Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C>[CH3:33][O:9][C:7]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:26]([F:29])([F:27])[F:28])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: CI
Reactant: CC(O)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 0.33 h

Procedure:
1-Phenyl-1-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]ethanol (Example 39, 0.096 g, 0.243 mmol) was taken into DMF (3 mL) then NaH (0.020 g, 0.487 mmol) was added and stirred for 20 minutes. Lastly, iodomethane (0.08 mL, 1.22 mmol) was added and stirring was continued for 30 minutes. The reaction was quenched with water and extracted with ether. The combined organics were dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 5% ethyl acetate in hexane as the eluent. MS (ESI) m/z 408 ([M+H]+); 1H NMR (CDCl3) δ 9.59 (s, 1H), 8.01 (d, J=6.8 Hz, 1H), 7.31 (m, 3H), 7.12 (m, 5H), 7.0 (m, 2H), 6.74 (dd, J=7.5 and 1.2 Hz, 1H), 6.63 (dd, J=7.7 and 1.3 Hz, 1H), 3.06 (s, 3H), 1.8 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of ethyl 3-(3-(trifluoromethyl)phenylamino)benzoate (0.334 g; 1.08 mmol) in dioxane (14 mL) was added a solution of sodium hydroxide (0.130 g; 3.24 mmol) in water (3.24 ml). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to remove the dioxane. The aqueous solution was acidified with 6N hydrochloric acid, extracted with ethyl acetate (2×100 mL), dried and concentrated under reduced pressure to provide 0.303 g (99%) of 3-(3-(trifluoromethyl)phenylamino)benzoic acid which was directly used in the next step.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[C:22]([CH3:23])=[CH:21][C:20]([C:24]([O:26]C)=O)=[C:19]4[CH3:28])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[C:22]([CH3:23])=[CH:21][C:20]([C:24]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:26])=[C:19]4[CH3:28])=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C)n(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1C
Reactant: C1CCNC1
Product: Cc1cc(C(=O)N2CCCC2)c(C)n1-c1ccc(OC2CCN(C3CCC3)CC2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of the methyl 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-2,5-dimethyl-1H-pyrrole-3-carboxylate (0.06 g) synthesized in Example 4 and pyrrolidine (0.112 g) was stirred in a sealed tube at 100° C. for 16 hours. The reaction mixture was left to cool to room temperature and concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (NH preparative silica gel plate 0.5 mm; eluent: n-hexane/ethyl acetate=50/50) to give the titled compound as a colorless solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([C:39]([C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([Sn](CCCC)(CCCC)CCCC)[S:46][C:45]=23)=[O:40])[CH2:35][CH2:34]1)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([C:39]([C:41]2[N:42]=[CH:43][N:44]3[CH:48]=[C:47]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[O:13])[S:46][C:45]=23)=[O:40])[CH2:35][CH2:34]1)=[N+:28]=[N-:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C3CCN(CCCN=[N+]=[N-])CC3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)C5CCN(CCCN=[N+]=[N-])CC5)c4s3)[C@H](C)[C@H]12
Yield: 71.6 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[1-(3-azidopropyl)piperidin-4-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (862 mg) was prepared in the same manner as in step a) of Example 1, except that 658 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.16 g of 7-[1-(3-azidopropyl)piperidin-4-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: C(C1C=CC(C([N:9]2[C:18]3[C:17]4[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=4[N:15]([C:24]([C:26]4[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([CH3:34])[CH:27]=4)=[O:25])[CH2:14][CH2:13][C:12]=3[N:11]=[C:10]2[CH3:35])=O)=CC=1C)#N.[OH-].[Na+]>CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:16]2[N:15]([C:24]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([CH3:34])[CH:27]=3)=[O:25])[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([CH3:35])[NH:9][C:18]=3[C:17]=2[CH:19]=1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(C(=O)c4ccc(C#N)c(C)c4)c3-c3cc(Cl)ccc32)ccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(C#N)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
4-[1-(4-Cyano-3-methyl-benzoyl)-9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl]-2-methyl-benzonitrile from E125.1 (124 mg, 0.24 mmol) was dissolved in MeOH 5 ml). 2M NaOH (2 ml) was added, and the mixture was stirred for 1 h. at room temperature. The solvents were removed in vacuo, and azeotroped with toluene. The residue was taken up in EtOAc, was with saturated NaHCO3 then brine, dried and concentrated in vacuo to yield the title compound (80 mg, 89%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH3:25])(O)[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[CH:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1
Reactant: Cc1ccc(C(O)(Cc2nnnn2C)c2ccc(C)cc2C)c(C)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(C(=Cc2nnnn2C)c2ccc(C)cc2C)c(C)c1
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A mixture of 1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (1.8 g, 5.4 mmoles) and potassium hydrogen sulfate (100 mg) was placed in an oil bath preheated to 190° C. After 15 minutes, the melt was cooled and methylene chloride added to the residue. The insolubles were removed and the solution evaporated. The residue was crystallized from isopropyl ether to give 1.2 g of the title compound; m.p.=143°-143.5° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([F:26])[CH:13]=1.[OH-:27].[K+].CC(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)C.Cl>O1CCOCC1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:26][C:14]1[CH:13]=[C:12]([N:6]2[C:7]3[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([OH:27])[C:3]=3[CH:4]=[N:5]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [OH-]
Reactant: Cc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(O)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A solution of 4-bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-6-methyl-1H-indazole (D12) (1.97 g, 4.5 mmol) and KOH (1 g, 18 mmol) in dioxane (50 mL) and water (50 mL) was sonicated under a flow of argon for 5 minutes after which the bis(1,1-dimethylethyl)[2′,4′,6′-tris(1-methylethyl)-2-biphenylyl]phosphane (115 mg, 0.27 mmol) and Pd2 dba3 (82 mg, 0.09 mmol) were added and it was heated to reflux for 2 hours. The mixture was then cooled to room temperature, diluted with EtOAc and water and the pH was adjusted to circa 7 with 1M HCl. The phases were separated, the aqueous re-extracted with EtOAc and the combined organics were finally dried over MgSO4. The crude material (2.1 g) was purified by flash chromatography (Biotage SP4, 40+M silica column) with a gradient of EtOAc 0 to 50% in hexane to afford 730 mg of desired compound (D13).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:24][C:25]2[CH:32]=[CH:31][C:28]([CH3:29])=[CH:27][CH:26]=2)[C:14]1=[O:22]
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Reactant: Cc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2ccc(C)cc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.72 g of NaH (80% suspension in mineral oil), 7 g. of 8-(2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester, 100 cc. of DMF, 3.4 g. of 4-methylbenzylchloride and 0.72 g. of NaJ. Eluant for chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:14])[C:8]=1[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[NH2:5].[C:15](Cl)(Cl)=[S:16].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:15]=[S:16])[CH:6]=[C:7]([Cl:14])[C:8]=1[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: S=C(Cl)Cl
Reactant: CCN(CC)c1c(Cl)cc(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1c(Cl)cc(N=C=S)cc1Cl
Yield: 97.5 %

Procedure:
Following procedures similar to those employed in Step A of Example 8, the reaction of 1.9 g (0.0082 mole) of 3,5-dichloro-4-diethylaminoaniline with 1.88 g (0.0163 mole) of thiophosgene and 5.0 g (0.036 mole) of potassium carbonate in 20 ml of water and 100 ml of chloroform yielded 2.2 g of 3,5-dichloro-4-diethylaminophenyl isothiocyanate as an oil. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH:2]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[CH3:15][O:1][CH:2]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3]
Reactant: CC(O)c1nc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)c1nc2ccccc2[nH]1
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of 4.05 g of 1-hydroxyethylbenzimidazole in 25 ml of dimethylformamide was added 1.2 g of 50% sodium hydride in oil, and the mixture stirred for 30 minutes. Methyl iodide (3.55 g) was added and the reaction mixture stirred at room temperature overnight. Water (200 ml) was added and the product extracted with ethyl acetate. The extracts were combined, dried and concentrated to an oil which was chromatographed on 130 g of silica gel using 5% methanol in chloroform as the eluent to give 2.36 g of brown oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:29]([C:39](=O)[CH:40]([CH3:42])[CH3:41])[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:23][CH:22]=1.CC(O)C>CCCCCCC.C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:1]([CH2:2][CH2:3][C@H:4]3[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]3)[C:39]([CH:40]([CH3:42])[CH3:41])=[C:29]([C:30]([NH:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[C:28]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:25][CH:26]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Temperature: 25 °C

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate, (Example 2) 1.36 g (4.97 mmol), and (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)], and [S-R*,S*)] isomers, (Example 3) 1.60 g (3.83 mmol), in 50 mL of heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled slightly and 15 mL of 2-propanol added. The mixture is allowed to cool to 25° C. and filtered to give 1.86 g of (4R-cis)-1,1-dimethylethyl 6-[2[2-(4-fluorophenyl)-5-(1-methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate as a yellow solid.
Reaction SMILES: O[C@H](CC1C=CC=CC=1)C(O)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[CH2:23][C@@H:24]([NH2:26])[CH2:25][C:17]=3[C:16]=2[CH:15]=1.C(N(C(C)C)CC)(C)C.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>C1(C)C=CC=CC=1>[CH:40]([O:39][C:37](=[O:38])[NH:26][C@@H:24]1[CH2:23][C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([Br:13])=[CH:15][C:16]=3[C:17]=2[CH2:25]1)([CH3:42])[CH3:41]
Reactant: N[C@@H]1Cc2[nH]c3ccc(Br)cc3c2C1
Reactant: CC(C)OC(=O)Cl
Agent: O=C(O)[C@H](O)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(Br)cc3c2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
(S)-7-Bromo-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-ylamine(R)-2-hydroxy-3-phenylpropionic acid salt (60.00 g, 143.78 mmol) and diisopropylethylamine (50 mL, 296.12 mmol) are combined in toluene (165 mL). The reaction vessel is purged with nitrogen three times. The mixture is cooled to 0° C. with stirring and is held at that temperature for 30 min. A solution of isopropyl chloroformate (20.00 g, 163.20 mmol) in toluene (165 mL) is added at 0-5° C. over 10 min. The mixture is stirred at 5° C. for 10 min. HPLC shows 98.6% complete. The reaction is quenched with water (1 L) and ethyl acetate (480 mL). The mixture is filtered and the solid is washed with ethyl acetate (2×240 mL). The combined organic layer is washed with brine twice, dried (MgSO4), and filtered. The organic solvent is reduced to 50 mL. The mixture is cooled to 25° C. and tert-butyl methyl ether (50 mL) and ethyl acetate (50 mL) are added. An off-white solid is precipitated. The solid is filtered and washed with heptanes (100 mL). The solid is dried under vacuum at 50° C. for 4 h to give 44.4 g (90.3%) of a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: O=C(O)c1[nH]c(-c2cccs2)cc1-c1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)nc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2[nH]c(-c3cccs3)cc2-c2ccc(F)cc2)nc1
Yield: 91 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrole-2-carboxylic acid and methyl 6-(aminomethyl)nicotinate hydrochloride, yielding the title compound. Methyl 6-[({[3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrol-2-yl]carbonyl}amino)methyl]nicotinate: Yield 91%; m.p. 174-176° C.; IR 3378, 3245, 1723, 1618, 1505, 1433, 1218, 1113, 843 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 9.45 (sb, 1H), 8.95 (s, 1H), 8.21 (dd, J=8.1 Hz, J′=2.1 Hz, 1H), 7.48 (dd, J=8.6 Hz, J′=5.4 Hz, 2H), 7.31-7.23 (m, 2H), 7.21 (d, J=3.6 Hz, 1H), 7.15 (t, J=8.6 Hz, 2H), 7.06 (dd, J=5.0 Hz, J′=3.7 Hz, 1H), 6.88 (tb, J=4.6 Hz, 1H), 6.40 (d, J=3.0 Hz, 1H), 4.65 (d, J=5.0 Hz, 2H), 3.96 (s, 3H); 13C-NMR (126 MHz, δ ppm, DMSO-d6) 165.9, 162.9, 161.0, 157.9, 150.0, 142.4, 138.7, 138.3, 136.7, 130.8, 128.6, 128.0, 127.6, 127.2, 122.6, 122.4, 119.3, 116.2, 116.0, 109.1, 51.5, 48.7.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N:14]([CH3:23])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=O.[CH3:24][NH:25][C:26]([NH2:28])=[S:27].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:23][N:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]1[N:28]=[C:26]([NH:25][CH3:24])[S:27][CH:2]=1)=[CH:13]2)[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16]
Reactant: CNC(N)=S
Reactant: CN(c1cccc2cc(C(=O)CCl)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)cs1
Yield: 76.6 %

Procedure:
A mixed solution of N-[2-(2-chloroacetyl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (100 mg), N-methylthiourea (30 mg) and N,N-dimethylacetamide (6 ml) was stirred at 60° C. for 5 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3-1:1), and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (84 mg, yield 77%) as pale-yellow prism crystals. melting point 162-163° C. MS:405 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:29]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8])(=[O:31])[CH3:30]
Reactant: O=C(CCOCCO)c1ccc(Cc2cccnc2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCCOCCC(=O)c1ccc(Cc2cccnc2)cc1
Yield: 85.7 %

Procedure:
In 30 ml of methylene chloride were dissolved 3.0 g of 3-[p-[3-(2-hydroxyethyl)oxypropionyl]benzyl]pyridine and 1.61 ml of triethylamine, and into the resulting solution was dropped 0.90 ml of acetyl chloride over 30 minutes with ice-cooling. The resulting mixture was subjected to reaction at room temperature for 2 hours, after which 20 ml of water was added to the reaction mixture. The pH of the mixture was adjusted to 7 with sodium hydrogencarbonate, and the organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 2.94 g (yield 85.7%) of pale yellow, oily 3-[p-[3-(2-acetoxyethyl)oxypropionyl]benzyl]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([C@@H:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)[NH:17][CH:18]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[ClH:31]>C(OCC)C>[ClH:31].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([C@@H:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)[NH:17][CH:18]=3)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(Br)cc3)cc2)c[nH]1
Agent: Cl
Solvent: CCOCC
Product: Brc1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A suspension of (S)-tert-butyl 2-(4-(4′-bromo-[1,1′-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (505 mg, 1.078 mmol) in HCl (4M in dioxane 5.4 mL, 21.6 mmol) is stirred at room temperature for 2 hours and diluted with diethyl ether (2 mL). The suspension is cooled in an ice bath and the product is collected by filtration to give (S)-4-(4′-bromo-[1,1′-biphenyl]-4-yl)-2-(pyrrolidin-2-yl)-1H-imidazole hydrochloride (436 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([I:10])[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([I:10])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: OCc1cnc(Br)cc1I
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cnc(Br)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
A mixture of (6-bromo-4-iodopyridin-3-yl)methanol (300 mg, 1.0 mmol) and pyridinium dichromate (720 mg, 1.9 mmol) in methylene chloride (4 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with methylene chloride (20 mL), filtered over Celite, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-40% ethyl acetate in heptane) to afford the title compound as a white solid (180 mg, 60%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([OH:21])=O)=[CH:13]3)[CH2:5]1)([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:44]1([CH2:47][NH:48][CH2:49][CH2:50][CH3:51])[CH2:46][CH2:45]1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CO>[CH:44]1([CH2:47][N:48]([CH2:49][CH2:50][CH3:51])[C:19]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:9][CH:6]2[CH2:7][CH2:8][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5]2)=[CH:18][CH:17]=3)=[O:21])[CH2:46][CH2:45]1
Reactant: CCCNCC1CC1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)C(=O)c1cc2cc(OC3CCN(C(C)C)C3)ccc2[nH]1
Yield: 37 %

Procedure:
A mixture of 0.07 mmol 5-(1-isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid, 1.25 equiv. 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborat, 1.25 equivalents cyclopropylmethyl-propyl-amine and 5 equivalents N-ethyldiisopropyl-amine in 0.7 ml DMF was stirred for 16 h at room temperature. The mixture was diluted with 0.8 ml methanol and subjected to preparative HPLC purification on reversed phase material eluting with a gradient of acetonitrile/water/triethyamine. The product fractions were evaporated to dryness to yield 9.1 mg (37%) of the title compound as light brown solid. MS (m/e): 384.5 (MH+, 100%).