Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ca+2].[Cl-].Br[C:5]1[C:15]2[CH2:14][NH:13][CH2:12][CH2:11][C:10]34[CH:21]=[CH:20][C@H:19]([OH:22])[CH2:18][CH:16]3[O:17][C:8]([C:9]=24)=[C:7]([O:23][CH3:24])[CH:6]=1>[Zn]>[CH3:24][O:23][C:7]1[CH:6]=[CH:5][C:15]2[CH2:14][NH:13][CH2:12][CH2:11][C:10]34[CH:21]=[CH:20][C@H:19]([OH:22])[CH2:18][CH:16]3[O:17][C:8]=1[C:9]=24
Reactant: COc1cc(Br)c2c3c1OC1C[C@@H](O)C=CC31CCNC2
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Product: COc1ccc2c3c1OC1C[C@@H](O)C=CC31CCNC2
Yield: 79 %

Procedure:
Activated zinc (89.0 g, 1.36 mol) and calcium chloride (44.0 g, 0.40 mol) were added to a solution of (6R)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol (3) (20.0 g, 56.8 mmol) in 50% EtOX (1000 ml). The reaction mixture was refluxed for 18 hours and filtered on Celite. The filtrate was concentrated by evaporation, the residue was diluted with 2N hydrochloric acid (500 ml) and extracted with EtOAc (3×400 ml). The pH of the aqueous phase was set at above 8.5 with concentrated ammonia and extracted with CH2Cl2 (3×100 ml) and with CH2Cl2:MeOH=9:1 (3×100 ml). The combined organic extracts were washed with brine (200 ml), dried (Na2SO4) and concentrated by evaporation to produce 12.3 g (79.0% of compound 4: 1H-NMR (CDCl3) δ 6.62 (b, 2H), 6.02 (m, 2H), 4.61 (b, 1H), 4.14 (t, J=4.3 Hz, 1H), 3.98 (d, J=5.0 Hz, 2H), 3.83 (s, 3H), 3.30 (m, 1H), 2.69 (t, J=15.7, 1H), 2.10–1.63 (m, 4H); 13C-NMR (CDCl3) δ 146.2 (s), 144.1 (s), 133.1 (s), 131.7 (s), 127.8 (d), 126.8 (d), 120.8 (d), 111.1 (d), 88.4 (d), 61.9 (d), 55.9 (q), 53.3 (t), 48.5 (s), 46.7 (t), 39.4 (t), 29.9 (t). Anal. (C20H26N2O4) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:4][C:3]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=2[F:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Nc1cc(F)ccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(F)ccc2F)cc1

Procedure:
Following Intermediate Method 1, a substituted aniline, for example 2,5-difluoroaniline, may be reacted with 4-methylphenylsulfonyl chloride in pyridine to form N-(4-methylphenylsulfonyl)-2,5-difluoroaniline, (V). Nitration of (V) with sodium nitrite in nitric acid, acetic acid and water produces N-(4-methylphenylsulfonyl)-2,5-difluoro-4-nitroaniline, (VI). The reaction of (VI) with aqueous sulfuric acid yields 2,5-difluoro-4-nitroaniline, (VII). Subsequent reaction of (VII) with acetic anhydride and a small amount of dimethylaminopyridine (DMAP) in methylene chloride produces N-(2,5-difluoro-4-nitrophenyl)acetamide (VIII). Treatment of (VIII) with a borane/dimethyl sulfide complex in tetrahydrofuran yields N-ethyl-2,5-difluoro-4-nitroaniline, (IX). Repeating the previous two steps, the reaction of (IX) first with acetic anhydride (to produce N-(2,5-difluoro-4-nitrophenyl)-acetamide, (X)) followed by treatment with a borane/dimethyl sulfide complex yields N,N-diethyl-2,5-difluoro-4-nitroaniline, (XI). Hydrogenation of (XI) with platinum oxide in ethanol produces the desired 2,5-difluoro-4-diethylaminoaniline, (XII). ##STR28##
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[CH:5][C:6]([Cl:22])=[C:7]([C:9]2[NH:10][C:11](=[O:21])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[Cl:22][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:21])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([F:23])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-78, 0.120 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.033 g of the desired product. 1H NMR (300 MHz, DMSO): δ 1.12 (s, 9H), 4.30 (br s, 2H), 7.53-7.63 (m, 4H), 7.95 (d, J=12.8 Hz, 2H), 8.14 (s, 1H), 12.61 (s, 1H); MS (m/z): 437.47 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)(=[O:15])=[O:14])[CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1>CO.[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)(=[O:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2cc(Cl)cc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)c2n1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2cccc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)c2n1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A mixture of 4-(2-amino-6-chloroquinoline-8-sulfonamido)benzoic acid (150 mg, 0.44 mmol), 10% Pd/C (20 mg) in methanol (5 mL) was stirred under H2 atmosphere overnight when LCMS indicated that the reaction was complete. The resulting mixture was filtered, and the filtrate was concentrated to yield 100 mg of title compound, which was used in the next step without further purification. LCMS (m/z): 344.6 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: Fc1ccccc1Cc1n[nH]c2ncccc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3cccnc32)n1

Procedure:
A solution of 150 mg (0.66 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine from example 12A, 96 mg (0.66 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 12 mg (0.013 mmol) of tris(di-benzylideneacetone)dipalladium, 19 mg (0.040 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 300 mg (0.92 mmol) of cesium carbonate in 4 ml of degassed toluene is heated at 90° C. for 20 h. It is then diluted with water and a little methanol and extracted with ethyl acetate. The organic phase is concentrated in vacuo, and the residue is stirred with methanol and filtered off with suction. 62 mg (28% of theory) of the desired compound are obtained as beige-colored crystals in this way.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[N:35]1([CH2:41][CH2:42]O)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:42][CH2:41][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OCCN2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
Diisopropyl azodicarboxylate (0.48 mL, 2.4 mmol) was added dropwise to a stirred solution of 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.56 g, 2 mmol), 2-morpholin-4-yl-ethanol (0.24 mL, 2 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) in THF (20 mL) cooled to 0° C. The resulting solution was warmed to r.t. and stirred for about 16 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (ethyl acetate) to afford the final compound (0.50 g, 64%) as a clear oil
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][C:7]([CH3:21])=[N:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=3)[C:4]=2[CH:3]=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)CC)C>C1CCCCC1>[C:28]1([O:27][C:25]([N:8]2[C:7]([CH3:21])=[CH:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=3)=[N:9]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C1
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)Oc1ccccc1
Yield: 57.9 %

Procedure:
15 g (45.7 mmoles) of 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-5H-2,3-benzodiazepine are boiled in a mixture of 28.85 ml (228.5 mmoles) of phenyl chloroformate and 6.34 ml (45.7 mmoles) of triethylamine for 3.5 hours. The reaction mixture is diluted with 150 ml of cyclohexane, the solvent is decanted off the separated oily product, the residue is dissolved in dichloromethane, washed first with saturated sodium hydrogen carbonate solution, then with water and dried over anhydrous sodium sulfate. After evaporation the crude product is recrystallized from ethanol. Thus 11.86 g (58%) of the desired compound (yellow) melting at 188-190° C. are obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8]>>[CH2:7]([NH:9][C:10]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:11])[CH3:8]
Reactant: CC(C)(N)CO
Reactant: CCN=C=O
Product: CCNC(=O)NC(C)(C)CO
Yield: 94 %

Procedure:
Prepared as in Example 206d from 2-amino-2-methylpropan-1-ol and ethyl isocyanate in 94% yield. MS 161 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([C:29]([NH:31][NH2:32])=[O:30])[CH:26]=[CH:25][N:24]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([C:29]([NH:31][NH:32][C:11](=[O:13])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:4]=2)=[O:30])[CH:26]=[CH:25][N:24]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NN)ccn1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)Nc1cc(C(=O)NNC(=O)CCc2cccc(C(F)(F)F)c2)ccn1
Yield: 80 %

Procedure:
In the same manner as in Reference Example 1 and using 3-[3-(trifluoromethyl)phenyl]propionic acid instead of benzothiazole-6-carboxylic acid and tert-butyl[4-(hydrazinocarbonyl)-2-pyridyl]carbamate instead of tert-butyl carbazate, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[NH:12][C:11]2=[S:21])[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:31]([S:21][C:11]1[N:10]([CH:9]2[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]2)[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=2[N:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)OCC1CC(n2c(=S)[nH]c3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OCC1CC(n2c(SCc3ccccc3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 65 %

Procedure:
A mixture of (±)-(1R*, 2S*, 3S*, 5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.50 g, 1.05 mmol), benzyl bromide (0.3 mL, 2.5 mmol) and anhydrous potassium carbonate (0.145 g, 1.05 mequiv as 98%) in dioxane (5 mL) was stirred vigorously at ambient temperature for 2.5 days. Volatiles were evaporated in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried(sodium sulfate) and concentrated to an oil which was stirred in ammonia-methanol (40 mL of half-saturated) for 18 hours. Volatiles were evaporated and the residue solidified from 3:1 methanol-water to give title compound as a white powder (300 mg, 65%), m.p. 160°-162° C.; 1H-NMR(DMSO-d6)δ: 8.04 and 7.89 (both s, 1 each, 2 aromatic CH), 7.5-7.2 (m, 5, C6H5), 5.06 (t, J=4.7 Hz, 1, OH), 4.98 (d, J=6.2 Hz, 1, OH), 4.75-4.55 (m overlapping d at 4.68, J=3.7 Hz, and s at 4.63, total 4, NCH, OH, and SCH2); mass spectrum(CI): 439 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)=[CH:21][CH:20]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: Brc1ccc(I)cc1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(Br)cc3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1-bromo-4-iodobenzene according to the procedure described in example 2. 1H NMR (DMSO-d6): δ 8.25 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.11 (dd, J=8.7, 2.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 6.87 (d, J=2.3 Hz, 1H), 3.26 (s, 3H), 1.95 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z 389/391 ([M+H]+); MS (ESI) m/z 387/389 ([M−H]−); Anal. calcd for C19H21BrN2O2: C, 58.62; H, 5.44 N, 7.20. Found: C, 58.59; H, 5.29; N, 7.03.
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24]([OH:26])[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCOC(C)=O>N1C=CC=CC=1>[OH:28][C@@H:18]1[CH2:19][C@H:20]2[C@:21]([CH3:27])([CH2:22][CH2:23][C@@H:24]([O:26][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:25]2)[C@@H:16]2[C@@H:17]1[C@H:12]1[C@:13]([CH3:30])([C@@H:14]([OH:29])[CH2:15]2)[C@@H:9]([C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:10][CH2:11]1
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
To a solution of cholic acid methyl ester (25 g, 59.2 mmol) in pyridine (75 mL), stirring at 0° C., was added methanesulfonyl chloride (5.04 mL, 65.1 mmol) dropwise over 30 minutes. The reaction was allowed to warm to room temperature and stir for 6 hours. The reaction mixture was poured into a mixture of EtOAc (200 mL), 1 N HCI (200 mL), and ice. The layers were separated, and the organic layer was washed with 1N HCI (2×50 mL), dried (Na2SO4) and concentrated to provide a light yellow oil. The crude material was passed through a plug of silica eluting with 50% EtOAc/hexanes to provide 24.5 g (83%) of the title compound as a light yellow oil that foamed into a white, sticky foam when placed on the high vacuum pump.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Cu](C#N)[C:14]#[N:15].O>CN(C=O)C>[CH:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:14]#[N:15])=[N:3][NH:4]2)=[CH:9][CH:8]=1)=[O:12]
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1n[nH]c2cc(C=O)ccc12
Temperature: 185 °C
Yield: 59.5 %

Procedure:
To a solution of 3-iodo-1H-indazole-6-carbaldehyde (3 g, 10.8 mmol) in DMF (25 mL) was added Copper cyanide (1.9 g, 21 mmol). The solution was heated by microwave irradiation at 185° C. for 10 min. Water (100 mL) was added and a white precipitate was collected. The precipitate was dissolved in EtOAc (250 mL), washed with water (2×25 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (1.1 g, 73%). 1H NMR (400 MHz, DMSO-d6) δ 14.92 (bs, 1H), 10.17 (s, 1H), 8.39 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])[CH2:9][CH3:10]>CN(C=O)C>[CH3:11][C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([C:36]([OH:1])=[O:37])=[CH:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:7])[CH2:9][CH3:10]
Reactant: O=S([O-])OO
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone (148 mg, 0.24 mmol) was added to a solution of 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde (89 mg, 0.20 mmol) in DMF (8 mL). The resulting mixture was stirred overnight at room temperature and used directly for step A. MS (ESI) (M+H)+=460.06.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)[CH:9]=O.C(OP([CH2:28][C:29](=[O:40])[NH:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)(=O)OCC)C>C1COCC1>[CH:31]1([NH:30][C:29](=[O:40])/[CH:28]=[CH:9]/[C:8]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:6]([O:5][CH3:4])[CH:7]=2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1
Reactant: CCOP(=O)(CC(=O)NC1CCc2ccccc21)OCC
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
Lithium hydroxide monohydrate (9 mg) was added to a THF (2 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (21 mg) and indan-1-ylcarbamoylmethylphosphonic acid diethyl ester (30 mg) obtained above, and the reaction solution was agitated at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: hexane-ethyl acetate system), and 13 mg of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:28])[CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[C:16]([C:18]1[N:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO>O1CCCC1>[OH:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]([N:15]([CH3:27])[CH2:14][CH2:13][CH2:12][N:11]([CH3:28])[C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:17])=[N:23][CH:22]=1
Reactant: CN(CCCN(C)C(=O)c1ccc(C(=O)O)cn1)C(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCCN(C)C(=O)c1ccc(CO)cn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.8 %

Procedure:
The compound (350 mg, 0.908 mmol) obtained in Example 5b was dissolved in tetrahydrofuran (4 mL), a borane-tetrahydrofuran complex (1.0 M tetrahydrofuran solution; 3.18 mL, 3.18 mmol) was added under ice cooling, and then the mixture was stirred at room temperature for 45 minutes. Methanol (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0→20:1, v/v) to give the title compound (124 mg; yield, 37%) as a colorless oily substance.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.[O:31]=[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N-:33]1.[K+]>CN(C=O)C.O>[CH:28]1([NH:27][C:25]([C:10]2[N:11]=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=3)[C:9]=2[CH2:8][CH2:7][CH2:6][N:33]2[C:34](=[O:41])[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:32]2=[O:31])=[O:26])[CH2:29][CH2:30]1
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (1.31 g, 3 mmol) obtained in Example 1201a) and potassium 1,3-dioxo-1,3-dihydroisoindol-2-ide (556 mg, 3 mmol, 1.0 eq.) were dissolved in DMF (20 ml) and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water (20 ml), and the precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (1.32 g, 90.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:7]=1.C([Li])CCC.N1(C=O)CC[O:21][CH2:20]C1.O>CCOCC>[C:8]1([C:6]2[CH:7]=[C:2]([CH:20]=[O:21])[CH:3]=[N:4][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Brc1cncc(C2=CCCC2)c1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: O=Cc1cncc(C2=CCCC2)c1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-cyclopenten-1-ylpyridine (9) (1 g, 4.5 mmol) in 25 ml of ether is added to a solution of n-butyllithium (1.6M in hexane, 4.2 ml, 6.7 mmol) in 25 ml of ether kept at −60° C. The reaction mixture is stirred for 2 h 30 min at −60° C. and then 1.4 ml of 4-morpholinecarboxaldehyde (13.4 mmol) are added. The reaction is stirred for 1 hour at −60° C. and then poured into water, the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). The title product is obtained in the form of a beige solid (0.38 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[F:17][C:2]([F:1])([F:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH:25]([CH3:27])[CH3:26])[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: COc1ccc2c(C(=O)C(F)(F)F)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-methoxy-1H-indol-3-yl)-ethanone (1.0 g, 4.11 mmol) in N,N-dimethylformamide (10 mL) at 25° C. was treated with potassium carbonate (1.42 mg, 10.28 mmol). The resulting mixture was stirred at 25° C. for 30 min and then was treated with 2-iodopropane (0.62 mL, 6.17 mmol). The reaction was heated at 65° C. for 20 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (25 mL), shaken, and separated. The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(1-isopropyl-6-methoxy-1H-indol-3-yl)-ethanone (99 mg, 85%) as a yellow solid: mp 58-60° C.; EI-HRMS m/e calcd for C14H14F3NO2 (M+) 285.0977, found 285.0974.