:9][C:10]([N:12]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH2:23])=[CH:24][CH:25]=1)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)CN(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Agent: B
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccc(CN)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
Under a nitrogen atmosphere, add borane-dimethylsulfide complex (13 mL, 26 mmol, 2M solution in THF) to 4-[N-(tert-butoxycarbonyl)-N-(iso-butyl)-aminomethyl]-benzonitrile (1.5 g, 5.2 mmol) in THF (20 mL) at 0° C. Heat the mixture under reflux overnight. Cool the mixture in an ice-bath and add methanol (20 mL). Warm to room temperature and add KHSO4 (7 g in 50 mL of water). Stir for 2 h at room temperature and basify with 3N aqueous NaOH. Extract with DCM, dry the organic phase over Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel (150 g) eluting with a gradient of DCM to 4:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound as an oil (0.72 g, 47%). MS (APCI+) m/z: 293 (M+H)+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][CH:19](OCC)[O:20]CC)[N:13]=[C:12]2[CH:26]=[CH:27][S:28][C:11]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>C1COCC1>[ClH:29].[C:1]([O:9][C:10]1[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][CH:19]=[O:20])[N:13]=[C:12]2[CH:26]=[CH:27][S:28][C:11]=12)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCNc1cc(OC(=O)c2ccccc2)c2sccc2n1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCCNc1cc(OC(=O)c2ccccc2)c2sccc2n1
Reaction time: 0.08 h

Procedure:
The crude 5-(3,3-diethoxypropylamino)thieno[3,2-b]pyridin-7-yl benzoate from above (677.3 g, 1.68 mol) was dissolved in 3.0 L of THF. Then, 12N HCl (1.68 mol, 0.14 L) was added dropwise while the reaction temperature was maintained below 20° C. with an ice-water bath. After stirring for 5 minutes, solids precipitated. The resultant mixture was stirred at room temperature for 1 h, followed by the addition of ethyl acetate (2.0 L). The mixture was stirred for 30 min. The solids were filtered, rinsed with ethyl acetate (250 ml×2), and then dried under reduced pressure at 55° C. to give the title compound 5-(3-oxopropylamino)thieno[3,2-b]pyridin-7-yl benzoate HCl salt as a light brown solid. 1H NMR (400 MHz, DMSO d6) δ 2.20 (m, 2H), 3.56 (m, 2H), 6.31 (t, 1H, J=3.6 NHz), 7.83-7.87 (m, 2H), 7.96 (d, 1H, J=6.0 Hz), 8.16-8.20 (m, 2H), 8.35 (d, 1H, J=5.6 Hz), 10.20 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=4)[N:14]=[C:15]([NH:18][C:19]4([C:24]([F:27])([F:26])[F:25])C[CH2:22][CH2:21][CH2:20]4)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=CC3N=C(NCC4C=CC(S(N)(=O)=O)=CC=4)N=C(NC4(C(F)(F)F)CCCCC4)C=3N=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:37])=[O:38])=[CH:32][CH:31]=4)[N:14]=[C:15]([NH:18][C:19]4([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:21][CH2:22]4)[C:16]=3[N:17]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(CNc2nc(NC3(C(F)(F)F)CCCC3)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Agent: NS(=O)(=O)c1ccc(CNc2nc(NC3(C(F)(F)F)CCCCC3)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Product: NS(=O)(=O)c1ccc(CNc2nc(NC3(C(F)(F)F)CCC3)c3nc(-c4ccc(F)cc4)ccc3n2)cc1

Procedure:
4-{[6-(4-Fluoro-phenyl)-4-(1-trifluoromethyl-cyclopentylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide; 4-{[6-(4-Fluoro-phenyl)-4-(1-trifluoromethyl-cyclohexylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O1C=CC(=O)C=C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(=O)([O-])O.[Na+]>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][N:32]([CH:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)[CH2:33][CH2:34]1
Reactant: C1CCOCC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=c1ccocc1
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(C3CCOCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (453 mg) and tetrahydropyran-4H-pyran-4-one (120 mg) in tetrahydrofuran (20 mL) was added sodium triacetoxyborohydride (318 mg), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] to give the title compound as a colorless amorphous compound (317 mg, 59%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2ccccc2s1
Yield: 68 %

Procedure:
476 mg of dibenzoyl peroxide were added to a solution of 5.87 g of 2-methylbenzothiazole and 15.4 g of N-bromosuccinimide in 60 ml of carbon tetrachloride at room temperature and the resulting mixture was stirred under reflux for 9 hours. At the end of this time, the reaction mixture was filtered and the resulting filtrate was concentrated by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate to give 6.10 g (yield 68%) of the title compound as a solid having a metling point of 43° to 45° C.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[C:29]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]Br)([CH3:32])([CH3:31])[CH3:30]>O>[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[N:20]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:43])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1
Reactant: COC(=O)c1ccccc1CSc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CSc1nc2ccccc2n1Cc1ccccc1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 70.8 %

Procedure:
Sodium hydride (104 mg, 2.86 mmol) and tetrahydrofuran (16 ml) were added to a previously dried reaction vessel. To the mixture were added 2-(benzimidazole-2-ylthiomethyl)benzoic acid methyl ester (428 mg, 1.43 mmol) and 2-(bromomethyl)benzoic acid t-butyl ester (466 mg, 3.46 mmol), and then the mixture was stirred at 60° C. for 50 minutes. Water was added thereto, followed by extraction with ethyl acetate. After the ethyl acetate phase was dried with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=3:1) to obtain 2-((1-((2-((t-butyl)oxycarbonyl)phenyl)methyl)benzimidazole-2-ylthio)methyl)benzoic acid methyl ester (495 mg, yield 71%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]3)=[CH:2]1.Cl.Cl.Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C@@H:35]([N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)[CH3:36])[CH2:30][CH2:29]1>>[OH:43][CH:40]1[CH2:39][CH2:38][N:37]([C@@H:35]([CH3:36])[CH2:34][N:31]2[CH2:30][CH2:29][CH:28]([NH:27][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:3]3[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][CH:2]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:33][CH2:32]2)[CH2:42][CH2:41]1
Reactant: O=C(O)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5ccccc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized analogously to example 1 from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example 50) and amine 50.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].N1C=CC=CC=1.[CH:12]1([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[CH:21]=[CH:20]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1(C)C=CC=CC=1.CO>[Cl:1][CH2:2][C:3]([C:21]1[C:22]2[C:27](=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][CH:23]=2)[N:19]([CH2:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2ccn(CC3CCCCC3)c12
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: COc1cccc2c(C(=O)CCl)cn(CC3CCCCC3)c12
Temperature: 55 °C
Yield: 16.1 %

Procedure:
To a solution of 7-methoxyindole (5.00 g, 34.0 mmol) in dimethylformamide (50 ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil; 1.50 g, 37.4 mmol). The mixture was stirred at room temperature for 10 minutes before the addition of bromomethylcyclohexane (5.20 ml, 37.4 mmol). The resulting mixture was stirred at room temperature for 42 hours and then partitioned between ethyl acetate (150 ml) and water (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) and the combined organic layers were washed with brine (150 ml), dried over sodium sulfate and concentrated in vacuo. The crude intermediate was purified by flash column chromatography eluting with 0-10% (v/v) ethyl acetate in n-heptane to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole (7.48 g, 30.7 mmol). Chloroacetyl chloride (8.66 ml, 109 mmol) was added dropwise over a period of 1.5 h, to a stirred solution of pyridine (2.20 ml, 27.2 mmol) and 1-(cyclohexyl)methyl-7-methoxy-1H-indole (6.60 g, 27.2 mmol) in toluene (50 ml) at 55° C. The resulting mixture was heated at 55° C. for a further 0.5 h then allowed to cool to room temperature. Water (60 ml) and methanol (10 ml) were added. The organic layer was separated and concentrated under reduced pressure to afford a dark brown residue. The residue was purified by column chromatography eluting with 5% (v/v) ethyl acetate in n-heptane. The solid obtained was repeatedly recrystallised from ether to give 2-chloro-1-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]ethanone as a white solid (1.40 g).