Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[NH2:37][CH2:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:37][CH2:38][C:39](=[O:40])[NH:41][CH2:42][CH3:43])=[O:25]
Reactant: CCNC(=O)CN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: CCNC(=O)CNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-N-ethyl-acetamide.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([N:13]1[CH2:17][CH2:16][C:15]([CH2:20][N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:18][OH:19])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:6]([N:13]1[CH2:17][CH2:16][C:15]([CH2:20][N:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([CH2:18][O:19][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Mesyl chloride (2.7 ml) was added to a solution of 1-benzyl-3-(dibenzylaminomethyl)-3-hydroxymethylpyrrolidine (7.88 g) and triethylamine (5.5 ml) in chloroform (80 ml) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was sequentially washed with an aqueous solution of sodium hydrogencarbonate and water, dried, concentrated and purified by silica gel column chromatography to give 6.97 g of the object compound as an oil.
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:11][C:12]([C:19]2[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[C:13]([C:15](F)(F)F)[N:14]=1)C1C=CC=CC=1.[OH-].[NH4+:32]>>[C:15]([C:13]1[N:14]=[C:10]([CH2:9][OH:8])[NH:11][C:12]=1[C:19]1[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25])#[N:32]
Reactant: COC(=O)c1cc(-c2[nH]c(COCc3ccccc3)nc2C(F)(F)F)c(C)cc1C
Reactant: [NH4+]
Agent: [OH-]
Product: COC(=O)c1cc(-c2[nH]c(CO)nc2C#N)c(C)cc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.4, 100 mg, 0.30 mmol) in ammonium hydroxide (5%) (30 mL). The reaction mixture was stirred for 2 h at 60° C. The reaction mixture was extracted with 2×50 mL of dichloromethane, the organic layers combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 80 mg (92%) of the title compound as a light yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1([C@@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1.Cl[C:19]1[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[N:22]=[CH:21][N:20]=1>CN(C)C=O.O>[CH3:7][C:8]1([C@@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][C:19]3[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[N:22]=[CH:21][N:20]=3)[CH2:13][CH2:12]2)[CH2:9][CH2:10]1
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: CC1([C@H]2CC[C@@H](N)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ncnc(N[C@H]2CC[C@@H](C3(C)CC3)CC2)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1.8 g (13.0 mmol) of K2CO3 were placed in 10 ml of dimethylformamide, 1.3 g (8.5 mmol) of cis-4-(1-methylcyclopropyl)cyclohexylamine and 1.5 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine were added, and the mixture was stirred at 80° C. for 4 hours. For working up, the cooled reaction solution was taken up in water. Extraction was carried out with ether, and the combined organic phases were washed with water, dried and concentrated. For purification, the mixture was chromatographed on silica gel with petroleum ether/ethyl acetate 3:1. 1.8 g (71.1% of theory) were obtained of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.ClC(OCC)=O.C(N1CCOCC1)C.[C:25]([C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH:33][C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])=[CH:29][CH:28]=1)#[N:26]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: N#Cc1ccc(CCN)cc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)Cl
Product: N#Cc1ccc(CCNC(=O)c2ccc(O)cc2)cc1

Procedure:
The starting material was prepared by reaction of 4-hydroxybenzoic acid with ethyl chloroformate/4-ethylmorpholine and subsequent addition of p-cyanophenethylamine to give p-(p-cyanophenethylcarbamoyl)phenol and then etherification with methyl bromoacetate/KOH in acetone.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.N#N.[F:15][C:16]1[N:30]=[CH:29][CH:28]=[CH:27][C:17]=1[C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19].CN([CH:34]=[O:35])C>C1COCC1>[F:15][C:16]1[N:30]=[CH:29][CH:28]=[C:27]([CH:34]=[O:35])[C:17]=1[C:18]([N:20]([CH:21]([CH3:22])[CH3:23])[CH:24]([CH3:25])[CH3:26])=[O:19]
Reactant: CC(C)N(C(=O)c1cccnc1F)C(C)C
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1c(C=O)ccnc1F)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (1.7 mL, 12.2 mmol) in THF (50 mL) at −78° C. was added n-BuLi (6.1 mL, 2.0 M hexanes) dropwise under N2. The reaction was stirred for 30 min and 2-fluoro-N,N-diisopropyl-nicotinamide (2.75 g, 12.2 mmol) was added dropwise in a solution of THF (15 mL). The reaction was stir for 1 h, then DMF (3 mL, 36 mmol, 3 eq) was added in one portion. The reaction was stirred at −78° C. for 5 min then warmed to RT over 1 h. The reaction was quenched with NH4Cl (saturated, 100 mL), and extracted with EtOAc (2×100 mL). The combined organics were washed with brine (saturated, 200 mL), dried with Na2SO4, and purified by passing through a plug of SiO2to give pure title compound as a white solid. MS (ES+): 253.1 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH2:5](O)[CH2:6][CH:7]([OH:9])[CH3:8]>>[CH:3]([CH:1]1[O:9][CH:7]([CH3:8])[CH2:6][CH2:5][O:2]1)=[CH2:4]
Reactant: C=CC=O
Reactant: CC(O)CCO
Product: C=CC1OCCC(C)O1
Yield: 99 %

Procedure:
When acrolein is condensed with 1,3-butanediol, the product obtained is 2-vinyl-4-methyl-1,3-dioxane (99 percent yield).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[NH:5][CH:4]=1)#[N:2].C(O)CCC.[O:22]([CH:26]([CH3:34])[CH2:27][C:28]([NH:30][CH2:31][CH2:32][NH2:33])=[O:29])[N+:23]([O-:25])=[O:24].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>CO>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:33][CH2:32][CH2:31][NH:30][C:28](=[O:29])[CH2:27][CH:26]([O:22][N+:23]([O-:25])=[O:24])[CH3:34])[NH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1c[nH]c2cccc(OCC3CO3)c12
Reactant: CC(CC(=O)NCCN)O[N+](=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCCCO
Product: CC(CC(=O)NCCNCC(O)COc1cccc2[nH]cc(C#N)c12)O[N+](=O)[O-]

Procedure:
4.2 g. 1-(3-cyanoindol-4-yloxy)-2,3-epoxypropane (see European patent specification No. 0,045,910) are suspended in 100 ml. n-butanol, mixed with 11.5 g. 2-(3-nitroxybutanoylamino)-ethylamine and stirred for 2 days at ambient temperature. After removal of the solvent, the residue is chromatographed on silica gel with methylene chloride/methanol (95:5 v/v) and methylene chloride/methanolic ammonia solution (95:5 v/v). From the appropriate fractions, after removal of the solvent, there are obtained 4.6 g. of base. By dissolving in methanol and adding the calculated amount of fumaric acid, there are obtained, after suction filtration, 3.9 g. (40% of theory) of the desired fumarate; m.p. 155°-156° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16].Cl>O.C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)C(CC(=O)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A solution of Meldrum's acid (5.0 g, 35 mmol) in anhyd THF (25 mL) was added cautiously to a stirred suspension of sodium hydride (95%, 960 mg, 38 mmol) in anhyd THF (25 mL). The resulting solution was stirred at room temperature for 1 h. A solution of 2,4′-dibromoacetophenone (11.6 g, 42 mmol) in anhyd THF (25 mL) was added dropwise, and the resultant solution was stirred at room temperature for 16-24 h (TLC control). The reaction mixture was poured into water (50 mL), acidified to pH 2-3 with 0.5 N hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined extract was washed with water, sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated in vacuo. Trituration and filtration from MeOH afforded the title compound as a white solid (6.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])(=[O:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][Cl:46]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:45][Cl:46])=[O:35])(=[O:25])=[O:24]
Reactant: ClCBr
Reactant: O=C(O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: O=C(CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)OCCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoic acid (0.060 mole) is dispersed with stirring in a methanol-water mixture (100 mL), and an aqueous solution of cesium carbonate (2 molar) is added dropwise until the solution pH is 6.6. The volatiles are removed by spin evaporation in vacuo. The resulting cesium salt is dried by addition of toluene and removal of the volatiles under reduced pressure. This is repeated several times. The dry cesium salt is dissolved in dimethylformamide (100 mL), and bromochloromethane (Aldrich) (0.060 mole) is slowly added to the solution. The reaction is stirred at ambient temperature in the dark for 12 hours. The mixture is filtered to remove cesium bromide, and the volatiles are removed by spin evaporation in vacuo. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give chloromethyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[CH2:18]([O:20][CH2:21]Cl)[CH3:19]>ClCCl>[CH2:18]([O:20][CH2:21][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([OH:8])=[CH:10][CH:11]=1)[CH3:19]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCOCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCOC(=O)c1ccc(O)cc1

Procedure:
36.7 ml (0.26 mole) Of triethylamine were added under a nitrogen atmosphere to a solution of 36.1 g (0.26 mole) of 4-hydroxybenzoic acid in 200 ml of dichloromethane. The mixture was cooled in an ice-water bath, and 24.5 ml (0.26 mole) of chloromethyl ethyl ether in 100 ml of dichloromethane were added dropwise.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>C1COCC1.CCN(CC)CC>[C:4]([C:3]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:2]=1[NH:1][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)(=[O:5])[NH2:6]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCOc1ccc(N)c(C(N)=O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1ccc(NC(=O)c2cccnc2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 2-amino-5-propoxy-benzamide (760 mg, 3.91 mmol) in THF (15 mL) and Et3N (1 mL) was added nicotinoyl chloride (607 mg, 4.30 mmol) in anhydrous THF (15 min) dropwise. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the volatiles were removed. The residue was washed with H2O (10 mL). The pH was adjusted to approximately 5 by adding dilute HCl (2N in water). The resulting solid was collected and dried in vacuo to give 1.00 g of iii-a as a pale yellow solid (89.0%). LCMS m/z=300.1 (M+1) (Method B) (retention time=1.60 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[OH:19])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[O:19][S:36]([C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCn1ncc(C(=O)c2ccc(Cl)c3ncccc23)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2ccc(Cl)c3ncccc23)c1OS(=O)(=O)c1ccc(Cl)cc1

Procedure:
1.00 g of 4-[(8-chloroquinolin-5-yl)carbonyl]-1-ethyl-5-hydroxy-pyrazole, 0.70 g of triethylamine and 0.70 g of 4-chlorobenzenesulfonyl chloride in 15 ml of methylene chloride were stirred at room temperature for 12 hours. The reaction mixture was then poured into aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated and the residue was purified by chromatograpy over silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(Cl)c3nn2C2CCCC2)cc1
Yield: 2.4 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and cyclopentylbromide (0.107 mL, 1.0 mmol) to give the title compound (0.004 g).
Reaction SMILES: C(O)(=O)C(O)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][NH:14][CH2:13]1.Br[CH2:27][CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][N:14]([CH2:27][CH2:28][CH3:29])[CH2:13]1
Reactant: CCCBr
Reactant: Clc1cccc(OC2CNCCc3ccccc32)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCc2ccccc2C(Oc2cccc(Cl)c2)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(m-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine of Example 4 (6.4 g, 0.023 mole), 1-bromopropane (5.7 g., 0.047 mole) and sodium bicarbonate (8.4 g, 0.10 mole) in DMF (100 ml) was stirred at 70° C. for three hours. The mixture was concentrated under high vaccum to an oil which was stirred with water then extracted with ether. The ether extracts were washed twice with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, then concentrated to an oil (6.3 g, 86%) which was distilled to yield an oil of 1-(m-chlorophenoxy)-3-(n-propyl)-2,3,4,5-tetrahydro-3-benzazepine, 190°-210° C./0.1 mm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][C:22]([NH2:24])=[O:23]>>[C:9]1([C@H:21]2[C@H:21]([C:15]3[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])[C:22](=[O:23])[NH:24][C:22]2=[O:23])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1c(Cl)cccc1Cl
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c(Cl)cccc1Cl

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(2,6-dichlorophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 2,6-dichlorophenylacetamide. Yield 52.2 mg, 13.0%. 1H NMR (DMSO-d6) 400 MHz δ: 11.82 (s, 1H), 7.34 (m, 3H), 7.10 (d, 1H, J=7.2 Hz), 6.87 (m, 2H), 5.16 (d, 1H J=7.6 Hz), 5.10 (d, 1H, J=7.6 Hz), 2.91 (t, 2H, J=6.0 Hz) 2.10 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:49].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:31])=[O:32])[C:20]([CH2:33][O:34][CH2:35][CH3:36])=[N:19][C:14]=3[C:15]([NH2:49])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCN1CCCS1(=O)=O
Reaction time: 1 h

Procedure:
7-Benzyloxy-1-[4-(1,1-dioxoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (2.83 g) was dissolved in chloroform (30 mL). 3-Chloroperoxybenzoic acid (60% pure, 2.21 g, 7.7 mmol) was added in one portion and the mixture was stirred for 1 hour. Ammonium hydroxide (30 mL) was added and the biphasic mixture was stirred for 20 minutes. p-Toluenesulfonyl chloride (1.07 g, 5.6 mmol) was added in one portion and the reaction was stirred for 16 hours. A white precipitate formed. The mixture was diluted with dichloromethane (solid remains in the organic fraction) and the layers were separated. The organic fraction was washed with 5% aqueous sodium bicarbonate (solid moves to the aqueous fraction). The layers were separated, followed by filtration of the solid from the aqueous fraction. The solid was sequentially washed with water and diethyl ether; slurried in acetonitrile; filtered; and dried to yield 1.5 g of 7-benzyloxy-1-[4-(1,1-dioxoisothiazolidin-2-yl)butyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 225-227° C.
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([N:11]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:13][C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>CO>[CH:1]([N:4]([CH2:35][CH3:36])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)=[CH:13][C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC=O
Reactant: CC(C)N[C@H]1CC[C@@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)C(C)C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(C(C)C)[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 1-[(1R,2R,4S)-4-isopropylamino-2-(propane-2-sulfonylmethyl)cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one (43 mg) in methanol (1 mL) was treated with acetaldehyde (0.025 mL) and stirred at room temperature. After 35 min, sodium cyanoborohydride (8 mg) was added, and the mixture was stirred at room temperature for 22.5 h. The mixture was concentrated and partitioned between water and ethyl acetate. The aqueous phase was extracted with additional ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide 1-((1S,2R,4R)-4-(isopropyl(ethyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-4-(3-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one (41 mg) as a white glassy solid. MS found: (M+H)+=529.39.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:15][N:14]=1.N.ClCCl>CN1C(=O)N(C)CC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:15][N:14]=2)=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: CC(=O)c1ccc(N)cc1O
Agent: N
Solvent: ClCCl
Solvent: CN1CCN(C)C1=O
Product: CC(=O)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1O

Procedure:
302 mg (2.0 mmol) 2-acetyl-5-aminophenol (Maybridge) and 256 mg (1.00 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (Example 67A.1) in 2 ml DMEU are heated for 3-18 h to 100° C. The reaction mixture is stirred with 10 ml NH3 solution (10% in water) and 25 ml ethyl actetate (or dichloromethane) and filtered via Celite. The organic phase of the filtrate is dried (Na2SO4), evaporated, and chromatographed (SiO2; ethyl acetate/CH3OH, 40:1→10:1) Crystallization from acetonitrile yields the title compound: m.p.: 234-236° C.; HPLC: tRet(Grad5-40)=9.5; FAB MS (M+H)+=371.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]Br)=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.[I-:29].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][I:29])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-n2nc(CBr)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(-n2nc(CI)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
According to Scheme 7 Step 6: A mixture of N-(3-(4-(4-chlorobenzyl)-6-(bromomethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (200 mg, 0.43 mmol) and sodium iodide (97 mg, 0.65 mmol) in acetone (10 mL) was stirred overnight at room temperature. The mixture was diluted with water (100 mL) and the aqueous layer was extracted twice with 100 mL of DCM. The organic layer were combined and successively dried over MgSO4, filtered and concentrated under reduced pressure to afford N-(3-(4-(4-chlorobenzyl)-6-(iodomethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 14(A) (220 mg) as a white solid. The tittle product was used in the next reaction without any further purification.