Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:21][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][NH:10][C:9](=[O:19])[CH2:8][C:7]=3[CH:20]=[C:3]2[O:2]1.C(N(CC)CC)C.[CH3:29][N:30]=[C:31]=[O:32].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]1[O:21][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][N:10]([C:31]([NH:30][CH3:29])=[O:32])[C:9](=[O:19])[CH2:8][C:7]=3[CH:20]=[C:3]2[O:2]1
Reactant: CN=C=O
Reactant: O=C1Cc2cc3c(cc2C(c2ccccc2)=NN1)OCO3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)N1N=C(c2ccccc2)c2cc3c(cc2CC1=O)OCO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of 7,8-methylenedioxy-1-phenyl-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (130 mg, 0.46 mmol) in CH2Cl2 (5 ml) was added triethylamine (1 mL), DMAP (5 mg) and methylisocyanate (60 mg) and the mixture was stirred at 25° C. for 24 h. The reaction mixture was then poured into a separatory funnel containing water (50 mL) and the product was extracted with CH2Cl2 (3×40 mL). The combined extracts were dried over Na2SO4 and solvent removed in vacuo. Purification of the residue by chromatography (1:1 of ethyl acetate: hexane) resulted in the product as a white solid (92 mg, 59%), mp, 180°-182.5° C. 1H NMR (CDCl3) 8.60 (bs, 1H), 7.74 (m, 2H), 7.46 (m, 3H), 6.88 (s, 1H), 6.67 (s, 1H), 6.07 (bs, 1H), 6.03 (bs, 1H), 3.54 (s, 1H) 3.54 (s, 1H), 2.93 (s, 1.5H), 2.92 (s, 1.5H).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11].Cl[CH2:18][CH:19]=O.Cl>O>[C:10]([CH2:9][C:8]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:18]=[CH:19][C:13]=1[C:14]([OH:16])=[O:15])([OH:12])=[O:11]
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: NC1CCCC1
Reactant: O=CCCl
Agent: Cl
Solvent: O
Product: O=C(O)Cc1c(C(=O)O)ccn1C1CCCC1
Temperature: 10 °C
Reaction time: 14 h

Procedure:
To a solution of cyclopentanamine (175 g) in water (150 mL) was added 3-oxopentanedioic acid (30 g) at 20° C. or lower, 2-chloroacetaldehyde (40% aqueous solution, 43 mL) was added dropwise thereto at 10° C. or lower, and the mixture was stirred at room temperature for 14 hr. 6N Hydrochloric acid (150 mL) was added thereto at 0° C., and the black precipitate was removed by filtration. To the filtrate was added 6N hydrochloric acid (50 mL) at 0° C., and the precipitate was collected by filtration to give the title compound (40 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([Cl:15])(=O)[CH2:12][CH3:13].[CH2:16](N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:15][C:11]1[C:12]([CH3:16])=[CH:13][C:9]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=2)[N:8]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2cc([N+](=O)[O-])ccc2nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitroaniline (10 g, 72 mmol) in chloroform at 0° was added propionyl chloride (7 mL, 80 mol) followed by triethylamine (11.1 mL). The resulting solution was stirred for 2 h at r.t. at which time the reaction mixture was washed with aq. 2N HCl. The organic layer was dried filtered and the solvent removed under vacuum to provide a solid. A solution of phosphorous oxychloride (25 mL) and N,N-dimethylformamide (4.5 mL) was stirred at 0° for 0.15 h then the above solid was added. The resulting reaction mixture was heated at 75° for 12 h at which time the volatiles were removed under vacuum. The residue was cooled in an ice bath. To the cooled mixture was carefully added water (50 mL). The resulting solids were filtered and then washed with water. The solids were extracted with chloroform, the extracts were combined, dried, filtered and the solvent removed under vacuum to afford the product, MS: m/z 224 (MH+), which was used directly in the next step.
Reaction SMILES: [CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23](=[O:26])[CH2:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:10]=[C:9]([NH:25][CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Cl)CC(C1CCCCC1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)CNC(=O)CC(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 3,3-dicyclohexylpropionyl chloride (6.1 g, 0.063 mol) in 70 ml of chloroform was treated portionwise at 7°-12° C. with a solution of 8.3 g (0.063 mol) of glycine tert-butyl ester and 8.9 ml (0.064 mol) of triethylamine in 30 ml of chloroform. After the addition, the solution was stirred at room temperature for 2 hours, kept overnight, refluxed for 0.5 hours, cooled, washed with water (5×25 ml), dried (magnesium sulfate), and the solvent removed on a rotary evaporator, to give a light yellow viscous oil. The latter, which crystallized partly on standing, was dissolved in 50 ml of boiling hexane, cooled, seeded, and rubbed; a crystalline solid gradually separated. After crystallizing at room temperature and cooling overnight, the voluminous colorless solid was filtered, washed with cold hexane and air-dried (13.3 g, melting point 72°-74° C. s, 69° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Br
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c([N+](=O)[O-])cc1F

Procedure:
Add 1-bromo-4,5-difluoro-2-nitrobenzene (24 g, 100 mmol) to a solution of sodium methoxide (1.2 eq) in MeOH. After addition, stir the reaction at room temperature for 2.5 hours. Remove the solvent in vacuo and dilute the residue with water and extract with Et2O (2×250 mL). Combine the organic layers, dry over MgSO4, filter, and the remove solvent in vacuo to give 1-bromo-4-fluoro-5-methoxy-2-nitrobenzene as a yellow solid: 1H NMR (300 MHz, CDCl3): 3.99 (s, 3H), 7.26 (m,1H), 7.83 (d, 1H); MS(FD+): m/z 249, 251 (M+); Analysis for C7H5BrFNO3: Calcd.: C, 33.63; H, 2.02; N, 5.60; found: C, 33.79; H, 1.98; N, 5.62.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.OS(O)(=O)=O.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>O1CCOCC1>[Cl:2][C:3]1[C:4]2[NH:9][C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][C:19]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccccc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
To a suspension of 2-chlorophenyl hydrazine hydrochloride (19.7 g, 0.110 mol) in dioxane (190 mL) at RT was added conc. H2SO4 (8 mL, 0.150 mol) dropwise and the reaction mixture was stirred for 10 min. To this was added N-methyl-4-piperidone (17.53 g, 0.154 mol) and the reaction mixture was stirred at RT for 20 min, then heated at 80° C. for 4 h. The reaction was monitored by TLC. The solvent was evaporated and pH adjusted to pH 8-9 with saturated sodium bicarbonate solution. The product was extracted with EtOAc (3×300 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by recrystallization (Ether/Hexane). The filtered solid was dried in vacuo to obtain 7.5 g of product as a brown solid. 1H NMR (CDCl3, freebase) d (ppm): 8.10 (bs, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 7.0 (t, 1H), 3.62 (s, 2H), 2.90 (m, 2H), 2.82 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:45])[N:29]([C@H:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH3:30][N:29]([C@H:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[C:28](=[O:45])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
At 0° C., trifluoroacetic acid (4 ml) was added to a solution of N-((1R)-1-(N-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (997 mg, 1.8 mmol) in dichloromethane (4 ml). The solution was stirred for 15 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was dissolved in dichloromethane and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (45 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 646 mg of N-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropyl)methanesulfonamide.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N:23]4[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:36](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:36][N:16]1[C:17]2[C:22](=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:24]3)=[CH:19][CH:18]=2)[C:14]([S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])=[N:15]1.[CH3:36][N:15]1[C:14]([S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:24]3)=[CH:21]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(S(=O)(=O)c2cccc3ccccc23)c2cc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Product: Cn1nc2ccc(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)cc2c1S(=O)(=O)c1cccc2ccccc12
Reaction time: 0.17 h
Yield: 17 %
Yield: 72 %

Procedure:
To an N,N-dimethylformamide solution of tert-butyl {(3R)-1-[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]pyrrolidin-3-yl}carbamate (0.300 g, 0.609 mmol) was added cesium carbonate (0.198 g, 0.609 mmol). After 10 min, methyl iodide (0.046 mL, 0.104 mmol) was added and the reaction mixture was stirred for one hour. The reaction mixture was quenched with water, extracted with ethyl acetate (three times), dried over magnesium sulfate, concentrated and purified by column chromatography to afford tert-butyl {(3R)-1-[1-methyl-3-(naphthalen-1-ylsulfonyl)-1H-indazol-5-yl]pyrrolidin-3-yl}carbamate (223 mg, 72%) and tert-butyl {(3R)-1-[2-methyl-3-(naphthalen-1-ylsulfonyl)-2H-indazol-5-yl]pyrrolidin-3-yl}carbamate (53 mg, 17%)
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9](Br)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].[I-:37].[Na+]>CC(C)=O>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([I:37])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6]
Reactant: [I-]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(C)(CC)C(I)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 78.5 %

Procedure:
A solution of diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 29) and sodium iodide (1.30 g) in acetone (15 ml) was allowed to stand for twenty hours at room temperature in the absence of light. It was then filtered through Hyflo Super-Cel, evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-iodo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.85 g, m.p. 98-100° C.). NMR (CDCl3): δ 1.3(6H,t), 1.7-1.9(2H,m), 2.5-2.6(2H,m), 4.05(4H,m), 5.3(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). M/S: M+ 615.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[CH:6]=[C:5]([NH2:10])[N:4]=1.[C:11]([O-:14])(=O)[CH3:12].[Na+].ClCC=O>O>[CH3:1][S:2][C:3]1[NH:8][C:7]2[C:12]([N:10]=[CH:5][CH:6]=2)=[C:11]([OH:14])[N:4]=1
Reactant: CC(=O)[O-]
Reactant: CSc1nc(N)cc(O)n1
Agent: O=CCCl
Agent: [Na+]
Solvent: O
Product: CSc1nc(O)c2nccc-2[nH]1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2-(Methylthio)4-hydroxy-6-aminopyrimidine (3.1) (40 g) and sodium acetate (40 g, 2 eq.) were mixed with water (600 ml) and the slurry heated to 80° C. with vigorous stirring. To the mixture was then added chloroacetaldehyde (50 wt. % in water, 40 g, 1 eq.), slowly over 10 mins. The mixture turned yellow in colour and the solid mostly dissolved, before a new solid precipitated. After a further 30 mins, the mixture was allowed to cool overnight, then the solid was collected by filtration, washed well with water and then with acetone. Dried under vacuum at 50° C. to give (3.2), 8.7 g. δH (300MHz, DMSO-db); 2.49 (3H, s, SCH3), 6.33 (1H, m, H7), 6.89 (1H, m, H8), 11.74 and 12.03 (2×broad s, D2O exch.) ppm.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>C1COCC1>[CH3:7][N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCC(O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of potassium tert-butoxide (1.43 g, 12.9 mmol) in THF (6 mL) was added 1-methylpyrrolidin-3-ol (645 mg, 6.39 mmol). The reaction mixture was stirred at room temperature for 1 h. Then 1-fluoro-4-nitrobenzene (900 mg, 6.39 mmol) was added to the above solution and stirred for another 2 h. After the removal of the volatile, the residual was dissolved in ethyl acetate (40 mL), and then washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EA:PE=1:4) to give desired product as a yellow oil (626 mg, 44%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)=[O:28].[CH2:38]([NH:40][CH2:41][CH2:42][OH:43])[CH3:39]>>[F:37][C:32]1[CH:31]=[C:30]([O:29][C:27](=[O:28])[N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:40]([CH2:38][CH3:39])[CH2:41][CH2:42][OH:43])[CH2:7][CH2:8]2)[CH3:1])[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: CCNCCO
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(F)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(F)c(F)c2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.trifluoroacetic acid salt and 3,4-difluoro-phenyl chloroformate were reacted, followed by treatment with 2-ethylamino-ethanol to yield trans-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-methyl-carbamic acid 3,4-difluoro-phenyl ester, MS: 427 (MH+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:52])([CH3:51])[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:51])([CH3:52])[CH2:15][O:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(C)(C)O)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.26 g), sodium hydrogen carbonate (0.42 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.14 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.049 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.041 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.069 g, 46%).
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.C(N(CC)CC)C.[CH2:23]([SH:27])[CH2:24][CH2:25][CH3:26].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[CH2:23]([S:27][C:2]1[C:3](=[O:15])[CH:4]=[C:5]2[C:14](=[N:13][C:12]3[C:7]([S:6]2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCS
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCSc1cc2nc3ccccc3sc-2cc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3H-phenothiazin-3-one (0.64 g) in 75 ml methanol was added triethylamine (1.0 ml) and n-butanethiol (0.58 ml). The mixture was stirred at room temperature for 48 hours. Then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.67 g) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was chromatographed on neutral alumina (Act III) and eluted with 15% EtOAc/hexane to afford the title compound (0.4 g), m.p. 133° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][N:14]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:33].[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:13][N:14]1[CH:23]=[C:22]([C:2]2[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=2[NH:4][C:37]([CH:34]2[CH2:36][CH2:35]2)=[O:38])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:33]
Reactant: O=C(Cl)C1CC1
Reactant: CS(=O)(=O)c1ccc(N)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2NC(=O)C2CC2)c2ccccc2c1=O

Procedure:
2-bromo-4-methanesulfonylaniline was coupled to the title compound of Example 89, step 1 in a manner similar to Example 89, step 2. The resulting product was reacted with cyclopropanecarbonyl chloride using diisopropylethylamine in THF to prepare the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.38 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.53-7.64 (m, 3H), 6.94 (d, J=8.0 Hz, 1H), 3.59 (s, 3H), 3.25 (m, 3H), 1.64 (brs, 1H), 0.52-0.75 (m, 4H). LCMS: 397.0 (M+1)+
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:27](=S)=[S:28]>CCO.O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3=[N:23][C:27](=[S:28])[N:24]=[C:19]3[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: S=C1N=c2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2=N1
Yield: 68.4 %

Procedure:
A mixture of 4-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (326 mg, 1.0 mmol), KOH (66 mg, 1.1 mmol) and CS2 (66 μL, 1.1 mmol) in 95% EtOH (1.5 mL) and H2O (0.2 mL) was refluxed for 3 h, then evaporated, and the residue was purified by chromatography over silica gel (CHCl3 --MeOH, 4:1) to give 250 mg (68%) of the title compound as a foam solid. 1H NMR (DMSO-d6): 1.40-1.48 (m, 2H), 1.54-1.61 (m, 1H), 1.67-1.71 (m, 2H), 2.09-2.18 (m, 2H), 2.517 (d, 2H, J=6), 2.841 (t, 2H, J=5), 3.17-3.20 (m,2H), 4.139 (t, 2H, J=5), 6.551 (d, 1H, J=2), 6.605 (dd, 1H, J=8.5; 2), 6.950 (d, 1H, J=8.5), 7.11-7.28 (m, 5H). The hydrochloride, mp. 273-5° C. Analysis, Calcd. for C21H26ClN3OS: C 62.44, H 6.49, N 10.40; Found: C 62.28, H 6.42, N 10.21.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:9]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.Cl>ClCCCl>[CH:9]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[CH:11][C:10]=1[C:1]([CH3:2])=[O:3]
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)Cc1ccccc1O2
Temperature: 16 °C
Reaction time: 0.5 h

Procedure:
A 21.4 ml portion of acetyl chloride in 30 ml of 1,2-dichloroethane was added dropwise to 40 g of aluminum chloride in 105 ml of 1,2-dichloroethane. This mixture was stirred 1/2 hour and then added portionwise to an ice-cooled solution of 54.66 g of xanthene in 225 ml of 1,2-dichloroethane. The reaction was then allowed to warm to 16° C. and poured onto ice. A 180 ml portion of concentrated hydrochloric acid was added, the mixture was allowed to stand overnight and the layers separated. The aqueous layer was extracted with two 100 ml portions of chloroform then the organic layers was combined, dried, filtered through hydrous magnesium silicate and evaporated, giving the desired intermediate as a white crystalline solid, mp 103°-104° C.