Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58]([C:60]1[NH:64][C:63]2[CH:65]=[CH:66][C:67]([NH2:69])=[CH:68][C:62]=2[N:61]=1)=[O:59]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:69][C:67]2[CH:66]=[CH:65][C:63]3[NH:64][C:60]([C:58]([O:57][CH3:56])=[O:59])=[N:61][C:62]=3[CH:68]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2cc(N)ccc2[nH]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Reaction time: 0.33 h

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.3 mg, 0.129 mmol) in dichloromethane (3 ml) was reacted with DIPEA (66.8 mg, 0.514 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (75.7 mg, 0.320 mmol) and stirred for 20 min under argon. 5-AMINO-1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID METHYL ESTER (25.7 mg, 0.134 mmol, Biofine) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane and extracted with water then with sat'd NaHCO3, water, and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving a white lyophilized solid, chiral methyl 542R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-1H-benzo[d]imidazole-2-carboxylate (43 mg, 52%). MS (ES+) m/z Calcd: [(M+H)+]: 640.16. found: 640.1.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[OH:10][C:11]1[CH:24]=[CH:23][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: BrCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(OCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
100 ml of a 10 percent aqueous sodium hydroxide solution were added to a solution of 34.5 g of 1,5-dibromopentane, 9.9 g of 4-hydroxybenzophenone and 1.6 g of tetrabutylammonium bromide in 100 ml of methylene chloride. The heterogeneous mixture was stirred at room temperature overnight. The organic phase was separated, dried over sodium sulphate and evaporated. By chromatography of the residue on silica gel with hexane:ethyl acetate (7:3) there were obtained 13.47 g (78%) of 4-[(5-bromopentyl)oxy]benzophenone as a colorless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1.[CH:14](Br)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH:14]([N:9]1[C:8]2[CH:13]=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc2ccc(Br)cc2n1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a cold (0° C.) suspension of sodium hydride (0.589 g of a 60% w/w dispersion in mineral oil, 14.7 mmol) in N,N-dimethylformamide (50 mL) was added in portions 5-bromo-benzo[d]oxazol-2(3H)-one (3.0 g, 14.0 mmol). The reaction mixture was stirred for 1 h at 0° C. and benzhydryl bromide (3.81 g, 15.4 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. Further benzhydryl bromide (1.7 g. 6.9 mmol) was added and the reaction mixture was heated at 70° C. for 16 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was suspended in ethyl acetate (300 mL), washed with water (2 20 mL) and brine (2 20 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 0-50% gradient of ethyl acetate in hexanes to afford 3-benzhydryl-5-bromobenzo[d]oxazol-2(3H)-one as an orange solid in 71% yield (3.87 g): 1H NMR (300 MHz, CDCl3) δ7.41-7.34 (m, 6H), 7.27-7.21 (m, 4H), 7.19-7.14 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.78 (s, 1H), 6.46 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=3[O:20][CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:6]=2[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br-].[Br-].[C:37]1([CH3:44])[C:38]([CH3:43])=[CH:39][CH:40]=[CH:41][CH:42]=1.[I-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:43][C:38]5[C:37](=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:44]4)=[CH:15][C:14]=3[O:20][CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:6]=2[CH:28]=1
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(N)cc2OC)c2ccc(Cl)cc21
Reactant: Cc1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CCO
Product: COC(=O)CC1CCCN(C(=O)c2ccc(N3Cc4ccccc4C3)cc2OC)c2ccc(Cl)cc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
To a suspension of 7-chloro-5-methoxycarbonylmethyl-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (2.6 g) in ethanol (100 ml) are added sodium carbonate (1.5 g), o-xylene dibromide (1.87 g) and sodium iodide (2.42 g), and the mixture is stirred at 60-70° C. for three hours. The mixture is evaporate to remove the solvent, and to the residue is added water, and the mixture is extracted with ethyl acetate. The extract is dried, and evaporate to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate:n-hexane =1:10→1:5) to give 7-chloro-5-methoxycarbonylmethyl-1-[2-methoxy-4-(2-isoindolinyl)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.32 g) as colorless amorphous.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[N+](=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[N-]>CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[CH:1]12[C:9]([C:14]([O:16][CH3:17])=[O:15])([C:10]([O:12][CH3:13])=[O:11])[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: C1=CCCCC1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Product: COC(=O)C1(C(=O)OC)C2CCCCC21
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To stirred, refluxing mixture of 100.0 grams (1.22 mole) of cyclohexene and 0.037 gram (0.0001 mole) of cupric acetylacetonate was fed 22.7 grams (0.14 mole) of dimethyl diazomalonate over a 25-hour period by means of a syringe pump. Refluxing was continued for an additional 8 hours after which distillation of the reaction mixture was begun, employing a small Vigreux column. After removing about 32 grams of cyclohexene overhead, to a head temperature of 80° C., the residue was allowed to cool. The solidified residue was worked up by flash column chromatography on silica gel to give 17.53 grams (0.08 mole) of dimethyl bicyclo[4.1.0]heptane-7,7-dicarboxylate having a melting point of 83° C.-86° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][C@@H:11]([O:14]/[N:15]=[C:16]2\[CH2:17][CH:18]3[C@:31]([CH3:35])([CH2:32][C@H:33]\2[F:34])[C@@H:30]2[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]2)([CH3:27])[C@@H:25]([OH:36])[CH2:24][CH2:23]4)[CH2:20][C:19]3=O)[CH2:10]1.Cl.[CH3:39][O:40][NH2:41]>>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][C@@H:11]([O:14]/[N:15]=[C:16]2\[CH2:17][CH:18]3[C@:31]([CH3:35])([CH2:32][C@H:33]\2[F:34])[C@@H:30]2[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]2)([CH3:27])[C@@H:25]([OH:36])[CH2:24][CH2:23]4)[CH2:20]/[C:19]/3=[N:41]\[O:40][CH3:39])[CH2:10]1
Reactant: CON
Reactant: C[C@]12CC[C@H]3[C@@H](CC(=O)C4C/C(=N\O[C@@H]5CCNC5)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: CO/N=C1\C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C[C@@H](F)/C(=N/O[C@@H]3CCNC3)CC12

Procedure:
The title compound was obtained in 56% yield following the procedure described in Example 34 starting from (E)-3-[3-(R)-pyrrolidinyl]oxyimino-2α-fluoro-17β-hydroxyandrostan-6-one fumarate (Example 35, 72 mg) and methoxyamine hydrochloride (14 mg). After evaporation of the solvent the crude reaction mixture was purified by flash chromatography (SiO2, CHCl3/MeOH/26% NH4OH 90/10/1). To the concentrated fractions, a stoichiometric amount of fumaric acid in MeOH was added. The resulting precipitate was rinsed with heptane and filtered to give the title compound I-bk.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](N)[CH2:3]C1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[C:27]([O:31][C:32](=[O:44])[NH:33][CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28].BrC1C=C2C(=CC=1)NC=C2.C(=O)([O-])[O-].[K+].[K+]>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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[C:27]([O:31][C:32](=[O:44])[NH:33][CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH2:36][CH2:35]1)([CH3:30])([CH3:28])[CH3:29].[C:27]([O:31][C:32](=[O:44])[NH:33][CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[NH:1][CH:3]=[CH:4]3)[CH2:36][CH2:35]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: NC1CCNc2ccccc21
Agent: [Pd]
Agent: Brc1ccc2[nH]ccc2c1
Agent: CC(C)(C)OC(=O)NC1CCNc2ccccc21
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc3[nH]ccc3c2)c2ccccc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(1,2,3,4-Tetrahydro-quinolin-4-yl)-carbamic acid tert-butyl ester was prepared by treatment of commercially available 1,2,3,4-tetrahydro-quinolin-4-ylamine (JW Pharmaceutical #7578-79-2) with BOC anhydride. The (1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid tert-butyl ester (1.28 g, 5.15 mmol), together with 5-bromoindole (0.67 g, 3.44 mmol), Pd2dba3 (0.063 g, 0.069 mmol), XPHOS (0.082 g, 0.17 mmol), potassium carbonate (1.2 g, 8.6 mmol) and tert-butabol (10 mL) were combined in a 50 mL tube. The tube was sealed and heated to 100° C. with stirring for 18 hours. The tube was then cooled to room temperature and the contents were partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was separated and concentrated under reduced pressure, and the residue was purified by flash chromatography (0% to 25% EtOac/hexanes) to give 1.3 g of [1-(1H-indol-5-yl)-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[I-].[K+].Br[CH:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:24][O:23][C:21](=[O:22])[CH:20]([O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(Oc1cccc(Oc2ccccc2)c1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 104.2 %

Procedure:
As described in Example 30, a mixture of 5.2 g of m-phenoxyphenol, 1.06 g of 60% sodium hydride-oil dispersion, 3.82 g of potassium iodide, one ml of hexamethylphosphoramide and 10.4 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate in 80 ml of tetrahydrofuran is refluxed for 18 hours and worked-up to give 13.6 g of gum. The gum is chromatographed over silica gel with dichloromethane as eluent to give 11.2 g of product as a viscous oil.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].O[CH2:14][NH:15][C:16](=[O:20])[CH:17]([Cl:19])[Cl:18]>>[CH2:1]([C:3]1[C:12]2[C:7](=[C:8]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([Cl:19])[Cl:18])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: O=C(NCO)C(Cl)Cl
Reactant: CCc1nccc2ccccc12
Product: CCc1nccc2c(CNC(=O)C(Cl)Cl)cccc12

Procedure:
1-Ethylisoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-ethyl-5-dichloroacetylaminomethylisoquinoline. The product was reacted successively in the same way as in steps (c), (d), (e) and (f) of Example 18 to afford 1-ethylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-ethylisoquinoline-5-acetic acid having a melting point of 166.2° to 180.8° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC.[CH2:28]([C:30]1[C:31]([NH:38][C@H:39]2[C@@H:43]([O:44][CH2:45][CH2:46][F:47])[CH2:42][N:41](C(OCC3C=CC=CC=3)=O)[CH2:40]2)=[N:32][C:33]([CH2:36][CH3:37])=[CH:34][N:35]=1)[CH3:29]>>[CH2:28]([C:30]1[C:31]([NH:38][C@H:39]2[C@@H:43]([O:44][CH2:45][CH2:46][F:47])[CH2:42][NH:41][CH2:40]2)=[N:32][C:33]([CH2:36][CH3:37])=[CH:34][N:35]=1)[CH3:29]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2OCCF)n1
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1cnc(CC)c(N[C@@H]2CNC[C@@H]2OCCF)n1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.65, 5.21, 4.64, 4.53, 4.07, 3.81-3.61, 3.40, 3.22, 3.14, 2.82, 2.62, 1.33-1.25; IR (liq.) 3437, 2969 (s), 2936 (s), 2874, 2348 (w), 1580 (s), 1546 (s), 1498 (s), 1464, 1449 (s), 1395, 1162, 1129, 1043 (s), 870, cm−1; HRMS (FAB) calcd for C14H23FN4O+H 283.1934, found 283.1928.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[Br:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:13]([O:18][Si:2]([CH3:5])([CH3:4])[CH3:1])[C:14]([CH3:16])([CH3:17])[CH3:15])=[CH:24][CH:25]=1
Reactant: CC(C)(C)C(O)C(Oc1ccc(Br)cc1)n1cncn1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(O[Si](C)(C)C)C(Oc1ccc(Br)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
At 0° C., a solution of 8.5 g of trimethylchlorosilane in 20 ml of THF is dripped into a solution of 3.4 g of 1-p-bromophenoxy-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol and 1.5 g of triethylamine in 40 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature and evaporated, and the residue is taken up in CHCl3, washed several times with water and dried over Na2SO4. After evaporation, the crude product is chromatographed (SiO2, CHCl3). There is obtained 2 g of 1-p-bromophenoxy-3,3-dimethyl-2-trimethylsiloxy-1-(1,2,4-triazol-1-yl)-butane as a colorless resin.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:9]([C:17]#[N:18])=[N:10][C:11]([CH2:15][CH3:16])=[C:12]([CH3:14])[N:13]=1.ClC1C(C#N)=NC(C)=C(CC)N=1.[C:31]1([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:15]([C:11]1[N:10]=[C:9]([C:17]#[N:18])[C:8]([N:40]2[CH2:41][CH2:42][N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:38][CH2:39]2)=[N:13][C:12]=1[CH3:14])[CH3:16]
Reactant: CCc1nc(C#N)c(Cl)nc1C
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CCc1nc(Cl)c(C#N)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc(C#N)c(N2CCN(c3ccccc3)CC2)nc1C
Temperature: 0 °C
Yield: 21.8 %

Procedure:
0.416 mg (3.0 mmol) of potassium carbonate were added to a solution of 0.182 g (1.0 mmol) of the 1:1 mixture of the 3-chloro-6-ethyl-5-methyl-pyrazine-2-carbonitrile and the 3-chloro-5-ethyl-6-methyl-pyrazine-2-carbonitrile and of 0.199 g (1.2 mmol) of 1-phenylpiperazine in 10.0 ml of N,N-dimethylformamide and the reaction mixture was stirred at room temperature for 16 hours. It was subsequently poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 4:1 to 0:100 v/v gradient of hexane and dichloromethane as the eluent giving 0.067 g (0.218 mmol, 21.8% of theory) of the 5′-ethyl-6′-methyl-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as orange oil; MS: 308 (M+H)+; and 0.043 g (0.14 mmol, 14% of theory) of the 6′-ethyl-5′-methyl-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as yellow solid; m.p. 99-101° C.; MS: 308 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:11][CH2:12][S:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCSCC2)cc1
Reaction time: 3 h
Yield: 80.7 %

Procedure:
4-(4-Nitro-phenyl)-thiomorpholine(3.0 g, 13.4 mmol), as prepared in Reference Example 13a above, was dissolved in ethanol (250 mL) and 10% palladium on carbon (250 mg) was added. This mixture was shaken on a Parr hydrogenator for 3 h. The reaction mixture was then filtered through diatomaceous earth and concentrated under vacuum. The residue was triturated with hexane to yield an gray solid (2.1 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH:6][C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[N:2]1.[Br:16]Br>ClCCl.C(O)(=O)C>[Br:16][C:4]1[C:3]([NH:6][C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH:9]([CH3:10])[CH3:11])=[N:2][S:1][CH:5]=1
Reactant: BrBr
Reactant: COC(=O)[C@H](CC(C)C)Nc1ccsn1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@H](CC(C)C)Nc1nscc1Br
Reaction time: 0.75 h
Yield: 102.3 %

Procedure:
To a solution of methyl N-isothiazol-3-yl-L-leucinate (160 mg, 0.70 mmol) in dichloromethane (3 mL) and acetic acid (0.5 mL) was added bromine (0.04 mL, 0.78 mmol). The solution was stirred for 45 min, then diluted with dichloromethane and washed with saturated aqueous NaHCO3 and brine, filtered through cotton and evaporated to give 220 mg of methyl N-(4-bromoisothiazol-3-yl)-L-leucinate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:14][C:13]=1[C:23]([F:26])([F:25])[F:24]>Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:14][C:13]=1[C:23]([F:25])([F:24])[F:26]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCOCC3)nc2C(F)(F)F)c1
Agent: Cl
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1C(F)(F)F

Procedure:
A solution of methyl 4-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-5-yl)benzoate (compound 287.2, 50 mg, 0.14 mmol) in HCl (6 M) (2 mL) was stirred for 5 h at 80° C., then concentrated under reduced pressure. This resulted 200 mg (crude) of the title compound as a brown solid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].[Cl-].[NH4+]>C(Cl)Cl>[CH3:42][S:43]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 23 h
Yield: 79.7 %

Procedure:
6.62 gram (14.1 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 282 ml of methylene chloride, followed by the addition of 4.7 ml (57.8 mmol) of pyridine and 4.1 ml (53.6 mmol) of methanesulfonyl chloride at 0° C. The reaction solution was stirred at room temperature for 23 hours. To the reaction solution, 200 ml of saturated aqueous solution of ammonium chloride was added and extracted with 200 ml of methylene chloride. The extract was washed with 200 ml of brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 2:3 mixture of ethyl acetate and hexane) to obtain 6.15 gram of the titled compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32]C)=[O:31])[CH:18]=[C:17]3[C:34]([O:36]C)=[O:35])[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([OH:32])=[O:31])[CH:18]=[C:17]3[C:34]([OH:36])=[O:35])[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)cc(C(=O)OC)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.3 %

Procedure:
50.6 mg (0.0969 mmol) of methyl 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonylphenyl)-4-quinolinecarboxylate obtained in Example 8 was mixed with 33.5 mg (0.388 mmol) of sodium hydroxide, 1 ml of water and 0.3 ml of ethanol and the mixture was stirred at the room temperature for 24 hours. After concentrated under reduced pressure, the concentrate was partitioned between water and ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate to obtain 44.2 mg of 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-carboxyphenyl)-4-quinolinecarboxylic acid. NMR (270 MHz, CD3OD):