Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:1][N:2]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[NH2:3]
Reactant: CNN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Into a 100 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, and dropping funnel under an atmosphere of nitrogen was added THF (25 mL), methylhydrazine (2.53 g, 2.92 mL, 55 mmol), and triethylamine (4.35 g, 5.99 mL, 55 mmol). The temperature of the mixture was lowered to approximately 5° C. and 4-methylbenzenesulfonyl chloride (9.5 g, 50 mmol) dissolved in 25 mL of THF was added dropwise at a rate such that the temperature did not rise over 10° C. The cooling bath was removed and the mixture was allowed to stir overnight at RT. Ether (100 mL) was added to the reaction mixture and the resulting slurry was washed with water (50 mL), brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo to give 9.5 g (95% yield) of the title product. 1H NMR (CDCl3) δ 7.7 (d, 2H), 7.4 (d, 2H), 3.6 (s, b, 2H), 2.8 (s, 3H), 2.4 (s, 3H)
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12](=[O:29])[CH2:13][N:14]([C:24](=[O:28])[C@H:25]([CH3:27])[NH2:26])[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:10])([CH3:9])[CH3:8].[CH2:30]([N-:34][C:35](=[O:46])[C:36](=O)[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH3:33]>>[C:7]([O:11][C:12](=[O:29])[CH2:13][N:14]([C:24](=[O:28])[C@H:25]([CH3:27])[NH:26][CH:36]([C:35]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[O:46])[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:8])([CH3:10])[CH3:9]
Reactant: C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reactant: CCCC[N-]C(=O)C(=O)CCc1ccccc1
Agent: O=C(O)C(=O)O
Product: CCCCNC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 19.1 %

Procedure:
By reacting L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate (2.0 g) with N-butyl-2-oxo-4-phenylbutyrylamide (4.0 g) in a similar manner to that of Example 2, there is obtained N-(1-butylaminocarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester (0.5 g) as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[SH:13])([O-])=O.[NH2:14][C:15](N)=S>CN(C)C=O.O>[NH2:14][C:15]1[S:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1ccc(S)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1

Procedure:
A solution of 10 g of 2,4-dinitrothiophenol and 7.6 g of thiourea in 50 ml of dimethylformamide is heated at 120° C. for 3 hours. The mixture is diluted with 300 ml of water, and the solid is filtered off with suction and washed with water. 7.3 g of crude 2-amino-5-nitrobenzothiazole, the identity of which was confirmed by TLC comparison with authentic material, are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH2:9][C:8]2=[O:16])=[O:4].C([O:22][N:23]=O)CCC.Cl>CO.O1CCOCC1>[CH3:17][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][C:9](=[N:23][OH:22])[C:8]2=[O:16])=[O:4]
Reactant: CCCCON=O
Reactant: COc1cc2c(cc1C(=O)N(C)C)C(=O)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(cc1C(=O)N(C)C)C(=O)C(=NO)C2
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 6-Methoxy-3-oxo-indan-5-carboxylic acid dimethylamide (2.56 g, 10.97 mmol) in the methanol (40 ml) and dioxane (40 ml) was added n-butylnitrite (1.48 ml, 12.067 mmol) followed by concentrated HCl (1 ml). The solution was stirred at r.t overnight during which time a precipitate was formed. The precipitate was collected and dried to yield a yellow solid (2.8 g, 97%). LC-MS: m/e 263 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:24][C:25]([NH:27][C:28]1[N:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][N:29]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:26])[NH:27][C:28]1[N:33]=[CH:32][C:31]([C:34](=[O:35])[NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[CH:30][N:29]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cn1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)cn1

Procedure:
(5-{[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-pyrimidin-2-yl)-carbamic acid tert-butyl ester was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-tert-butoxycarbonylamino-pyrimidine-5-carboxylic acid (prepared by BOC protection of ethyl 2-amino-5-pyrimidine carboxylate [prepared as described by P. Schenone, et al., J. Heterocyclic Chem., 27:295–305(1990)] using di-tert-butyl dicarbonate and 4-dimethylaminopyridine in acetonitrile, followed by saponification with sodium hydroxide and neutralization with dilute aqueous HCl) as described in EXAMPLE 1, Step 2:
Reaction SMILES: I.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=N)SC.[CH3:19][NH:20][CH2:21][CH2:22][NH2:23].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[CH3:19][N:20]1[CH2:21][CH2:22][NH:23][C:9]1=[N:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSC(=N)Nc1ccccc1-c1ccccc1
Reactant: CNCCN
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CN1CCNC1=Nc1ccccc1-c1ccccc1

Procedure:
A mixture of 1-(2-biphenylyl)-2-methyl-2-thiopseudourea hydriodide (5.6 g) and N-methylethylenediamine (3.3 g) in ethanol (70 ml) was heated under reflux for 48 hours. Removal of the solvent gave an oil which was dissolved in methanol (25 ml) and treated with fumaric acid (1.7 g) to give 2-(1-methyl-2-imidazolidinylideneamino)biphenyl fumarate (m.p. 168°-169° C.) which was recrystallised from a 1:1 mixture of methanol and ether.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[NH:11][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)C.[OH-].[Na+]>C(O)C.O>[C:21]1([C:12]2[N:11]=[C:10]([S:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])[NH:14][C:13]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 55 %

Procedure:
Part B. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid ethyl ester (7.6 g, 0.02 mol) in ethanol (200 mL), was added dropwise a solution of sodium hydroxide (7.6 g) in water (200 mL), and the reaction mixture was stirred at reflux under nitrogen for 3 hours. The reaction mixture was concentrated to half the original volume and then extracted with ether. The ether extracts were discarded. The reaction mixture was acidified to pH 1 with 1N hydrochloric acid and extracted with ether, and the combined organic extracts were dried over magnesium sulfate and concentrated under vacuum. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4.5-diphenyl-1H-imidazol-2-ylthio) pentanoic acid (3.88 g, 0.011 mol) as a white solid, mp 190°-195°. 1H NMR (DMSO-d6) δ 12.6(s,1H) , 7.6-7.1(m,10H), 3.3-3.1 (m,2H), 2.3-2.1 (m,3H), 1.8-1.6 (m,4H).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[C:12]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])[CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[CH2:10][CH2:9][C:8]2=[O:27])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:38].Cl>ClCCl>[CH2:40]([O:39][C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[C:12]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])[CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[CH2:10][CH2:9][C:8]2=[O:27])=[CH:28][CH:29]=1)=[O:38])[CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(N)cc1)C(=O)CC2
Reactant: CCCCCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCOC(=O)Nc1ccc(CN2C(=O)CCc3c(CC4SC(=O)NC4=O)ccc(OC)c32)cc1
Reaction time: 1 h
Yield: 489.3 %

Procedure:
0.6 g of 5-[1-(4-aminobenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione was suspended in dichloromethane (6 ml), and 4 ml of pyridine was added with ice cooling to form a solution. 0.26 g of amyl chloroformate was added to this solution, followed by stirring for 1 hour. 1 N hydrochloric acid was added to the reaction liquid, and extracted with ethyl acetate. The extract was washed twice with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), and recrystallized from diisopropyl ether, giving 3.75 g (97% yield) of 5-[1-(4-pentyloxycarbonylaminobenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][C:9]([C:21]([F:24])([F:23])[F:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:30][O+](C)C>>[CH3:30][O:20][C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([C:21]([F:23])([F:22])[F:24])[CH:10]=2)[N:19]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(Cc2cc(C(F)(F)F)nn2-c2ccccc2)N1
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2cc(C(F)(F)F)nn2-c2ccccc2)CCCC1

Procedure:
The title material of Example 137 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [Br:1][C:2]1(Br)[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1.O.Cl>N1C=CC=CC=1>[Br:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)(Br)CO2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cc2occ(Br)c(=O)c2cc1Oc1ccccc1
Yield: 82.1 %

Procedure:
In 20 ml of pyridine was dissolved 4.81 g of 3,3-dibromo-2,3-dihydro-7-methylsulfonylamino-6phenoxy-4H-1-benzopyran-4-one. The solution was refluxed for 20 minutes. The reaction mixture was introduced into 200 ml of water. The mixture was adjusted to pH 4 with concentrated hydrochloric acid and then extracted with two 100-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from acetonitrile to obtain 3.30 g (yield: 82%) of 3-bromo-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 215°-216° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15])([O-:10])=[O:9]>ClCCCl.C(N(CC)CC)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:15])([O-:10])=[O:9]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)CCO
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[Si](C)(C)CCOC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
H--2-Trimethylsilylethyl 3-nitrobenzoate may be prepared as follows: a solution of 41.8 g of 2- trimethylsilylethanol in 200 cm3 of 1,2-dichloroethane and 51 cm3 of triethylamine is added to a solution of 66.0 g of 3-nitrobenzoyl chloride in 1000 cm3 of 1,2-dichloroethane cooled to 5° C. The reaction mixture is stirred for 12 hours at a temperature in the vicinity of 25° C., then the insoluble product is separated by filtration and washed with 2 times 50 cm3 of 1,2-dichloroethane. The filtrate is concentrated to dryness under reduced pressure at 40° C. The oily residue obtained is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 76.9 g of 2-trimethylsilylethyl 3-nitrobenzoate are thus obtained in the form of an oil used as it is in subsequent syntheses.
Reaction SMILES: Cl.[CH3:2][CH:3]([C:11]1([OH:23])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[C:24]([Cl:27])(=[O:26])[CH3:25].[OH-].[Na+].Cl>CCOCC>[ClH:27].[C:24]([O:23][C:11]1([CH:3]([CH3:2])[CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(CN1CCOCC1)C1(O)CCCCC1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(=O)OC1(C(C)CN2CCOCC2)CCCCC1c1ccccc1

Procedure:
1-(1-Methyl-2-morpholinoethyl)-2-phenylcyclohexanol hydrochloride (Example XVIII) is converted to the free base and treated with acetyl chloride according to the procedure of Example I (c) using 14 ml acetyl chloride and a reaction time of 90 hours. The product is treated with NaOH to give the base which is dissolved in ether and acidified with HCl gas to give 10.7 g., m. 176.5-7.5 after recrystallization from isopropanol.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH2:31][CH2:32][CH3:33])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: CCCNCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.092 g, 84%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.13 g, 0.28 mmol) and propylamine (0.165 g, 2.80 mmol). mp >250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[S:12][CH:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:14]([OH:18])[C:15](O)=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[OH:18][CH:14]1[CH:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[S:12][C:3]2[C:4]3[C:9]([CH:10]=[CH:11][C:2]=2[NH:1][C:15]1=[O:16])=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: COc1ccc(C(Sc2c(N)ccc3ccccc23)C(O)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(C2Sc3c(ccc4ccccc34)NC(=O)C2O)cc1

Procedure:
A mixture of 1.0g (0.0027 mol) of (-)-β-[(2-amino-1-naphthalenyl)thio]-α-hydroxy-4-methoxybenzenepropanoic acid and 0.1 g of p-toluenesulfonic acid in 50 ml of xylene was stirred and heated at reflux for 1.5 hours using a Dean-Stark water strap. After cooling the crystals were collected to provide 0.80 g (80%) of [2R-(2α,3α)] 2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b] [1.4]thiazepin-4(5H)-one, mp 238-239°, [α]D 25 -22.97° (C 0.51, acetone).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: O=Cc1cccc(Cl)c1
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CCC(N2Cc3c(NCc4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (1.04 g, 4 mmol) was dissolved in acetic acid (7 ml) with heat. The mixture was cooled slightly and methylene chloride (50 ml) was added slowly followed by 3-chlorobenzaldehyde (0.91 ml, 8 mmol) and sodium triacetoxyborohydride. (2.54 g, 12 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 h, diluted with methylene chloride (100 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give a white solid. The solid was recrystallized from methylene chloride/methanol to give 0.48 g (31%) of product as a white solid: mp 253-255° C.; 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 7.45 (s, 1H), 7.37-7.19 (m, 4H), 6.95 (d, J=7.4 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.45 (t, J=5.9 Hz, 1H), 5.14 (dd, J=5.1 and 13.1 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 4.34 (d, J=17.3 Hz, 1H), 4.20 (d, J=17.2 Hz, 1H) 3.01-2.87 (m, 1H), 2.66-2.60 (m, 1H), 2.42-2.25 (m, 1H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.90, 171.24, 168.74, 143.03, 142.59, 133.08, 132.16, 130.19, 129.12, 126.80, 126.70, 125.73, 112.27, 110.55, 51.54, 45.73, 45.47, 31.25, 22.79; Anal. Calcd. For C20H18ClN3O3: C, 62.58, H, 4.73; N, 10.95. Found: C, 62.32; H, 4.61; N, 10.80.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH2:15]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>COCCOC>[CH2:15]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:33])[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)C(C(=O)OCC)C(=O)OCC

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 2-(1-tetradec-4-enylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 2-(1-tetradec-4-enylamino)benzoylmalonate.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](#[N:11])[CH3:10].C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:7]1[C:2]([CH2:10][C:9]#[N:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC#N
Reactant: Fc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCc1ncccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 2-chloro-3-fluoropyridine (3.0 g, 23 mmol, 1.0 equiv) and acetonitrile (1.3 mL, 25 mmol, 1.1 equiv) in toluene (50 mL) was added sodium hexamethyldisilazide (NaHMDS) (2.0 M in THF, 13 mL, 25 mmol, 1.1 equiv). The resulting mixture was stirred for 2 hours at 0° C. and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the crude desired product as an oil which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([O-])=O>[Pd].O1CCCC1>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]=1[NH:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1c(N)cccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Under hydrogen gas atmosphere, a mixture of tert-butyl {2-[(2,6-dinitrophenyl)amino]ethyl}carbamate (8.44 g, 25.9 mmol) and 10% palladium on carbon (50% wet, 1.67 g) in tetrahydrofuran (260 mL) was stirred at room temperature for 4 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound as a brown oil (6.82 g, 25.6 mmol, 99%).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:4]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO.[Ni]>[ClH:1].[CH3:14][O:13][C:11]([CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([NH:2][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:12]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CC[C@H]1CC[C@H](N)CC1
Agent: [Ni]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CC[C@H]1CC[C@H](NCc2ccccc2)CC1

Procedure:
8.0 g of methyl 3-(trans-4-aminocyclohexyl)propionate-hydrochloride, 4.3 g of benzaldehyde and 5.0 ml of triethylamine in 150 ml of methanol are hydrogenated with 1.0 g of Raney nickel at 50° C. under a hydrogen pressure of 50 psi for 4 hours. After cooling, the mixture is suction filtered and the filtrate is evaporated down. The residue is divided between ethyl acetate and water, the aqueous phase is adjusted to pH 8-9 with sodium hydroxide solution and extracted with ethyl acetate. The combined ethyl acetate phases are washed with saturated saline solution, dried and evaporated down. The residue is suspended in diethylether and mixed with methanolic hydrochloric acid. The precipitate is suction filtered, washed with diethylether and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:15]([CH:18]=1)[CH:16]=[O:17].[CH3:28][Mg]Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:15]([CH:16]([OH:17])[CH3:28])[CH:18]=1
Reactant: O=Cc1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 5-[(E)-2-(2,4-difluorophenyl)vinyl]-2-(phenylsulfonyl)benzaldehyde (prepared from Example 58 according to the method of Example 50 Step 1, 74 mg, 0.193 mmol) in tetrahydrofuran (2 mL) was cooled to −78° C. under nitrogen. Methylmagnesium chloride (3.0M in tetrahydrofuran, 0.15 mL, 0.424 mmol) was added and the reaction stirred for 30 minutes then quenched with 1N HCl (5 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 30% ethyl acetate/isohexane to obtain the title compound as a white solid (56 mg, 72%). δH (360 MHz, d6 DMSO): 8.02 (1H, d, J=8.3 Hz), 7.95-7.59 (8H, m), 7.39 (2H, s), 7.33-7.27 (1H, m), 7.14 (1H, td, J=2.1, 8.5 Hz), 5.37 (2H, t, J=5.4 Hz), 1.07 (3H, d, J=5.9 Hz).