Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([C:26]2[CH2:27][CH2:28][O:23][CH2:24][CH:25]=2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C2=CCOCC2)c(Br)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 462 mg, 1.11 mmol), 2-(3,6-dihydro-2h-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (262 mg, 1.22 mmol), Pd(Ph3P)4 (64.1 mg, 0.056 mmol), Na2CO3 (3 mL of 2 M, 5.99 mmol), EtOH (1 mL) and toluene (3 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 70° C. for 18 h. The RM was diluted with EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, n-heptane/EtOAc, from 10% B to 100% EtOAc) to afford the title compound. HPLC (Condition 3) tR=6.04 min, UPLC-MS (Condition 2) m/z=443.1 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:13][C@H:10]2[CH2:9][CH2:8][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@H](c2ccccc2)CC1
Product: O=C(N[C@H]1CC[C@H](c2ccccc2)CC1)c1ccc(Cl)cc1

Procedure:
from trans-4-phenylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 232°-234° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:12]=[N:13][CH:14]=2)O1.Cl[C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]2[C:30]=1[CH3:31].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:30]([CH3:31])=[C:21]([C:9]3[CH:10]=[C:11]([C:15]([OH:18])([CH3:16])[CH3:17])[CH:12]=[N:13][CH:14]=3)[N:22]=2)[CH:25]=1
Reactant: CC(C)(O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1c(Cl)nc2ccc(F)cn12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(-c2cncc(C(C)(C)O)c2)nc2ccc(F)cn12
Temperature: 100 °C

Procedure:
To a solution of the title compound from Example 2 Step D (0.135 g, 0.514 mmol) and the title compound from Example 3 Step B (0.079 g, 0.428 mmol) in tetrahydrofuran (4.28 mL) were added palladium acetate (9.61 mg, 0.043 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.035 g, 0.086 mmol), and potassium phosphate tribasic (0.273 g, 1.284 mmol). The resulting mixture was heated at 100° C. for 18 hours, then filtered with the aid of ethyl acetate and concentrated under reduced pressure. Purification by flash chromatography on silica gel (50% acetone in dichloromethane) provided the title compound: LCMS m/z 286.17 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.83 (s, 1H), 8.75 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.63 (dd, J=9.8, 5.1 Hz, 1H), 7.16-7.12 (m, 1H), 2.64 (s, 3H), 2.28 (br s, 1H), 1.67 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:38])[N:7]([CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][N:22]3[C:31](=[O:32])[C:30]4[CH:33]=[CH:34][C:35](Cl)=[C:28]5[C:29]=4[C:24](=[CH:25][CH:26]=[CH:27]5)[C:23]3=[O:37])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH2:44]>>[S:19]([CH2:20][CH2:21][N:22]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][C:35]([NH:44][CH2:43][CH2:42][CH2:41][N:40]([CH3:45])[CH3:39])=[C:28]3[C:29]=2[C:24](=[CH:25][CH:26]=[CH:27]3)[C:23]1=[O:37])[S:18][CH2:17][CH2:16][N:7]1[C:6](=[O:38])[C:5]2[CH:4]=[CH:3][C:2]([NH:44][CH2:43][CH2:42][CH2:41][N:40]([CH3:45])[CH3:39])=[C:13]3[C:14]=2[C:9](=[CH:10][CH:11]=[CH:12]3)[C:8]1=[O:15]
Reactant: O=C1c2cccc3c(Cl)ccc(c23)C(=O)N1CCSSCCN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Reactant: CN(C)CCCN
Product: CN(C)CCCNc1ccc2c3c(cccc13)C(=O)N(CCSSCCN1C(=O)c3cccc4c(NCCCN(C)C)ccc(c34)C1=O)C2=O
Temperature: 110 °C
Reaction time: 12 h

Procedure:
4 g of (6-chloro-2-(2-{[2-(6-chloro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)ethyl]-disulphanyl}ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione are suspended in 40 ml of N,N-dimethylpropane-1,3-diamine. The mixture is heated with stirring at 110° C. for 12 hours. After cooling, a yellow precipitate is collected, and 500 ml of a 1/1 ethanol/water mixture are added dropwise to the filtrate. The yellow paste obtained is isolated and triturated with 200 ml of acetone. The solids obtained are washed with 300 ml of water and dried. 4.5 g of yellow powder are recovered. The analyses show that the product is in accordance with the expected product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[C:8]([OH:10])=O)[N:6]=1.P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.Cl.[NH2:36][CH:37]1[C:62](=[O:63])[N:39]2[C:40]([C:46]([O:48][CH:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])=[C:41]([CH:44]=[CH2:45])[CH2:42][S:43][C@H:38]12>C(OCC)(=O)C.O.CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[C:8]([NH:36][CH:37]2[C:62](=[O:63])[N:39]3[C:40]([C:46]([O:48][CH:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[O:47])=[C:41]([CH:44]=[CH2:45])[CH2:42][S:43][C@H:38]23)=[O:10])[N:6]=1
Reactant: Nc1nc(C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)O)cs1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
To a mixture of 2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetic acid (syn isomer) (1.13 g) and phosphorus oxychloride (0.56 g) in ethyl acetate (20 ml) was added trimethylsilylacetamide (0.30 g) at 4° C., and the mixture was stirred at 4° to 6° C. for 15 minutes. To the mixture was added additional phosphorus oxychloride (0.56 g), followed by stirring at the same temperature for 15 minutes. Thereto was added N,N-dimethylformamide (0.26 g), and the mixture was stirred at 4° to 6° C. for 50 minutes to prepare the activated acid solution. This solution was added to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (1.1 g) and trimethylsilylacetamide (2.0 g) in ethyl acetate (20 ml) at -20° C., and the mixture was stirred at -20° to 0° C. for an hour. After addition of ethyl acetate and water, the organic layer was separated and washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over magnesium sulfate. The solution was evaporated, and the residue was pulverized with diethyl ether to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:20]1([C:19]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[CH2:37][O:38][C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])[CH2:32][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=3[CH3:18])=[CH:6][CH:7]=2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2ccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)cc2)c(C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 2.0 g (8.7 mmol) of methyl 4′-hydroxy-2-methylbiphenyl-4-carboxylate with 4.3 g (9.8 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 1.29 g (9.3 mmol) of potassium carbonate, the desired product is obtained in the form of a yellow oil (m=4.88 g; Y=91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[CH:8][CH:9]=1)=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.[CH:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([C:43]([CH:40]2[CH2:42][CH2:41]2)=[O:44])[CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCNCc2ccc3c(c2)OCCO3)s1
Reactant: O=C(O)C1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCN(Cc2ccc3c(c2)OCCO3)C(=O)C2CC2)s1
Yield: 102 %

Procedure:
A solution of 5-{3-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylic acid methyl ester (0.435 g, 0.125 mmol), DCC (0.0284 g 0.137 mmol) and cyclopropanecarboxylic acid (0.0119 g, 0.137 mmol) in 10 mL CH2Cl2 was stirred at room temperature for 16 h. The mixture was filtered and the mother liquor was concentrated in vacuo. The residue was dissolved in 15 mL EtOAc and was filtered. The organic solution was washed with water followed by brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound of Step B as an oil (53 mg). MS 416 (M+).
Reaction SMILES: [C:1](=[O:39])([O:10][CH2:11]/[C:12](/[C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)=[C:13](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)\[CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9]>C(#N)C.C1(C)C=CC=CC=1>[C:1](=[O:39])([O:10][CH2:11]/[C:12](/[C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:31][CH:30]=1)=[C:13](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)\[CH2:14][OH:15])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCCCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCCBr)=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
To a solution of 24 g of 6-bromohexyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 200 mL of acetonitrile was added 9 mL of PyrHF and the mixture was stirred at 25° C. for 1.5 h. The reaction mixture was diluted with 1 L of toluene, loaded on silica gel and washed with EtOAc. The solvent was evaporated to afford 16.8 g of the titled compound. The crude compound was used directly for the next step.
Reaction SMILES: [OH:1][C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5](O)=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(O)=O.C(OC(=O)C)C>C(Cl)Cl>[CH:2]12[O:1][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]2
Reactant: CC(C)(C)OC(=O)N1CC(O)=CC=C1O
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Reaction time: 5 h
Yield: 91.3 %

Procedure:
2.1 g (11.5 mmol) of t-butyl 3,6-dihydroxypyridin-1(2H)-carboxylate (product of step 1) and 3.1 g (12.6 mmol) of m-chloro benzoic acid was dissolved in 30 mL of methylene chloride, and after stirring for 5 hour, 100 mL of ethylacetate was added thereto. After washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to give 2.1 g (10.5 mmol) of the title compound in a yield of 87%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[C:22]([F:28])=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1)=[CH:11][CH:10]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1>O1CCOCC1.O.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[O:37]1[CH2:38][CH:39]=[C:40]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:21]2[C:22]([F:28])=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)=[CH:11][CH:10]=4)[CH2:41][CH2:42]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1cnc(F)c(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(Cl)ncc2O3)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(F)c(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(C4=CCOCC4)ncc2O3)c1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with (S)-3-chloro-7-(2-fluoro-5-methylpyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.100 g, 0.252 mmol), potassium phosphate (0.160 g, 0.756 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.106 g, 0.504 mmol) and Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (8.92 mg, 0.013 mmol) in dioxane (1.2 mL) and water (0.40 mL). The reaction mixture was stirred and heated in microwave at 120° C. for 30 minutes before being diluted with EtOAc and saturated Na2CO3. The organic layer was washed twice with saturated Na2CO3, dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography (2-10% MeOH—CH2Cl2), followed by preparative HPLC (15-60% CH3CN (with 0.1% TFA)-water (with 0.1% TFA) in 20 min) to provide (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoro-5-methylpyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as a white solid (MS: MH+=445).
Reaction SMILES: C(CN)O.[OH:5][CH2:6][CH2:7][NH:8][C:9](=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][CH:13]=1.S(Cl)(Cl)=O.O.Cl>CCOC(C)=O>[C:28]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:20][CH2:19][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]3[O:5][CH2:6][CH2:7][N:8]=3)=[CH:17][CH:16]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)NCCO
Agent: Cl
Solvent: NCCO
Solvent: O=S(Cl)Cl
Solvent: O
Product: c1ccc(C(CCOc2ccc(CCC3=NCCO3)cc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 85 %

Procedure:
By the method of example 25, ethanolamine was converted to N-(2-hydroxyethyl)-3-[4-(3,3,3-triphenylpropoxy)-phenyl]propionamide. To this amide (400 mg; 0.84 mmol) in EtOAc (15 mL), was added dropwise over 5 minutes thionyl chloride (0.20 mL, 2.74 mmol) in EtOAc (2 mL) under a nitrogen atmosphere at room temperature. After stirring overnight, the precipitate was collected and washed with EtOAc to give the title compound (354.1 mg; 85% yield) as the hydrochloride monohydrate, a white powder. mp=130°-131° C. 1H NMR δ 7.19-7.34 (m, 15H), 7.02 (d, J=8.6 Hz, 2H), 6.62 (d, J=8.6 Hz, 2H), 3.70 (t, J=7.7 Hz, 2H), 3.53 (br s, 4H), 3.12 (t, J=7.7 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.43 (t, J=7.5 Hz, 2H). IR 2954, 1513, 1245 cm-1. MS 462 (MH+), 243. Anal. calcd. for C32H31NO2 ·HCl·H2O: C, 74.48; H, 6.48; N, 2.71. Found: C, 74.26; H, 6.32; N, 2.70.
Reaction SMILES: [BrH:1].[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[C:11]2[NH:12][C:13]([CH3:33])=[C:14]([C:31]#[N:32])[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.C(Cl)(Cl)Cl>[C:2]1([CH:8]([Br:1])[CH2:10][CH2:9][C:11]2[NH:12][C:13]([CH3:33])=[C:14]([C:31]#[N:32])[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: CCOC(=O)C1=C([C@@H]2C[C@H]2c2ccccc2)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(CCC(Br)c2ccccc2)NC(C)=C(C#N)C1c1cccc([N+](=O)[O-])c1

Procedure:
5 ml of a solution of hydrobromic acid in 30% acetic acid are added at 25° C. and under inert atmosphere to a solution of the less polar diastereoisomer of trans-2-(2-phenyl-1-cyclopropyl)-3-carboethoxy-5-cyano-6-methyl-4-(m-nitrophenyl)-1,4-dihydropyridine (0.5 g) in chloroform (5 ml). After 1 1/5 hours the mixture is poured into water (50 ml) and extracted with diethyl ether (25 ml). The phases are separated and the organic one is washed with a 5% NaHCO3 aqueous solution (3×50 ml) and water (2×50 ml), dried on sodium sulphate, filtered and the solvent is evaporated under reduced pressure. 500 mg of the more polar diastereoisomer of 2-(3-phenyl-3-bromopropyl)-3-carboethoxy-5-cyano-6-methyl -4-(m-nitrophenyl)-1,4-dihydropyridine are obtained as an amorphous solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[N:10]=1>CN(C=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[N:10]=1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2cc(-n3cccn3)cc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
To a dry 2 dram vial equipped with a stir bar was added 1H-pyrazole (16 mg, 0.23 mmol), then DMF (1 mL). To the solution was added sodium hydride (60% disp. in oil, 11 mg, 0.27 mmol) upon which effervesence was immediately observed. The mixture was stirred at room temperature for 15 minutes. To the solution was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (60 mg, 0.21 mmol) as a solution in DMF (0.2 mL). The solution was stirred at room temperature for 3 hours and then at 60° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then directly purified via C18 chromatography (water:MeOH w/0.1% TFA) to afford 2-chloro-6-(4-isopropoxyphenyl)-4-(1H-pyrazol-1-yl)pyridine as an off-white solid (41 mg, 62%). 1H-NMR (400 MHz, CDCl3) δ 8.05 (d, J=2.5 Hz, 1H), 7.99 (d, J=9.0 Hz, 2H), 7.96 (d, J=1.8 Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 6.56 (dd, J=2.5, 1.8 Hz, 1H), 4.64 (dquin, J=12.2, 6.0 Hz, 1H), 1.40-1.35 (m, 6H); MS: MS m/z 314.2 (M++1).
Reaction SMILES: [F:1][C:2]([S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:3]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1)/[CH:4]=C/C1C=CC(CC(C)C)=CC=1.[O:44]=[O+][O-].O=O.[BH4-].[Na+].[Cl-].[NH4+]>CO.C(Cl)Cl>[F:1][C:2]([S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:3]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1)[CH2:4][OH:44]
Reactant: CC(C)Cc1ccc(/C=C/C(c2ccc(CC(C)C)cc2)C(F)(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)cc1
Reactant: O=[O+][O-]
Agent: O=O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(CO)C(F)(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)cc1
Yield: 98 %

Procedure:
A solution of (E)-4-fluoro-1,3-bis(4-isobutylphenyl)-4,4-bis(phenylsulfonyl) but-1-ene (5a, 506 mg, 0.818 mmol, 1.0 eq) in 20 mL of MeOH and 7 mL of CH2Cl2 was cooled to −78° C. Ozone gas generated by an ozone generator was introduced to this solution for 30 minutes, and then O2 was introduced for 5 minutes to remove excess ozone. Next, the solution was charged with NaBH4 (93.1 mg, 2.49 mmol, 3.0 eq), and the temperature was increased over two hours to room temperature. The reactant solution was then charged with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with methylene chloride and then the extract was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure by distillation, and then the reactant was purified by column chromatography (hexane:ethyl acetate=6:4) to obtain 3-fluoro-2-(4-isobutylphenyl)-3,3-bis(phenylsulfonyl)propan-1-ol as a white solid (393 mg, 98%).
Reaction SMILES: Cl.C([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17][C:16]3[CH:24]=[CH:25][C:26]([Br:28])=[CH:27][C:15]=3[CH2:14]2)[CH2:9][CH2:8]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[Br:28][C:26]1[CH:25]=[CH:24][C:16]2[S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:13]([N:10]3[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]3)[CH2:14][C:15]=2[CH:27]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(Br)ccc3Sc3ccccc32)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Brc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2

Procedure:
47.2 g of 1-carbethoxy-4-(2-bromo- 10,11-dihydro-dibenzo-[b,f]thiepin-10-yl)-piperazine hydrochloride, 585 ml of ethylene glycol, 32.8 g of potassium hydroxide and 1.95 ml of water are heated to 160° C for 90 minutes. Then the mixture is poured on to water and extracted with chloroform. The organic solution is extracted with 2-N hydrochloric acid. The hydrochloric acid solution is made alkaline, extracted with chloroform, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. There is obtained crystalline 1-(2-bromo- 10,11-dihydro-dibenzo[b,f]-thiepin-10-yl)-piperazine of melting point 112°-115° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][C:17]([NH:19][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27]C)=[O:26])(=[O:22])=[O:21])=[O:18])[N:10]=1.O>CS(C)=O>[CH3:7][O:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][C:17]([NH:19][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])=[O:18])[N:10]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Yield: 51.9 %

Procedure:
A solution of 0.5 g of potassium tert-butoxide and 1.0 g of methyl 2-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]aminosulfonylbenzoate in 25 ml of dimethyl sulfoxide was stirred at ambient temperature for 3 hours. The yellow solution was then poured into 250 ml of cold water. The free carboxylic acid was precipitated by the addition of enough concentrated hydrochloric acid to reach pH 3. The crude product was filtered, washed with water and dried in vacuo. Recrystallization from acetonitrile yielded 0.5 g of the title compound, m.p. 157°-158° C. The mass spectrum of this compound exhibited the expected molecular ion at m/e=367. The infrared bands at 3300 cm-1 and 1725 cm-1 are consistent with the desired structure. The nuclear magnetic resonance spectrum showed peaks at 2.5 ppm (triazine CH3), 3.9 ppm (triazine OCH3) and 7.4-8.2 ppm (phenyl). The methyl ester peak present in the starting material was not observed in the spectrum of the product.