Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[P:10](OCC)([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11]>[Ni](Cl)Cl.O>[CH2:13]([O:12][P:10]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9])([O:15][CH2:16][CH3:17])=[O:11])[CH3:14]
Reactant: Cc1cccc(Br)c1C
Reactant: CCOP(=O)(OCC)OCC
Agent: Cl[Ni]Cl
Solvent: O
Product: CCOP(=O)(OCC)c1cccc(C)c1C
Yield: 61.2 %

Procedure:
A mixture solution of 25.0 g (0.135 mol) of 3-bromo-o-xylene and 2.0 g (0.015 mol) of anhydrous nickel chloride was heated to 150° to 160° C., to which 26.9 g (0.162 mol) of triethyl phosphate was added for 1 to 2 hours. After the completion of the addition, it was mixed at that temperature and then cooled. To the cooled solution, 30 ml of water was added and mixed for another 30 minutes. It was then extracted three time with 100 ml of diethyl ether. The extracted solution was rinsed three times with a 5% sodium hydrogencarbonate solution and dried with anhydrous sodium sulfate. The ether solution was condensed and subjected to column chromatography to obtain 20 g of transparent liquid which had a chart (FIG. 2) of NMR spectrum in CDCl3 to find the following chemical structure; ##STR14##
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:6][CH:5]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH2:22][CH2:21]1.CCN(CC)CC>CC#N>[N:17]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][C:9]=1[O:8][C:7]1[CH:18]=[CH:19][C:4]([CH2:3][N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])[CH2:24][CH2:25]2)=[CH:5][CH:6]=1
Reactant: ClCc1ccc(Oc2nc3cccnc3s2)cc1
Reactant: O=C1CCCN1C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCN1C1CCN(Cc2ccc(Oc3nc4cccnc4s3)cc2)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 57.1 %

Procedure:
To a solution of 2-[4-(chloromethyl)phenoxy][1,3]thiazolo[5,4-b]pyridine hydrochloride (70 mg, 0.223 mmol) and 1-piperidin-4-yl-pyrrolidin-2-one (64 mg, 0.379 mmol, 1.7 equiv.) in CH3CN (1.3 mL) was added Et3N (110 μL, 0.759 mmol, 3.4 equiv.). The reaction was allowed to stir at 60° C. for 6 h. The solution was cooled to rt, filtered and purified using preparative reverse phase HPLC to afford the desired product as a cream-colored solid (52 mg, 57%). 1H NMR (600 MHz, DMSO-d6): 8.45 (dd, J=4.7, 1.5, 1H), 8.09 (dd, J=8.1, 1.5, 1H), 7.50 (dd, J=8.2, 4.8, 1H), 7.47-7.40 (m, 4H), 3.80-3.69 (m, 1H), 3.52 (s, 2H), 3.35-3.29 (m, 2H), 2.91-2.85 (m, 2H), 2.20 (t, J=8.1, 2H), 2.07-2.00 (m, 2H), 1.94-1.85 (m, 2H), 1.73-1.62 (m, 2H), 1.54-1.48 (m, 2H). MS (ESI): mass calcd. for C22H24N4O2S, 408.16; m/z found, 409.2 [M+H]+.
Reaction SMILES: C[NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][N:11]=1)=S.[N:15]#CN.[Pb]>>[O:12]1[CH:13]=[CH:14][C:10]([CH2:9][S:8][CH2:7][CH2:6][N:5]=[C:3]([NH2:15])[NH2:2])=[N:11]1
Reactant: CNC(=S)NCCSCc1ccon1
Reactant: N#CN
Agent: [Pb]
Product: NC(N)=NCCSCc1ccon1

Procedure:
Reaction of N-methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 121 gives N-cyano-N'-methyl-N"-[2-(2-(3-isoxazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7].Br[CH2:35][CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:35][CH2:36][CH2:37][OH:38])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc2ccccc2c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1ccc2ccccc2c1
Reaction time: 17 h
Yield: 105.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperazine (1.0 g) and 3-bromopropanol (330 mg) in N,N-dimethylformamide (2.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (444 mg). After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(2-naphthylmethyl)piperazine (1.19 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([CH2:33][C:34]([NH:36][CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])[CH3:22]>C(Cl)Cl.[Cu]Cl>[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([CH2:33][C:34]([NH:36][CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][C:25]=1[C:26]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27])[CH3:22]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1ccc(C(=O)OC(C)(C)C)c(OCC)c1)c1ccccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 1.9 g (9.6 mmols) of N,N′-dicyclohexylcarbodiimide, 1.06 ml (11.2 mmols) of absolute tert.butanol and 0.020 g (0.20 mmol) of copper(I) chloride was stirred for 60 hours at room temperature. Then, 6.6 ml of methylene chloride were added, and the resulting solution was added dropwise to a solution of 0.44 g (1 mmol) of 2-ethyoxy-4-[N-{1-(2-piperidinophenyl)-1-butyl}-aminocarbonylmethyl]-benzoic acid in 15 ml of methylene chloride. After 60 hours' stirring at 20° C., the precipitate which had formed was filtered off, washed with methylene chloride, and the methylene chloride solution was evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=9/1).
Reaction SMILES: [C:1]([O:9][CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[C:1]([O:9][CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH:12]=[CH:20][N:21]([CH3:23])[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Reactant: CCOC(OCC)N(C)C
Product: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CN(C)C

Procedure:
3-benzoyloxy-2,4-pentanedione is reacted with N,N-dimethyl-formamide diethyl acetal to form 4-benzoyloxy-1-dimethylamino-1-hexene-3,5-dione, and,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]=[C:9]=[S:10])[CH:3]=1.[CH2:11]([N:21]=[C:22]=[S:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:22](=[S:23])[N:21]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:9](=[S:10])[N:8]=[C:4]2[CH:3]=1
Reactant: CCCCCCCCCCN=C=S
Reactant: S=C=Nc1cc(Cl)ccn1
Product: CCCCCCCCCCn1c(=S)nc2cc(Cl)ccn2c1=S
Temperature: 85 °C
Reaction time: 192 h

Procedure:
0.511 G. of 4-Chloro-2-pyridyl isothiocyanate and 1.8 g. of n-decylisothiocyanate are combined and heated at 85° C. for 20 hours. The temperature is lowered to 75° C. and continued for 8 days. The reaction mixture is cooled, triturated with ether, filtered, washed with water and dried affording 8-chloro 3-(n-decyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione m.p. 153°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=O)=[CH:19][CH:18]=1>>[Cl:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH2:10][CH3:11])=[CH:19][CH:18]=1
Reactant: CCC(=O)c1ccc(O)c(F)c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1
Yield: 87.5 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(3-fluoro-4-hydroxyphenyl)propan-1-one (255 mg, 1.52 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (629 mg, 2.27 mmol) to give 549 mg desired product (88% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].O.C(N(CC)CC)C.[C:20](ON1C(=O)CCC1=O)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CC(C)=O>[C:20]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of L-lysine monohydrochloride (1.66 g, 9.1 mmol) in 16 of water, 16 ml of acetone and 3.83 ml (27.3 mmol) of triethylamine, succinimidyl caprylate (2.21 g, 9.1 mmol) was added portion-wise under stirring at room temperature within the period of 1h. Stirring was continued for 3h. The organic solvent was removed in vacuo and the reaction mixture was neutralized using diluted hydrochloric acid and allowed to stand at 0° overnight. The white precipitate was collected by filtration, washed with cold water, dried yielding 2.41 g (97%) of the crude product. Infrared spectrum exhibited typical pattern of ε-N-mono-substituted lysine derivative: 1580-1590 cm-1 (ionized carboxyl group), 1635 and 1520-1535 (amide bands). The compound was further purified by washing with ethanol and crystallizing from glacial acetic acid giving 2.08 g (84%) of the pure title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>C(OCC)(=O)C.[Pd]>[N:15]1[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[NH:12][C:11]=1[S:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=2)=[S:29])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Sc2nc3ccccc3[nH]2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4[nH]3)cc2)ccc1Cl
Yield: 5 %

Procedure:
2-(4-Nitrophenylthio)benzimidazole (5.0 mmoles, 1.37 g) was reduced in ethyl acetate over 1.37 g 5% Pd/C, filtered and condensed and then reacted with 4-chloro-3-trifluoromethylphenylisothiocyanate (5.0 mmoles, 1.0 g) according to procedure C to yield the title compound 0.12 g, 5% product. Mass Spec (FD) 479. Calculated for C21H14ClF3N4 S2 : C, 52.66; H, 2.95; N, 11.70. Found: C, 52.85; H, 3.18; N, 10.47.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33](=[O:38])[CH2:32]3)=[CH:25][CH:24]=1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:32]3[C:31]4[C:35](=[CH:36][CH:37]=[C:29]([C:26]5[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=5)[CH:30]=4)[NH:34][C:33]3=[O:38])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: COc1ccc(-c2ccc3c(c2)CC(=O)N3)cc1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccc(OC)cc5)cc43)c(C)c2C1=O
Yield: 67 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as starting materials to give 5-(2-diethylamino-ethyl)-2-[5-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (60 mg, 67.0%) as a yellow solid.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:5]=[C:6]([S:11][C:12]2[CH:13]=[C:14]3[C:20]([NH:21][C:22](=[O:33])[CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH:7]=[C:8]([F:10])[CH:9]=1>O.C(O)C.O.C(O)(=O)C.[Fe]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]([NH:21][C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([S:11][C:6]4[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=4)[CH:13]=3)[NH:18][N:19]=2)=[O:33])=[CH:25][CH:26]=1
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(CC(=O)Nc2n[nH]c3ncc(Sc4cc(F)cc(F)c4)cc23)cc1
Temperature: 60 °C
Yield: 4.9 %

Procedure:
A solution of 152 mg (2.72 mmol) of iron and 70 mg (1.3 mmol) of ammonium chloride in 100 μl of water is added to a solution of 0.24 g (0.544 mmol) of N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(4-nitrophenyl)acetamide in 10 ml of a 2:1 ethanol/water mixture. Several drops of acetic acid are added to this mixture and it is heated at 60° C. for 4 hours. After cooling and concentration of the solvents, the crude reaction product is extracted with ethyl acetate and is washed with saturated sodium bicarbonate solution. The organic phases are combined, dried on magnesium sulfate and then concentrated. The crude product is purified by silica gel chromatography (DCM/MeOH) to yield 11 mg (4%) of 2-(4-aminophenyl)-N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl) acetamide in the form of a brown solid.
Reaction SMILES: C(C[CH2:5][N:6]([CH3:24])[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(O)=O.C(Cl)(=O)C(Cl)=O.[C:31]1([C:37]2[O:38][C:39](=[O:52])[CH:40]([CH2:42][C:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[NH:45][CH:44]=3)[N:41]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[C:37]([NH:41][CH:40]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:39](=[O:52])[CH2:5][N:6]([CH3:24])[C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN(CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C1OC(c2ccccc2)=NC1Cc1c[nH]c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(CC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[[[(2-Carboxyethyl)methylamino]carbonyl]-L-proline, phenylmethyl ester (3.2 g., 10 mmole) is taken into 33 ml. of dry tetrahydrofuran with stirring at 5°. Oxalyl chloride (1.05 ml., 12 mmole) is added dropwise followed by 4 drops of dimethylformamide. After 20 minutes the ice bath is removed and after stirring for one hour at room temperature the reaction mixture is concentrated to dryness, taken into 20 ml. of tetrahydrofuran, chilled and added dropwise to 2-phenyl-4-[(1H-indol-3-yl)methyl]-5(4H)-oxazolone (3.0 g., 10.5 mmole) in 16 ml. of dry tetrahydrofuran with stirring in an ice bath. Triethylamine (1.7 ml., 12 mmole) is then added to the reaction mixture. After 15 minutes the ice bath is removed and the reaction is run overnight at room temperature. The triethylamine hydrochloride salt is filtered off and the filtrate is concentrated to dryness, taken into 10.6 ml. of pyridine, 33.3 mg. of 4-dimethylamino pyridine is added, and the mixture is stirred for 3 hours. Acetic acid (10.6 ml.) is added and the reaction is heated for 45 minutes at 100° under an argon atmosphere. The reaction mixture is concentrated to dryness, taken into ethyl acetate, and washed with saturated sodium bicarbonate and dilute hydrochloric acid. The crude product (4.6 g.) is purified on a silica gel column in ethyl acetate: benzene (2:1) to yield 523 mg. of (±)-1-[[[3-(benzoylamino)-4-(1H-indol-3-yl)-2-oxbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([C:25]([NH:27][CH3:28])=[O:26])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:22])([CH3:23])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([C:25]([NH:27][CH3:28])=[O:26])[CH:4]=1
Reactant: CNC(=O)c1cc(OC)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 55.3 %

Procedure:
A solution of (1R,10R,11S,16S)-5-methoxy-N,1,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxamide (75) (0.17 g, 0.42 mmol) in anhydrous CH2Cl2 (5.0 mL) was cooled with an ice bath under N2. To the mixture BBr3 (1 M in CH2Cl2, 1.6 mL, 1.6 mmol) was added dropwise. The mixture was stirred at 0° C. for 2.5 h then at room temperature for 3.25 h. The solution was cooled to 0° C. and quenched with anhydrous MeOH. The solution was evaporated and the residue co-evaporated with anhydrous MeOH. The solid was suspended in EtOAc and washed with 0.09 M HCl (11 mL). The mixture was taken to pH=7.5 using sodium bicarbonate. The organic layer was separated was concentrated to dryness. The crude material was triturated with MeOH then filtered and washed with MeOH to yield (1R,10R,11S,16S)-5-hydroxy-N,1,11,15,15-pentamethyl-8-thiatetracyclo-[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxamide (76) (0.09 g, 57%) as a white solid. 1H NMR (DMSO-d6): δ 9.37 (s, 1H), 8.10 (m, 1H), 6.36 (d, 1H), 6.18 (d, 1H), 2.94 (dd, 1H), 2.80 (d, 1H), 2.65 (d, 3H), 1.81 (d, 1H), 1.62-1.26 (m, 12H), 1.09 (ddd, 1H), 0.87-0.81 (m, 7H), 0.78 (s, 3H). MS m/z 388 (C23H33NO2S+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]([C@@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][CH2:20][C@@H:21]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=5)[CH2:22]4)[CH2:15][CH2:14]3)[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]([C@@H:13]3[CH2:14][CH2:15][C@H:16]([N:19]([CH2:20][C@@H:21]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([C:30]#[N:31])[CH:27]=5)[CH2:22]4)[C:41](=[O:43])[CH3:42])[CH2:17][CH2:18]3)[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(O)c1nc2cc(Cl)ccc2n1[C@H]1CC[C@@H](NC[C@H]2Cc3ccc(C#N)cc3C2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C[C@H]1Cc2ccc(C#N)cc2C1)[C@H]1CC[C@@H](n2c(C(C)(C)O)nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 55 %

Procedure:
To a solution of cis-(S)-2-({4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-cyclohexylamino}-methyl)-indan-5-carbonitrile (25 mg, 0.054 mmol) in methylene chloride (5 mL) was added triethylamine (11 mg, 0.108 mmol), acetyl chloride (5 mg, 0.063 mmol) and trace amount of 4-dimethylaminopyridine. The mixture was stirred at room temperature for 65 hours. The reaction mixture was diluted with dichloromethane and the solution was washed with saturated aqueous sodium bicarbonate solution followed by brine. The organic extract was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography, eluting with dichloromethane and ethyl acetate in the presence of 4% methanol to give cis-(S)—N-{4-[5-chloro-2-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-cyclohexyl}-N-(5-cyano-indan-2-ylmethyl)-acetamide (15 mg). LC-MS showed a single peak, C29H33ClN4O2 (m/e) calcd 504.2292, obsd 505.3. 1H-NMR (CD3OD) □ 7.67 (br, 1H) 7.59 (s, 2H), 7.50 (d, 1H), 7.40 (d, 1H), 7.23 (d, 1H), 5.57 (m, 1H), 3.48 (br d, 2H), 3.15 (m, 2H), 2.97 (m, 1H), 2.84 (m, 2H), 2.59 (br, 2H), 2.32 (br, 1H), 2.11 (br s, 2H), 1.93 (m, 4H), 1.72 (s, 6H), 1.28 (s, 3H).
Reaction SMILES: C(ON=[C:5]([C:14]1[C:23]([CH3:24])=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][S:21]2(=[O:26])=[O:25])=[CH:16][CH:15]=1)[C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])C.[OH:27]C1NN=CC=1>>[CH3:12][N:9]1[C:10]([OH:11])=[C:6]([C:5]([C:14]2[C:23]([CH3:24])=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][S:21]3(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:27])[C:7]([CH3:13])=[N:8]1
Reactant: Oc1ccn[nH]1
Reactant: CCON=C(c1ccc2c(c1C)S(=O)(=O)CCC2)c1c(C)nn(C)c1O
Product: Cc1nn(C)c(O)c1C(=O)c1ccc2c(c1C)S(=O)(=O)CCC2

Procedure:
Yield: 0.35 g (89% of theory) of 7-(1,3 dimethyl-5-hydroxypyrazole-4-carbonyl)-8-methyl-1,1-dioxo-thio-chroman O-ethyloxime)-5-hydroxypyrazole; 1H NMR (CDCl3): δ [ppm]=9.90 (1H, bs), 8.12 (1H, d), 7.35 (1H, d), 4.32 (2H, q), 3.65 (3H, s), 3.44 (4H, m), 2.70 (3H, s), 1.73 (3H, s), 1.38 (3H, tr).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=[O:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=1[NH:1][C:12]([C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the 2-amino-4-bromoaniline (6.0 g, 32.1 mmol), Boc-Pro-OH (6.90 g, 32.1 mmol) and HATU (13.42 g, 35.3 mmol) in dry DMSO (160 mL) was treated with diisopropylethylamine (14.0 mL, 10.4 g, 80 mmol) followed by stirring at room temperature for 18 h. The mixture was diluted with ethyl acetate and extracted with water (3×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a brown solid which was used directly in the next step.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1cccc(Cl)c1B(O)O
Product: COc1cccc(Cl)c1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 4.1 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted 2-chloro-6-methoxyphenylboronic acid (available from Aldrich Chemical Company, Inc.; 93 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-6′-methoxy-biphenyl-2-carboxylic acid (5 mg, 4%). 1H NMR (300 MHz, DMSO-d6), δ 12.87 (br s, 1H), 8.53 (d, J=1.7 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.4, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.32-7.41 (m, 2H), 7.10 (dd, J=18.2, 8.0 Hz, 2H), 3.67 (s, 3H).