Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.C(N(CC)CC)C>N1C=CC=CC=1>[NH2:2][C:3]1[C:8]([C:9](=[S:1])[NH2:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: S
Reactant: CSc1ncc(C#N)c(N)n1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CSc1ncc(C(N)=S)c(N)n1
Reaction time: 1.75 h

Procedure:
Hydrogen sulfide is passed through a suspension of 4-amino-2-methylthio-5-pyrimidinecarbonitrile (16.621 g., 0.100 mole) in a mixture of pyridine (150 ml.) and triethylamine (14.0 ml., 0.100 mole) for 2 hours. The nitrile dissolves in the course of the reaction. After ca. 1.75 hours a solid begins to separate. The mixture is poured into water (500 ml.), and the yellow solid collected by filtration washed with water, dried at 100° C., house vac. The yield of product melting at 230° C. dec. (uncorr.) is 18.93 (94.5%). This material is recrystallized from dimethylformamide-water (Darco G-60) to give yellow rods melting at 229° C. dec. (uncorr.) in a yield of 15.685 g. (78.3%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>O1CCCC1.CCCCCC.C(OCC)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:15]([OH:20])[OH:16]
Reactant: COc1ccccc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1B(O)O
Reaction time: 1.5 h

Procedure:
To a stirred, cold (-78° C.) solution of 2-iodoanisole (2.85 ml, 5.6 g) in 50 ml of tetrahydrofuran under nitrogen was added 10.0 ml of 2.5M n-butyl lithium in hexane. After 15 min. triisopropyl borate (3.38 ml, 4.7 g) was added and the reaction was allowed to come to and remain at room temperature for 1.5 hr. The mixture was poured into an excess of 2N hydrochloric acid and diethyl ether was added. The resulting mixture was stirred vigorously for 30 min. and the phases were separated. The ether layer was washed with aqueous sodium bisulfite until colorless and then with saturated sodium chloride solution and then dried over magnesium sulfate. Concentration of the ether layer gave the crude boronic acid which crystallized from ether to give the title product.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=[O:3])[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C1COCC1.C(Cl)Cl>[C:27]1([NH:26][C:15](=[O:17])[C@H:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[NH:9][C:7](=[O:8])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a solution of N-(2-acetylthiomethyl-4-phenylbutanoyl)-(L)-leucine (derived from the higher RfTLC fraction) (182 mg. 0.5 mmole) in 2 mL of THF at 0° C. was added aniline (93 mg, 1.0 mmole) and 1-hydroxybenzotriazole hydrate (HOBT·H2O, 101 mg, 0.75 mole) and N-methylmorpholine (202 mg, 2.0 mmole). The mixture was stirred at 0° C. for 15 minutes, then 192 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 1.0 mmole) was added and the mixture stirred overnight. The solution was worked up by adding 7 mL methylene chloride and the mixture extracted with 3×3 ml of 5% sodium bicarbonate, then 2×2 mL of brine. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with methylene chloride/ethyl acetate (90/10) to obtain 110 mg of product (yield =50%). By 1H-NMR, we see two rotomers present at room temperature.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH2:55])=[CH:49][CH:48]=1>CN(C=O)C.O>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH:55][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])=[CH:49][CH:48]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]ncc2c1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a stirred solution of the 1H-indazole-5carboxylic acid (215 mg, 1.32 mmol) and HBTU (553 mg, 1.45 mmol) in DMF (5 mL) was added DIEA (277 μL, 1.59 mmol) followed by 2-(4chlorophenyl)ethylamine (222 μL, 1.59 mmol). The reaction was stirred overnight, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The crude product was purified over silica gel on a Biotage Horizon high-performance flash chromatography system (25+M silica gel cartridge) eluting with a gradient of 0.5% MeOH/DCM to 10% MeOH/DCM to give N-(4-chlorophenethyl)-1H-indazole-5-carboxamide (0.165 g, 42%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CO.[NH4+:12]>>[NH2:12][CH2:3][C@@H:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1]
Reactant: [NH4+]
Reactant: c1cncc([C@@H]2CO2)c1
Solvent: CO
Product: NC[C@H](O)c1cccnc1

Procedure:
The title compound was prepared from 3-[(2R)-oxiranyl]pyridine (which was obtained in Example 134) and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as a brown oil; 1H NMR (300 MHz, DMSO-d6) δ 1.70 (brs, 2H), 2.62-2.74 (m, 2H), 4.46-4.50 (m, 1H), 5.20 (brs, 1H), 7.30-7.34 (m, 1H), 7.68-7.71 (m, 1H), 8.42-8.50 (m, 2H); MS (ES) m/z: 139 (MH+).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]3[Se:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Li][CH2:22]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH3:22][C:18]1[Se:17][C:16]([CH:13]2[CH2:14][CH2:15][CH:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)=[CH:20][CH:19]=1
Reactant: CCCC1CCC(C2CCC(c3ccc[se]3)CC2)CC1
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: CCCC1CCC(C2CCC(c3ccc(C)[se]3)CC2)CC1
Temperature: -60 °C
Reaction time: 8.5 h

Procedure:
2.0 g (5.9 mmol) of 2-(4′-propylbicyclohexyl-4-yl)selenophene are initially introduced in 20 ml of diethyl ether, and 5.0 ml (8.0 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −60° C. 1.5 ml (24.1 mmol) of methyl iodide are added, and the batch is stirred for 8.5 h with slow thawing to RT. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane n-heptane:EtOAc=95:5). The further purification is carried out by recrystallisation from IPA/n-heptane (10:1) and from acetone. 2-Methyl-5-(4′-propylbicyclohexyl-4-yl)selenophene is obtained as a colourless solid (m.p. 26° C.).
Reaction SMILES: [Mg].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.C(Cl)(=O)C(Cl)=O.[Cl:17][C:18]1[C:26]([N+:27]([O-:29])=[O:28])=[C:25]([F:30])[C:24]([CH3:31])=[CH:23][C:19]=1C(O)=O>O1CCCC1.CN(C)C=O.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(O)C>[Cl:17][C:18]1[C:26]([N+:27]([O-:29])=[O:28])=[C:25]([F:30])[C:24]([CH3:31])=[CH:23][C:19]=1[C:4]([CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1cc(C(=O)O)c(Cl)c([N+](=O)[O-])c1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Mg]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cc(C)c(F)c([N+](=O)[O-])c1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Magnesium (115 mg), ethanol (1 ml) and carbon tetrachloride (0.1 ml) were stirred at room temperature to activate them. A solution of ethyl malonate (0.69 ml) in tetrahydrofuran (5 ml) was added dropwise to the activated mixture, followed by stirring at 80° C. for 3 hours. After the reaction mixture was allowed to cool, it was chilled to -40° C. Oxalyl chloride (650 mg) and N,N-dimethylformamide (1 drop) were added to a solution of 2-chloro-4-fluoro-5-methyl-3-nitrobenzoic acid (1.0 g) in methylene chloride (10 ml). The mixture was stirred overnight at room temperature, and the solvent and the like were distilled off. Toluene was added to the residue to conduct azeotropic distillation. The resultant residue was dissolved in tetrahydrofuran (5 ml), and the solution was added dropwise at -40° C. to the reaction mixture obtained previously. After the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. The solvent was distilled off, and 12N hydrochloric acid (1 ml) was added to the resultant residue to keep its pH at about 2. The residue was then extracted with chloroform, and the solvent was distilled off. Water (10 ml) and p-toluenesulfonic acid monohydrate (50 mg) were added to the resultant residue, and the mixture was stirred for 1 hour while heating under reflux. After the reaction mixture was allowed to cool, it was extracted with chloroform. An organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant residue was subjected to column chromatography on silica gel to obtain the title compound (630 mg) as a pale yellow oil from a fraction eluted with a 1:10 mixture of ethyl acetate and hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:18](O)[CH3:19])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:33]([CH:18]([C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH3:19])=[N+:34]=[N-:35]
Reactant: CC(O)c1ccc2cccnc2c1-c1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[8-(2-fluorophenyl)quinolin-7-yl]ethanol (0.039 g, 0.14 mmol) in methylene chloride (0.9 mL) was added triethylamine (0.0305 mL, 0.22 mmol), followed by methanesulfonyl chloride (0.014 mL, 0.18 mmol). After stirred at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The crude mesylate was dissolved in N,N-dimethylformamide (0.4 mL) and treated with sodium azide (0.0474 g, 0.73 mmol) at room temperature overnight. After diluting with ethyl acetate, the mixture was washed with water and brine, dried over magnesium sulfate and then evaporated to dryness. The crude product was used in next step (33 mg, 77%). LCMS calculated for C17H14FN4(M+H)+: m/z=293.1; found: 293.1.
Reaction SMILES: [NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1.Cl>C(OCC)C>[NH2:1][CH:2](/[CH:9]=[C:10](/[CH2:19][P:20]([OH:23])([OH:22])=[O:21])\[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)=[O:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:10]=[CH:9][CH:2]=[CH:3][CH:4]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CCC/C(=C\C(N)CC(=O)OCC)CP(=O)(O)O
Agent: Cl
Solvent: CCOCC
Product: NC(/C=C(\CCCC(=O)OCc1ccccc1)CP(=O)(O)O)CC(=O)OCc1ccccc1

Procedure:
To a suspension of 3.0 g (9.3 mmol) of diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate in 19.1 ml (185.6 mmol) of benzyl alcohol are added 40 ml of a 4N solution of hydrochloric acid in diethyl ether. The solution formed is allowed to stand for 1 week. The reaction mixture is evaporated to dryness. The residue is dissolved in 35 ml of ethanol, and a solution of 35 ml of propylene oxide in 35 ml of ethanol is added. The crystalline precipitate formed is collected, re-crystallized twice from water and dried over phosphorus pentoxide, affording dibenzyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate of m.p. 220°-221° (decomp).
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4]O.[F:6][C:7]1[CH:8]=[C:9]2C(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:16][C:17]=1[F:18].Cl>O>[F:6][C:7]1[CH:8]=[C:9]([NH2:4])[C:10](=[CH:16][C:17]=1[F:18])[C:11]([OH:13])=[O:12]
Reactant: NO
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(F)c(F)cc1C(=O)O
Yield: 95 %

Procedure:
Sodium hydroxide (7.5 g, 0.19 mol) and hydroxylamine hydrochloride (5.4 g, 0.0781 mol) were combined in 100 mL of water. 4,5-difluorophthalic anhydride (11.5 g, 0.062 mol) was added, and the reaction was heated to 90°-100° C. for 0.5 hour. The reaction was cooled, and acidified with HCl to a pH between 4 and 5. The precipitate was collected and dried to yield 10.2 g (91%) of 4,5-difluoroanthranilic acid.
Reaction SMILES: CO[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:19]2[O:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:27]([N:28]4[CH2:31][CH2:30][CH2:29]4)[C:21]=3[CH:20]=2)[C:14](=[O:18])[CH:15]=[CH:16][CH3:17])=[CH:6][CH:5]=1.[NH2:33][OH:34].CO.[ClH:37]>C1COCC1.O.[OH-].[Na+]>[ClH:37].[N:28]1([C:27]2[C:21]3[CH:20]=[C:19]([N:13]([C:14](=[O:18])[CH:15]=[CH:16][CH3:17])[CH2:12][CH2:11][O:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([NH:33][OH:34])=[O:32])=[CH:9][CH:8]=4)[O:23][C:22]=3[CH:24]=[CH:25][CH:26]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: NO
Reactant: CC=CC(=O)N(CCOc1ccc(C(=O)OC)cc1)c1cc2c(N3CCC3)cccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC=CC(=O)N(CCOc1ccc(C(=O)NO)cc1)c1cc2c(N3CCC3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(4-azetidin-1-yl-3-benzofuran-2-yl-but-2-enoylamino)ethoxy]-benzoic acid methyl ester (158 mg, 0.362 mmol) in THF (4 ml), a solution of hydroxylamine in 50% water (2.78 ml) and 1N NaOH (0.1 ml) were added. Methanol was added dropwise until a homogeneous solution was obtained. The reaction mixture was stirred overnight at rt. After cooling the mixture at 0° C., 6 N HCl was added until pH 7 was reached. The solid was separated by filtration and the crude solid purified by HPLC to give the title compound (25 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Br[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:18]([O:17][CH2:16][C@@H:15]([CH3:25])[CH2:14][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: C[C@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2cc(F)ccc21
Yield: 71 %

Procedure:
7-Fluoro-4H-benzo[1,4]oxazin-3-one (111MF12) (2.52 g, 15.1 mmol), (S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol) and Cs2CO3 (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) gave the title compound (111MF14) (3.79 g, 71%). 1H NMR (CDCl3) δ 7.12 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.67-6.34 (m, 2H), 4.60 (q, J=14.8 Hz, J=25.4 Hz, 2H), 4.03 (dd, J=8.4 Hz, J=14.0 Hz, 1H), 3.82 (dd, J=5.6 Hz, J=14.0 Hz, 1H), 3.57 (dd, J=4.8 Hz, J=10.0 Hz, 1H), 3.45 (dd, J=7.0 Hz, J=9.8 Hz, 1H), 2.15-2.05 (m, 1H), 0.93-0.89 (m, 12H), 0.06 (s, 6H); 13C NMR (CDCl3) δ 164.1, 158.9 (d, J=243.7 Hz), 146.4 (d, J=11.6 Hz), 125.3 (d, J=3.0 Hz), 116.4 (d, J=9.6 Hz), 109.1 (d, J=22.7 Hz), 105.1 (d, J=25.8 Hz), 67.8, 66.0, 44.1, 34.5, 26.0, 18.4, 14.9, −5.3, −5.4.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:35]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:35]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(C(=O)C1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCN(C(=O)C1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylcarbonyl-n-hexylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=[O:9])[N:6]=1.C1C(=O)N([Cl:21])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:21])=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)O)c1nc(N)sc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.2 %

Procedure:
To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid (15.0 g) in anhydrous DMF (150 mL) was added NCS (11.95 g) and the mixture was stirred at rt for 2-3 hrs. The reaction mixture was concentrated to remove most of the DMF. The resulting oil was added dropwise to DCM (˜600 mL) at 0° C. with stirring. Solid precipitation was collected by filtration, rinsed with DCM and dried under high vacuum to provide a brownish solid (11.8 g, 67%). ESI-MS (EI+, m/z): 236.0. 1H NMR (300 MHz, DMSO-d6) δ 7.60 (br s, 2H), 3.88 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[C:17]([C:18](OC)=[O:19])=[CH:16][N:15]=[C:14]([Cl:22])[CH:13]=1>CCOCC>[Cl:11][C:12]1[CH:13]=[C:14]([Cl:22])[N:15]=[CH:16][C:17]=1[CH2:18][OH:19]
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: OCc1cnc(Cl)cc1Cl
Yield: 39.5 %

Procedure:
To lithium aluminum hydride (2.4 g, 64 mmol) and aluminum chloride (17 g, 128 mmol) in Et2O (200 mL) at 0° C. was added a solution of methyl 4,6-dichloronicotinate (13.1 g, 64 mmol) in Et2O (100 mL) dropwise with stirring. The resulting solution was heated at reflux for one hour. The reaction mixture was quenched with 100 mL of H2O/ice. The resulting solution was extracted with EtOAc (2×500 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to afford 4.5 g (43%) of (4,6-dichloropyridin-3-yl)methanol.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:11][S:12]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)(=[O:14])=[O:13]
Reactant: CSc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccc(COS(C)(=O)=O)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
In a sulfonating flask, 50 g (0.32 mol) of 4-methylthiobenzyl alcohol and 46.3 g (0.32 mol) of methylsulfonyl chloride are dissolved in 250 ml of toluene and, with cooling at 10° C., 32.5 g (0.32 mol) of triethylamine are added dropwise. The reaction mixture is then heated to room temperature and stirred overnight. 400 ml of 2N hydrochloric acid are then added to the reaction solution slowly and with cooling. The phases are separated and the organic phase is washed with water, dried over MgSO4 and concentrated in a rotary evaporator. 60 g (80%) of 4-methylthiobenzyl alcohol methanesulfonate are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[Cl:11][CH2:12][C:13](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[Cl:11][CH2:12][C:13]1[NH:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=2[N:10]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C(O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc2nc(CCl)[nH]c2cc1C
Temperature: 25 °C
Yield: 54.5 %

Procedure:
To a stirred solution of 4,5-dimethylphenylene-1,2-diamine (680 mg, 5 mmol) in 4N HCl (12 mL) was added chloroacetic acid (940 mg, 10 mmol). The solution was then heated to reflux for 17 hours, then cooled to room temperature. Solid sodium carbonate was then added slowly, with stirring, until the pH of the solution was approximately 9.0, at which point a beige precipitate formed. The aqueous phase was then diluted with water (10 mL) and extracted repeatedly with ethyl acetate. The combined organic fractions were then dried, concentrated and the residue was purified by column chromatography on silica gel (10% MeOH in CH2Cl2) to afford the desired 2-(chloromethyl)-5,6-dimethylbenzimidazole (530 mg, 54%). 1H NMR (CDCl3) δ 1.59 (br s, 1H), 2.31 (s, 6H), 4.83 (s, 2H), 7.42 (s, 2H).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@@H:17]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]([OH:46])=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=2)[C:26]([CH3:47])=[C:25]3[CH3:48])=[O:21])[CH3:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.C(C1C=CC=C([C:59]2[CH:64]=[CH:63][C:62]([CH2:65][N:66]3C4C(=CC(C(=O)N[C@H](C5CCNCC5)C)=CC=4)C(C)=C3C)=[CH:61][CH:60]=2)C=1C(O)=O)(C)(C)C.N1CCCCC1.C(N=C=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>CC(O)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl.[Pd].CO.C(#N)C.O.C(Cl)Cl>[CH2:65]([NH:66][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C@@H:17]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]([OH:46])=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=2)[C:26]([CH3:47])=[C:25]3[CH3:48])=[O:21])[CH3:18])[CH2:15][CH2:16]1)=[O:10])[C:62]1[CH:63]=[CH:64][CH:59]=[CH:60][CH:61]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)C3CCN(C(=O)OCc4ccccc4)CC3)cc12
Reactant: Cc1c(C)n(Cc2ccc(-c3cccc(C(C)(C)C)c3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)C3CCNCC3)cc12
Agent: [Pd]
Agent: O=C=NCc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC#N
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)C3CCN(C(=O)NCc4ccccc4)CC3)cc12

Procedure:
The title compound was prepared from (S)-4′-((5-((1-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic-acid (0.175 g, 0.250 mmol) following palladium catalyzed hydrogenation (18 mg, 10% Pd/c) in AcOH (5 mL) and subsequent coupling of the resulting piperidine ((S)-tert-butyl-4′-((2,3-dimethyl-5-((1-(piperidin-4-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate) with benzyl isocyanate (6.8 mg, 0.049 mmol) in dicholoromethane (DCM) (1 mL)/di-isopropylethylamine (9.2 μL, 0.053 mmol) and then removal of t-butyl ester in TFA/DCM (1:1, 2 mL). Completion at each synthetic step was monitored by analytical HPLC and the title compound was isolated by reverse phase prep-HPLC (MeOH/Acetonitrile/water) ESI-MS (m/z): 642 [M+1]+.