Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:33][CH:32]([NH:34][C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:31][CH:32]([NH:34][C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:33]3)=[O:29])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 88.3 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (850 mg, 1.27 mmol) (obtained as described in Reference Example 57(4)) in anhydrous tetrahydrofuran (43 ml) were added successively acetic acid (87 μl, 1.52 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (1.52 ml, 1.52 mmol) in an ice bath. The mixture was stirred in the ice bath for 30 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue were added ethyl acetate and diisopropyl ether, and the resulting mixture was filtered off and washed with diisopropyl ether to give 3-hydroxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (486 mg, yield 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]3[O:36][CH2:35]3)[C:29]([O:31]C)=[O:30])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]([OH:36])[CH2:35][S:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:29]([OH:31])=[O:30])(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(CS)cc1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
Example 51 is prepared from 4-fluorobenzylmercaptan and 1d using the procedure described for compound 20.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(-c2nn(C(C)(C)C)c3ncnc(N)c23)cc1
Agent: Cl
Solvent: O=CO
Product: CC(C)(C)c1ccc(-c2n[nH]c3ncnc(N)c23)cc1

Procedure:
1-tert-butyl-3-(4-tert-butylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was dissolved in a solution of formic acid (1 mL) and conc. HCl (0.1 mL) and heated to reflux for 2 hours. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield ZK125 (quant.). ESI-MS (M+H)+ m/z calcd 268.2, found 268.4.
Reaction SMILES: [CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:2]
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 120 °C
Yield: 33.2 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 63, 0.09 g) and lithium hydroxide monohydrate (0.047 g) in a mixture of dioxane (10 mL) and water (5 mL) was stirred and heated at 120° C. for 32 hours. After cooling, the mixture was concentrated under vacuum and the residue was acidified to pH4 with formic acid. The resultant solid was collected by filtration and washed with water to give (1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.029 g) as a grey solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11]([N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1
Reactant: CCNCC
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: CCN(CC)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-(3,4-Difluorobenzyloxy)-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-pyrimidine (Reference Example 7) (29 mg, 0.05 mmol) was reacted with diethylamine (38.0 mg, 0.52 mmol) by the same general procedure described in Example 103 to afford the title compound: HPLC/MS: m/e=548 (M++1); Rt=3.84 min. 1H-NMR 400 MHz (CDCl3): δ 0.96-1.00 (m, 6H), 3.20-3.30 (m, 4H), 5.30-5.40 (m, 2H), 6.90 (d, J=9 Hz, 1H), 7.01-7.21 (m, 8H), 7.35-7.40 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2-chloro-5-nitrophenyl)-5-phenyl-1H-imidazole (27 g, 90.3 mmol) in EtOH (200 ml) is added 5 nCl2.2H2O (71 g, 316 mmol). The mixture is refluxed for 2 hours, cooled to room temperature and then concentrated. Ethyl acetate (200 ml) and NaOH (25 g in 100 ml water) are added to the residue and the mixture is stirred for 10 minutes at room temperature. The solid is removed by filtering through celite pad. The filtrate is separated and the organic layer is further washed with brine, dried over anhydrous MgSO4 and concentrated. The crude product is purified by silica gel flash chromatography, eluted with 40% ethyl acetate in dichloromethane to afford 4-Chloro-3-(5-phenyl-1H-imidazol-2-yl) aniline as a brown solid. LC-MS m/z: 270.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]2[OH:29])=[CH:12][CH:11]=1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH:17]2[O:29][CH2:34][C:35]2[CH:36]=[CH:37][C:38]3[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=3[CH:50]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(Cl)c3)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(Cl)c4)cc3)cc21

Procedure:
Analogously to Method D, 1.10 g of tert-butyl 4-{4-[3-(3-chlorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.662 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.36 (1:1 EtOAc-heptane); Rt=6.19.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:12])[CH3:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][C:27]=1[F:28])[NH:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19]>C(O)(=O)C>[NH2:13][C:14]1[CH:15]=[C:16]([NH:17][S:18]([C:21]2[C:22](=[O:23])[O:12][C:5]3[C:6]([CH:7]=2)=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][CH2:1][CH3:2])(=[O:20])=[O:19])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1cc(NS(=O)(=O)CC(=O)O)ccc1F
Reactant: CCOc1cccc(C=O)c1O
Solvent: CC(=O)O
Product: CCOc1cccc2cc(S(=O)(=O)Nc3ccc(F)c(N)c3)c(=O)oc12

Procedure:
A solution of 3-ethoxysalicylaldehyde (1 mmol) and 3-amino-4-fluoroanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 160-162° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[C@H](NCCC1C=CC(O)=CC=1)[C@H](O)C1C=CC(O)=CC=1.[OH-].[Na+].C1COCC1>O.CO>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]([OH:32])=[O:31])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Agent: C[C@H](NCCc1ccc(O)cc1)[C@H](O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Temperature: 65 °C
Reaction time: 6 h
Yield: 90.5 %

Procedure:
In a similar manner as described in step 2 of Example 6, the title compound was prepared from methyl {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate (0.17 g, 0.39 mmol), prepar in the previous step, and 1N NaOH (0.59 mL, 0.59 mmol) in 5:5:1 THF:MeOH:water (55 mL) with the exception that this reaction required heating to 65° C. and was complete after 6 hours. The still warm reaction mixture was filtered and then allowed to cool to ambient temperature. The mixture was acidified with 1N HCl (2.5 mL) and the volatiles were removed under reduced pressure (without the addition of heat). The resulting slurry was diluted with water (25 mL) and the solids were isolated by filtration to give {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid as an off-white solid (0.148 g, 90%), mp 258–260° C. (dec). Elemental Analysis for C28H21NO3.0.23 H2O Calc'd: C, 79.39; H, 5.11; N, 3.31. Found: C, 78.84; H 5.03; N, 3.00.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:17])=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2].[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29]O)=[N:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([C:4]1[C:5]([O:17][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:32])([F:18])[F:31])=[CH:25][N:24]=2)=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of protective gas, 1.2 g of 3-acetyl-1-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-hydroxybenzene, 0.9 g of 3-(5-trifluoromethylpyrid-2-yloxy)propan-1-ol and 1.12 g of triphenylphosphine were dissolved in 35 ml of dry tetrahydrofuran (THF). With ice-bath cooling, 0.74 g of diethyl azodicarboxylate was added dropwise. After about 30 minutes, the ice-bath was removed, and the mixture was stirred at room temperature for 15 hours. The mixture was then concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate and water. After shaking, the organic phase was isolated, dried and concentrated under reduced pressure. The crude product was purified chromatographically. Yield: 1.52 g (74%)
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10](=O)([O:12]C)[NH2:11].C1(C)C=CC=CC=1>C([Sn](=O)CCCC)CCC.CO>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:10]([NH2:11])=[O:12])[CH3:2]
Reactant: COC(N)=O
Reactant: CCCCC(CC)CN
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCC(CC)CNC(N)=O
Temperature: 110 °C
Yield: 91.7 %

Procedure:
Into a 300 ml reaction vessel equipped with a distillation apparatus were introduced 50 g of 2-ethylhexylamine, 29 g of methyl carbamate and 100 ml of toluene, and to the mixture was added 0.1 g of dibutyl tin oxide as a catalyst and heated with stirring. Methanol formed during the reaction was removed, when the reflux temperature was raised to 110° C., i.e., the boiling point of toluene, the distillation apparatus was taken off and instead a reflux condenser was attached and the mixture was refluxed by heating for 30 minutes with stirring, then allowed to cool. The toluene was distilled off under reduced pressure, and the residue was washed with n-hexane and collected by filtration to obtain 61 g of N-(2-ethylhexyl)urea.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[N:26]([CH3:30])[N:27]=[CH:28][CH:29]=2)[C:22]([CH:31]([CH3:33])[CH3:32])=[CH:21][C:20]=1[NH:34][C:35](OC1C=CC(Cl)=CC=1)=[O:36]>O1CCOCC1>[CH:31]([C:22]1[CH:21]=[C:20]2[C:19]([C:18](=[O:17])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:35](=[O:36])[NH:34]2)=[CH:24][C:23]=1[C:25]1[N:26]([CH3:30])[N:27]=[CH:28][CH:29]=1)([CH3:33])[CH3:32]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C(C)C)cc1NC(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)NN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc2[nH]c(=O)n(NS(C)(=O)=O)c(=O)c2cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
CH3SO2NHNH2 (79.5 mg, 1.1 equiv) and i-Pr2NEt (225 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (281 mg, 0.65 mmol) in dioxane (8 mL). The mixture was stirred for 16 h (TLC control) at 80° C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (MeOH/DCM (1:9)) to provide N-[7-isopropyl-6-(2-methyl-2H-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide as a white solid (120 mg, 48%) (ESI-MS: m/z 378 [M+H]+, rt 4.20 min).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[C:19]2[N:18]=C(C)O[C:15](=[O:21])[C:14]=2[CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1.O1CCCC1>[NH2:18][C:19]1[C:10]([Cl:9])=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1nc2c(Cl)cccc2c(=O)o1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Nc1c(Cl)cccc1C(=O)c1ccccc1
Yield: 38.8 %

Procedure:
Phenylmagnesium bromide (3.11 mL, 3.0 M in ether, 9.34 mmol) was added at room temperature to a solution of 8-chloro-2-methyl-4H-3,1-benzoxazin-4-one (2.15 g, 10.9 mmol) in benzene (10 mL) and tetrahydrofuran (3 mL). The reaction was refluxed for 2h, cooled, and quenched with 2N hydrochloric acid (10 mL). The layers were separated and the organic phase washed with 5% sodium hydroxide, dried over magnesium sulfate, and concentrated. The residue was refluxed in ethanol (12 mL) and 6N hydrochloric acid (6 mL) overnight, then concentrated in vacuo. The residue was dissolved in benzene (30 mL) and treated with 5N ammonium hydroxide (20 mL). The organic extract was dried and concentrated. The crude product was purified by chromatography (silica gel, 0 to 5% ethyl acetate in hexane gradient elution), giving the title compound (0.84 g). 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J=7 Hz, 2H), 7.54 (t, J=7 Hz, 1H), 7.49–7.42 (m, 3H), 7.39 (d, J=8 Hz, 1H), 6.56 (t, J=8 Hz, 1H), 6.58 (br s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[CH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:26][C:23]1[C:22]([CH:27]=[CH:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C=CCCc1ccccc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-(4-phenyl-but-1-enyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.072 g, 0.15 mmol) in THF (2 mL) and EtOH (1 mL) was treated with 3 N aqueous NaOH (0.75 mL, 2.25 mmol) and the reaction was stirred at 75° C. overnight. The mixture was acidified with 1 N aqueous HCl (2.25 mL) and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:15]=1[NH:16][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:12]
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: COc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)ccc2Cl)c1
Yield: 56.4 %

Procedure:
Using 5-methoxysalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c(C)c1

Procedure:
156.4 mg of the target compound (0.44 mmol, 53.7%) was obtained using 1-(2,4-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[CH:12]=1.C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[C:5]2[O:9][CH:8]([CH2:10][NH:11][C:33](=[O:34])[O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:7][C:6]=2[CH:12]=1
Reactant: NCC1Cc2cc(F)cc(-c3ccccc3C(F)(F)F)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(F)cc(-c3ccccc3C(F)(F)F)c2O1)OCc1ccccc1

Procedure:
Treatment of (±)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (1.87 g, 5.38 mmol) with diisopropylethylamine (1.74 g, 13.4 mmol) and benzyl chloroformate (1.01 g, 5.92 mmol) following the procedure described for Intermediate 12 provided 2.03 (85%) of (±)-benzyl {5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a white solid. Rf=0.69 (silica, ethyl acetate:hexanes 1:9); mp 76-80° C.; Anal. calcd. for C24H19F4NO3: C, 64.72; H, 4.3; N, 3.14. Found: C, 65.01; H, 4.3; N, 2.99.
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2S)-3-chloro-2-methylpropyl]oxy}-4-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.8 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:10][NH:11][C:12](OCC)=O)=[CH:5][CH:4]=1.B>>[CH3:12][NH:11][CH2:10][CH2:9][CH:8]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:7][C:6]1[CH:23]=[CH:24][C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][CH:5]=1
Reactant: CCOC(=O)NCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: B
Product: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
reducing said N-[3-[4-(trifluoromethyl)phenoxy]-3-phenylpropyl)urethane with borane or a metal hydride to provide N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:9]=2[NH:8][C:7]1=[O:24])=[O:5])[CH3:2].[CH2:25]1[O:27][CH2:26]1.[OH-].[NH4+]>C(Cl)CCl>[CH2:1]([O:3][C:4]([CH:6]1[N:12]2[CH2:25][CH2:26][O:27][C:11]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:9]=2[NH:8][C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Reactant: C1CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCOC(=O)C1C(=O)Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12

Procedure:
To a solution of 3.1 g. (0.0118 M) of stannic chloride in 35 ml. of dry ethylene dichloride under nitrogen was added 1.5 g. (0.00438 M) of 7-chloro-1,3-dihydro-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-carboxylic acid ethyl ester. The reaction was stirred in an ice bath, when a solution of 1.0 g. (0.0233 M) of ethylene oxide in 5 ml. of ethylene dichloride was added. The mixture was stirred at room temperature for 3 hr. and then made basic with mixture of ammonium hydroxide and ice. The mixture was filtered, and the filtrate was dried with anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether. Recrystallization from a mixture of dichloromethane and petroleum ether gave 10-chloro-11b-phenyl-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one-5-carboxylic acid ethyl ester as white rods, m.p. 205°-207°.