Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]([OH:13])([C:11]#[CH:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:14][CH2:15][C:16]3[C@@H:22]([C@H:5]1[CH2:4][CH2:3]2)[CH2:21][CH2:20][C:18](=O)[CH:17]=3.Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[CH3:1][C@@:2]12[C@:10]([OH:13])([C:11]#[CH:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:14][CH2:15][C:16]3[C@@H:22]([C@H:5]1[CH2:4][CH2:3]2)[CH2:21][CH2:20]/[C:18](=[N:24]\[OH:25])/[CH:17]=3
Reactant: NO
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Agent: Cl
Solvent: c1ccncc1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C/C(=N/O)CC[C@@H]4[C@H]3CC[C@@]21C
Temperature: 98 °C
Yield: 95 %

Procedure:
A solution of norethindrone, 6.5 m moles, and hydroxylamine hydrochloride, 16.4 m moles, in 10 ml of dried pyridine was stirred at room temperature for 48 hours. The progress of the reaction was followed by tlc (thin layer chromatography). The reaction mixture was then heated at 98°C. (bath temperature) for 15 minutes, allowed to cool to 55°C and the pyridine was evaporated in vacuo. The residue was extracted with ether. Drying and removal of the ether gave a residue which was recrystallized from methanol-water and methanol to yield 1.93 g (95%) of norethindrone oxime, mp 121.5°-123°C. Tlc with ethyl acetate: petroleum ether; acetone 1:1:0.2 indicated the product to be a mixture of the syn and anti isomers of the oxime.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH:2]=[CH2:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(C)C.CCCCCC>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1/[CH:7]=[N:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Br)ccc1C=O
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: C=CCOc1cc(Br)ccc1/C=N/c1ccccc1
Temperature: 50 °C
Yield: 86.1 %

Procedure:
2-(Allyloxy)-4-bromobenzaldehyde (5.05 g, 20.9 mmol) was dissolved with warming in isopropanol (18 mL). Freshly distilled aniline (1.99 g, 21.3 mmol) was added with isopropanol (4 mL) and the reaction was heated to 50° C. A yellow precipitate formed within 30 min and isopropanol (5 mL) was added to aid stirring. The reaction was stirred at 50° C. for 16 h, by which time proton NMR showed no aldehyde present. The reaction was cooled with stirring. The mixture was diluted with hexane (20 mL), the solid was filtered and washed with the mother liquor, washed with hexane and air dried to afford N-{(1E)-[2-(allyloxy)-4-bromophenyl]methylene}aniline (5.69 g, 86% yield) as a light yellow powder; 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.27-7.17 (m, 4H), 7.099 (d, J=1.8 Hz, 1H), 6.06 (ddt, J=17.2, 10.5, 5.3 Hz, 1H), 5.43 (AB q, J=17.3, 3.0 Hz, 1H), 5.33 (AB q, J=10.5, 2.8 Hz, 1H), 4.62 (ddd, J=5.2, 1.5, 1.5 Hz, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:11])[CH3:10].[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:11])[CH2:10][C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(=O)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2′,6′-dichloroacetophenone (12.5 g, 66 mmol) and diethyl oxalate (14.6 g, 100 mmol) in 450 mL of anhydrous toluene, cautiously add sodium hydride (60% dispersion in mineral oil, 2.8 g, 70 mmol). Cautiously heat the reaction mixture to reflux under N2 for 1 h, cool to ambient temperature and pour onto ice-cold 1M HCl. Separate the layers and extract the aqueous phase with EtOAc (2×200 mL). Wash the combined organic extracts with brine, dry over MgSO4 and evaporate to obtain the title compound which is used in the next step without further purification.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11].[F:14][C:15]1([F:36])[C:33]2[C:18](=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4F)=[N:22][C:21]=3[CH:32]=2)[C:17]([F:35])([F:34])[O:16]1>O>[F:36][C:15]1([F:14])[C:33]2[C:18](=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][C:30]=4[O:11][CH2:10][C:9]([F:13])([F:12])[F:8])=[N:22][C:21]=3[CH:32]=2)[C:17]([F:34])([F:35])[O:16]1
Reactant: OCC(F)(F)F
Reactant: Fc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 44 mg of 60% sodium hydride (in oil) and 2 ml of DMF was stirred at room temperature. To the mixture, a mixture solution of 0.11 g of 2,2,2-trifluoroethanol and 0.5 ml of DMF was added. The mixture solution was stirred for 15 minutes, and then, 0.28 g of 5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole was added and stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 5,5,7,7-tetrafluoro-2-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 89”).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18]C)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29].[OH-].[Na+].CO.Cl>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:27][C:28]=1[CH3:29]
Reactant: COC(=O)Cc1cccc(OCc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(COc2cccc(CC(=O)O)c2)cc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylacetate (420 mg), 1N sodium hydroxide (2 mL), methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water, and the mixture was neutralized with 2N hydrochloric acid to give crystals of 3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylacetic acid. Recrystallization from ethyl acetate gave colorless prism crystals (350 mg, 86%). melting point: 114-115° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[NH:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][S:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH2:2][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][S:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2
Reactant: C=Cc1ccccn1
Reactant: c1ccc2c(c1)CSc1ccccc1N2C[C@@H]1CCCN1
Product: c1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)nc1
Temperature: 120 °C
Yield: 58.3 %

Procedure:
A mixture of 2-vinylpyridine (250 mg) and (S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine (see Preparations 13 and 14) (166 mg) was heated at 120° C. for 2 hours, cooled to room temperature and purified by chromatography on silica gel using ethyl acetate/methanol (10:1) as eluant. Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a pale brown gum, (131 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:12]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:14])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Product: COc1ccc(C2(C(=O)NCC(C)C)CC2)cc1
Yield: 97 %

Procedure:
Prepared in a similar manner to Example 35a starting from 1-(4-methoxyphenyl) cyclopropanecarboxylic acid and isobutyl amine. Yield: 97%. MS+H (248).
Reaction SMILES: [H-].[Na+].C(ONC(=O)OC(C)(C)C)C1C=CC=CC=1.[C:19]([O:23][C:24](=[O:38])[N:25]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26]C(C)C)([CH3:22])([CH3:21])[CH3:20].IC>CN(C)C=O>[CH2:31]([O:30][N:25]([CH3:26])[C:24](=[O:38])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.48 g of 80% in mineral oil, 16 mmol) was added to a solution of tert-butyl N-benzyloxycarbamate (Compound 54 Part A, 3 g, 13 mmol) in N,N-dimethylformamide (25 mL). The reaction mixture was stirred for 20 minutes then iodomethane (1.1 mL, 18 mmol) was added dropwise with cooling in an ice bath. The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere overnight. The reaction mixture was quenched with water (50 mL) then extracted with diethyl ether (150 mL). The organic layer was washed with water (5×50 mL), dried over magnesium sulfate then concentrated to provide 3.1 g of tert-butyl N-benzyloxy-N-methylcarbamate as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:33])[F:34])[CH:18]=2)[CH:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Yield: 66.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-(trifluoromethyl)phenylamino)benzamide was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.220 g; 0.951 mmol), 3-(3-(trifluoromethyl)phenylamino)benzoic acid (0.294 g; 1.05 mmol), HATU (0.470 g; 1.24 mmol) and N,N-diisopropylethylamine (0.439 mL; 2.38 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.290 g (65%) of the title compound as a white solid.
Reaction SMILES: C([Li])CCC.[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])#[CH:7].[N:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[N:14][CH:13]=1>C1COCC1.O>[N:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])([C:7]#[C:6][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH3:19])=[N:14][CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)c1ccncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(C#C[Si](C)(C)C)c1ccncn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5M in hexane, 2.1 ml, 5.32 mmol) in THF (3 mL) at −78° C. was added dropwise ethynyl(trimethyl)silane (0.7 mL, 4.91 mmol). The reaction was stirred at −78° C. for 10 minutes and then 1-(pyrimidin-4-yl)ethanone (0.5 g, 4.09 mmol) was added in more THF (2 mL). The reaction was stirred at −78° C. to RT overnight. The mixture was diluted with water and the volatiles removed in vacuo. The product was then extracted with CHCl3:IPA (2:1 ratio, 2×25 mL). The organic phase was washed with water (20 mL), brine (20 mL); dried over Na2SO4 and the solvent removed in vacuo. Purification by column chromatography (Biotage), eluting with 0-100% EtOAc-heptane afforded 2-(pyrimidin-4-yl)-4-(trimethylsilyl)but-3-yn-2-ol; 1H NMR (500 MHz, CDCl3) delta 0.19 (9H, s), 1.78 (3H, s), 4.65 (1H, s), 7.65 (1H, dd, J=5.20, 1.10 Hz), 8.79 (1H, d, J=5.36 Hz), 9.20 (1H, s); LC-MS: m/z=+221 (M+H)+; and 2-(pyrimidin-4-yl)but-3-yn-2-ol; 1H NMR (500 MHz, CDCl3) delta 1.79 (3H, s), 2.62 (1H, s), 4.99 (1H, s), 7.67 (1H, dd, J=5.28, 0.87 Hz), 8.77 (1H, d, J=5.36 Hz), 9.19 (1H, s); LC-MS: m/z=+148.95 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[N:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:11])[CH3:10])=[N:6][C:7]=1[Br:19]
Reactant: CC(O)Cc1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(O)Cc1cnc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+/−)-1-(5-aminopyrazin-2-yl)propan-2-ol (47 mg, 0.307 mmol) in DCM (3.0 mL) was added NBS (49.1 mg, 0.276 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. After quenched with sat NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 234. 0 (MH+), 0.40 min.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1>[Cl:24][CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[O:34])=[CH:31][CH:30]=1)=[O:27]
Reactant: O=C(CCl)Nc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
2.18 g of 4-chlorobenzylpiperazine are dissolved in 40 ml of absolute tetrahydrofuran. With stirring, 1.73 g of Hunig base and 2.64 g of 4-chloroacetylaminobenzoic acid chloride are added thereto in succession. The internal temperature rises to approximately 38°. After 30 minutes, the solution is concentrated by evaporation. The oily residue is digested with water, yielding 1-[4-(N-chloroacetylamino)benzoyl]-4-(4-chlorobenzyl)piperazine having a melting point of 205°-207°.
Reaction SMILES: [CH:1](=[N:8]/[OH:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].[CH2:26]([Sn:30]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[C:31]#[CH:32])[CH2:27][CH2:28][CH3:29].[OH-].[Na+].[OH-].[NH4+]>C(O)(C)(C)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].[Cu]>[C:2]1([C:1]2[CH:32]=[C:31]([Sn:30]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: O/N=C/c1ccccc1
Agent: [Cu+2]
Agent: [Cu]
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Solvent: O
Solvent: CC(C)(C)O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccccc2)no1
Reaction time: 6 h

Procedure:
(E)-benzaldehyde oxime (Sigma Aldrich; 3.3 g, 20 mmol) in tert butanol and water (1:1) 80 mL, is treated with chloramine T trihydrate (Sigma Aldrich; 5.9 g, 21 mmol) in small, portions over 5 min. The reaction is then treated with copper sulfate pentahydrate (0.15 g, 0.6 mmol) and copper turnings ˜50 mg and tributylethynylstannane (6.3 g, 20 mmol). The reaction is then adjusted to pH 6 with sodium hydroxide solution and stirred for 6 h. The reaction mixture is treated with dilute ammonium hydroxide solution to remove all copper salts. The product is collected by filtration, redissolved in ethyl acetate and filtered through a short plug of silica gel. The filtrate is concentrated in vacuo to give 3-phenyl-5-(tributylstannyl) isoxazole.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[S:37]([NH2:40])(=[O:39])=[O:38]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:29]3[S:28][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=3)(=[O:39])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1nc2ccccc2s1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2nc3ccccc3s2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-benzothiazolesulfonamide (J Org Chem, 1958, 1768) in accordance with Procedure 1, Method A described hereinabove. Yield (52%); 1H NMR (d6-DMSO) δ 8.07 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.53-7.05 (m, 15H), 6.78 (d, J=8.1 Hz, 2H), 6.27 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 551 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])=[O:5])C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Mg]Br>C1COCC1>[Cl:12][C:11]1[CH:10]=[C:9]([Cl:13])[N:8]=[N:7][C:6]=1[C:4]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH3:14])=[O:5]
Reactant: COc1ccccc1[Mg]Br
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1nnc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (1.032 g, 4.67 mmol, prepared as described by Xie et al., WO 2004031174) was dissolved in 25 ml dry THF, and the reaction mixture was cooled in a dry ice/acetone bath for 15 minutes. 2-Methoxyphenyl magnesium bromide (7 mL of 1M solution in THF, 7.00 mmol) was added, and the reaction mixture was stirred for 8 hours under nitrogen at −78° C. Silica gel (11.0 g) was added, and the reaction mixture was allowed to warm to room temperature. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography (0% to 20% EtOAc/Hexanes) to yield 1.029 g (3.65 mmol, 78%) of (4,6-dichloro-pyridazin-3-yl)-(2-methoxy-phenyl)-methanone as a yellow solid. Mass Spec. M+H=283.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccccc1Br
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccccc1Br
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.47 g (2.3 mmol) of 2-bromobenzamide and 0.34 g (2.7 mmol, 1.2 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-bromobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.64 g (2.3 mmol) of 2-bromo-4-chloro-5-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.25 g (Yield 22%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13].C([BH3-])#N.[Na+]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[C:6]([C:12]([F:13])([F:14])[F:15])[CH:7]=1
Reactant: CON=Cc1ccc(F)cc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)cc1C(F)(F)F

Procedure:
Reduction of 4-fluoro-2-trifluoromethyl-benzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (35% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.55 (3H, s, OCH3), 4.21 (2H, s, NCH2), 5.76 (1H, broad, NH), 7.26 (1H, m, aromatic), 7.38 (1H, m, aromatic), 7.64 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 138-140° C. Anal. calcd for C9H9F4NO—HCl: C, 41.64; H, 3.88; N, 5.39. Found: C, 41.49; H, 3.68; N, 5.26.
Reaction SMILES: CO[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[C@:5]([NH2:16])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH3:6].[CH3:20][NH:21][C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=S>>[C:27]([O:26][C:25](=[O:31])[NH:24][C:22]1[N:21]([CH3:20])[C:3](=[O:19])[C:4]([CH3:17])([CH3:18])[C@@:5]([CH3:6])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:16]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C)[C@](C)(N)c1cccc([N+](=O)[O-])c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (R)-3-amino-2,2-dimethyl-3-(3-nitro-phenyl)-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(R)-1,4,5,5-tetramethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as a white solid. MS (ESI): m/z=391.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH3:17][NH:18][CH:19]([CH3:22])[CH2:20][OH:21]>C(#N)C.CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:17])[CH:19]([CH3:22])[CH2:20][OH:21])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CNC(C)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CO)N(C)c1cc(Cl)nc(Cl)n1
Reaction time: 1 h

Procedure:
To a mixture of 2,4,6-trichloropyrimidine (5.0 g, 27 mmol) and triethylamine (11 mL, 82 mmol) in acetonitrile (20 mL) was slowly added a solution of 2-(methylamino)propan-1-ol (2.9 g, 33 mmol) in N,N-dimethylformamide (DMF) (2 mL) at 0° C. The reaction mixture was stirred at same temperature for 1 h, then filtered through a thin pad of celite and concentrated. Purification via silica gel flash chromatography (petroleum ether/ethyl acetate=4/1˜1/1) afforded the title product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:30](=[O:32])[CH3:31])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(OC)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(OC)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution of 500 mg of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 358 mg of pyridine in 8 ml of dimethylformamide is ice-cooled, and a solution of 130 mg of acetyl chloride in 2 ml of dimethylformamide is dropwise added thereto. The mixture is stirred at room temperature for one hour. After the reaction is completed, the mixture is poured into ice-water. The aqueous mixture is extracted with chloroform, and the extract is washed with 10% hydrochloric acid and water, successively. Then, the extract is dried and evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of dimethylformamide and ethanol. 465 mg of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1/3 hydrate are obtained.