Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][S:27][C:28]1[N:33]([CH3:34])[C:32](=[O:35])[C:31](=[O:36])[N:30]([CH2:37][CH:38](OCC)[O:39]CC)[N:29]=1)[CH:20]([NH:45][C:46](=[O:76])[C:47](=[N:73][O:74][CH3:75])[C:48]1[N:49]=[C:50]([NH:53]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:51][CH:52]=1)[C:19]2=[O:77])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O.O>[NH2:53][C:50]1[S:51][CH:52]=[C:48]([C:47](=[N:73][O:74][CH3:75])[C:46]([NH:45][CH:20]2[C:19](=[O:77])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][S:27][C:28]2[N:33]([CH3:34])[C:32](=[O:35])[C:31](=[O:36])[N:30]([CH2:37][CH:38]=[O:39])[N:29]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:76])[N:49]=1
Reactant: CCOC(Cn1nc(SC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C3SC2)n(C)c(=O)c1=O)OCC
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CSc3nn(CC=O)c(=O)c(=O)n3C)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
A solution of product (9c) (1.9 g) in formic acid (20 cc) is stirred for 30 minutes at 50° C. and then diluted with water (2 cc) and stirred for 10 minutes at 50° C. After cooling to 20° C., the reaction mixture is filtered and the filtrate is concentrated under reduced pressure (0.1 mm Hg; 0.013 kPa) at 35° C. The residue is triturated with ethanol (20 cc), which is evaporated off under reduced pressure (30 mm Hg; 4 kPa) at 40°. This operation is repeated 3 times and the residue is then taken up in ethanol (30 cc). The solid is isolated on a vacuum filter, washed with ethanol (3×10 cc) and with ethyl ether (3×10 cc) and dried. This yields the E form of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-3-[2-(5,6 -dioxo-1-formylmethyl-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)thiovinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (product 9) (0.96 g) in the form of a cream-coloured solid.
Reaction SMILES: [CH3:1][P:2]1(=[O:16])[O:7][CH2:6][C:5]2([CH2:12][CH2:11][N:10](C([O-])=O)[CH2:9][CH2:8]2)[CH2:4][O:3]1.[ClH:17]>O1CCOCC1>[ClH:17].[CH3:1][P:2]1(=[O:16])[O:3][CH2:4][C:5]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][O:7]1
Reactant: CP1(=O)OCC2(CCN(C(=O)[O-])CC2)CO1
Agent: Cl
Solvent: C1COCCO1
Product: CP1(=O)OCC2(CCNCC2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-methyl-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undecane-9-carboxylate 3-oxide (975 mg, 3.19 mmol) was combined with 4.0 M HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The resulting suspension was evaporated to a white solid that was slurried in EtOAc and filtered to give 3-methyl-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undecane 3-oxide hydrochloride as a colorless solid. 1H NMR (DMSO-d6, 600 MHz) δ 8.99 (bs, 2H), 4.21-4.11 (m, 4H), 3.12-3.07 (m, 2H), 3.04-2.99 (m, 2H), 1.82-1.78 (m, 2H), 1.59-1.56 (m, 2H), 1.55 (d, J=17.0 Hz, 3H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][C:9]1[NH:13][CH:12]=[N:11][C:10]=1[N+:14]([O-:16])=[O:15].[N+]([O-])(O)=O.[F:21][C:22]1[CH:28]=[CH:27][C:25](N)=[CH:24][CH:23]=1>O.CO>[CH3:8][C:9]1[N:13]([C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)[CH:12]=[N:11][C:10]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1[nH]cnc1[N+](=O)[O-]
Solvent: CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1c([N+](=O)[O-])ncn1-c1ccc(F)cc1
Reaction time: 72 h
Yield: 43.7 %

Procedure:
Acetic anhydride (1.65 mL) was added to 5-methyl-4-nitro-1H-imidazole (254 mg, 2.00 mmol) at room temperature. Nitric acid (70%, 200 μL) was added and the reaction was stirred for three days. The reaction was then poured onto ice. The product was extracted with dichloromethane three times. The combined organic layers was washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude 5-methyl-1,4-dinitro-1H-imidazole (235 mg) was dissolved in methanol (3 mL) at ambient temperature. A methanol (0.8 mL) solution of 4-fluoroaniline (157 μL, 1.63 mmol) was added dropwise and the reaction was stirred at this temperature for five days. Water was added to the reaction mixture and the product was extracted with dichloromethane three times. The combined organic layers were dried over anhydrous sodium sulfate. After removal of solvent under reduced pressure, the crude material was purified using silica gel column chromatography (33-60% ethyl acetate in hexanes) to give 5-methyl-4-nitro-1-(4-fluorophenyl)-1H-imidazole (157 mg, 0.712 mmol, 36% yield over two steps).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Si]([O:35][CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.Cl.C(=O)([O-])O.[Na+].C(OC(C)C)(C)C>O1CCCC1.CN(C)C=O.CC(C)=O.C(OCC)(=O)C.O>[OH:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41][C:18]([C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:21][C:12]=3[CH:13]=2)=[O:19])=[CH:42][CH:43]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(N)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 107.5 %

Procedure:
To a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.6 g, 2.1 mmol) in tetrahydrofuran (10 ml) were added oxalyl chloride (0.33 ml, 4.3 mmol) and N,N-dimethylformamide (1 drop) at 0° C., and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran (6 ml). To the mixture was dropwise added 4-(t-butyldimethylsilyloxymethyl)aniline (0.56 g, 2.4 mmol) and triethylamine (0.36 ml, 2.6 mmol) in tetrahydrofuran (2 ml) at 0° C., and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography. Crude amide (1.1 g) was obtained from fractions of hexane:ethyl acetate=5:1. This product was dissolved in acetone (8 ml), and to the mixture was dropwise added 6N hydrochloric acid. The mixture was stirred for 1 hour. To the mixture were added 1% sodium hydrogen carbonate (100 ml) and diisopropylether (100 ml), and precipitate was filtered, which were dissolved in acetone. The mixture was dried with magnesium sulfate, and the solvent was evaporated. The resulting powder was recrystallized from acetone-diisopropyl-ether to give N-(4-hydroxymethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.87 g) as colorless crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([F:18])[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:18][C:9]1[CH:8]=[C:7]([C:26](=[O:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]=[CH:15][S:16][CH:17]=1
Reactant: O=S(=O)(Oc1ccc(-c2cscn2)c(F)c1)C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a stirred solution of 3-fluoro-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate (1.45 g, 4.43 mmol) in dioxane (42 ml) was added tributyl(1-ethoxyvinyl)tin (1.92 g, 5.32 mmol), tetrakis(triphenylphosphine) palladium (512 mg, 0.44 mmol), lithium chloride (466 mg, 11.0 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was concentrated in vacuo. To the residue was added THF (20 ml), 2N HCl aqueous solution (20 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (666 mg, 68% yield).
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH3:31]>>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH2:24][NH:23][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:31]
Reactant: CCN1CCCC1CN
Reactant: COc1cccc(C(=O)O)c1OC/C=C(\C)CCC=C(C)C
Product: CCN1CCCC1CNC(=O)c1cccc(OC)c1OC/C=C(\C)CCC=C(C)C
Yield: 89 %

Procedure:
In a manner identical to Example 15, 2-geranyloxy-3-methoxybenzoic acid(1.52 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.84 g(89%) of the aimed compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18]>ClCCCl.O>[C:5]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:9][C:10](=[O:18])[CH2:11]2)(=[O:7])[CH3:6]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
171 g (1.28 mol) aluminium chloride in 500 ml 1,2-dichloroethane are cooled in the ice bath. Then 78 g (1.1 mol) acetylchloride are added dropwise, so that the temperature does not exceed 10° C. After 1 h, 71.3 g (0.53 mol) 2-indolinone (1,3-dihydro-indol-2-one) are added in 4 batches and the temperature is kept at 10–12° C. The reaction mixture is left overnight to warm up slowly to ambient temperature. Then the solution is slowly added to 1 kg ice with vigorous stirring. The slurry is diluted with 1 l water and stirred for another 30 min. Then the precipitate is suction filtered.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccc(F)c2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13a, and 3-fluorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 552 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])=[O:15]
Reactant: OCCOCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The 2-(2-phenylethoxy)ethanol obtained according to the preceding paragraph was dissolved in 100 ml of pyridine. The solution was treated with 4.48 g of methanesulfonyl chloride and the mixture was stirred at room temperature for 0.5 hour. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and 2N hydrochloric acid. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated to give 8.1 g (85%) of 2-(2-phenylethoxy)ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: C(OC(N1CCC(C(O[C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[CH2:44]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([CH:60]([O:65]S(C(F)(F)F)(=O)=O)[C:61]([F:64])([F:63])[F:62])[CH2:56][CH2:55]1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:44]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([CH:60]([O:65][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[C:61]([F:64])([F:63])[F:62])[CH2:56][CH2:55]1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(OCc1ccccc1)N1CCC(C(OS(=O)(=O)C(F)(F)F)C(F)(F)F)CC1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C4CCN(C(=O)OCc5ccccc5)CC4)C(F)(F)F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (300 mg, 0.92 mmol), 4-(2,2,2-trifluoro-1-trifluoromethanesulfonyloxyethyl)piperidine-1-carboxylic acid benzyl ester (870 mg, 2.1 mmol) and Cs2CO3 (680 mg, 2.1 mmol) were suspended in DMF (5 mL), stirred at RT for 2 h and then heated at 80° C. for 18 h. The reaction mixture was then quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) affording the title compound (210 mg, 37%). LCMS: RT 4.04 min [M+H]+ 625.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:22][CH3:23])[C:10]=1[F:24].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:22][CH3:23])[C:10]=1[F:24])[C:4]#[C:5][CH3:6]
Reactant: CCC1CCCCCN1c1ncnc(Cl)c1F
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2CCCCCC2CC)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
0.07 g of sodium hydride (60% oil suspension) was suspended in 2 ml of tetrahydrofuran. 0.3 ml of tetrahydrofuran solution of 0.11 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.3 ml of tetrahydrofuran solution of 0.30 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-2-ethyl-hexahydro-1H-azepine at room temperature, and stirred for 9 hours at 60° C. After the reaction mixture was cooled to near room temperature, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.31 g of 1-(6-(2-butynyloxy)-5-fluoropyrimidin-4-yl)-2-ethyl-hexahydro-1H-azepine (hereinafter, referred to as Compound (50)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(C(C)=O)C>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[S:7][C:6]=3[CH:11]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Oc1ccc2oc(=O)sc2c1

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (16.8 grams) was mixed with 3-(trifluoromethyl)phenyl isocyanate (18.7 grams) and 1.01 grams of triethylamine in 200 milliliters of methyl ethyl ketone. This solution was heated at reflux temperature for one hour, after which the solvent was removed by evaporation in vacuo. The resulting residue was recrystallized twice from ethyl acetate, leaving the desired purified product, 5-[3-(trifluoromethyl)phenylcarbamoyloxy]-1,3-benzoxathiol-2-one. The product was a white crystalline solid which exhibited a melting point of 166.5°-168° C. Elemental analysis calculated for C15H8F3NO4S (percent): carbon--50.71; hydrogen--2.27; nitrogen--3.94. Found: carbon--51.0; hydrogen--2.29; nitrogen--4.11.
Reaction SMILES: C([O:5][C:6](=[O:52])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:49])[CH2:30][CH:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH:38][CH2:39][CH2:40][NH:41]C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:41][CH2:40][CH2:39][NH:38][CH2:37][C@H:34]1[CH2:35][CH2:36][C@H:31]([CH2:30][C:29]([NH:28][C@H:14]2[CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:52])[C:8]=3[O:16][B:15]2[OH:23])=[O:49])[CH2:32][CH2:33]1
Reactant: COc1c(CC(NC(=O)CC2CCC(CNCCNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCCNC[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-[2-(2-{4-[(2-tert-Butoxycarbonylamino-ethylamino)-methyl]-cyclohexyl}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 404 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=O>>[NH2:15][C:16]1[CH:17]=[C:18]([C:19]2[O:14][C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:7][C:2]=3[N:1]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Product: Nc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1

Procedure:
Prepared by the method of Example 1a), from 2-amino-4-phenylphenol (674 mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitle compound was obtained, 84 mg (8%). 1H NMR (CDCl3) δ 7.97(bs, 1H), 7.70–7.57(m, 5H), 7.49(t, 1H), 7.45–7.35(m, 2H), 6.96(d, J=7.9 Hz, 1H). MS 287 m/z (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:21]1([O:27][CH2:28][CH2:29][NH:30][CH3:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:30]([CH3:31])[CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCOc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCOc1ccccc1)CC2

Procedure:
Here, 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane (18.5 g, 0.0623 mol) is heated to 110° C. for 2 hours in an autoclave with N-(2-phenyloxyethyl)-methylamine (10.3 g, 0.0623 mol) and triethylamine (8.7 ml, 0.062 mol). After cooling, the reaction mixture is distributed between methylene chloride and water, the organic phase is separated off, dried over sodium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel (eluant: methylene chloride/methanol=9/1). The base thus obtained is converted into the hydrochloride in the usual way.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])=[CH2:2].[NH3:12]>CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:12])=[O:7])=[CH2:2]
Reactant: N
Reactant: C=Cc1cccc(C(=O)Cl)c1
Solvent: CCOC(C)=O
Product: C=Cc1cccc(C(N)=O)c1

Procedure:
3-Vinylbenzoyl chloride is saturated with ammonia gas to afford an immediate precipitate. This mixture is poured into EtOAc and extracted with water and brine. The EtOAc is dried, filtered, and concentrated to afford the title compound: mp=128-130° C.; 1H NMR (CDCl3) δ 7.86 (d, J=1.3 Hz, 1H), 7.66 (dd, J=8.6, 1.0 Hz, 1H), 7.57 (d, 7.8 Hz, 1H), 7.41 (t, 7.8 Hz, 1H), 6.75 (dd, J=17.4, 10.9 Hz, 1H), 6.05 (br s, 1H), 5.83 (d, J=17.9 Hz, 1H), 5.61 (br s, 1H), 5.34 (d, J=10.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([CH3:22])[CH2:7][C:6]([F:9])([F:8])[C@:5]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[F:20])([CH3:10])[NH:4][C:3]1=[O:21].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:12]([F:20])=[C:11]([C@@:5]2([CH3:10])[NH:4][C:3](=[O:21])[C:2]([F:1])([CH3:22])[CH2:7][C:6]2([F:9])[F:8])[CH:16]=1
Reactant: CC1(F)CC(F)(F)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)NC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
(6R)-3,5,5-Trifluoro-6-(2-fluoro-5-nitrophenyl)-3,6-dimethylpiperidin-2-one (2.08 g, 6.50 mmol) (1:1.8 mixture of diastereomers) was dissolved in methanol (28 ml). Ammonium formate (2.05 g, 32.5 mmol) was added followed by portionwise addition of palladium on carbon (1.38 g, 1.30 mmol, 10%). The reaction is slightly exothermic and the reaction mixture was briefly immersed into an ice/water bath to control the temperature increase. After the initial temperature increase had settled, the reaction was stirred at room temperature for another 10 min. The reaction was filtered through a plug of celite using methanol for elution. The filtrate was concentrated under reduced pressure and partitioned between ethyl acetate (100 mL) and saturated aqueous NaHCO3 (50 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to afford (6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidin-2-one (1.73 g, 5.96 mmol, 92% yield) (1:1.8 mixture of diastereomers). LC-MS Major: (m/z) 291.0 (MH+-tert-butyl) tR=0.40 minutes (Method B); Minor: (m/z) 291.0 (MH+) tR=0.41 minutes (Method B). The crude material was used in the next reaction step without further purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]3[O:11][CH2:12][O:13][C:8]3=[CH:7][C:5]=2[N:6]=1.NC(N)=[S:16]>C(O)C>[SH:16][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[O:11][CH2:12][O:13][C:8]3=[CH:7][C:5]=2[N:6]=1
Reactant: NC(N)=S
Reactant: Clc1nc2cc3c(cc2s1)OCO3
Solvent: CCO
Product: Sc1nc2cc3c(cc2s1)OCO3

Procedure:
The product from Step 2 (0.67 g) and thiourea (0.26 g) were mixed in ethanol (20 cm3) and stirred and heated to reflux under an atmosphere of nitrogen for 18 hr. The pale yellow solid which precipitated was filtered from the solution at ambient temperature, washed with ethanol and sucked to dryness to give the required product. 1H NMR (DMSO): δ7.26(1H,s); 6.80(1H,s); 6.02(2H,s); mp 265° C. (dec); M+ =211.