Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[O:10][CH:11]=[C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=23)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOC1.[Br:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C1COCC1>[Br:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:12]2=[CH:11][O:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[C:13]12)=[O:40]
Reactant: c1ccc(-c2occ3c2[nH]c2ccccc23)cc1
Reactant: O=C(Cl)c1ccccc1Br
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Br)n1c2ccccc2c2coc(-c3ccccc3)c21
Reaction time: 1 h

Procedure:
2.1 g (52.5 mmol) of NaH (60% in mineral oil) are dissolved in 500 ml of THF under a protective-gas atmosphere. 11.5 g (50 mmol) of 3-phenyl-4H-furo[3,4-b]indole and 11.5 g (52.5 mmol) of 15-crown-5, dissolved in 200 ml of THF, are added. After 1 h at room temperature, a solution of 12 g (55 mmol) of 2-bromobenzoyl chloride in 250 ml of THF is added dropwise.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:11][C:12]1[C:13]([Cl:20])=[CH:14][C:15]([CH2:18]Cl)=[N:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.CS(C)=O>[CH2:4]([O:11][C:12]1[C:13]([Cl:20])=[CH:14][C:15]([CH2:18][O:2][CH3:1])=[N:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCc1cc(Cl)c(OCc2ccccc2)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COCc1cc(Cl)c(OCc2ccccc2)cn1
Temperature: 100 °C
Yield: 91 %

Procedure:
A solution of 9.30 g (172 mmol) of sodium methylate in 132 ml methanol was added drop wise to a solution of 5-benzyloxy-4-chloro-2-chloromethyl-pyridine (Australian Journal of chemistry, 1977, 30, 649) in 130 ml DMSO. The suspension was heated at 100° C. for 6 h, poured on ice, extracted with four portions of CH3Cl. The organic phases were dried (Na2SO4), evaporated and distilled (Kp 0.2 mm Hg, 150-152° C.) to give 12.80 g (91%) of the title compound. MS: 264.0 (MH+).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3Cl)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[N-:20]=[N+:21]=[N-:22].[Li+]>CN(C=O)C>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[N:20]=[N+:21]=[N-:22])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H](O)[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.3 %

Procedure:
A solution of 4 (170 mg, 0.63 mmol) in DMF (5 ml) was treated with lithium azide (270 mg, 5.52 mmol) and stirred for two days at room temperature. The solvent was evaporated under reduced pressure at 40° C. and the crude oil was recrystallized from MeOH to obtain pure 5 (67 mg, 38.4%): mp 185-190° C. (dec.); UVλmax (water) pH 2: 205.0 (15,506), 287.0 (6,496); pH 7: 208.5 nm (12,943), 287.5 nm (6033); pH 11: 222.5 nm (6,730); 1H NMR (DMSO-d6) δ 3.66-3.90 (m, 3H, H-5′, H-4′), 4.16-4.33 (m, 2H, H-2′, H-3′), 5.14 (t, 1H, 5′-OH, exchangeable with D2O), 6.50 (d, 1H, H-1′), 8.75 (s, 1H, H-8), 10.12 (s, 1H, H-2); IR (KBr) 2037, 1649; Anal. (C10H11N7O4&Circlesolid;0.65 CH3OH): C, H, N.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[N:18]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:17]3[N:18]=[C:14]([CH3:13])[S:15][CH:16]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1nc(C(=O)O)cs1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cs1
Yield: 68 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methylthiazole-4-carboxylic acid (311 mg, 2.17 mmol), and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP-Cl (203 mg, 2.17 mmol). After 1 hour the solid formed was filtered and washed with CH2Cl2 (3×4 mL) to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide (210 mg, 68% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.14 (s, 1H), 9.83 (s, 1H), 8.38 (d, 1H), 8.26 (s, 1H), 7.74 (d, 1H), 2.77 (s, 3H); LCMS (APCI+) m/z 354.9, 356.9 (M+H)+, Retention time=3.39 minutes (Method 2).
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](=[O:49])[N:34]([CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH2:35][CH2:36][CH3:37])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:33](=[O:49])[N:34]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:35][CH2:36][CH3:37])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(N)CC(C(=O)N(CCC)CCCO)=C3)cc1
Reaction time: 1 h

Procedure:
Propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded propyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.68 (m, 2H), 7.20-7.41 (m, 5H), 6.73-6.85 (m, 3H), 4.42-4.52 (m, 1H), 4.05-4.16 (m, 2H), 3.71 (s, 2H), 3.24-3.52 (m, 6H, partially obscured by water peak), 2.75 (s, 2H), 1.66-1.78 (m, 2H), 1.50-1.65 (m, 2H), 1.15-1.23 (m, 3H), 0.75-0.92 (m, 3H); m/z (APCI-pos) M+1=464.2.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:36]([NH:35][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:37])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1
Yield: 78.3 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (200 mg, 0.55 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.01 mmol/g; 550 mg, 1.65 mmol) and cyclohexyl isocyanate (72 μL, 0.55 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (16 mL), then evaporated to afford the desired product as a colourless glass (194 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=2[CH2:18][CH2:19][CH3:20])=[CH:8][CH:7]=[CH:6][C:5]=1[F:21].[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40]Cl)[C:34]([CH2:42][CH3:43])=[CH:33][C:32]=1[Br:44])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:40][CH2:39][CH2:38][O:37][C:35]3[CH:36]=[C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:32]([Br:44])=[CH:33][C:34]=3[CH2:42][CH3:43])[C:12]=2[CH2:18][CH2:19][CH3:20])=[CH:8][CH:7]=[CH:6][C:5]=1[F:21]
Reactant: CCCc1c(O)cccc1Oc1cccc(F)c1C(=O)OC
Reactant: CCc1cc(Br)c(OCc2ccccc2)cc1OCCCCl
Product: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(Br)cc2CC)cccc1Oc1cccc(F)c1C(=O)OC

Procedure:
2-Fluoro-6-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester (1.84 g, 4.80 mmol) was alkylated with 2-benzyloxy-1-bromo-5-ethyl-4-(3-chloro-1-propyloxy)benzene to provide crude product as an oil. Silica gel chromatography provided 2.05 g (66%) of the purified title intermediate as a colorless oil: NMR (CDCl3) 7.49 (d, J=7.1 Hz, 2H), 7.20-7.45 (m, 5H), 7.14 (t, J=8.2 Hz, 1H), 6.82 (t, J=8.5 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 6.52 (d, J=8.5 Hz, 1H), 5.13 (s, 2H), 4.20 (t, J=6.0 Hz, 2H), 4.13 (t, J=6.0 Hz, 2H), 3.92 (s, 3H), 2.58 (m, 4H), 2.30 (quintet, J=6.0 Hz, 2H), 1.51 (hextet, J=7.6 Hz, 2H), 1.16 (t, J=7.9 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1Br.C(=O)([O-])[O-].[Na+].[Na+].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[C:19]1[S:18][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(C=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)cc1-c1cccs1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.21 mmol) was added to a solution of 4-methoxy-3-bromobenzaldehyde (1.5 g, 6.98 mmol) in toluene (15 mL) and ethanol (15 mL), followed by a 2 M aqueous solution of sodium carbonate (14 mL, 28 mmol). To this mixture was added thiophene-2-boronic acid (0.98 g, 7.68 mmol), and the mixture was heated to reflux. After 3 hours, the reaction was partitioned between water (100 mL) and ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL), dried with magnesium sulfate and concentrated. Chromatography (silica, 20% ethyl acetate/hexanes) afforded 1.3 g (87%) of 4-methoxy-3-thiophen-2-yl-benzaldehyde as a yellow oil.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1(C2CCCC2)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C2CCCC2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 456 μL, 1.14 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (177 μL, 0.1.14 mmol) in THF (3 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 120 mg, 0.38 mmol) in THF (2 mL) was added and stirred for 2 h at 70° C. The reaction mixture was then purified by automated flash chromatography. Pure fractions were combined and concentrated under reduced pressure. The material was recrystallized from MeOH to obtain the desired product 3-cyclopentyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (60 mg, 31% yield) as white crystals. LC-MS: Rt (retention time): 3.32 min, MS: (ES) m/z 513.2 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.4 (s, 1H), 8.05 (s, 2H), 7.6 (s, 1H), 7.08-7.13 (m, 2H), 7.02-7.06 (m, 2H), 4.14 (d, 1H, J=11.5 Hz), 3.56 (d, 1H, J=11.5 Hz) 3.17 (d, 1H, J=16.9 Hz), 2.74 (d, 1H, J=16.9 Hz), 2.42-2.52 (m, 1H), 2.2 (s, 3H), 2.14 (s, 3H), 1.75-1.88 (m, 2H), 1.6-1.68 (m, 4H), 1.25-1.48 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[O:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27]OS(C)(=O)=O)[O:24][C:23]3=[O:33])=[CH:18][C:17]=2[F:34])[CH2:12][CH2:11]1>CN(C)C=O>[O:10]1[CH2:11][CH:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][N:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]4=[O:1])[O:24][C:23]3=[O:33])=[CH:18][C:17]=2[F:34])[CH2:14][CH2:15]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2ccccc2=O)CN1c1ccc(C2=CCOCC2)c(F)c1
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
2-Hydroxypyridine (108 mg, 1.14 mM) was added at room temperature, under an atmosphere of nitrogen, to a stirred suspension of sodium hydride (60% dispersion in oil, 48 mg, 1.2 mM) in N,N-dimethylformamide (5 ml). The reaction was stirred for 30 minutes then (5R)-3-(4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (400 mg, 1.08 mM; WO 97-09328) was added in one portion. The mixture was stirred and heated at 60° for 5 hour before quenching in water (20 ml) and extracting with ethyl acetate. The extract was washed twice with water and once with saturated brine, dried (magnesium sulfate) and evaporated to an orange oil, which was purified by flash chromatography on silica, eluting with 2.5% methanol in dichloromethane to give the title compound (115 mg) as a colourless solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:24])=[C:11]([C:16]([CH2:22][CH3:23])=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].CO>[Si:1]([O:8][C:9]1[C:10]([F:24])=[C:11]([CH:16]([CH2:22][CH3:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(=CC(=O)OC)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Agent: [Pd]
Solvent: CO
Product: CCC(CC(=O)OC)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A 75 mL pressure tube was charged with 90.E (mixture of geometric isomers) (0.26 g, 0.73 mmol), MeOH (7 mL), and Pd/C (10 wt. %) (0.039 g, 0.036 mmol). The tube was purged 3 times with H2 at 50 psi and sealed. The mixture was stirred for 8 hours at room temperature, filtered through silica gel (EtOAc), and concentrated to afford 90.F (0.23 g, 88% yield) as a colorless oil. The product thus obtained was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:8]=[CH:7][C:6]=2[N:23]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:24]([N:4]1[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:8]=[CH:7][C:6]=2[N:23]=[C:3]1[S:2][CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2n1Cc1ccccc1
Yield: 54.7 %

Procedure:
A solution of 1.0 g (3.10 mmol) of 2-methylsulphanyl-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 15 ml of dimethylformamide was combined with 547 mg (3.20 mmol) of benzylbromide and then with 442 mg (3.20 mmol) of potassium carbonate and stirred overnight at ambient temperature. Then it was diluted with approx. 40 ml of water and extracted three times with 15 ml of ethyl acetate. The organic extracts were washed with water, dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant:petroleum ether with 10–20% ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[O:21][CH3:22])([CH3:12])[CH3:11]>>[NH2:18][C:17]1[CH:16]=[C:15]([O:21][CH3:22])[C:14]([O:13][CH:10]([CH3:12])[CH3:11])=[CH:20][C:19]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1cc(N)ccc1OC(C)C
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC(C)C

Procedure:
(2-amino-4-methoxy-5-(1-methylethoxy)phenyl)-(2-chlorophenyl)-methanone (Xjj) was prepared by reacting 2-chlorobenzaldehyde with 0.0267 moles of 4-isopropoxy-3-methoxy aniline in a manner analogous to Example 1. MH+/Z=320.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][CH3:22])=[C:10]([CH2:19]O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.S(Cl)(Cl)=O>[N:23]([CH2:19][C:10]1[C:9]([CH2:21][CH3:22])=[N:8][C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[C:11]=1[NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 218.1 %

Procedure:
To [1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (24.9 g, 82 mmol) was added thionyl chloride (90 mL, 1.23 mmol) and the mixture was heated to 80° C. under an atmosphere of nitrogen. After 2 h the mixture was cooled, evaporated and the residue azeotroped with toluene. The residue was then dissolved in a solution of sodium azide (7.98 g, 123 mmol) in DMSO (120 mL). The mixture was stirred for 16 h. The above procedure was repeated on the same scale and the 2 reactions combined for work-up. The combined DMSO mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was extracted thoroughly with ethyl acetate and the combined organics were washed with water, then brine, dried and evaporated to afford 58.9 g of a brown solid. The product was purified by flash chomatography on 1.5 kg of silica using a step gradient from 3:1 to 2:1 cyclohexane/ethyl acetate to afford 39.94 g of the title compound. LC-MS m/z 330 (M+H)+, 2.21 min (ret time).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:12]([C:22](O)=[O:23])=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][C@H:27]([C:36]([NH2:38])=[O:37])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(NC(C)C)(C)C>CN(C)C=O>[C:36]([CH:27]([NH:26][C:22]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[C:15]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:23])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:37])[NH2:38]
Reactant: NC(=O)[C@@H](N)CCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccccc3)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: NC(=O)C(CCc1ccccc1)NC(=O)c1ccc2[nH]c(-c3ccccc3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.16 g (0.5 mmol) of 2,3-diphenyl-1H-indole-5-carboxylic acid (see process variant A) was dissolved at RT in 10 ml of dry dimethylformamide (DMF) and admixed successively with 0.11 g (0.5 mmol) of L-homophenyl-alaninamide hydrochloride, 0.16 g of TOTU (O-[(cyano(ethoxycarbonyl)-methylidene)amino-1,1,3,3-tetramethyl]uronium tetrafluoroborate) and 0.14 ml (1 mmol) of diisopropylamine. The reaction mixture was stirred at RT for 6 h and then concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic phase was washed successively with water, saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gave N-(1-carbamoyl-3-phenylpropyl)-2,3-diphenyl-1H-indole-5-carboxamide of melting point 120° C. to 125° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([OH:19])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:19][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:18][CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OC1CCC1
Product: CS(=O)(=O)c1ccc(OC2CCC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and cyclobutanol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 269.3 ([M−H]−, 100%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:20]3=[N:21][C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:23]=4[N:19]3[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][N:8]=1)(=O)=O.[CH3:36][N:37](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:27]1[C:22]2[N:21]=[C:20]3[N:14]([C:10]4[C:11]([CH3:13])=[CH:12][C:7]([C:36]#[N:37])=[N:8][CH:9]=4)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23]=2[C:24]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:25][CH:26]=1
Reactant: CN(C)C=O
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(OS(=O)(=O)C(F)(F)F)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(C#N)cc1C
Temperature: 120 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Under argon atmosphere a mixture of 5-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-4-methylpyridin-2-yl trifluoromethanesulfonate (Example 58; 285 mg, 0.537 mmol), zinc cyanide (94.5 mg, 0.805 mmol), tetrakis(triphenylphosphine)palladium(0) (62.1 mg, 0.0537 mmol) and N,N-dimethylformamide (2.7 mL) was stirred at 120° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (166 mg, 0.407 mmol, 76%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[N:13][NH:14][C:15]=1[CH:16]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:16]([C:15]3[C:11]([Br:10])=[CH:12][NH:13][N:14]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1[nH]ncc1Br
Reactant: Nc1cc(Br)cnc1N
Product: Brc1cnc2[nH]c(-c3n[nH]cc3Br)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-bromo-1H-pyrazole-5-carbaldehyde.