Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].FC(F)(F)C(O)=O>CS(C)=O>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:17][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccccc1N
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
1.62 g (10 mmole) of N,N′-carbonyldiimidazole were added to a dimethyl sulfoxide (10 ml) solution including 1.12 g (10 mmole) of benzoic acid, followed by stirring at room temperature for 1 hour. After the addition of 2.16 g (20 mmole, 2 equivalents) of 1,2-phenylenediamine, 1.9 ml of trifluoroacetic acid were added dropwise at room temperature. After reaction had been further carried out at room temperature for 15 hours, a post-treatment was performed in the same manner as in Example 6 to obtain 1.27 g (yield: 59%) of N-(2-aminophenyl)benzamide.
Reaction SMILES: C[N:2](C)C=O.[CH3:6][O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=1)=[O:9].C([O-])(=O)C.[NH4+].O>C(OCC)(=O)C>[NH2:2][C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:11][CH:12]=1)=[CH:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethylformamide (50 ml), 1-(4-methoxycarbonyl-phenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (10.0 g) and ammonium acetate (9.9 g) were charged in 500-ml three-necked flask at room temperature and heated, and the reaction was carried out at the inner temperature of 90 to 100 ° C. for 4 hours. After completion of the reaction, the mixture was cooled down to room temperature, water (250 ml) and ethyl acetate (250 ml) were added, the mixture was stirred, and an ethyl acetate layer was separated. The ethyl acetate layer was further washed with water (250 ml) and a saturated saline solution (100 ml). The ethyl acetate layer was concentrated in vacuo to make 50 ml, and n-heptane (250 ml) was added to separate crystals of 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene. The crystals were filtered at room temperature and washed with a solution (50 ml) consisting of n-heptane and ethyl acetate (5:1). The crystals were dried overnight in vacuo and purified by suspending in a 70% aqueous acetone (100 ml) to give 1-amino-1-(4-methoxycarbonyl-phenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (6.56 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1.Cl[C:20]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:22][N:21]=1>C1(C)C=CC=CC=1>[C:26]1([C:24]2[C:23]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:22][N:21]=[C:20]([NH:7][C@H:8]3[CH2:9][CH2:10][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]3)[N:25]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CC[C@H](Nc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
550 mg (1.69 mmol) of cesium carbonate were added to a suspension of 175 mg (0.84 mmol) of ethyl trans-4-aminocyclohexanecarboxylate in 5 ml of toluene, and the mixture was stirred at room temperature. After 30 minutes, 150 mg (0.56 mmol) of 2-chloro-4,5-diphenyl-pyrimidine were added, and the mixture was stirred at 120° C. for 4 days. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was dried and concentrated under high vacuum. An attempt was made to purify the residue on a silica gel column (heptane/isopropanol, gradient 100% to 5% in 15 minutes). A mixed fraction was obtained, and the product crystallized therefrom. The precipitate was filtered off with suction. 78 mg (34%) of the desired product were obtained in this way.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[C:20]2[O:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[C:20]2[O:21][C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.7 %

Procedure:
1.0 M Solution of boron tribromide in dichloromethane (1.25 ml) was added dropwise to a stirred solution of 2-[2-[(3-methoxyphenyl)methyl]cyclohexyl]-4,5-diphenyloxazole (370 mg) in dichloromethane (2.0 ml) under ice cooling. The resulting mixture was stirred at the same temperature for 2 hours and at room temperature for 22 hours, and then a mixture of ethyl acetate and sodium bicarbonate aqueous solution was added thereto. The organic layer was washed with sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed over silica gel using n-hexane--ethyl acetate as an eluent to afford 2-[2-[(3-hydroxyphenyl)methyl]-cyclohexyl]-4,5-diphenyloxazole (303 mg) as a syrup.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH:9](Br)Br)[N:3]=1.C(=O)([O-])[O-:13].[Ca+2].O>CS(C)=O>[Br:1][C:2]1[N:3]=[C:4]([CH:9]=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(C(Br)Br)nc1Br
Agent: [Ca+2]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(F)c(Br)n1
Temperature: 150 °C
Reaction time: 15.5 h
Yield: 66.5 %

Procedure:
After a solution of 2-bromo-6-(dibromomethyl)-3-fluoropyridine (615 mg) and calcium carbonate (391 mg) in dimethylsulfoxide (6.5 mL) was stirred while heating at 150° C. for 4.5 hr, the reaction mixture was reverted to room temperature and stirred for 15.5 hr. After water was added thereto, the mixtue was stirred and then extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-82:18) to afford the title compound (240 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[CH2:23][C:24]([CH3:46])([CH3:45])[O:25][C:26]1[C:27]([CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[CH2:31][CH2:30][CH2:29]2>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:45][C:24]([CH3:46])([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[CH2:31][CH2:30][CH2:29][C:28]=2[C:27]=1[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:23])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(CO)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(COS(=O)(=O)C(F)(F)F)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Trifluoromethanesulfonic anhydride (0.12 mL, 0.74 mmol) was added to a solution of pyridine (0.14 mL, 1.77 mmol) in dichloromethane (0.5 mL). The resulting mixture was added over 15 min to an ice-cooled solution of 6-(2-hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone (100 mg, 0.30 mmol) in dichloromethane (0.5 mL). The resulting mixture was stirred for 15 min and was then quenched by the addition of water (2 mL). The mixture was diluted with 1 M aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with 1 M aqueous hydrochloric acid (10 mL), saturated aqueous copper sulfate (3×5 mL), and was then dried (brine, Na2SO4) and concentrated. The residue was purified by dry-flash column chromatography (SiO2, 5-40% ethyl acetate-hexane) to give 2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyl trifluoromethanesulfonate as a colorless oil, 125 mg, 90% yield. NMR spectrum was consistent with structure. MS EI: M+• 470.1376 (M+• 470.1375).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[C:39](O)(=[O:43])/[CH:40]=[CH:41]\[CH3:42].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:25][C:24]1[C:23]([O:26][CH3:27])=[CH:22][C:21]([O:28][CH3:29])=[C:20]([Cl:30])[C:19]=1[NH:18][C:16](=[O:17])[N:15]([C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:39](=[O:43])/[CH:40]=[CH:41]\[CH3:42])[CH:10]=1)[CH3:31]
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Reactant: C/C=C\C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C\C(=O)Nc1ccccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (20 mg, 0.043 mmol), triethylamine (21.8 g, 0.22 mmol), and (Z)-but-2-enoic acid (4.5 g, 0.052 mmol) in DCM (0.86 ml, 13.3 mmol) was added a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (49.4 g, 0.78 mmol, 50% solution EtOAc) at 0° C., and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel column to obtain the title compound (8.5 mg, yield: 37%). 1H NMR (400 MHz, CDCl3) δ 2.20 (dd, J=7.28, 1.76 Hz, 3H) 3.30 (s, 3H) 3.92 (s, 6H) 5.85 (dd, J=11.42, 1.76 Hz, 1H) 5.99 (s, 1H) 6.29 (dd, J=11.36, 7.34 Hz, 1H) 6.52 (s, 1H) 7.23-7.34 (m, 2H) 7.46 (d, J=7.40 Hz, 1H) 7.55 (br. s., 1H) 7.78 (d, J=7.53 Hz, 1H) 8.40 (d, J=0.88 Hz, 1H) 12.50 (s, 1H); MS (ESI): 531.3 [M+H]+.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:30]=3)[C:25](O)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:43][C:44]1[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[CH:30]=3)[C:25]([NH:43][C:44]3[CH:49]=[N:48][C:47]([CH3:50])=[CH:46][N:45]=3)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Cc1cnc(N)cn1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.11 mL, 0.80 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoic acid (0.3 g, 0.62 mmol) in DCM (10 mL) and stirred for 1 hour. 2-Amino-5-methylpyrazine (135 mg, 1.23 mmol), then pyridine (0.1 mL, 1.23 mmol), were added and the mixture stirred for a further 30 mins before being reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a colourless oil (82 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([B:17]4[O:21]C(C)(C)C(C)(C)[O:18]4)=[CH:13][N:12]3[CH:26]=2)[CH:6]=[CH:7][CH:8]=1.[ClH:27]>CC(C)=O.O>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([B:17]([OH:21])[OH:18])=[CH:13][N:12]3[CH:26]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cn3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(-c2cn3cc(B(O)O)ccc3n2)c1

Procedure:
7.47 g of 2-(3-methoxyphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine are dissolved in 236 ml of acetone and 118 ml of water; 213 ml of 1N hydrochloric acid are added thereto, dropwise and with stirring, and the mixture is stirred at ambient temperature for 24 h. The reaction mixture is subsequently concentrated under reduced pressure. The solid obtained is triturated from diethyl ether, collected by filtration and then dried in an oven under reduced pressure at 60° C. 5.80 g of compound are obtained.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[O:32][CH3:33])=[O:11])=CC=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[O:23]([CH2:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:31])[N:17]2[C:12]([C:10]([OH:11])=[O:9])=[C:13]([O:32][CH3:33])[CH2:14][S:15][C@H:16]12)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 1 h

Procedure:
A solution of 250 mg (0.5 mmol) of 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 2 ml of methanol/tetrahydrofurane, 1:1, is added to a mixture of 5% palladium/charcoal in 2 ml of the same solvent, which mixture has been prehydrogenated for one hour under atmospheric pressure, and the reaction mixture is hydrogenated for 3 hours at room temperature and under atmospheric pressure. After this time, about 90% of the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is taken up in 10 ml of methylene chloride and extracted with twice 10 ml of 5% strength aqueous sodium bicarbonate solution. The combined bicarbonate extracts are neutralised at 0° C with dilute hydrochloric acid and extracted with 3 times 10 ml of methylene chloride. The organic phase is dried over sodium sulphate and freed from the solvent in vacuo. After crystallisation from chloroform/pentane, the residue gives 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid of melting point 173°-174° C.
Reaction SMILES: FC(F)(F)OC1C=CC(N2CCNCC2)=CC=1.[CH3:18][C@H:19]1[CH2:24][N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[CH2:22][C@@H:21]([CH3:36])[N:20]1[S:37]([C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH2:42][CH:43]([C:49]#[N:50])[CH2:44]2)(=[O:39])=[O:38].C([Sn](=O)CCCC)CCC.[N:61]([Si](C)(C)C)=[N+:62]=[N-:63]>C1(C)C=CC=CC=1>[CH3:18][C@H:19]1[CH2:24][N:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=2)[CH2:22][C@@H:21]([CH3:36])[N:20]1[S:37]([C:40]1[C:41]2[CH2:42][CH:43]([C:49]3[NH:63][N:62]=[N:61][N:50]=3)[CH2:44][C:45]=2[CH:46]=[CH:47][CH:48]=1)(=[O:39])=[O:38]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(C#N)C2
Agent: CCCC[Sn](=O)CCCC
Agent: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1CC(c1nnn[nH]1)C2
Temperature: 105 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
cis-2,6-Dimethyl-1-|2-(1H-tetrazol-5-yl)-indane-4-sulfonyl|-4-(4-trifluoromethoxy-phenyl)-piperazine: To a solution of 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carbonitrile (23 mg, 0.0440 mmol) in toluene (1 ml) was added dibutyltin oxide (13 mg, 0.0281 mmol) and azidotrimethylsilane (5 μL, 0.0377 mmol). The reaction mixture was stirred at 105° C. for 20 h upon which an additional amount of dibutyltin oxide (13 mg, 0.0281 mmol) and azidotrimethylsilane (25 μL, 0.1884 mmol) was added and stirred at 105° C. for 4 h. The reaction mixture was cooled to room temperature and then directly purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to afford cis-2,6-dimethyl-1-[2-(1H-tetrazol-5-yl)-indane-4-sulfonyl]-4-(4-trifluoromethoxy-phenyl)-piperazine (14 mg, 61%). 1H NMR (400 MHz, CD3OD) δ ppm 7.75 (d, 1H), 7.54 (d, 1H), 7.39 (t, 1H), 7.09 (d, 2H), 6.90 (d, 2H), 4.18-4.02 (m, 3H), 3.89 (dd, 1H), 3.59-3.51 (m, 2H), 3.36-3.31 (m, 3H), 2.66-2.60 (m, 2H), 1.48 (d, 6H). LCMS: 523.11 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1Br)=[O:11].[C:18](=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:18][C:15]1[S:14][C:13]2[O:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[NH:9][C:10](=[O:11])[C:12]=2[CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NC(=O)c2ccsc2Br)c(O)c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)Oc1sc(C)cc1C(=O)N2
Temperature: 145 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of N-(2-hydroxy-4-methylphenyl)-2-bromo-3-thiophenecarboxamide (3.4 g) in dimethyl sulfoxide (30 ml) was added potassium carbonate (2.9 g) and the mixture was stirred at 140-150° C. for 1 hour. The reaction system was cooled to room temperature and the reaction mixture was poured into water. The precipitated crystals were collected by filtration, washed with water and purified by silica gel column chromatography (chloroform) to give 2, 8-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][CH2:26]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:26][CH2:25][O:24][CH3:23])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: COCCO
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COCCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 100.5 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.5 g of 2-methoxyethanol were dissolved in 50 ml of benzene, followed by addition of 0.5 g of p-toluene sulfonic acid. Then, the mixture was heated under reflux for 3 hours. After completion of the reaction, to the reaction mixture was added 50 ml of ether. The resulting mixture was washed with water by the customary method and dried over anhydrous sodium sulfate, followed by evaporation-removal of the solvent under reduced pressure, thereby to obtain 3.9 g of 2-methoxyethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[C:7]([C:20]([O:22]C)=[O:21])[N:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:9]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([C:20]([OH:22])=[O:21])[N:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: COC(=O)c1cc(Br)cn1CC(=O)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1cc(Br)cc1C(=O)O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
LiOH H2O (0.2 M, 6.8 mL, 1.36 mmol) was added portionwise to a solution of crude methyl 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (210 mg, 0.39 mmol) in THF (0.5 mL), and the mixture stirred at 40° C. for 3 h, after which time the TLC analysis showed consumption of starting material ester. The reaction mixture was diluted with aqueous NaOH solution (1M) (50 mL) and the mixture washed with CH2Cl2 (100 mL). The aqueous layer was acidified to pH 2 with aqueous HCl solution (1M) and was extracted with CH2Cl2 containing 30% of propan-2-ol (2×150 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (100 mg, yield 75%). This crude material was used in the next step without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][Mg+].[Br-].[NH4+].[Cl-]>CCOCC>[C:4]([O:3][C:1]([N:8]1[CH2:11][C:10]([OH:12])([CH3:13])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
A solution of 1-Boc-azetidin-3-one (3.5 g, 20 mmol) in 50 mL and Et2O was cooled to 0° C. and 3M MeMgBr in Et2O (10 mL, 30 mmol) was added dropwise over 1 h. After 45 min, the reaction was allowed to warm to rt and stir an additional for 18 h. Then ½ sat'd NH4Cl (aq.) was added and the mixture extracted with EtOAc (2×). The combined organic layers were dried and the resulting semisolid was purified by RP HPLC (Agilent) to give the title compound as a white solid (3.2 g, 84%). 1H NMR (CDCl3): 3.84 (q, J=9.2 Hz, 4H), 1.97 (bs, 1H), 1.52 (s, 3H), 1.44 (m, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2ccccc2c1O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ccccc2c1O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dry 1-hydroxy-2-naphthoic acid (50 gms., 0.266 mole) was suspended in 350 ml. dry benzene in a flame-dried 1 liter 1-neck round bottom flask under an air condenser and drying tube. Thionyl chloride (31.7 gms., 0.266 mole) was added in one portion followed by 1.5 ml. dry N,N-dimethylformamide. The reaction mixture was stirred magnetically 2-3 days at room temperature. Insoluble material (6.5 gms.) was removed by filtration, and the yellow-tan filtrate was evaporated to dryness to give pale yellow 1-hydroxy-2-naphthoyl chloride, m.p. 87°-88° C. Chilled anhydrous methanol (100 ml.) was added quickly to the solid chloride in an exothermic reaction. The partial solution was heated about 5 minutes on the steam bath under a drying tube then allowed to cool. The suspension was chilled and the solid was collected to give 43 gms. (92% by weight) of 1-hydroxy-2-methyl naphthoate.