Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:11]>CO>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)(=[O:11])[CH3:9]
Reactant: Clc1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(Cl)cc2)c([N+](=O)[O-])c1

Procedure:
4-Chloroiodobenzene and 4-bromo-3-nitroacetophenone were reacted under Ullmann conditions to give the novel intermediate 4-acetyl-4'-chloro-2-nitrobiphenyl, m.p. 103°-105° C. (from methanol). This compound was reduced with stannous chloride and concentrated hydrochloric acid to give 4-acetyl-2-amino-4'-chlorobiphenyl, m.p. 139°-140° C. (from methanol).This compound was converted to the novel intermediate 4-acetyl-4'-chloro-2-hydroxybiphenyl and thence to the novel intermediate 4-acetyl-4'-chloro-2-methoxybiphenyl, b.p. 167°-170° C./0.4 mm., by diazotization and methylation methods analogous to those described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:19][C@@H:20]2[CH2:22][O:21]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1>C(O)C>[Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:19][C@@H:20]([OH:21])[CH2:22][NH:31][CH2:30][C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18]
Reactant: NCc1ccncc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C[C@@H]3CO3)c(=O)c1Cl)C2(C)C
Solvent: CCO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C[C@@H](O)CNCc3ccncc3)c(=O)c1Cl)C2(C)C
Yield: 30.2 %

Procedure:
4-Chloro-2-[(2R)-oxiran-2-ylmethyl]-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (0.141 mmol) in ethanol (2 mL) was stirred with 1-(pyridin-4-yl)methanamine (17 μL, 0.17 mmol) at 80° C. for 8 hours. After cooling, the reaction solution was concentrated, mixed with water and extracted with ethyl acetate, and the extract was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol=9/1) to give the desired product (19 mg, 29% yield).
Reaction SMILES: [OH:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>O>[CH3:17][O:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC=CCc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC=CCc1ccccc1
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
25 g of o-hydroxyallylbenzene was dissolved in 100 ml of water and to the mixture was added 8g of sodium hydroxide. To the resulting mixture was added dropwise 25.2 g of dimethyl sulfate over a period of about 2 hours, while maintaining the temperature at 5° - 10° C. The thus obtained mixture was heated with stirring at 80°- 100° C for approximately 30 minutes, and then the oil layer was separated. This layer was distilled under reduced pressure, there was obtained 22.3 g (yield 81%) of o-methoxyallylbenzene having a boiling point of 51° C/2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][S:14][C:15](SC)=[N:16][C:17]#[N:18].[OH-].[Na+].Cl>C(O)C.O>[C:17]([N:16]=[C:15]([S:14][CH3:13])[NH:12][S:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:11])#[N:18]
Reactant: NS(=O)(=O)c1cc(Cl)ccc1Cl
Reactant: CSC(=NC#N)SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(=NC#N)NS(=O)(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of 10.6 g (43.2 mmol) of 2,5-dichloro-benzenesulfonamide, 7.15 g (44.0 mmol) of 90 percent dimethyl N-cyanodithioiminocarbonate and 1.8 g (44 mmol) of NaOH in 60 ml of ethanol and 10 ml of H2O was heated at reflux for 6 hours. After cooling to room temperature the reaction mixture was poured into 600 ml of ice water. The resulting solution was acidified with 6N HCl to separate 2.2 g of the desired product as a white solid. Concentration of the filtrate gave an additional 8.5 g of the desired product. The total yield of material was 10.7 g (76 percent) of white solid, mp 145° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]1([S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([CH:21]=[CH:22][C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)(=[O:13])=[O:12])[C:10]2[C:5](=CC=CC=2)[CH:4]=[CH:3][CH:2]=1.Cl.NCCC1C=CC(C=CC(OCC)=O)=CC=1.C1(OS([Cl:61])(=O)=O)C2C(=CC=CC=2)C=CC=1>>[Cl:61][C:4]1[CH:5]=[CH:10][C:1]([S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)(=[O:13])=[O:12])=[CH:2][CH:3]=1
Reactant: O=S(=O)(Cl)Oc1cccc2ccccc12
Reactant: CCOC(=O)C=Cc1ccc(CCNS(=O)(=O)c2cccc3ccccc23)cc1
Agent: CCOC(=O)C=Cc1ccc(CCN)cc1
Agent: Cl
Product: O=C(O)C=Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 88 %

Procedure:
ethyl 4-[2-(1-naphthylsulphonamido)-ethyl]-cinnamate from ethyl 4-(2-aminoethyl)-cinnamate hydrochloride and 1-napthylsulphochloride; m.p. 85°-86° C. (recrystallized from ethanol); yield 88% of theory, and therefrom by hydrolysis
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH:25]2[CH2:28][CH2:27][CH2:26]2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C1CCC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C2CCC2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively aminated with cylobutanone in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-cyclobutyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 408.3 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:10][CH2:9][C:8]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][C:8]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC2(CC1)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3 ml of acetyl chloride in 10 ml of chloroform are added dropwise to a stirred suspension of 6.0 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7, and 14.0 g of sodium bicarbonate in 75 ml of chloroform. After total addition, the reaction mixture is successively stirred at ambient temperature for 16 hours, filtered, washed sequentially with water, dilute hydrochloric acid and a saturated sodium chloride solution, dried and the solvent is removed under reduced pressure, leaving a residue which solidifies upon standing. The solid is recrystallized twice from hexane to give the product, 2,3-dihydro-1'-acetylspiro[benzofuran-2,4'-piperidine], mp 94°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9]([S:17][CH3:18])[N:10]=[C:11]([O:14]CC)[C:12]=2[N:13]=1.O1CCOCC1.Cl>O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9]([S:17][CH3:18])[N:10]=[C:11]([OH:14])[C:12]=2[N:13]=1
Reactant: CCOc1nc(SC)nc2sc(Cc3c(Cl)cccc3Cl)nc12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(O)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 62.2 %

Procedure:
To a mixture of 2-(2,6-dichloro-benzyl)-7-ethoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidine (1.7 g, 4.4 mmol), 1,4-dioxane (20 mL), and H2O (4 mL) was added 4 N HCl in dioxane (13 mmol, 3.3 mL) and the resulting solution was heated to 90° C. After 12 h, the solution was cooled and concentrated. The resulting residue was purified by FCC to afford the title compound (980 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[C:7](/[N:8]=N/C2C=CC(C)=CC=2)=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.[H][H]>CC(O)C.[Pt]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:17])[N:5]=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1
Reactant: [H][H]
Reactant: CCCSc1nc(Cl)c(/N=N/c2ccc(C)cc2)c(Cl)n1
Agent: [Pt]
Solvent: CC(C)O
Product: CCCSc1nc(Cl)c(N)c(Cl)n1
Temperature: 20 °C

Procedure:
A stirred solution of 4,6-dichloro-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine (Step (3), 1.1 kg) in 2-propanol (16.6 kg) was hydrogenated for 1 h at 40° C./3.2 bar over a platinum on carbon catalyst (0.81 kg, 50% w/w Pt/C). The hydrogen gas pressure was released and the reactor flushed with nitrogen. The reaction mixture was filtered. The collected solid was washed with 2-propanol (1.7 kg) and the combined filtrates were concentrated under reduced pressure. The residual oil was cooled to 20° C. and dissolved in ethyl acetate (5 kg) and water (5.51) was added. The pH of the stirred mixture was adjusted to pH 2 by the addition of 3M aqueous hydrochloric acid (800 ml). The phases were allowed to separate and the aqueous phase was discharged. Water (2.751) was added to the organic phase and the pH was adjusted to 2 by the addition of a small amount of 3M HCl (45 ml). The aqueous phase was separated and the organic phase concentrated under reduced pressure at 30-50° C., to give 4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine as a reddish viscous oil containing ethyl acetate that was dissolved in ethanol (8.5 kg). Solvent (6.51 of ethanol/ethyl acetate) was then removed by distillation at reduced pressure. A further portion of ethanol (4.5 kg) leas added to the residue and the distillation repeated to remove 6.5 l of solvent. The ethanol solution of the product was used without further purification in the following step.
Reaction SMILES: O=[O+][O-].[O:4]=O.[CH2:6]([C:13]1[O:19][C@@H:18]2[C@@H:15]([C:16](=[O:24])[N:17]2[CH:20]=C(C)C)[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CSC>ClCCl>[CH2:6]([C:13]1[O:19][C@@H:18]2[C@@H:15]([C:16](=[O:24])[N:17]2[CH:20]=[O:4])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=O
Reactant: CC(C)=CN1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: O=CN1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
An ozone-oxygen mixture was passed through a solution, cooled to -70° C., of 2.56 g (10 millimols) of (1S,5R)-3-benzyl-6-(2-methylprop-1-enyl)-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one (R. J. Stoodley et al., J. C. S. Perkin I 1974, 181) in 75 ml of anhydrous dichloromethane, until a blue coloration was obtained. Thereafter, flushing with nitrogen was carried out for 10 minutes, and 5.9 ml (80 millimols) of dimethyl sulphide were then added at -70° C. The mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature, and then evaporated down in vacuo. The residue was dissolved in dichloromethane, and the solution was washed with saturated NaHCO3 solution and water, and dried over MgSO4. After the solvent had been removed in vacuo, the residue was triturated with ether. 1.2 g (52%) of (1S,5R)-3-benzyl-6-formyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one were obtained as colorless crystals, melting point 90°-92° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:9]([C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CN(C)c1ccc(CNc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Yield: 44.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-dimethylaminophenyl)[(4-dimethylaminophenyl)methyl]amine (1.05 g) and 2,6-diisopropylphenyl isocyanate (1.03 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-dimethylaminophenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.815 g) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[N:10]=[CH:9][NH:8][N:7]=2)[CH2:3][CH2:2]1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].O>N1C=CC=CC=1>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:7]1)=[O:15])[CH3:12]
Reactant: c1nc(SCC2CC2)n[nH]1
Reactant: CCN(CC)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(SCC2CC2)n1
Reaction time: 10 h
Yield: 83.5 %

Procedure:
To a solution of 3-cyclopropylmethylthio-1,2,4-triazole (3.8 g) in pyridine (30 ml), diethylcarbamoyl chloride (3.4 g) was added, and the resultant mixture was allowed to stand at room temperature for 10 hours. Water (250 ml) was added to the reaction mixture, which was then extracted with chloroform (150 ml) two times. The chloroform extract was washed with 1N hydrochloric acid (150 ml) two times and water (200 ml) one time, dried over magnesium sulfate, and concentrated under reduced pressure to give 5.2 g of 1-diethylcarbamoyl-3-cyclopropylmethylthio-1,2,4-triazole (Compound No. 1). Yield, 84%. M.P. 51°-52° C.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:19]1([C:25]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=2[C:27](Cl)=[O:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:25]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=2[C:27]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:8]=3[C:9]#[N:10])[CH2:2][CH2:3]2)=[O:28])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCNCC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCN(C(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-piperazin-1-yl-5-trifluoromethyl-benzonitrile and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (69%, yellow solid, MS (m/e): 490.2 (M+H, 100%)
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4](=[O:12])[CH2:3][C:2]1=[O:13].[Br:14]Br>CC(O)=O>[Br:14][CH:3]1[C:2](=[O:13])[CH2:1][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4]1=[O:12]
Reactant: O=C1CC(=O)CC2(CCCCC2)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1CC2(CCCCC2)CC(=O)C1Br

Procedure:
To a stirred solution of spiro[5,5]undecane-2,4-dione (1.29 g, 5 mmol) in AcOH (10 mL) at r.t. was added bromine (0.8 g, 0.25 ml, 5 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid which was used without further purification. LCMS (ES+) 258.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(=O)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].C1(O)C=CC=CC=1.[CH3:26][O:27][CH2:28][CH2:29]Br>CN(C=O)C>[CH3:26][O:27][CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: COCCOc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(4-(2-Methoxyethoxy)phenyl)piperazine is prepared from 4-(4-hydroxy-phenyl)-1-acetylpiperazine. To NaH (60% in mineral oil, 0.79 g, 20 mmol) in DMF (25 ml) add the phenol (3.0 g, 13.6 mmol), followed by 2-bromoethyl methyl ether (2.27 g, 16.3 mmol). Stir at RT 18 h, concentrate, and partition between EtOAc and 5% citric acid. Wash the organic with 1N NaOH, then brine. Dry over MgSO4, and concentrate to obtain the alkylated product as a white solid. Heat this material (2.2 g, 7.9 mmol) in 6N HCl (30 ml) at reflux for 1 h. Allow to cool and basify to pH=10 with NaOH. Extract with CH2Cl2 and wash with water and then brine. Dry the organic with MgSO4 and concentrate to give the piperazine as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>>[C:28]([NH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(N)cc1OCC2)c1ccccc1Cl
Agent: Cl
Product: C=CC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure of Example 68 for 158, 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide HCl salt and acryloyl chloride reacted to give 8-acrylamido-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide which was treated with dimethylamine to give 161. MS: (ESI+) 484.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:16].[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH3:17])=[CH:4][C:3]=1[F:16]
Reactant: O=C(c1ccccc1)c1ccc(Br)c(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(Br)c(F)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-bromo-3-fluorophenyl)-phenylmethanone (200 mg, 0.717 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:25][CH3:26])[C@@H:22]([OH:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([OH:32])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:36]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:25][CH3:26])[C@@H:22]([OH:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([O:32][CH3:36])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC[C@@H]([C@H](C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H]([C@H](C)O)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 260 mg (0.543 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 152) in 5 mL of THF was added 60% sodium hydride (217 mg, 5.43 mmol) at 0° C. After being stirred at 0° C. for 20 min, iodomethane (271 uL, 4.35 mmol) was added. The reaction was allowed to warm to ambient temperature, and stirred for an additional 3 h until completion. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated NaCl, dried over MgSO4, filtered and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (39 mg, 0.11 mmol) and benzylamine (13 mg, 0.12 mmol). The title product was obtained as a yellow solid (15 mg, 28% yield). 1H NMR (300 MHz, d6-DMSO) δ: 8.72 (1H, s), 8.71 (1H, s), 8.35-8.39 (3H, m), 7.31 (2H, m), 7.27 (2H, m), 2.6 (2H, m). MS m/z: 439.85, 441.80 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20]C)=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[CH3:23][NH:24][CH3:25].O>CO.S(=O)(=O)(O)O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[N:24]([CH3:25])[CH3:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Reactant: CNC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (6 g; 18.6474 mmole) in 33% w/w dimethylamine in methanol (50 ml) was heated at 100° C. under pressure (autoclaved) for 24 hours. The mixture was cooled, and treated with water, concentrated, and extracted with chloroform. The extract was washed with water, dried and evaporated to give a brown solid. The solid was heated in 70% sulphuric acid (150 ml) on a steambath for 6 hours. The mixture was cooled and the pH adjusted to about 7 before extraction into chloroform. The extract was dried and evaporated to give a yellow solid (1.25 g). NMR and mass spectra were consistent with the required structure.
Reaction SMILES: [C:1]([C:4]1([CH2:13][OH:14])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:3])=[CH2:2].N1C=CC=CC=1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>CCOCC>[S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)([O:14][CH2:13][C:4]1([C:1]([CH3:3])=[CH2:2])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: C=C(C)C1(CO)Cc2ccccc2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)C1(COS(=O)(=O)c2ccc(C)cc2)Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
To a mixture of 3.20 g (0.017 mole) of 2-isopropenyl-2-indanemethanol and 3.16 g (0.04 mole) of pyridine, with ice-cooling, was added 3.90 g (0.02 mole) of tosylchloride. The mixture was stirred for 24 hours, with ice-cooling, to complete the reaction. The reaction mixture was poured into ice water, mixed with 50 ml of ether. And then the ether layer was separated, the aqueous layer was extracted twice with 25 ml of ether. The ether layers were combined, washed with 2% aqueous hydrochloric acid solution, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 5.80 g of 2-iso-propenyl-2-indanylmethyl tosylate.