Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](B(O)O)[CH2:11][CH3:12]>>[CH2:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCB(O)O
Product: CCCc1ccc(C=O)cc1
Yield: 29 %

Procedure:
The compound was synthesized as in Example 3.1 using 4-bromobenzaldehyde (250 mg, 1.35 mmol) in place of 5-bromo-2-formylfuran and propylboronic acid (196 mg, 2.23 mmol) in place of hexylboronic acid to give 4-propylbenzaldehyde (58 mg, 29%). Used without further characterization.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[O:18][CH:19]2[OH:27])[C@H:14]2[O:29][C@@H:13]32)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[ClH:30].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[O:18][CH:19]2[OH:27])[C@H:14]([Cl:30])[C@H:13]3[OH:29])[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC(O)[C@]4(C)[C@H]3CC[C@@]21C
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC(O)[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 20 mg of 17α-acetoxy-6α,7α-epoxy-1ξ-hydroxy-2-oxa-4pregnene-3,20-dione and 3 ml of 16% hydrochloric acid-ethyl acetate solution was stirred at room temperature for 10 minutes. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 21 mg of 17α-acetoxy-6β-chloro-1ξ,7α-dihydroxy-2-oxa-4-pregnene-3,20dione.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(OC)(OC)(O[CH3:25])=O.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:25])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COP(=O)(OC)OC
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Yield: 85.1 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To this was added 4.2 g of trimethyl phosphate and the mixture was refluxed for 6 hours. After the reaction was complete, the solvent was distilled off from the mixture, and to the residue obtained was added water to precipitate a crude product. The product was recrystallized from acetone to yield 2.5 g of 1-(m-nitrophenyl)-3-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 234°-235°C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])=CC2C=CC=CC=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]=[O+][O-]>ClCCl.CO>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:19]([OH:35])[CH2:18][O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:9](=[O:34])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: O=C(N[C@H]1CC[C@H](OCC(=Cc2ccccc2)c2ccccc2F)CC1)OCc1ccccc1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](OCC(O)c2ccccc2F)CC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of 41 g of trans-[4-(2-(2-fluorophenyl)-3-phenyl-allyloxy)-cyclohexyl]-carbamic acid benzyl ester in 750 mL of dichloromethane and 250 mL of methanol cooled to −78° C. was dispersed a stream of ozone from an ozone generator until a blue color persisted. The excess ozone was purged with nitrogen until the blue color dissipated, and 7.8 g of sodium borohydride was added. After warming to room temperature over 30 min, the solution was diluted with 50 mL of water and concentrated under reduced pressure. The residue was treated with 500 mL of 3N hydrochloric acid and extracted into 3×500 mL of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-30% ethyl acetate in hexane gave 30 g of product as a white crystalline solid: MS (m+1)=388.4; 1H NMR (400 MHz, CDCl3) 7.53 (m, 1H), 7.33 (m, 5H), 7.25 (m, 1H), 7.14 (m, 1H), 7.0 (m, 1H), 5.15 (d, 1H), 5.07 (s, 2H), 4.6 (m, 1H), 3.7 (d, 1H), 3.5 (br m, 1H), 3.4 (t, 1H), 3.3 (m, 1H), 2.9 (s, 1H), 2.0 (m, 4H), 1.2 (q, 2H), 1.15 (q, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.Cl[C:13](C(O[Na])=O)([F:15])[F:14].C1OCCOCCOCCOCCOCCOC1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=[N:8]\[C:9](=[O:11])[CH3:10])/[N:6]([CH:13]([F:15])[F:14])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Br)cn1
Reactant: O=C(O[Na])C(F)(F)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CC#N
Product: CC(=O)/N=c1\ccc(Br)cn1C(F)F

Procedure:
To a stirred solution of N-(5-Bromo-pyridin-2-yl)-acetamide (1 g, 4.6 mmol) in 30 ml CH3CN was added ClCF2COONa (848 mg, 5.58 mmol), followed by 18-Crown-6 (244 mg, 0.93 mmol). The reaction mixture was heated to reflux for 12 hrs. Then the reaction mixture was cooled down and the solvent was removed under reduced pressure. To this was added methylene dichloride and washed with water. Organic layer was dried over any sodium sulphate and concentrated under reduced pressure to furnish the crude N-[5-Bromo-1-difluoromethyl-1H-pyridin-(2E)-ylidene]-acetamide. This was carried to the next step without purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[NH:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28]2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:14][C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([C:5]2[N:4]=[N:3][C:2]([N:22]3[CH2:27][CH2:26][C:25]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28]4)[CH2:24][CH2:23]3)=[CH:7][CH:6]=2)[N:9]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)n(-c2ccc(N3CCC4(C=Cc5ccccc54)CC3)nn2)n1

Procedure:
The object product (67 mg, 19%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (209 mg), spiro[indene-1,4′-piperidine] trifluoroacetate (300 mg) and potassium carbonate (275 mg).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1>C(O)C.C(N(CC)CC)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][Br:2])[CH2:21][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(CCO)CC3)c2cc1OC
Reactant: BrP(Br)Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(CCBr)CC3)c2cc1OC
Reaction time: 16 h

Procedure:
Phosphorus tribromide (9.7 g) was added at room temperature to a stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)-4-(2-hydroxyethyl)piperidine (7.5 g) in ethanol free chloroform (200 cm3) and triethylamine (5.0 cm3). After stirring for 16 hours the volatile material was removed in vacuo and the residue was taken into aqueous sodium carbonate solution and extracted with chloroform (3×50 cm3). The dried (MgSO4) extracts were evaporated and the residue was chromatographed on "Florisil" (Trade Mark, Hopkin and Williams) eluting with chloroform to afford 1-(6,7-dimethoxyquinazoline-4-yl)-4-(2-bromoethyl) piperidine 1/4 H2O as a white solid, m.p. 191° (5.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:35])=[C:32]([CH:34]=1)[NH2:33].C[Al](C)C>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:35])=[C:32]([NH:33][C:19](=[O:20])[C:18]2[CH:23]=[CH:24][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][C:17]=2[O:25][CH3:26])[CH:34]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(Cl)ccc1C
Yield: 45 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 5-chloro-2-methyl aniline (0.057 g, 0.39 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.057 g of desired product. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 4.05 (s, 3H), 7.13 (d, J=9.9 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.49 (t, 1H), 7.59 (d, 1H), 7.61-7.75 (m, 2H), 7.84 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.19 (s, 1H), 9.94 (br s, 1H), 12.83 (br s, 1H); MS (m/z): 487.11 [M]+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH3:16]>>[NH2:16][C:9]1[C:10](=[O:11])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: N
Reactant: CC(C)(C)n1ncc([N+](=O)[O-])c(Cl)c1=O
Product: CC(C)(C)n1ncc([N+](=O)[O-])c(N)c1=O

Procedure:
6.95 g of 2-tert-butyl-4-chloro-5-nitropyridazin-3-(2H)-one and 50 ml of 28% aqueous ammonia were mixed, sealed and reacted for 5 hours in an oil bath of 110° C. After cooling, the precipitate was collected by filtration and washed a few times with water and then dried to obtain 5.97 g of 4-amino-2-tert-butyl-5-nitropyridazin-3-(2H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]S)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=C([N+]([O-])=O)C=CC=1CS)([O-])=O.[N+](C1C=CC(CCl)=CC=1)([O-])=O.[C:37]([OH:40])(=[S:39])[CH3:38]>C1COCC1.N1C=CC=CC=1>[C:37]([O:40][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[S:39])[CH3:38]
Reactant: CC(O)=S
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Agent: O=[N+]([O-])c1ccc(CCl)cc1
Agent: O=[N+]([O-])c1ccc(CS)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=S)OCc1ccc([N+](=O)[O-])cc1
Yield: 77 %

Procedure:
The two step procedure for the preparation of 4-nitrobenzyl, (see, for example, Horn, W. J., J. Am. Chem. Soc., 43, 2603, 1921), and 2,4-dinitrobenzyl, (see, for example, Zhao Zhengyun, Ph.D. Thesis, London University, 181-182, 1993), mercaptans (17a and 17b, respectively) is indicated in outline in Scheme 3(a). Thus, when 4-nitrobenzyl chloride 15a was treated with an excess both of thioacetic acid and pyridine in THF solution at 50° C., 4-nitrobenzyl thioacetate 16a was obtained in 77% yield. When the latter compound 16a was heated, under reflux, in sulfuric acid--water (1:1 v/v), 4-nitrobenzyl mercaptan 17a was obtained in almost quantitative yield. 2,4-dinitrobenzyl mercaptan, (see, for example, Zhao, loc cit), 17b was similarly prepared from 2,4-dinitrobenzyl chloride, (see, for example, Cohn, P., and Friedlander, P., Ber., 35, 1265, 1902) 15b in 73% overall yield. N-(4-nitrobenzylmercapto)succinimide 18 was prepared [Scheme 3(b) and Experimental below] in 65 % yield by heating a suspension of the lead(II) salt, (see, for example, Pant, B.C., and Noltes, J. G., Inorg. Nucl. Chem. Lett., 7, 63, 1971), of the mercaptan 17a with N-bromosuccinimide (NBS) in benzene. Preliminary attempts to convert 2,4-dinitrobenzyl mercaptan 17b into the corresponding succinimide and phthalimide derivatives (13 and 14, R=2,4-(O2 N)2C6H3) were unsuccessful. However, di-(2,4-dinitrobenzyl) disulfide 19, (see, for example, Zhao, loc cit), which was easily prepared in good yield by the iodine-promoted oxidation [Scheme 3(c) and Experimental below] of the mercaptan 17b, proved (see below) to be an equally effective reagent for the required purpose. Finally, 2-cyanoethyl mercaptan 20, (see, for example, Bauer, L., and Welsh, T. L., J. Org. Chem., 26, 1443, 1961) was converted (see, for example, Behforouz, M., and Kerwood, J. E., J. Org. Chem., 34, 51, 1969), [Scheme 3(d) and Experimental below] via a putative intermediate sulfenyl chloride into N-(2-cyanoethylmercapto)phthalimide 21 which was isolated without chromatography as a crystalline solid in 58% yield. ##STR10## Scheme 4 Reagents and conditions: i, a, PCl3, 1,2,4-1H-triazole, Et3N, THF, -35° C., b, Et3N, H2O, RT; ii, for 24a: 18, Me3SiCl, Et3N, CH2Cl2, RT, for 24b: 19, Me3SiCl,4-methylmorpholine, CH2Cl2, RT, for 24c: 21, Me3SiCl, 4-methylmoxpholine, CH2Cl2, RT; iii, aq. Et NH+ HCO3 --.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Reactant: NCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(NCc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A mixture of 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 7 days. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with H2O (3×15 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in CH2Cl2) to give a yellow solid. The yellow solid was triturated with MeOH (1 mL) and the solid was collected by filtration to give intermediate (I-3a) as a white solid (48.5 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](O)[CH:10]([CH2:14][N:15]=[N+:16]=[N-:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([Cl:21])[CH:10]([CH2:14][N:15]=[N+:16]=[N-:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NCC1CN(Cc2ccccc2)CC1O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CC1Cl
Yield: 40.3 %

Procedure:
1-Benzyl-4-hydroxy-3-azidomethylpyrrolidine (59.7 g) is added to chloroform (100 ml), and the mixture is saturated with dry hydrogen chloride gas. A solution of thionyl chloride (61.2 g) in chloroform (100 ml) is added dropwise to the mixture under reflux. After refluxing for 2 hours, the mixture is concentrated. To the residue is added ethanol and the excess thionyl chloride is removed, and then, the mixture is again concentrated. After neutralizing the concentrate with an aqueous sodium hydrogen carbonate, the mixture is extracted with dichloromethane. The dichloromethane layer is washed with water, dried and concentrated, and the resulting residue is then purified by silica gel column chromatography (solvent, ethyl acetate-n-hexane) to give 1-benzyl-3-azidomethyl-4-chloropyrrolidine (26.0 g) as an yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([CH2:23][C:24]#[N:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C>[NH2:25][C:24]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (0.245 g) in ethanol (2 ml) was added to a stirred solution of benzoylacetonitrile (0.145 g) in ethanol (8 ml) and the resulting solution heated under reflux for 6 hours. Glacial acetic acid (1 ml) was added and the resulting mixture heated under reflux for a further 6 hours and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (10 g), using dichloromethane as eluant, followed by reverse phase HPLC on C18 silica, using acetonitrile:methanol:water (50:10:40) as eluant, to afford the title compound as a white solid, m.p. 141.5-142.5° C. δ(CDCl3): 3.60 (br.s,2H), 6.08 (s,1H), 7.30-7.45 (m,3H), 7.80 (s,2H), 7.80-7.85 (m,2H). MS (thermospray): M/Z [M+H] 372.1; C16H10Cl2F3N2 +H requires 372.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:49])[CH:32]([C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH3:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:49])[CH:32]([C:34]1[CH:39]=[CH:38][C:37]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[CH3:25])=[CH:36][CH:35]=1)[CH3:33])[CH3:29]
Reactant: Cc1cc(-c2onc(C)c2NC(=O)O[C@H](C)c2ccccc2F)ccc1Br
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2C)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-3-methyl-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester were reacted to provide 2-(4′-{4-[(R)-1-(2-fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-2′-methyl-biphenyl-4-yl)-propionic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=[S:19])[NH:7][C:6]=2[CH:17]=1
Reactant: CN1c2ccc(Cl)cc2NC(=O)c2cscc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CN1c2ccc(Cl)cc2NC(=S)c2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.5 g. of 7-chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one and 0.5 g. of phosphorus pentasulfide in 5 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The mixture is concentrated to dryness and is stirred with 10 ml. of 1N sodium carbonate solution for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol to give a yellow solid, m.p. 238°-240°C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([S:22](Cl)(=[O:24])=[O:23])=[N:20][CH:21]=1>ClCCl.[NH4+].[Cl-]>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:24])=[O:23])=[N:20][CH:21]=1
Reactant: CCOC(=O)CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNS(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C

Procedure:
Triethylamine (543 μL, 3.90 mmol) followed by ethyl glycinate (161 mg, 1.56 mmol) were added to a solution of 5-bromopyridine-2-sulfonyl chloride (200 mg, 0.780 mmol) in dichloromethane (2.6 mL) was added. The reaction mixture was stirred at room temperature and was monitored by LCMS. Upon completion, the reaction was diluted with saturated aqueous NH4Cl and the organic layer was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH in DCM:hexanes) to yield ethyl N-[(5-bromopyridin-2-yl)sulfonyl]glycinate. MS APCI calc'd for C9H12BrN2O4S [M+H]+ 323 and 325. found 323 and 325.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl>[C:14]([O:13][C:12]([NH:11][C@@H:3]([CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)[CH2:2][NH:1][C:20](=[O:21])[O:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CN)C[C@H]1CCCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CNC(=O)Oc1ccc([N+](=O)[O-])cc1)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (20.8 mg, 0.081 mmol) in anhydrous DCM (9 mL) was added 4-nitrophenyl chloroformate (17.1 mg, 0.085 mmol), followed by TEA (12.2 mg, 17 μL, 0.12 mmol). The resulting solution was stirred at rt for 5 min (monitored by LC-MS) and diluted to 12 mL. An aliquot of the carbamate mixture solution (2 mL) was used for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[C:19](=S)(OCC)[S-:20].[K+]>[C].[Pd].C(OCC)(=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:19]([SH:20])[O:1][C:2]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])=[O:6]
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1C(=O)OC
Agent: [Pd]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(S)oc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A 10% palladium carbon catalyst (2.5 g) was added to a solution of the nitro compound mixture (4.3 g, 16.8 mmol) in ethyl acetate (60 ml) and stirred under hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered off through celite and the filtrate was concentrated. The residue was dissolved in methanol (50 ml), potassium O-ethyl dithiocarbonate (1.76 g, 11.0 mmol) was added thereto and the mixture was heated to reflux for 16 hours. After cooling, the solvent was evaporated in vacuo. The residue was diluted and acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The residue was crystallized from ether to provide 1.61 g (yield 60%) of 6,7-bis(methoxycarbonyl)-2-mercaptobenzooxazole as yellow crystals.