Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:19][CH3:20])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C([Li])(C)(C)C.[I:26]I>C1COCC1>[I:26][C:6]1[C:7]([O:19][CH3:20])=[C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:4][N:5]=1
Reactant: COc1ccc(COc2c(OC)cncc2OC)cc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(COc2c(OC)cnc(I)c2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of 3,5-dimethoxy-4-(4-methoxy-benzyloxy)-pyridine (120 mg, 0.436 mmol) in dry THF (3 ml) at −78° C. was added t-butyllithium (0.48 mmol, 1.7 M solution in pentane) and the resulting orange mixture was stirred at low temperature for 10 minutes. A solution of iodine (166 mg, 0.654 mmol) in dry THF (2 ml) was added drop-wise and the reaction allowed to warm to room temperature and stir for 15 minutes, then quenched with 10% Na2S2O3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated onto silica-gel under reduced pressure. The solid residue was purified by flash chromatography (silica-gel, eluted with hexanes:EtOAc, 4:1) to give the product as a tan solid (100 mg, 57%). 1H-NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.33 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.11 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[CH:10][C:9]2(C(OC)=O)[C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH:31]1(Br)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(Cl)(Cl)Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[C:9]=2[C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:4][N:3]=1
Reactant: BrC1CCCC1
Reactant: COC(=O)C1(C(=O)OC)C=Cc2cc(O)c(OC)cc2C1c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(OC3CCCC3)c(OC)cc2c(-c2ccnc(Cl)c2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 1-(2-chloro-4-pyridyl)-2,2-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene (3.34 g) in dimethylformamide (150 ml) is added sodium hydride (0.4 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added dropwise cyclopentyl bromide (1.8 ml), and the mixture is heated with stirring at 80° C. overnight. The mixture is heated at 130° C. for two hours. To the resultant are added chloroform and water, and the chloroform layer is separated, washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is crystallized from 1-(2-chloro-4-pyridyl)-2,3-bis(methoxycarbonyl)-6-cyclopentyloxy-7-methoxynaphthalene (1.24 g, yield; 32%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)=[O:31])[CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C2NCCc3c(Br)cccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2c(Br)cccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 5-bromo-1-(4-(trifluoromethyl)-phenyl)-1,2,3,4-tetrahydroisoquinoline (44 mg, 124 μmol, from step 3, example 146), CH2Cl2 (2 mL), 4-fluorophenyl isocyanate (17 mg, 124 μmol, Aldrich). The reaction mixture was stirred at RT for 1 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 50% EtOAc/hexanes to give 5-bromo-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 493 (M+1).
Reaction SMILES: Cl.[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3].[CH:25]1([C:28]2[C:37]3[C:32](=[C:33]([O:41][CH2:42][CH2:43][OH:44])[CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=3)[CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26]1.C1(C2C3C(=C(OC)C=C(C(O)=O)C=3)C=CN=2)CC1>>[NH2:3][C:2](=[O:4])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][N:17]([C:38]([C:35]3[CH:36]=[C:37]4[C:32]([CH:31]=[CH:30][N:29]=[C:28]4[CH:25]4[CH2:26][CH2:27]4)=[C:33]([O:41][CH2:42][CH2:43][OH:44])[CH:34]=3)=[O:39])[CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8]
Reactant: O=C(O)c1cc(OCCO)c2ccnc(C3CC3)c2c1
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: COc1cc(C(=O)O)cc2c(C3CC3)nccc12
Agent: Cl
Product: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(OCCO)c4ccnc(C5CC5)c4c3)CC1)O2

Procedure:
The intended compound was produced according to the procedure described in reference Example 37 but using 4-oxospiro(chroman-2,4′-piperidin)-6-yl-carboxylicacidcarbamoylmethyl amide hydrochloride and 1-cyclopropyl-5-(2-hydroxy-ethoxy)-isoquinoline-7-carboxylic acid in place of methyl 5″-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinate di-hydrochloride and 1-cyclopropyl-5-methoxy-isoquinoline-7-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.75 (1.0H, t, J=5.7 Hz), 8.36 (1.0H, d, J=5.7 Hz), 8.31 (1.0H, d, J=2.4 Hz), 8.09 (1.0H, dd, J=8.8, 2.4 Hz), 8.05 (1.0H, s), 7.85 (1.0H, d, J=5.9 Hz), 7.34 (1.0H, s), 7.22-7.14 (2.0H, m), 6.99 (1.0H, s), 5.00 (1.0H, t, J=5.7 Hz), 4.39-4.25 (1.0H, m), 4.21 (2.0H, t, J=4.8 Hz), 3.84 (2.0H, q, J=4.8 Hz), 3.78 (2.0H, d, J=5.9 Hz), 3.62-3.17 (3.0H, m), 2.95 (2.0H, s), 2.93-2.85 (1.0H, m), 2.15-1.77 (4.0H, m), 1.15-0.99 (4.0H, m). MS [M]+572.
Reaction SMILES: [Br:1]C1C(C(OC)=O)=NC(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=CN=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[C:32]([C:48]([O:50][CH3:51])=[O:49])=[N:33][C:34]([NH:37][C@@H:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][C@@H:39]2[OH:47])=[CH:35][N:36]=1>>[Br:1][C:35]1[N:36]=[C:31]([C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Cl:23])[C:32]([C:48]([O:50][CH3:51])=[O:49])=[N:33][C:34]=1[NH:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][C@@H:39]1[OH:47]
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate but substituting methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 2.99-3.04, 3.20-3.25, 3.70, 3.99-4.08, 4.77, 5.59-5.62, 6.11, 7.24-7.38; MS (ESI+) for C21H16BrCl2N3O3 m/z 509 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(c2ccc(Br)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(4-bromophenyl)piperidin-4-one (600 mg, 2.36 mmol) in EtOH (10 mL) was added NaBH4 (134 mg, 3.54 mmol) slowly at 0° C. The resulting mixture was stirred at rt for 1 h. The reaction was quenched with sat. NH4Cl solution, extracted with EtOAc, dried over MgSO4, filtered, and concentrated to dryness. The title compound was isolated by silica gel chromatography (EtOAc/hexanes, 2:3 to 3:2) as a yellow solid (606 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.9 Hz, 2H), 6.81 (d, J=8.9 Hz, 2H), 3.89-3.84 (m, 1H), 3.55-3.49 (m, 2H), 2.95-2.89 (m, 2H), 2.06-1.99 (m, 2H), 1.72-1.64 (m, 2H); MS ESI 255.9 [M+H]+, calcd for [C11H14BrNO+H]+ 256.03.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH2:21]O)=[CH:19][N:20]=2)[CH:17]=1.Cl.[OH-].[Na+]>C(O)(=O)C>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH2:21][S:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:19][N:20]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Cc1ccc2ncc(CO)n2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2ncc(CSc3ccc([N+](=O)[O-])cc3)n2c1
Temperature: 100 °C
Reaction time: 120 h
Yield: 80.9 %

Procedure:
A mixture of 4-nitrothiophenol (2.87 g), 6-methylimidazo[1,2-a]pyridin-3-ylmethanol (3.0 g), concentrated hydrochloric acid (60 ml) and acetic acid (60 ml) was stirred for 5 days at 100° C. The mixture was neutralized with 12N sodium hydroxide at 0° C., and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 2:1→4:1), to give 6-methyl-3-[[(4-nitrophenyl)thio]methyl]imidazo[1,2-a]pyridine (4.48 g) as pale yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:43])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[O:41][N:40]=[C:39]([CH3:42])[CH:38]=4)[CH:32]=3)[CH2:28][C:27](=[O:43])[NH:20][C:9]=2[CH:10]=1
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl)C1CC1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C5CC5)c(Cl)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(cyclopropyl-methyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example J11) (156 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (170 mg, 0.56 mmol) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (49 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15](Cl)=[N:16][CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[CH3:19][OH:20].C[O-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15]([O:20][CH3:19])=[N:16][CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(Cl)nc2)s1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2sc(N)nc2-c2ccco2)cn1
Temperature: 95 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Amino-5-(2-chloropyridin-5-yl)-4-(2-furyl)thiazole (2.22 g, 80.0 mmol) obtained in Step 1 and a methanol solution of 28% sodium methoxide (4.63 g, 24.0 mmol) were suspended in 1,4-dioxane (8 mL), followed by stirring at 95° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to afford 2-amino-4-(2-furyl)-5-(2-methoxypyridin-5-yl)thiazole (1.32 g, 60%).
Reaction SMILES: [F:1][C:2]1([F:41])[CH2:5][N:4]([C:6](=[O:40])[C@H:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH3:8])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:41][C:2]1([F:1])[CH2:5][N:4]([C:6](=[O:40])[C@H:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH3:8])[CH2:3]1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)(F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (88 mg, 0.146 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.45 ml, 5.84 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.6 ml, 8.74 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 45 mg (62%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow powder. MS: (M+H)+=474; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 10.55-11.71 (b. s, 1H), 9.13 (s, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.40-8.54 (m, 2H), 7.97 (d, J=1.5 Hz, 1H), 7.26 (dd, J=8.7, 1.5 Hz, 1H), 4.67-4.99 (m, 3H), 4.38 (t, J=12.7 Hz, 2H), 4.17 (s, 3H), 1.44 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH:19]=O)=[O:18].Cl>C(O)(=O)C.C1(C)C=CC=CC=1>[C:11]([C:7]1[C:6](=[O:15])[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9](=[CH:16][C:17](=[O:18])[CH3:19])[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(=O)C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Yield: 2.9 %

Procedure:
4.12 g (0.02 Mol) of 2,6-di-tert-butylphenol and 4.0 g (0.022 mol) of 40% aqueous pyruvic aldehyde are dissolved in 20 ml of acetic acid. The solution is then saturated at 15°-25° C. with hydrogen chloride gas and stirred at room temperature for additional two hours. The mixture is then diluted with 200 ml of toluene, washed several times with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The oily residue is then chromatographed on silica gel with toluene. The pure fractions are recrystallized three times from methanol to give 0.15 g of the title compound as orange needles, melting at 70°-72° C.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([I:12])[C:9]([O:13]C)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]>ClCCl>[Cl:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:8][C:9]([OH:13])=[C:10]([I:12])[CH:11]=1
Reactant: COc1cc(-c2ccccc2F)c(Cl)cc1I
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(-c2ccccc2F)c(Cl)cc1I
Temperature: 25 °C
Yield: 94.6 %

Procedure:
Boron tribromide (251 mg, 2.61 mmol) was added to a solution of 2-chloro-2′-fluoro-4-iodo-5-methoxybiphenyl (Preparation 95, 671 mg, 1.85 mmol) in dichloromethane (4.7 mL) at −20° C. and the mixture allowed to warm slowly to room temperature for 18 hours. The reaction was quenched by addition of water (10.0 mL), before being diluted with dichloromethane (30 mL). The organic phase was separated and washed with water (3×5.0 mL), brine (5.0 mL), dried over MgSO4, filtered and evaporated to give a purple oil. Column chromatography purification on silica, eluting with 1:4 ethyl acetate:heptanes gave the title compound (610 mg, 94%) as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:9][C@@H:10]1[CH2:15][N:14]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=2)[N:21]=1
Reactant: O=Cc1cccnc1
Reactant: C[C@@H]1CNCCN1c1ccc2nnc(C(F)(F)F)n2n1
Product: C[C@@H]1CN(Cc2cccnc2)CCN1c1ccc2nnc(C(F)(F)F)n2n1

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(2R)-2-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(2R)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in quantitative yield.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH2:14]([O:19][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CC(C)CCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in isopentanol (20 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.CS(O[C@H:17]([C@@H:19]1[CH2:23][C:22](=[O:24])[N:21]([C@@H:25]([C:27]2[CH:32]=[CH:31][C:30](OC)=[CH:29][CH:28]=2)[CH3:26])[CH2:20]1)[CH3:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:17]([C@H:19]2[CH2:20][N:21]([C@@H:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH3:26])[C:22](=[O:24])[CH2:23]2)[CH3:18])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1
Reactant: Oc1cc(Br)cn2nccc12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C[C@H]([C@@H](C)Oc2cc(Br)cn3nccc23)CC1=O
Temperature: 90 °C

Procedure:
To a solution of 6-bromopyrazolo[1,5-a]pyridin-4-ol (125 mg, 0.587 mmol) in DMF (4 mL) was added (S)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl methanesulfonate 1.30 (220 mg, 0.645 mmol) and Cs2CO3 (239 mg, 0.733 mmol) and the reaction mixture was heated at 90° C. for 2 h. The reaction mixture was diluted with EtOAc and water, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried, filtered, and concentrated. The residue was purified by flash chromatography to afford (R)-4-((R)-1-(6-bromopyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one 6.01.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)=O)=[CH:11][C:10]=1[O:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OP([CH2:37][C:38]#[N:39])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)=[CH:37][C:38]#[N:39])=[CH:11][C:10]=1[O:27][CH3:28])([CH3:6])([CH3:5])[CH3:7]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(OC)c2)c1
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(O[Si](C)(C)C(C)(C)C)c(OC)c2)c1
Yield: 78 %

Procedure:
[4-(tert-Butyldimethylsilanyloxy)-3-methoxyphenyl]-(3,5-dimethoxyphenyl)methanone (3.64 g, 9.04 mmol), cyanomethylphosphonic acid diethyl ester (2.85 ml, 18.08 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 18.08 ml, 18.08 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (5% EtOAc in hexane gradient to 20% EtOAc in hexane in about 30 min.) to give 3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrile as a white solid (3.00 g, 78%). The product was carried over to the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.CN(C=O)C.[C:23]1([C:29](=O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]/[C:29](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)O/C(=C/c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
Oxalyl dichloride (236 μl, 2.78 mmol) was added dropwise to a solution of 1-methylpiperidine-4-carboxylic acid hydrochloride (500 mg, 2.78 mmol) in DCM (30 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum, and the crude was taken up with pyridine (40 ml). 1,2-Diphenylethanone (546 mg, 2.78 mmol) was added, and the resulting suspension was heated under microwave irradiation at 140° C. for 1 hour. Pyridine was removed under vacuum, and the crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (E)-1,2-diphenylvinyl 1-methylpiperidine-4-carboxylate (62 mg).
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[Cl:14][S:15](O)(=[O:17])=[O:16].P(Cl)(Cl)(Cl)=O>CN(C)C(=O)C.C(#N)C>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[S:15]([Cl:14])(=[O:17])=[O:16]
Reactant: COc1ccc(OC)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Into 1100 ml of methylene chloride was dissolved 552 g (4.00 mol) of commercially available 1,4-dimethoxybenzene, and then 308 ml (4.63 mol) of chlorosulfonic acid was added dropwise thereto under cooling with ice in such a manner that the internal temperature was not over 5° C. After the addition, the reaction system was put under a condition of room temperature, and the solution was further stirred for 1 hour. Next, 1000 ml of acetonitrile and 600 ml of DMAC (N,N-dimethylacetoamide) were poured into the solution. Next, the reaction system was heated in a warm bath of 35° C. temperature, and thereto was added dropwise 404 ml (4.33 mol) of phosphorous oxychloride at an internal temperature of 30° C. At this time, attention was paid that the internal temperature was not over 40° C. After the addition, the solution was allowed to react at 35° C. for 1 hour. Thereafter, the reaction solution was charged into ice water. The organic phase was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, to obtain 2,5-dimethoxybenzenesulfonylchloride.