Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:34])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:35][NH2:36].C(OCC)C>O1CCOCC1.O>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:36][CH3:35])[CH2:13][CH2:12]4)[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 167e, 5.00 g) dissolved in dioxane (15 mL) was treated with methylamine (15 mL of a 40 wt % solution in water). The resulting suspension was stirred at 100° C. for 4 h in an autoclave. The solution was evaporated to dryness. The crude product was purified (SiO2 chromatography, eluting with a 5:1:94 (v/v) mixture of methanol:triethylamine:dichloromethane respectively). The product containing fractions were evaporated in vacuo and re-purified by RPHPLC (Xterra column, 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as mobile phase). The product containing fractions were combined and freeze dried to leave a solid. Trituration with diethyl ether followed by drying in vacuo overnight gave the title compound as a white powder (3.14 g).
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N:17]=1)/[C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5]/[N:6]=[C:7](\[C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N+:17]=1[O-:32])/[C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O/N=C(/c1cc(Br)ccc1O)c1ncccc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)O/N=C(/c1cc(Br)ccc1O)c1c(C#N)ccc[n+]1[O-]
Yield: 32.9 %

Procedure:
A solution of (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-cyanopyridine O-t-butyloxime (350 mg) and 50% m-chloroperbenzoic acid (710 mg) in chloroform (5 ml) was stirred for 6 hours at 50° C. The reaction mixture was cooled by aeration, which was poured into an aqueous solution of sodium sulfite. The mixture was stirred and subjected to extraction with chloroform. The extract solution was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-cyanopyridine N-oxide O-t-butyloxime (120 mg) (Compound 145).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[NH:12]1[CH:16]=[C:15]([C:17](=[S:19])[NH2:18])[N:14]=[CH:13]1>>[NH:12]1[CH:16]=[C:15]([C:17]2[S:19][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:18]=2)[N:14]=[CH:13]1
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)c1c[nH]cn1
Product: c1ccc2c(c1)Cc1sc(-c3c[nH]cn3)nc1-2

Procedure:
Starting compounds: 2-bromo-1-indanone, 4-imidazole carbothioamide
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1)[N:8]([CH3:27])[C:7]2=[O:28].IC1C=CC=C2C=1N=C([NH:40][C@H:41]1[CH2:46][CH2:45][CH2:44][C@@H:43]([NH:47][C:48](=[O:54])OC(C)(C)C)[CH2:42]1)N(C)C2=O.C[C@@H]1C2NC(B3OC(C)(C)C(C)(C)O3)=CC=2C(=O)N1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:27][N:8]1[C:7](=[O:28])[C:6]2[C:11](=[C:2]([C:41]3[NH:40][C:44]4[C@@H:43]([CH3:42])[NH:47][C:48](=[O:54])[C:45]=4[CH:46]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1
Reactant: Cn1c(N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(Br)cccc2c1=O
Reactant: Cn1c(N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(I)cccc2c1=O
Agent: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(N[C@@H]5CCC[C@H](NC(=O)OC(C)(C)C)C5)nc34)[nH]c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
A mixture of (rac)-tert-butyl ((1R,3S)-3-((8-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate and (rac)-tert-butyl ((1R,3S)-3-((8-iodo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509a, 1.49 g, 3.30 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 1.331 g, 3.96 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium (II) (0.117 g, 0.165 mmol), and potassium phosphate (2.102 g, 9.90 mmol) in 1,4-dioxane (26.4 mL)/water (6.60 mL) was sparged with nitrogen for 3 min at RT; the red reaction mixture was then heated to 80° C. for 1 h. More (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.33 g) was added, and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (150 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×100 mL); the aqueous layer was extracted with EtOAc (4×100); the organic layers were separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-8% 2 M ammonia in MeOH/DCM to give (rac)-tert-butyl ((cis)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509, 0.59 g, 0.582 mmol, 17% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.34 (m, 3H) 1.37 (s, 9H) 1.40 (d, J=6.65 Hz, 3H) 1.42-1.54 (m, 2H) 1.73-1.89 (m, 2H) 1.99-2.20 (m, 2H) 3.44 (s, 3H) 3.92-4.11 (m, 1H) 4.48-4.59 (m, 0.5; H) 4.60-4.74 (m, 0.5; H) 6.79-6.99 (m, 3H) 7.15 (t, J=7.73 Hz, 1H) 7.63 (d, J=4.30 Hz, 1H) 7.82 (d, J=7.04 Hz, 1H) 7.97 (dd, J=11.54, 7.82 Hz, 1H) 11.99 (br. s., 0.4; H) 12.09 (br. s., 0.6; H). MS (ESI, pos. ion) m/z: 507.2 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH:13]2[NH:19][CH2:18][CH2:17][NH:16][C:15](=O)[CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>C1COCC1.O>[C:7]1([CH:13]2[NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CC(c2ccccc2)NCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(C2CCNCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
2.0 g LiAlH4 were suspended in THF under a nitrogen atmosphere, and then 5.0 g hexahydro-7-phenyl-1,4-diazepin-5-one were added thereto at 10° C. Then the mixture was stirred for 8 hours at room temperature. Under a nitrogen atmosphere, 5 ml water, 2.2 g NaOH, dissolved in 5 ml water, and again 3 ml water were then added dropwise in succession, and the mixture was stirred for 15 minutes at room temperature. Once the resulting salts had been filtered out, the filtrate was reduced to dryness under vacuum. 4.9 g of 7-phenyl-1,4-diazepane were obtained, which was reacted without further purification.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[Cl:30].[I-].[Na+]>CN(C=O)C>[Cl:30][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[CH2:19][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice cooled (0° C.) stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.25 g, 1.1 mmol) in dry DMF (15 ml) is added sodium hydride (0.484 g of a 60% dispersion in mineral oil, 12.1 mmol). After stirring at room temperature for 3 hours, the reaction mixture is re-cooled to 0° C. and treated with 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene (5.0 g, 17.6 mmol) and sodium iodide (2.64 g, 17.6 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is poured onto water (300 ml) and extracted with 1:1 ethyl acetate/diethyl ether. The organic portions are washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:4 increasing to 1:2) to yield the titled product. (MH+ 407)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@H:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@H:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@@H](C)c2c(-c3ccc(Cl)cc3)noc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@H](C(=O)O)Cc2onc(-c3ccc(Cl)cc3)c21
Yield: 85 %

Procedure:
0.079 g (0.25 mmol) of methyl cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylate in 10 ml of dioxane was stirred at room temperature for 1 hour with 5 ml of 1N aqueous sodium hydroxide solution. Water was added and the solution was partially evaporated. The solution was acidified with 1N hydrochloric acid and the precipitate was collected, washed with water and dried to give 0.065 g of cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 213° C.
Reaction SMILES: O.[NH:2]1[C:10](=[O:11])[C:8](=O)[C:6](=[O:7])[NH:5][C:3]1=[O:4].S(=O)(=O)(O)O.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Hg]>[C:17]1([CH3:23])[CH:22]=[CH:21][C:20]([C:8]2([C:20]3[CH:21]=[CH:22][C:17]([CH3:23])=[CH:18][CH:19]=3)[C:10](=[O:11])[NH:2][C:3](=[O:4])[NH:5][C:6]2=[O:7])=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: O=S(=O)(O)O
Agent: [Hg]
Solvent: O
Product: Cc1ccc(C2(c3ccc(C)cc3)C(=O)NC(=O)NC2=O)cc1

Procedure:
In a 500 cc. 3-necked flask fitted with a reflux condenser, a mercury seal stirrer and a thermometer in a well, were placed 16 g. of alloxan monohydrate and 60 g. of sulfuric acid, sp.gr. 1.84. Then 75 cc. of toluene were added through the reflux condenser and the mixture heated in an oil-bath, with stirring for four and one-half hours at 75°-80°. After this time the reaction mixture was cooled, most of the toluene later decanted, and the sirupy sulfuric acid later poured into 150 cc. of cold water. The precipitated material was filtered and washed in a beaker with 100 cc. of water and refiltered. After drying in a vacuum this material was dissolved in 160 cc. of boiling glacial acetic acid, filtered and allowed to crystallize.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH3:7])[CH3:2].C(O[CH:21](OCC)[N:22]([CH3:24])[CH3:23])C.CN(C=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=[CH:21][N:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C(=O)OC
Reactant: CCOC(OCC)N(C)C
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)=C(C=CN(C)C)C(=O)OC
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of 2-ethoxycarbonyl-3-methoxycarbonyl-but-2-enoic acid ethyl ester (15 g, 61.5 mmol), dimethylformamide diethyl acetal (11.1 mL, 64.5 mmol) and DMF (15 mL) was heated at 80° C. for 5 h. After the mixture was cooled, 200 mL of benzene was added, and the resulting mixture was washed several times with 1 M HCl and water. The organic layer was dried over MgSO4 and concentrated to give an orange solid, which was recrystallized from hexanes/CCl4 to give 8.1 g of the title compound as a bright yellow solid. 1H NMR (CDCl3, 200 MHz): δ=6.70 (d, 1H, J=13.2 Hz), 5.66 (d, 1H, J=13.4 Hz), 4.10-4.40 (m, 4H), 3.88 (s, 3H), 2.96 (br s, 6H), 1.20-1.40 (m, 6H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[O:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenyloxazole (290 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-pyrrolyl]propionate (550 mg, yield: 72%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=[C:2]2[CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccnc(N)c1
Solvent: CCO
Product: CCOC(=O)c1cn2ccc(OC)cc2n1
Yield: 58.3 %

Procedure:
A mixture of 2-amino-4-methoxypyridine (1.0 g, 8.1 mmol) and ethyl 3-bromo-2-oxopropanoate (1.77 g, 9.1 mmol) in ethanol (10 mL) was refluxed for 6 h. After the reaction was concentrated, ethyl acetate (20 mL) was added to the residue. The mixture was basified by saturated aqueous sodium bicarbonate. The separated organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=1/1) to afford ethyl 7-methoxyimidazo[1,2-a]pyridine-2-carboxylate as a solid (1.04 g, 58%). 1H-NMR (DMSO-d6, 300 MHz): δ 8.37 (m, 2H), 6.91 (s, 1H), 6.70 (m, 1H), 4.25 (m, 2H), 3.81 (s, 3H), 1.28 (m, 3H) ppm; MS (ESI): 221.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:49])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]=C(C5C=CC=CC=5)C5C=CC=CC=5)=[CH:31][CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C([O-])(=O)C.[Na+].Cl.NO.P([O-])([O-])([O-])=O>CO>[NH2:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:1])([CH3:49])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:34][CH:33]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(N=C(c5ccccc5)c5ccccc5)cc4)C(=O)O3)ccc2O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(N)cc4)C(=O)O3)ccc2O1
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-({4-[(diphenylmethylene)amino]benzyl}oxy)ethoxy]hexyl}-1,3-oxazolidin-2-one (860 mg) in MeOH (13 ml) was treated with sodium acetate (255 mg) followed by hydroxylamine hydrochloride (162 mg) and the mixture was stirred at 20° for 0.5 h. Phosphate buffer solution (30 ml, pH6.5) was added and the mixture was extracted with EtOAc. The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by SPE (silica, 10 g). Elution with EtOAc-cyclohexane (1:1) then (4:1) gave the title compound (321 mg). LCMS RT=3.18 min.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][NH:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[CH:5]1([CH2:4][O:6][NH:7][C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccccc1NO
Reactant: ICC1CC1
Product: CCOC(=O)c1ccccc1NOCC1CC1
Yield: 50 %

Procedure:
The titled compound was prepared using similar procedure as that of Example-1 (step-2) using product of step 1 described above and ethyl 2-(hydroxyamino)benzoate in 50% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:13][CH:12]([CH3:14])[C:11]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: C=C(C)C(=O)O
Reactant: COc1ccc(CS)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CSCC(C)C(=O)O)cc1

Procedure:
p-Methoxy-α-toluene thiol (15.4 g., 0.1 mol.) is added to a solution of methacrylic acid (8.6 g., 0.1 mol.) in 50 ml. 2 N sodium hydroxide. The mixture is heated on the steam bath for three hours, then refluxed for two hours and cooled. The mixture is extracted with ether, then the aqueous layer is acidified with concentrated HCl and extracted with dichloromethane. The acidic extracts are washed with brine, dried (MgSO4) and evaporated in vacuo. The resulting semi-solid is taken up in 50 ml. of dichloromethane, diluted with 50 ml. hexane, and chilled. 3-[(4-methoxyphenyl)methylthio]-2-methylpropanoic acid is collected as a white crystalline solid, m.p. 74°-82° (5.5 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>CO.C(Cl)(Cl)Cl>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH:32]2[CH2:33][CH2:34]2)[C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: CC(C)[C@H](N)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-T), the title compound was prepared. The reaction was monitored by tlc (Rf=0.3, 2.5% MeOH/CHCl3) and product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]([N:28]([CH2:32][CH2:33][CH3:34])[C:29]([NH2:31])=[S:30])[CH2:25][O:26][CH3:27].C(N(CC)CC)C>C(O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:31]=[C:29]([N:28]([CH:24]([CH2:25][O:26][CH3:27])[C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:32][CH2:33][CH3:34])[S:30][C:2]=1[CH3:13]
Reactant: CCCN(C(N)=S)C(COC)c1ccc2ccccc2c1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(COC)c1ccc2ccccc2c1
Temperature: 70 °C
Yield: 56.2 %

Procedure:
0.93 g of 2-bromo-1-(2,4-dichlorophenyl)propan-1-one, 1 g of N-(1-naphth-2-yl-2-methoxyethyl)-N-propyl-thiourea and 0.47 ml of triethylamine are dissolved in 20 ml of ethanol and the reaction mixture is heated for 3 hours at 70° C. The ethanol is removed by evaporation and then, successively, water is added, extraction is carried out with methylene chloride and the organic phases are washed, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified on a column of silica gel, using a 9/1 (v/v) cyclohexane/ethyl acetate mixture as eluent, to provide 0.9 g of the expected product, the hydrochloride of which is prepared; M.p.=50° C. 1H NMR (DMSO): 0.73 (m, 3H), 1.12-1.59 (m, 2H), 2.09 (s, 3H), 3.35 (s, 3H), 3.31-3.46 (m, 2H), 3.97-4.23 (m, 2H), 5.48-5.60 (m, 1H), 7.48-7.95 (m, 10H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:4]1.[Cl:22][S:23](O)(=[O:25])=[O:24]>>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:4]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CC(CCl)c2c1ccc1ccccc21)C(F)(F)F
Product: O=C(N1CC(CCl)c2c1ccc1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Temperature: 60 °C
Yield: 25.2 %

Procedure:
Solid 108 (1.6 g, 5.1 mmol) was gradually added to chlorosulfonic acid (6.0 mL, 90 mmol) with ice bath cooling. The mixture was then heated to 60° C. for 2 h, and the reaction was quenched by pouring slowly, with stirring, into ice-water. The precipitated solid was collected, washed with water, dried and chromatographed on silica gel. Elution with EtOAc/petroleum ether (from 1:4 to 1:1) gave 1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-7-sulfonyl chloride (113) (0.53 g, 25%) as a pale yellow solid: mp (EtOAc/petroleum ether) 189-192° C.; 1H NMR (CDCl3) δ 8.70-8.64 (m, 2H), 8.13-8.08 (m, 2H), 8.00 (d, J=9.0 Hz, 1H), 4.72-4.68 (m, 1H), 4.55-4.48 (m, 1H), 4.33-4.25 (m, 1H), 3.98-3.93 (m, 1H), 3.68-3.61 (m, 1H), 13C NMR δ 154.9 (q, JC-F 38.4 Hz), 143.9, 140.7, 132.7, 131.8, 130.1, 130.0, 125.8, 124.8, 123.2, 119.6, 115.9 (q, JC-F 288 Hz), 52.8, 45.4, 42.4. Anal. (C15H10Cl2F3NO3S) C, H, N, Cl.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17](O)=[O:18])=[N:15][CH:16]=1)=[O:10]>C(OCC)(=O)C>[N:1]1([C:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([O:8][CH3:7])=[O:10])=[CH:16][N:15]=2)=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)N2CCOCC2)nc1

Procedure:
63 mg of morpholine was coupled to 120 mg of 5-(methoxycarbonyl)pyridine-2-carboxylic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried (MgSO4) and evaporated to afford methyl 6-(morpholine-4-carbonyl)nicotinate. 180 mg of methyl 6-(morpholine-4-carbonyl)nicotinate was hydrolyzed via Procedure M to give 6-(morpholine-4-carbonyl)nicotinic acid. 100 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 6-(morpholine-4-carbonyl)nicotinic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholine-4-carbonyl)nicotinamide. MS (Q1) 423.4 (M)+.