Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH:14]1[CH:20]([CH3:22])[CH3:21])=[O:12].[C:23]([Cu])#[N:24]>CN1C(=O)CCC1>[C:23]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH:14]1[CH:20]([CH3:22])[CH3:21])=[O:12])#[N:24]
Reactant: CC1CCC(C(C)C)C(C(=O)NCCc2ccccc2Br)C1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CC1CCC(C(C)C)C(C(=O)NCCc2ccccc2C#N)C1
Reaction time: 0.67 h
Yield: 95.3 %

Procedure:
A 20 mL microwave reaction vessel equipped with a stir bar was charged with 2-isopropyl-5-methyl-cyclohexanecarboylic acid [2-(2-bromo-phenyl)-ethyl]-amide (1.54 g, 4.2 mmol), CuCN (0.60 g, 6.4 mmol) and NMP (10 mL). The reaction vessel was subjected to microwave at 180° C. for 40 minutes. The reaction mixture was transferred to a round bottom flask and concentrated. The residue to purified by flash chromatography on silica gel (10% ethyl acetate/hexane for elution) to give a colorless solid (1.25 g, 81%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.O[C@@H:32]1[CH2:37][C@@H:36]([CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[O:35][C@:34]([C@@H:45]2[CH2:49][S:48][C:47](=[O:50])[N:46]2[CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)([O:43][CH3:44])[CH2:33]1>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOCC>[C:1]([O:9][C@@H:32]1[CH2:37][C@@H:36]([CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[O:35][C@@:34]([O:43][CH3:44])([C@@H:45]2[CH2:49][S:48][C:47](=[O:50])[N:46]2[CH2:51][C:52]2[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)[CH2:33]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C=CCCC[C@@H]1C[C@@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)c2ccccc2)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To a solution of benzoic acid (31.7 mg, 0.260 mmol) in dry toluene (5 mL) under a nitrogen atmosphere was added diisopropylethylamine (0.0435 mL, 0.250 mmol) and 2,4,6-trichlorobenzoyl chloride (0.0391 mL, 0.250 mmol). The mixture was stirred at room temperature for 3 h, after which the title compound from Example 14 (21.5 mg, 0.051 mmol) and DMAP (32.9 mg, 0.269 mmol) were added. This mixture was stirred at room temperature for 18 h, after which it was diluted with ether and washed with satd aq NH4Cl and brine, and the organic phase was dried and evaporated. Chromatography of the residue on silica gel, eluting with an ethyl acetate/dichloromethane gradient, afforded the title compound (21.7 mg, 81%) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].[ClH:11].[NH:12]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]3[N:31]=[CH:30][NH:29][C:27]3=2)[N:22]=[C:21]([CH3:32])[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[OH2:3].[ClH:11].[C:2]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[NH:10][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]3[N:31]=[CH:30][NH:29][C:27]3=2)[N:22]=[C:21]([CH3:32])[CH:20]=1)(=[O:3])[CH3:1].[C:2]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]3[N:31]=[CH:30][NH:29][C:27]3=2)[N:22]=[C:21]([CH3:32])[CH:20]=1)(=[O:3])[CH3:1].[ClH:11]
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: CC(=O)c1cccc(N)c1
Agent: Cl
Solvent: CCO
Product: CC(=O)c1cccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)c1
Product: O

Procedure:
A mixture of 13.5 g. (0.1 m.) of 3-aminoacetophenone, 21.7 g. (0.1 m.) of the compound of Example I, C. and 500 ml. of ethanol was heated at reflux overnight with stirring. The solution was concentrated in vacuo to give 30 g. m.p. 156°-223°C. The crude product was recrystallized from 1000 ml. of MeOH, followed by concentration of the filtrate to the cloud point. The product was oven-dried (100°C) to yield 24 g. m.p. 225° -228°, completely 251°C.
Reaction SMILES: I.[C:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([NH:18][C:19](=[NH:22])SC)[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH3:3].[CH3:23][O:24][CH2:25][CH2:26][NH2:27]>C(O)C>[C:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:22])[NH:27][CH2:26][CH2:25][O:24][CH3:23])[S:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH3:3]
Reactant: CSC(=N)Nc1nc(-c2cccc(CNC(C)=O)c2)cs1
Reactant: COCCN
Agent: I
Solvent: CCO
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(C)=O)c2)cs1

Procedure:
A solution of 4-(3-acetylaminomethylphenyl)-2-(2-methyl-1-isothioureido)thiazole hydriodide (2.0 g) and 2-methoxyethylamine (5 ml) in ethanol (50 ml) was refluxed for 25 hours. The solvent was removed under reduced pressure and the residue was suspended in water (100 ml). The mixture was alkalized with 30% aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (50 ml). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate. Recrystallization from ethyl acetate afforded 4-(3-acetylaminomethylphenyl)-2-[[(amino)(2-methoxyethylamino)methylene]amino]thiazole (0.65 g).
Reaction SMILES: COC1C=CC=CC=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43]>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:45]([NH:44][C:42](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[S:46])=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccccc1C(=O)Cl
Agent: COc1ccccc1C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4OC)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
2-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 96%).
Reaction SMILES: N1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3]C1=O.C[N:14](C)C=O.NCCN1CCC(NC2N(CC3C=CC(F)=CC=3)C3C=CC=CC=3N=2)CC1>O>[C:4]([NH2:14])(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN(C)C=O
Agent: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O
Product: NC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
To a stirred and hot (50° C.) mixture of 4.1 parts of 2H-3,1-benzoxazine-2,4(1H)-dione and 31.5 parts of N,N-dimethylformamide was added dropwise a solution of 9.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in 31.5 parts of N,N-dimethylformamide at 50° C. Upon completion, stirring was continued for 3 hours at 50° C. Water was added and the product was extracted with 4-methyl-2- pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 9.8 parts (80%) of 2-amino-N-[2-[4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide; mp. 171.7° C. (58).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.Cl.[CH3:48][C:49]1[C:53]([NH2:54])=[CH:52][O:51][N:50]=1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:54][C:53]1[C:49]([CH3:48])=[N:50][O:51][CH:52]=1)=[O:8]
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Reactant: Cc1nocc1N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1nocc1NC(=O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 22; 150 mg, 0.34 mmol) in N,N-dimethylformamide (4 ml) was added diisopropylethylamine (0.12 ml, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (55.4 mg, 0.41 mmol), 3-methyl-4-isoxazolamine hydrochloride (39.9 mg, 0.41 mmol) and EDC (98 mg, 0.51 mmol). The reaction was stirred for 18 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2; ethyl acetate) to yield the title compound as a solid. 162 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>CO>[CH2:27]([O:26][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 65.5 %

Procedure:
The 1,2-dibenzyloxy-4-[2-(4-nitrophenyl)ethenyl]benzene (10 g, 22 mmole) is dissolved in methanol (50 ml), THF (100 ml) and reacted with Ra--N1 (1.5 g). Reduction under a pressure of 512 psi at 19.5° C. affords 5.9 g (60%) of 4-[-2-(-3,4-dibenzyloxyphenyl)ethyl]benzenamine, mp 97°-101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[SH-].[Na+].CO>O>[NH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: O
Product: Nc1cccc([N+](=O)[O-])c1C(=O)O

Procedure:
In one non-limiting reaction scheme, dinitrobenzoic acid may be reacted with about one to about five equivalents of an alkali hydrosulfide in a methanol:water mixture at reflux temperature for about 20 to about 40 minutes to produce an aminonitrobenzoic acid. As is described in the Example below, 2,6-dinitrobenzoic acid may be allowed to react with about three equivalents of sodium hydrosulfide in a methanol:water mixture at reflux temperature for about 30 minutes to produce 2-amino-6-nitrobenzoic acid. In some non-limiting embodiments, three equivalents of sodium hydrosulfide may be reacted with one equivalent of the sodium salt of 2,6-dinitrobenzoic acid in refluxing methanol/water followed by acidification.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C@H:13]2[C@H:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 95.7 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (130 mg, 0.24 mmol) in CH2Cl2 (5 ml) was added TFA (1 ml) at RT. Stirring was continued over night. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq.NaHCO3 and the organic phase was dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 100 mg (92%) of the title compound as light yellow oil. ES-MS m/e: 435.37 (M+H+).
Reaction SMILES: C1COCC1.[CH3:6][NH2:7].[CH3:8][C:9]([Si:12]([CH3:47])([CH3:46])[O:13][C@H:14]([C@@H:19]([CH3:45])/[CH:20]=[C:21](/[CH3:44])\[CH2:22][C@H:23]([CH3:43])[C@@H:24]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C@H:25]([CH3:34])[C@@H:26]([OH:33])[C@@H:27]([CH3:32])/[CH:28]=[CH:29]\[CH:30]=[CH2:31])[C@@H:15]([CH3:18])[CH:16]=O)([CH3:11])[CH3:10]>CC(O)=O.CCOC(C)=O>[CH3:40][C:39]([Si:36]([CH3:38])([CH3:37])[O:35][C@H:24]([C@@H:23]([CH3:43])[CH2:22]/[C:21](/[CH3:44])=[CH:20]\[C@H:19]([CH3:45])[C@@H:14]([O:13][Si:12]([C:9]([CH3:8])([CH3:11])[CH3:10])([CH3:47])[CH3:46])[C@@H:15]([CH3:18])[CH2:16][NH:7][CH3:6])[C@H:25]([CH3:34])[C@@H:26]([OH:33])[C@@H:27]([CH3:32])/[CH:28]=[CH:29]\[CH:30]=[CH2:31])([CH3:41])[CH3:42]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=O
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CNC
Reaction time: 0.33 h
Yield: 58.4 %

Procedure:
To a stirred THF solution of methylamine (2 M, 1.01 mL, 4 eq, 2.02 mmol) is added THF (10 mL) solution of (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[(1,1-dimethylethyl) dimethylsilyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal (300 mg, 0.505 mmol, 1 eq) at 23° C. After stirring for 20 minutes, NaBHAc3 is added followed by addition of 1 drop of AcOH. The solution is stirred for an additional 2 hours and diluted with EtOAc (10 mL), washed with aqueous saturated Na2CO3 (2×5 mL), brine, dried with Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, gradient 10–30% MeOH/EtOAc) to give the desired compound (180 mg, 59%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[CH3:15][C:2]([CH3:1])([CH3:16])[CH2:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=CC(C)(C)C)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CC(C)(C)C)C(=O)OCC

Procedure:
In 2-liter stainless steel pressure reactor, to a solution of 114 g (0.50 mol) of diethyl (2,2-dimethylpropylidene)malonate in 650 ml of ethanol 1.60 g of 10% Pd/C was added. Hydrogenation was carried at 5 atm of hydrogen gas for 6 h at 40° C. The following GC analysis showed that conversion of the starting material into the title product was almost quantitative. The reaction mixture was added to 1500 cm3 of cold water, and the product was extracted by 3×300 ml of dichloromethane. The combined organic extract was passed through short layer of silica gel 60 (40-63 um), evaporated in vacuum, and then used without an additional purification. Yield of the title material was almost quantitative.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:17])[CH2:15]Cl)([CH3:3])[CH3:2].[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>O.CS(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:17])[CH2:15][S:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CS
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CSCC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A mixture of 18.8 g of N-(2,6-diisopropylphenyl)-2-chloroacetamide, 8.9 g of ethyl 2-mercaptoacetate, 20.4 g of potassium carbonate, and 100 ml of dimethyl sulfoxide was stirred at room temperature for 1 hour, and a mixture of 25 ml of concentrated hydrochloric acid and 100 ml of water was added thereto. The reaction mixture was extracted with 300 ml of ethyl acetate, and the extract was washed successively with a 1N hydrochloric acid aqueous solution, a sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to yield 22.6 g of N-(2,6-diisopropylphenyl)-2-(ethoxycarbonylmethylthio)acetamide as white needle crystals (m.p.=124.0°-125.0° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.C(O)(=O)C.ClC(Cl)C.[CH2:38]([N:40]([CH2:43][CH2:44][NH2:45])[CH2:41][CH3:42])[CH3:39].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH2:7][NH:45][CH2:44][CH2:43][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH:9]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Reactant: CCN(CC)CCN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: CCN(CC)CCNCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.100 g, 0.25 mmol) in 10:1 dichloroethane acetic acid (2.2 mL) was added (diethylamino)ethylamine (0.088 mL, 0.625 mmol) and the resulting solution was stirred for 1 hour at ambient temperature. To this was added sodium cyanoborohydride (0.0094 g, 0.15 mmol) and the reaction was stirred overnight at ambient temperature. Upon completion water was added and the mixture was basified with solid sodium bicarbonate (pH>10). The product was extracted with dichloromethane (2×) and diethyl ether (2×). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.039 g, x 30% yield)
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28](=[O:35])[N:29]=[C:30](SC)[NH:31][CH:32]=2)=[CH:22][N:21]=1.[CH2:36](O)C>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH3:36])[C:30]3[NH:31][CH:32]=[C:27]([CH2:26][C:23]4[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=4)[C:28](=[O:35])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: NCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Product: COc1ncc(Cc2c[nH]c(N(C)CCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine (0.204 mmol, 1 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.082 mmol, 0.4 eq) were dissolved in dry ethanol (200 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified by Waters Mass Direct Autopurification system giving 2-({2-[4-(4-fluoro-phenoxy)phenyl]-ethyl}-methyl-amino)-5-(2-methoxy-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.039 mmol, yield: 19%, HPLC-MS/UV: [M+H]+=462.24; rt: 10.59 min; purity: 99%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.85 (t, J=7.17, 2H), 2.98 (s, 2H), 3.51 (s, 2H), 3.73 (t, J=6.72, 2H), 3.95 (s, 3H), 6.85-7.05 (m, 5H), 7.11-7.17 (m, 2H), 7.23-7.28 (m, 1H), 7.65 (s, 1H), 8.37 (s, 1H), 10.09 (br.s., 1H)
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.[F:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[C:31]=4[F:32])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cccc(F)c1F
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cccc(F)c1F
Yield: 69.2 %

Procedure:
Using the conditions of General Procedure B 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; 89 mg, 0.2 mmol) was reacted with 2,3-difluorophenylboronic acid (available from Combi-Blocks Inc.; 63 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′,3′-difluoro-biphenyl-2-carboxylic acid (64 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ 13.26 (br s, 1H), 8.52 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.34 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.74-7.81 (m, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.42-7.53 (m, 1H), 7.19-7.36 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([NH:8][CH3:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[O:13]1[CH2:37][CH:14]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]3[O:36][CH2:35]3)=[CH:28][CH:27]=2)([CH3:25])[CH3:24])=[CH:19][CH:18]=1>CO>[OH:13][CH:14]([CH2:37][N:8]([CH3:9])[CH:6]1[CH2:7][C:2]([CH3:1])([CH3:12])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]1)[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH:34]([OH:36])[CH2:35][N:8]([CH:6]3[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:7]3)[CH3:9])=[CH:30][CH:31]=2)([CH3:25])[CH3:24])=[CH:21][CH:22]=1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: CO
Product: CN(CC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)CN(C)C3CC(C)(C)NC(C)(C)C3)cc2)cc1)C1CC(C)(C)NC(C)(C)C1

Procedure:
To 50 ml of methanol were added 3.4 g of 2,2,6,6-tetramethyl-4-methylaminopiperidine and 3.4 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then reacted in a manner similar to that described in Example 1, giving the desired compound in the form of a white powder. The compound had an Rf value of 0.50 on thin layer chromatography on silica gel developed with a 1:3:1 by volume mixture of methanol, ethyl acetate and triethylamine.
Reaction SMILES: C(OC(=O)C)(=O)C.O[C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([OH:27])=[O:26]>C1C=CC=CC=1>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[O:27][C:25](=[O:26])[CH2:24][CH2:23]2
Reactant: O=C(O)CCc1cccc(Oc2ccccc2Cl)c1O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: O=C1CCc2cccc(Oc3ccccc3Cl)c2O1
Yield: 83.1 %

Procedure:
Acetic anhydride (10 ml) was added to a solution of 3-[2-hydroxy-3-(2-chlorophenoxy)phenyl]propionic acid (5.0 g) in benzene (30 ml), and refluxed under heating for 1.5 hours. The reaction mixture was evaporated, and toluene was added to the residue and then evaporated again. The crystalline residue (4.30 g) was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-(2-chlorophenoxy)chroman-2-one (3.9 g). mp 123°-125° C.