Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:20]([N:37]3[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]3)=[O:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(-c2cccc(Cl)c2)o1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3cccc(Cl)c3)o2)CCN1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
600 mg (1.07 mmol) of the compound from Example 25A are provided in 14 ml of dry toluene, 0.24 ml (3.22 mmol) of thionyl chloride are added and the mixture is heated under reflux for 2.5 hours. The reaction mixture is concentrated, and the residue is taken up in 10 ml of dichloromethane and cooled to 0° C. 0.24 ml (1.72 mmol) of triethylamine and then 172 mg (1.72 mmol) of piperazin-2-one are then added, and the reaction mixture is stirred at RT overnight. The mixture is subsequently concentrated and the residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 302 mg (68% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CCOC(=O)c1n[nH]c2cc(-c3ccc(N)cc3)ccc12
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1n[nH]c2cc(-c3ccc(NC(=O)Nc4ccc(Cl)c(Cl)c4)cc3)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of ethyl 6-(4-aminophenyl)-1H-indazole-3-carboxylate (40 mg) and 3,4-dichlorophenylisocyanate in tetrahydrofuran (3 Ml; THF) was stirred at room temperature for 24 h. Ethyl acetate and saturated sodium bicarbonate solution were wadded. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated by THF/hexane to give ethyl 6-(4-(3-(3,4-dichlorophenyl)ureido)phenyl)-1H-indazole-3-carboxylate (17.4 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[C:33]2([CH3:41])[CH3:40])[N:3]=1>CO.[Rh]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[C:33]2([CH3:41])[CH3:40])[N:3]=1
Reactant: CN(C)C1CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)C1(C)C
Agent: [Rh]
Solvent: CO
Product: CN(C)C1CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)C1(C)C
Reaction time: 0.83 h
Yield: 45.6 %

Procedure:
To a solution of [(2R)-3-(2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1737 g, 0.294 mmol) in MeOH (10 mL) was added 5% Rh/C (175 mg). The mixture was hydrogenated at 50 psi overnight, and was then filtered through a 0.2 μM membrane and concentrated in vacuo. To a solution of the residue in MeOH (4 mL) was added 20% Pd(OH)2/C (50% water, 5 mg). The mixture was hydrogenated under balloon pressure for 50 min. The mixture was then filtered though a 0.2 μM membrane, and the solution was concentrated in vacuo. The residue was purified by Gilson RPLC to give [(2R)-3-(2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.0670 g, 46% yield, mixture of diastereomers) as a while solid following crystallization from EtOAc-hexanes. LCMS: (M+H)+: 500.3.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20](Cl)[CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=[O:2].C(OCCCN1C(=O)C2C(CCC(C)C)=C(C3C=CC=C([Cl:55])C=3)NCC=2N(C)C1=O)=O>C(Cl)Cl.O.O=[Mn]=O>[CH:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:55])=[CH:20][CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=[O:2]
Reactant: CC(C)CCc1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Reactant: CC(C)CCC1=C(c2cccc(Cl)c2)NCc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: O
Product: CC(C)CCc1c(-c2ccc(Cl)cc2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a solution of 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate and 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (21 mg, 0.047 mmol) in DCM (1 mL) was added MnO2 (40.8 mg, 0.47 mmol). The reaction was stirred at RT for 3 h then diluted with DCM (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4, and concentrated to give 3-(6-(4-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (14 mg, 66.7% yield) as an oil. LCMS: MH+ 444 and TR=1.942 min. Used without further purification.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]P(Cl)(Cl)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[OH-].[NH4+]>O>[C:18]1([N:17]([CH3:16])[S:2]([C:5]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=P(Cl)(Cl)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
A suspension of N-(4-chlorosulfonylphenyl)phosphoramidic dichloride (1.0 g) and N-methylaniline (2.49 g) in water (5 ml) was heated at reflux for 18 hours. After cooling to 0° C. and adjustment to pH2 with concentrated hydrochloric acid, the suspension was heated at reflux for 30 minutes, then cooled to 0° C. and adjusted to pH 8 with concentrated ammonium hydroxide. The suspension was extracted with ethyl acetate (3×40 ml), the combined organic extracts were washed with brine, dried (Na2SO4), and concentrated to an oil. Purification by chromatography (3:2 hexane: ethyl acetate) gave 4-(N-phenyl-N-methylaminosulfonyl)aniline as a colourless crystalline solid (0.65 g); MS: m/z=263(M+1); NMR (CDCl3): 3.13 (s,3), 4.11 (broad s,2), 6.58-6.62 (m, 2), 7.10-7.13 (m,2), 7.23-7.31 (m,s).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:15]=[C:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1.CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CCOC(C)=O.CCOCC>[OH:13][CH2:12][C:11]1[C:2]([N:20]2[CH2:19][CH2:18][NH:17][C:16](=[O:15])[CH2:21]2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:14]
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Reactant: O=C1CNCCN1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Cc1cccc2cc(CO)c(N3CCNC(=O)C3)nc12
Temperature: 140 °C
Yield: 50.6 %

Procedure:
(2-Chloro-8-methylquinolin-3-yl)methanol (250 mg, 1.13 mmol), 2-oxopiperazine (566 mg, 5.66 mmol), DIPEA (1 mL, 5.66 mmol) and NMP (3 mL) were combined in a sealed tube and heated to 140° C. for 24 h. After cooling, the reaction mixture was dissolved in a 1:1 mixture of EtOAc and Et2O (100 mL) and washed with saturated brine (3×25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification by column chromatography on silica, eluting with 5% MeOH in DCM, afforded the title compound (155 mg, 51%) as a white solid. LCMS (ES+) 272 (M+H)+.
Reaction SMILES: [Mg].II.BrCC.[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([CH:19]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]([O:28][SiH:29]([CH3:31])[CH3:30])[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16].Cl>CCOCC.O>[CH2:7]([C:23]1([OH:27])[CH2:24][CH2:25][CH2:26][CH:19]([C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:20][CH2:21][CH:22]1[O:28][SiH:29]([CH3:30])[CH3:31])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[SiH](C)OC1CCC(C(C)(C)C)CCCC1=O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: CCBr
Solvent: O
Product: C[SiH](C)OC1CCC(C(C)(C)C)CCCC1(O)Cc1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
1.2 g of magnesium was suspended in 40 ml of anhydrous ether, and the resulting suspension was warmed in the water bath at 40° C. A small piece of iodine crystal and a drop of bromoethane were added to the solution, followed by adding 5.7 ml of benzyl chloride dropwise slowly. To the resulting grayish white mixture, 4.0 g of the above product (a) was added. The resulting solution was stirred at 40° C. for three hours followed by at room temperature for further two days. The reaction solution was poured into ice water, and 2N hydrochloric acid was added to the solution until pH of the aqueous phase was reached at approximately 3. Then, the reaction solution was extracted with ether. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:15) was collected, to afford 4.5 g of the titled compound (b) (mixture of cis- and trans-isoforms) as colorless liquid.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([CH2:24]Br)[CH:18]=[CH:17]2>CC(C)=O>[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([CH2:24][O:5][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:6])[CH:18]=[CH:17]2
Reactant: O=C(O)C1CC1
Reactant: Cc1ccc2cc(CBr)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2cc(COC(=O)C3CC3)ccc2c1
Temperature: 50 °C

Procedure:
1.89 g of cyclopropane carboxylic acid are dissolved in 50 ml of acetone, treated with 5.5 g of potassium carbonate and heated to 50° C. A solution of 4.7 g of 6-methyl-2-(bromomethyl)naphthalene in 20 ml of acetone is then added dropwise. The mixture is left to react at 65° C. for 15 hours. The mixture is cooled and filtered. The residue is then rinsed with acetone and the filtrate is evaporated. The residue is purified chromatography on silica gel with hexane/ethyl acetate (9:1) to yield pure cyclopropane carboxylic acid (6-methyl-2-naphthyl)methyl ester of melting point 75°-78° C. (from petane/ether).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH2:19])[CH:13]=1.C(N(CC)CC)C.Br[CH:28]([CH3:32])[C:29](Br)=[O:30]>O1CCCC1>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH:28]([CH3:32])[C:29](=[O:30])[NH:19][C:14]=2[CH:13]=1
Reactant: Cc1ccn2c(C)c(-c3ccc(O)c(N)c3)nc2c1
Reactant: CC(Br)C(=O)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)NC(=O)C(C)O4)nc2c1
Yield: 32.4 %

Procedure:
A solution of 3,7-dimethyl-2-(3-amino-4-hydroxyphenyl)imidazo[1,2-a]pyridine (1.27 g) and triethylamine (1.0 g) in tetrahydrofuran (100 ml) was added to 2-bromopropionyl bromide (1.3 g) at ambient temperature. The resultant mixture was stirred at ambient temperature for 2 hours and at 60° to 70° C. for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in a mixture of ethyl acetate and water. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1). The fractions containing the desired compound were combined and evaporated in vacuo to afford a crystalline residue, which was recrystallized from ethyl acetate to give 6-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.5 g). mp. 254°-256° C.
Reaction SMILES: [OH:1]C1C2C(=CN=C(Cl)C=2)N=CC=1.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1)[CH:20]=[O:1]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: Oc1ccnc2cnc(Cl)cc12
Product: O=Cc1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
A route to prepare 4-hydroxy 6-chloro 1,7 napthyridine is depicted in Scheme III. Starting with 2-chloro-4-methyl-5-nitropyridine, condensation with dimethylformamidedimethylacetal and subsequent oxidative cleavage yields 2-chloro-5-nitroisonicotinaldehyde. Chemoselective methyl addition to the aldehyde with methyllithium and titaniumtetrachloride at −50° C. followed by oxidation yields 1-(2-chloro-5-nitropyridin-4-yl)ethanone. Nitro reduction with iron in acetic acid, followed by a two step monotosylation yields N-(4-acetyl-6-chloropyridin-3-yl)-4-nitrobenzenesulfonamide. Upon heating with dimethylformamidedimethylacetal and diisopropylethylamine in DMF at 105° C. and subsequent treatment with thiophenol at room temperature, 6-chloro-1,7-naphthyridin-4-ol is obtained IV. Conversion of IV to the corresponding triflate or benzyl ether using standard conditions yields bifunctional intermediates which can be taken through the chemical transformation depicted in Schemes 1 and 2 to yield 4,6 disubstituted 1,7 naphthyridines V.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[N:19][N:18]=3)[CH2:13][CH2:12]2)=[N:7][CH:6]=1)C.[OH-].[Li+].C1COCC1.Cl>O.CO>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:35])=[O:3])=[CH:6][N:7]=4)[CH2:16][CH2:15]3)=[N:18][N:19]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Reaction time: 16 h

Procedure:
6-{4-[4-(4-Fluoro-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (188 mg, 0.4 mmol), Lithium hydroxide (96 mg, 4.0 mmol), THF (750 μL), MeOH (750 μL), and H2O (400 μL) are combined at room temperature and stirred 16 h. Adjust pH to between three and four with 1N HCl. Extract with CH2Cl2/EtOH 4:1 and combined organics are washed with brine. Concentrate in vacuo to yield the title compound without further purification (165 mg, 93%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]1[C:18]2[C:19]3[C:11](=[C:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:13]([CH2:20][C:21](OC)=[O:22])[C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9]1.O>O1CCCC1>[NH2:7][CH:8]1[C:18]2[C:19]3[C:11](=[C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:13]([CH2:20][CH2:21][OH:22])[C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)Cn1c(-c2ccccc2)c2c3c(cccc31)C(N)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC1CCc2c(-c3ccccc3)n(CCO)c3cccc1c23
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
Lithium aluminum hydride (35 mg) was suspended in anhydrous tetrahydrofuran (THF; 1 ml) and to the suspension was added a solution of the compound (197 mg) obtained in Example 115 in anhydrous THF (7 ml) at room temperature. The mixture was stirred for 5 minutes. To the reaction mixture were slowly added water, then 1N aqueous solution of sodium hydroxide, followed by extraction with two portions of ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from ether to yield 149 mg (83%) of the titled compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:18]3[C:19]4[N:11]([C:12](=S)[NH:13][C:14](=[O:20])[C:15]=4[CH:16]=[N:17]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].OO.[CH2:26]([NH2:30])[CH:27]([CH3:29])[CH3:28]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:18]3[C:19]4[N:11]([C:12]([NH:30][CH2:26][CH:27]([CH3:29])[CH3:28])=[N:13][C:14](=[O:20])[C:15]=4[CH:16]=[N:17]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CN
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(F)c1)=CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(=O)c2cnn3c2n1CC=C3c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution or 3.00 g of 8-(3-fluorophenyl)-4,5-dihydro-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (Example 10) in 60.0 ml of N,N-dimethylformamide was added 10 ml of 1N sodium hydroxide. The reaction mixture was cooled to 0° C. in an ice bath, then 3.40 ml of 30% hydrogen peroxide was added to the mixture dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then 6.0 ml of isobutylamine was added in one portion and the mixture was allowed to warm to room temperature, then was stirred for 2 hours. The solid was collected by filtration, washed with water, then ether to give 1.24 g of the desired product as a white solid, m.p. 256°-259° C. Following the procedure of Example 52 and reacting 8-(3-fluorophenyl)-4,5-dihydro-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one with the appropriate primary aliphatic amine or cyclic secondary amine, the products of Examples 53-57 were obtained as set forth in Table VI.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH:16]1[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[O:12]=[CH:13][CH2:14][CH:15]1[CH2:17][CH:16]1[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C3CC3CCO)c3cc(C#N)ccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C3CC3CC=O)c3cc(C#N)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
Oxalyl chloride (0.5 ml of 2.0 M solution in methylene chloride, 1.0 mmol) was diluted with dry methylene chloride (5.0 ml) and cooled to −78° C. under a nitrogen atmosphere. DMF (0.08 ml, 1.12 mmol) was added via a micro syringe and the solution was stirred at −78° C. for 10 min. A solution of 3-[2-(2-hydroxy-ethyl)-cyclopropyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (250 mg, 0.657 mmol) in dry methylene chloride (5 ml) was added drop wise, and the solution was stirred at −78° C. for 1 hr, and then triethylamine (1.0 ml) was added. The solution was concentrated in vacuo, and the residue was dissolved in ethyl acetate (10 ml). The ethyl acetate solution was extracted with HCl (5 ml of 1 N solution), and with brine (5 ml). The ethyl acetate solution was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using methylene chloride as the eluent to give 3-[2-(2-oxo-ethyl)-cyclopropyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (167 mg, 67%). 1H NMR (500 MHz, CDCl3): δ9.87 (s, 1H), 8.03 (d, 1H), 7.96 (s, 1H), 7.74 (d, 2H), 7.56(d, 1H), 7.35 (s, 1H), 7.25 (d, 2H), 2.59 (m, 2H), 2.36 (s, 3H), 1.67 (m, 1H), 1.30 (m, 1H), 1.30 (m, 1H), 1.02 (m, 1H), 0.89(m, 1H). MS m/e 379.16 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Oc1ccccc1F
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccccc3F)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-fluoro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-fluoro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[C:14](\[C:12]#[N:13])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])/[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)/C(C#N)=C1\CCc2cc(Cl)ccc21
Yield: 68 %

Procedure:
A mixture of 5-chloro-2,3-dihydro-1H-inden-1-one (150 g, 0.9 mol, commercially available) and ethyl cyanoacetate (125 g, 1.1 mol), ammonium acetate (150 g, 1.94 mmol) and glacial acetic acid (500 mL) in benzene (1 L) was refluxed with a Dean Stark water trap for 22 h. Then benzene was partially removed under vacuum, the residue was filtered and the solid obtain was crystallized from ethanol to give the title compound (161 g, y=68%).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[ClH:31].C(O)(C)C>N1C=CC=CC=1>[ClH:31].[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:12](=[O:13])[CH:2]3[CH:3]([CH:4]4[CH2:5][CH2:6][CH:1]3[CH2:8][CH2:7]4)[C:9]2=[O:11])[CH2:20][CH2:21]1
Reactant: O=C1OC(=O)C2C3CCC(CC3)C12
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: O=C1C2C3CCC(CC3)C2C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of bicyclo[2.2.2]octane-2,3-dicarboxylic anhydride (541 mg, 3 mmol), 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (708 mg, 3 mmol) and pyridine (12.1 ml) was refluxed for 10 hours. The solvent was removed from the mixture under reduced pressure. The residue was extracted with chloroform and water. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude crystals (1 g), which were treated with 6% hydrogen chloride/isopropanol. The solvent was removed to give N-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butyl]bicyclo[2.2.2]octane-2,3-dicarboximide hydrochloride (from ethanol). M.P., 198°-200° C.