Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][CH2:8][CH2:9][CH2:10]Cl.CN(C)CCN(C)C.[C:20]1([C@H:26]([N:28]2[C@H:32]3[CH2:33][S:34][C:35](=O)[C@H:31]3[N:30]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:29]2=[O:44])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:45](=[O:47])=[O:46].S(=O)(=O)(O)O>O1CCCC1>[C:20]1([C@H:26]([N:28]2[C@H:32]3[CH2:33][S:34][C:35](=[C:7]([CH2:8][CH2:9][CH3:10])[C:45]([OH:47])=[O:46])[C@H:31]3[N:30]([CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:29]2=[O:44])[CH3:27])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N(Cc2ccccc2)[C@@H]2C(=O)SC[C@@H]21
Reactant: ClCCCCCl
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCCC(C(=O)O)=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2[C@H](C)c1ccccc1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
8.6 g of magnesium chips was placed in 75 ml of tetrahydrofuran. Then a mixture of 3.2 g of 1,2-dibromoethane and 2.5 g of 1,4-dichlorobutane in 35 ml of tetrahydrofuran was added within 15 minutes so that the temperature could be kept between 30° and 35° C. Then another 20.5 g of 1,4-dichlorobutane in 75 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred for 3 hours at this temperature and then mixed with 9 g of tetramethylethylenediamine and 180 ml of tetrahydrofuran. The reaction solution was cooled to -40° to -45° C. and then mixed with a solution of 30 g of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-3-benzyl-dihydro-1H-thieno[3,4-d]imidazol-2,4(3H,3aH)-dione in 180 ml of tetrahydrofuran within 20 minutes. It was stirred at this temperature for 1 hour and then CO2 gas was introduced for 30 minutes. The reaction mixture was poured onto 400 ml of 10 percent aqueous sulfuric acid and extracted several times with toluene. The toluene phase was mixed with 0.8 g of conc. sulfuric acid, washed with water and concentrated on a rotary evaporator. The residue was mixed with 400 ml of 10 percent potassium carbonate solution and extracted with ethyl acetate. The organic phase was washed again with 10 percent potassium carbonate solution. The combined aqueous phases were adjusted to pH 7.3 with aqueous sulfuric acid and extracted several times with ethyl acetate. The organic phase was finally dried with magnesium sulfate and concentrated. The product was precipitated by addition of hexane, filtered off and dried. 32.5 g (89.3 percent) of the title product was obtained as snow-white powder with a content (HPLC) of more than 99 percent. Concerning the product:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[B:6]([OH:9])([OH:8])[OH:7]>O>[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[B:6]([O-:9])([O-:8])[O-:7].[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1.[NH+:1]1[CH:5]=[CH:4][NH:3][CH:2]=1
Reactant: OB(O)O
Reactant: c1c[nH]cn1
Solvent: O
Product: [O-]B([O-])[O-]
Product: c1c[nH+]c[nH]1
Temperature: 45 °C

Procedure:
A flask fitted with a reflux condenser, magnetic stirrer, and temperature controller was charged with 225 mL deionized water and 70.0 g (1.0 moles) imidazole (C3H4N2). The resulting solution was heated to about 45° C. and 185.5 (3.0 moles) boric acid was added with stirring. The mixture was then heated to 90° C. and maintained with stirring for 1 h, cooled to 45° C., filtered, and washed with water. The resulting white powder was washed with about 100 mL deionized water and dried at 105° C. It was identified as imidazolium nonaborate by x-ray diffraction and titration analysis. Elemental analyses for the product are shown in Table 5, along with the theoretical analyses for imidazolium nonaborate, [C3H5N2]2O.3B2O3.2H2O.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:11][O:10]1.[Na].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.ClCCl.CO>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:11][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: CC(c1cccnn1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(c1cccnn1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (iii) (1.15 g) with 1H-1,2,4-triazole sodium salt (0.80 g) in N,N-dimethylformamide (15 ml) according to the method of Example 1(ii), followed by chromatography of the crude product on silica gel using dichloromethane/methanol (50:1) as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.35 g), m.p. 134°-135° (from ether).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([S:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][N:5]=1.[SH:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1.[OH-].[Na+].[CH2:29]([OH:31])C>>[CH3:29][O:31][C:9]1[C:4]([CH2:3][S:17][C:18]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[N:19]=2)=[N:5][CH:6]=[CH:7][C:8]=1[S:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCO
Reactant: Sc1nc2ccccc2[nH]1
Reactant: ClCc1cc(SCc2cccs2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(SCc2cccs2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 69 %

Procedure:
2-Chloromethyl-4-(2-thienylmethylthio)-pyridine hydrochloride, 2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 60° C. for 5 h. After crystallization from toluene/methanol, the title compound is isolated. Yield: 69%, m.p. 221°-222° C. (decomp.). 9. 2-{[[4-(2-Furylmethylthio)-2-pyridinyl]methyl]thio}-1H-benzimidazole
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:34])[NH:15][C:16](=[O:33])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:33])[NH:15][C:14]2=[O:34])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(-c3ccccc3)cc12
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccc(-c3ccccc3)cc12

Procedure:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-phenyl-1H-indol-3-yl)pyrrole-2,5-dione, prepared as in Example 32, was reduced with Mg in methanol as described in Example 2, Procedure C, to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-phenyl-1H-indol-3-yl)pyrrolidine-2,5-dione. 1H NMR (CD3OD) δ: 2.00-2.16 (m, 2H), 2.94(t, J=6.0 Hz, 2H), 3.92-3.99(m, 1H), 4.00-4.08(m, 1H), 4.36(d, J=6.4 Hz, 1H), 4.68(d, J=6.4 Hz 1H), 6.88-6.97(m, 2H), 7.04(s, 1H), 7.12-7.15(m, 1H), 7.17-7.47(m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12]([C:15](Cl)=[O:16])[CH2:13][CH3:14].N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[OH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH:1][C:15](=[O:16])[CH2:12][CH2:13][CH3:14]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1O

Procedure:
To a solution of 2-amino-4-nitrophenol (Aldrich, 1.0 g, 6.5 mmol) in THF (25 ml) was added n-PrCOCl (694 mg, 6.5 mmol) and pyridine (2.6 ml, 32.4 mmol). The reaction was refluxed for 5 days, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:27])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].CO.O.O[Li].O>C1COCC1>[CH3:35][C:31]1([CH3:34])[CH2:30][CH2:29][CH:28]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]3[CH2:21][CH2:22][C@H:23]([O:26][CH3:27])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:33][CH2:32]1
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](N(c2cc(C3CCC(C)(C)CC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
5-(4,4-Dimethylcyclohexyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (890 mg, 1.76 mmol) was dissolved in a 3:2:1 mixture of THF: methanol: H2O (50 mL) and treated with a 1N solution of LiOH.H2O (5.29 mL, 5.29 mmol). After stirring for 2 h at 60° C., the reaction mixture was evaporated to dryness and suspended in water. The reaction mixture was acidified to pH 3. After extraction with EtOAc, the organic fraction was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2:MeOH (90:10) as eluent affording the 5-(4,4-dimethyl-cyclohexyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methylcyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid (535 mg, 58%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:22]1([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:6]#[N:7])=[C:8]([O:28][CH2:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:9]=1
Reactant: OCC1CCCC1
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(Br)cc1OCC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a stirred solution of the above benzonitrile intermediate (7.5 g, 34.4 mmol) in dry THF (50 mL) at 0° C. was added a mixture of sodium bis(trimethylsilyl)amide (1.0 M, 34 mL, 34 mmol) and cyclopentanemethanol (3.4 g, 34 mmol) in THF (100 mL). The reaction was allowed to warm up to room temperature and stirred overnight. Water (50 mL) was added to the reaction and the product was extracted by CH2Cl2 (2×50 mL). The solvent was washed with brine and dried over Na2SO4. The solvent was removed to give 4-bromo-2-cyclopentylmethoxy-6-fluorobenzonitrile (4.5 g, 43.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:22][CH3:23])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][O:6]1)=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[CH2:19][CH:20]=[CH2:21].CC1(C)N([O])C(C)(C)CCC1.F[B-](F)(F)F.CC#N.[OH2:44]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1([CH2:22][CH3:23])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[O:44])[CH2:7][O:6]1)=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[CH2:19][CH:20]=[CH2:21]
Reactant: O
Reactant: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Reaction time: 2 h

Procedure:
A solution of the ester (0.21 g, 0.63 mmol, prepared as described in Step A), in 10 ml of CH3CN--H2O(9:1, v/v) was added dropwise to a stirred solution of TEMPO-BF4 in 10 ml CH3CN--H2O (9:1, v/v). Stirring was continued for 2 h and the reaction mixture was concentrated in vacuo. The residue was partitioned between Et2O and H2O. The organic phase was washed with brine and dried (Na2 SO4). Removal of solvent provides a yellow oil which was purified by flash chromatography (silica gel, hexane-EtOAc 2:1) to give 0.18 g of product as an off white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[N:6]=1.Cl[C:25]1[N:30]=[C:29]([NH2:31])[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.C(N)CN>CN(C)C(=O)C>[NH2:31][C:29]1[N:30]=[C:25]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[NH:15][CH:14]=[CH:13][N:12]=3)=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[N:6]=2)[CH:26]=[CH:27][C:28]=1[N+:32]([O-:34])=[O:33]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNc1ccc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Temperature: 87.5 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of (2-aminoethyl)[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine (0.14 M), 6-chloro-3-nitro-2-pyridylamine (0.14 M), N,N-dimethylacetamide (40 ml), and Hünig's base (2.5 ml) was stirred for 12 hours at 85-90° C. under argon. Ethylene diamine (3.8 ml) was added to remove the unreacted chloropyridine, and the mixture was stirred for an additional 0.75-1 hour at 85-90° C. under argon. After cooling, the reaction was diluted with ethyl acetate (500-600 ml), extracted with saturated sodium bicarbonate (4×200 ml), distilled water (3×150 ml), saturated sodium chloride (150 ml). The organic layer was dried with sodium sulfate briefly (2-3 minutes) so as not to initiate precipitation of the product. The organic layer was filtered, concentrated, and dried in vacuo. To cause precipitation of the product, a minimal amount of methanol (3-5 ml) was added followed with the addition of an equal volume of ethyl acetate. The mixture was allowed to age for 2-3 hours. The solid was collected by filtration, washed with minimal 1:1 methanol/ethyl acetate (5 ml), and a finally 100% ethyl acetate (2×10 ml). The yellow solid was dried in vacuo to give {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine in 61% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[CH2:26][CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[CH:30]=[N:29][N:28]([CH2:27][CH2:26][C:25]4[CH:42]=[CH:43][CH:44]=[C:23]([F:22])[CH:24]=4)[CH:32]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(CCc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Yield: 35.39 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (200 mg, 0.41 mmol) was coupled with 1-(3-fluorophenethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 64B) (172 mg, 0.54 mmol) using sodium carbonate (130 mg, 1.23 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.020 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 80 mg (35.39% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. MS: m/z=539.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:22][C:15]3([C:19](=[O:20])[NH:18][C:17](=O)[NH:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[C:1]1([CH:7]2[CH2:22][C:15]3([C:19](=[O:20])[NH:18][C:17](=[S:32])[NH:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3)Oc3ccccc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1)Oc1ccccc12
Yield: 47.4 %

Procedure:
A suspension of 2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (600 mg, 2.04 mmol) and Lawesson's Reagent (825 mg, 2.04 mmol) in dry 1,4-dioxane (28 mL) is heated under reflux for 24 h. The mixture is concentrated in vacuo and the residue is purified by column to give 2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (300 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:18][C:19]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]([F:30])[C:20]=1[C:21](Cl)=[O:22]>ClCCl.CC#N>[Br:8][C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[C:24]([F:30])=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:19]=2[Cl:18])[CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1cc(F)c(C(=O)Cl)c(Cl)c1
Reactant: Nc1ccnc(Br)c1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(C(=O)Nc2ccnc(Br)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a cooled (0° C.) solution of 4-amino-2-bromopyridine (346 mg, 2.0 mmol) and diisopropylethylamine (461 mg, 4.0 mmol) in dichloromethane (5 mL) and CH3CN (0.5 mL) was added a solution of 2-chloro-4-cyano-6-fluorobenzoyl chloride (484 mg, 2.2 mmol) in dichlormethane (5 mL) drop wise. The reaction mixture was warmed up to room temperature and stirred for 16 hours. The reaction was quenched with saturated NH4Cl (40 mL) and extracted with EtOAc (3×50 mL). The combined organic extractss were dried with Na2SO4 and concentrated under reduced pressure. The residue wars purified by silica gel column chromatography (0-50% EtOAc/hexane) to give N-(2-bromopyridin-4-yl)-2-chloro-4-cyano-6-fluorobenzamide as an off-white solid (379 mg, yield: 53%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41]([NH:44][CH2:45][CH2:46][CH2:47][NH2:48])([CH3:43])[CH3:42]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:48][CH2:47][CH2:46][CH2:45][NH:44][CH:41]([CH3:43])[CH3:42])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CC(C)NCCCN
Product: CC(C)NCCCNC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and N-isopropyl-1,3-propanediamine (34 mg) according to Method B to give the title compound (26 mg). 1H-NMR (400 MHz, CD3OD) d 7.46 (d, J=2.2 Hz, 1H), 7.36 (dd, J=2.2 Hz, J=6.2 Hz, 1H), 7.29-7.20 (m, 5H), 7.08 (d, J=8.4 Hz, 1H), 4.68 (s, 2H), 4.44 (dd, J=5.7 Hz, J=9.9 Hz, 1H), 4.30 (dd, J=5.5 Hz, J=9.2 Hz, 1H), 3.27 (m, 2H), 3.06 (m, 2H), 2.89 (dd, J=10.1 Hz, J=13.0 Hz, 1H), 2.80 (m, 2H), 2.65 (m, 2H), 1.30 (dd, J=2.9 Hz, J=6.6 Hz); IR (KBr) cm−1; HRMS m/z 628.3082 (calc. of monoisotopic mass for C32H44N4O9 gives 628.3108).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:5]
Reactant: Nc1ccccc1F
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(O)C1(C(=O)Nc2ccccc2F)CC1
Temperature: 25 °C
Yield: 54 %

Procedure:
1,1-Cyclopropanedicarboxylic acid (2.5 g) was dissolved in tetrahydrofuran (25 ml) under a nitrogen atmosphere, triethylamine (2.68 ml) was added dropwise thereto while stirring in an ice water bath. After stirring at the same temperature for 30 min, thionyl chloride (1.4 ml) was added dropwise while stirring in an ice water bath. After stirring at the same temperature for 30 min, a solution of 2-fluoroaniline (2.04 ml) in tetrahydrofuran (15 ml) was added while stirring in an ice water bath, and the reaction mixture was allowed to gradually warm up to room temperature and stirred overnight. To the reaction mixture was added a 2N aqueous solution of sodium hydroxide (75 ml), and tetrahydrofuran was removed under reduced pressure. To the resultant aqueous solution was added tert-butyl methyl ether (25 ml) and stirred. The organic layer and aqueous layer were separated. The aqueous layer was cooled in an ice water bath, 5N hydrochloric acid (30 ml) was added and stirred. The precipitated solid was collected by filtration and washed with water. Drying under aeration and hot-air drying at 60° C. for 8 hr provided the titled compound as white powder (2.294 g, 54%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].CC1C=CC(S(O[CH2:22][CH2:23][O:24][CH3:25])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
To a solution of 60% sodium hydride (436 mg, 18.2 mmol) in DMF (2.0 mL) was added hydroquinone (1.0 g, 18.2 mmol) in DMF (10.0 mL) dropwisely. The solution was added with 2-methoxyethyl 4-methylbenzenesulfonate (12-2, 2.10 g, 21.8 mmol) dropwisely. The reaction was stirred at 65° C. for 16 h. The solution was cooled to room temperature, poured into icy H2O, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 4-(2-methoxyethoxy)phenol (12-3, 1.0 g), which was used directly for the next step without further purification.