Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[N:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[OH:33]S(O)(=O)=O.[NH4+].[OH-]>C(O)(=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[N:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]([NH2:5])=[O:33]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C#N)c3)nc2-c2ccc3nccnc3c2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C(N)=O)c3)nc2-c2ccc3nccnc3c2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile (Example 78, prepared according to the method described in US 2008/0319012 A1) (130 mg, 0.31 mmol) in acetic acid (3 mL) was added conc. H2SO4 (0.7 mL) and the mixture was stirred at 100° C. After 2 hours, more conc. H2SO4 (0.2 mL) was added and the mixture was stirred at 100° C. for 1 hour. Then the reaction mixture was cooled to room temperature, diluted with H2O (10 mL) in the ice bath, and neutralized by addition of NH4OH solution to pH 7. The mixture was extracted with CH2Cl2 (3 times) and then the organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:20 (v/v) to 1:10 (v/v)) to afford the solid, which was recrystallized from CH2Cl2/MeOH/Et2O to give the title compound (131.6 mg, 68%). 1H NMR (300 MHz, CD3OD) δ 2.53 (3H, s), 4.23 (2H, s), 7.16-7.23 (3H, m), 7.54-7.59 (2H, m), 7.84 (1H, dd), 8.04 (2H, bs), 8.25 (1H, bs), 8.85 (2H, dd). MS (ESI) m/z 439 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([O-:21])=[O:20])=[CH:17][C:16]=2[O:24][CH3:25])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=2[O:24][CH3:25])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COc1cc(C(=O)[O-])ccc1COc1cnc(OCC(C)C)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1COc1cnc(OCC(C)C)c(Cl)c1
Temperature: 60 °C

Procedure:
To a suspension of in 4-((5-chloro-6-isobutoxypyridin-3-yloxy)methyl)-3-methoxybenzoate (Preparation 34, 405 mg, 1.07 mmol) in methanol (30.0 mL) was added aqueous lithium hydroxide (1 M, 1.17 mmol, 1.17 mL) and heated at 60° C. for 16 hours. Aqueous lithium hydroxide (1 M, 0.212 mmol, 0.212 mL) was then added and the reaction mixture was heated at 60° C. for 5.5 hours. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure to yield the title compound as pale yellow solid:
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](\[CH2:13][CH2:14][O:15][CH3:16])/[C:10]([OH:12])=[O:11])=[C:6]([O:17]C)[C:5]([O:19][CH3:20])=[C:4]([O:21][CH3:22])[C:3]=1[O:23]C>CCOCC>[CH3:22][O:21][C:4]1[C:3](=[O:23])[C:2]([CH3:1])=[C:7](/[CH:8]=[C:9](\[CH2:13][CH2:14][O:15][CH3:16])/[C:10]([OH:12])=[O:11])[C:6](=[O:17])[C:5]=1[O:19][CH3:20]
Reactant: COCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)O
Solvent: CCOCC
Product: COCC/C(=C\C1=C(C)C(=O)C(OC)=C(OC)C1=O)C(=O)O

Procedure:
Compound 64 was prepared from 96 (0.070 g, 0.21 mmol) as described above for 10a using Method A to give 0.012 g (0.039 mmol, 19%) of the product as a red solid following flash chromatography (2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)C1CC1
Product: Cc1noc(-c2sc(NC(=O)C3CC3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and cyclopropanecarbonyl chloride.
Reaction SMILES: [N:1]#[N:2].C([O:5][C:6](=[O:45])[C@H:7]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[N:8]([C:10](=[O:37])[C@H:11]([CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])[NH:12][S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[CH3:9])C>C(O)C.[OH-].[Na+]>[N:1]#[N:2].[CH3:27][O:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:28][CH3:29])[CH:17]=[C:16]([S:13]([NH:12][C@H:11]([C:10]([N:8]([CH3:9])[C@H:7]([C:6]([OH:45])=[O:5])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:37])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:35])[NH2:36])(=[O:14])=[O:15])[CH:25]=[CH:24]2
Reactant: CCOC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(C)[C@@H](Cc3ccccc3)C(=O)O)cc2cc1OC
Yield: 77.8 %

Procedure:
A solution of 2.5 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-methylphenylalanine ethyl ester in 5 ml of ethanol and 7 ml of 1N NaOH solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-diethyl ether to give 1.86 g (78 percent) of N2 -(6,7-dimethoxy-2-naphthyl-sulfonyl)-L-arginyl-N-methylphenylalanine as an amorphous solid, I.R. (KBr): 3,300 (broad), 1,600 cm-1
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>O>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][O:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)cc(=O)oc12
Yield: 105.4 %

Procedure:
An N,N-dimethylformamide (5 mL) solution of 7-hydroxy-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (500 mg, 1.84 mmol), 1,4-dibromobutane (2.19 mL, 18.36 mmol), and potassium carbonate (375 mg, 2.76 mmol) was stirred overnight at room temperature. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using silica-gel chromatography (hexane:ethyl acetate=10:1), and the title compound (0.79 g) was obtained as yellow oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][CH:13]([CH2:17][CH:18]=[CH2:19])[CH2:14][CH2:15][OH:16].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][CH:13]([CH2:17][CH:18]=[CH2:19])[CH2:14][CH:15]=[O:16]
Reactant: C=CCC(CCO)OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: C=CCC(CC=O)OC
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (0.612 mL) was added dropwise to a solution of oxalyl chloride (0.652 mL) in dichloromethane (15 mL) at −55° C., and the mixture was stirred at −70° C. for 10 minutes. A solution of 3-methoxy-5-hexenol (Tetrahedron, 61, 3183-3194 (2005)) (660 mg) in dichloromethane (5 mL) was added dropwise to the solution at −60° C., and the mixture was stirred at −60° C. for 15 minutes. Triethylamine (4.95 mL) was added dropwise to the solution at −60° C., and the reaction solution was stirred at −60° C. to room temperature for 30 minutes. The reaction solution was poured into water, followed by extraction with dichloromethane. The extract was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound containing dichloromethane and triethylamine (3.0 g).
Reaction SMILES: C(=[N:8][N:9]1[CH:13]2[CH2:14][CH:15]([OH:17])[CH2:16][CH:12]2[N:11]([CH2:18][CH2:19][CH3:20])[C:10]1=[O:21])C1C=CC=CC=1.CO>[Pd].C(O)(=O)C>[NH2:8][N:9]1[CH:13]2[CH2:14][CH:15]([OH:17])[CH2:16][CH:12]2[N:11]([CH2:18][CH2:19][CH3:20])[C:10]1=[O:21]
Reactant: CCCN1C(=O)N(N=Cc2ccccc2)C2CC(O)CC21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1C(=O)N(N)C2CC(O)CC21
Temperature: 15 °C
Reaction time: 72 h
Yield: 103 %

Procedure:
The compound of step (f) (7.0 g) was added to a solution of methanol (280 ml) and acetic acid (2.25 ml) containing 10% Pd on carbon (2.5 g) and the resulting mixture stirred at 15° C. under an atmosphere of hydrogen for 3 days. The catalyst was removed by filtration through Celite and concentration of the filtrate in vacuo gave the desired product as an oil (5.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3oc12
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1Oc1cc(Cl)ccc1C2
Temperature: 25 °C

Procedure:
A solution of borane-tetrahydrofuran complex in tetrahydrofuran (1M., 38 ml.) is added slowly to a solution of 3-chloro-5-methoxyxanthone (15 g.) in tetrahydrofuran (200 ml.). The mixture is refluxed for 2 hours, cooled to room temperature and poured into water. The precipitate is filtered, dried and recrystallised from methanol to give 3-chloro-5-methoxyxanthene, m.p. 106°-108° C.
Reaction SMILES: [CH2:1]([CH:10]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[N:11]1[CH:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH:13]([CH:27]=[CH2:28])[C:12]1=[O:29])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[O:42]1CCCC1>O.[OH-].[Na+]>[CH2:30]([CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[N:11]1[CH:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH:13]([CH:27]([OH:42])[CH3:28])[C:12]1=[O:29])[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1
Reactant: C1CCOC1
Reactant: C=CC1C(=O)N(C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)C1C(=O)OCc1ccc(OC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(COC(=O)C2C(C(C)O)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(di-p-anisylmethyl)-3-ethenyl-4-p-methoxybenzyloxycarbonyl-2-azetidinone (10 g) and mercuric acetate (6.6 g) in terahydrofuran (40 ml) and water (20 ml) was stirred at room temperature for 5 hours. The reaction mixture was treated with 1N aqueous sodium hydroxide (40 ml) and then sodium borohydride (0.78 g) in 1N aqueous sodium hydroxide (2 ml) at ~0° C. The mixture was acidified with 2N hydrochloric acid, filtered to remove any insoluble materials. The filtrate was extracted with diethyl ether. The extract was washed successively with water and aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-p-methoxybenzyloxycarbonyl-2-azetidinone.
Reaction SMILES: Br[CH2:2][C:3](=[O:17])[C@@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[OH:26].[F-].[K+]>CN(C=O)C.ClCCl.O>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[O:26][CH2:2][C:3](=[O:17])[C@@H:4]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)CBr
Reactant: Oc1ccc(F)cc1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)COc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.2 %

Procedure:
A mixture of (S)-benzyl 4-bromo-3-oxobutan-2-ylcarbamate (prepared according to R. V. Hoffman et al., J. Org. Chem. 2001, 66, 5790-5795) (600 mg, 2.00 mmol), 2,4-difluorophenol (312 mg, 2.40 mmol) and potassium fluoride (380 mg, 6.54 mmol) in DMF (4 mL) was stirred at r.t. for 17 h. Water (15 mL) and dichloromethane (3 mL) were added and the mixture was stirred for 30 min. The mixture was added to a phase separator. The water phase was once more stirred with dichloromethane (3 mL), and added to the phase separator. The organic phases were concentrated and the residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 3/1) to give the title compound as a white solid (658 mg, 94% yield).
Reaction SMILES: [N:1]([C@@H:4]1[C@H:13]([O:14]C(=O)C)[C@@H:12]([O:18]C(=O)C)[C@H:11]([CH2:22][O:23]C(=O)C)[O:10][C@@H:5]1[O:6]C(=O)C)=[N+:2]=[N-:3].C(O)CCC>Cl>[N:1]([C@@H:4]1[C@H:13]([OH:14])[C@@H:12]([OH:18])[C@H:11]([CH2:22][OH:23])[O:10][CH:5]1[OH:6])=[N+:2]=[N-:3]
Reactant: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Solvent: CCCCO
Product: [N-]=[N+]=N[C@H]1C(O)O[C@@H](CO)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 82 %

Procedure:
A solution of Compound 9 (541 mg, 1.45 mmol) in 3N aqueous hydrochloric acid (100 mL) was warmed until solution became clear and then stirred at room temperature. After 10 hours, n-butanol was added and the solution was evaporated. The residue was chromatographed on a flash column with CHCl3—MeOH (4:1) to give 0.244 g of Compound 9a in 82 percent yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[CH3:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH2:34])=[NH:33])[CH:27]=[CH:28][C:29]=1[CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:33]=[C:32]([NH:31][C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=4)[N:34]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: Cc1ccc(NC(=N)N)cc1C
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: Cc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1C

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3,4-dimethyl-phenyl)-guanidine nitrate were converted to I-29 (59%): HRMS Calcd. for C20H17ClN40: 365.1169, Found 365.1143.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:39][CH:40]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:41](Cl)=[O:42]>C1C=CC=CC=1>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([O:26][CH2:27][CH2:28][O:29][C:41](=[O:42])[CH:40]([CH3:39])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:24][CH2:25]3)[C:5]=2[CH:4]=1
Reactant: CCCCCC(C)C(=O)Cl
Reactant: OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC(C)C(=O)OCCOC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
13.55 g of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine (prepared by Example XLIII), 5.4 ml of triethylamine and 100 ml of anhydrous benzene were added to a flask and a solution of 5.7 g of 2-methyl-heptanoic acid chloride in 50 ml of anhydrous benzene was added thereto. The mixture was agitated at room temperature for 24 hours and then the precipitate formed was removed by filtration. The benzene filtrate was washed with an aqueous solution of sodium bicarbonate, then with water. After drying and concentration of the benzene solution, the resulting oil was purified by chromatography on silica gel. After elution with ethanol and evaporation of the solvent, 5.2 g of 2-trifluoromethyl-10-[3-(4-β-{2-methylheptanoyloxy}ethoxypiperidino)-propyl]-phenothiazine as a clear oil were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)=[O:20]>>[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:18]
Reactant: CC(=O)c1cccc(N)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Product: COc1cc2ncc(C#N)c(Nc3cccc(C(C)=O)c3)c2cc1OC

Procedure:
In the manner of Example 274 reaction of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile with 3-aminoacetophenone gave the tide compound as a tan solid, mp 204-206° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:14]([O:16]C)=O)[C:10](OC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[CH:22]([NH2:24])=[NH:23].Cl>CO>[CH2:1]([O:8][C:9]1[C:14]([OH:16])=[N:23][CH:22]=[N:24][C:10]=1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(OCc1ccccc1)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1ncnc(O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.8 %

Procedure:
Dimethyl 2-(benzyloxy)malonate (16.1 g, 0.0675 mol) was dissolved in MeOH (27 ml), NaOMe (42.59 ml of a 30% solution in MeOH, 3.5 eq) was added and the mixture cooled to 0 C. Formamidine hydrochloride (5.68 g, 1.05 eq) was added and the mixture stirred at 0° C. for 30 minutes and then at reflux for 2 hours. After cooling to 0° C. concentrated HCl (21 ml) was added and the solid was collected by filtration (washing with cold water 3×20 ml) to give 15.14 g of the title compound.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[CH3:22][S:19]([C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:10][C:14]2=[N:15][CH:16]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncccn1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ncccn3)cc2c1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a suspension of the compound obtained in Example 6 (2) (1.10 g) in methanol (24 ml), a 1N aqueous potassium hydroxide solution (4.8 ml) was added and the mixture was stirred at 15 to 30° C. for 1 hour. The mixture was further heated under reflux for 15 minutes. After completion of the reaction, the reaction solution was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was washed with methanol/water and filtered off. Further, the unnecessary substances in the aqueous layer during extraction were filtered off, and they were combined and heated to dryness to obtain 417 mg of the desired product as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH2:26][CH2:25]2)[C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[NH:20]1>>[O:18]=[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:26][CH2:25]2)[C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[NH:20]1
Reactant: NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Batch size: 1.47 g (9.9 mmol) 3-(3-pyridyl)-acrylic acid, 1.15 ml (13.5 mmol) oxalyl chloride and 2.6 g (9.0 mmol) 4-[4-(2-oxo-2.3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-butylamine.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.O.NN.C([OH:26])C.[OH-].[Na+]>O.C(O)COCCO>[N:12]1[C:6]2[O:5][C:4]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:26])=[CH:16][C:3]=3[CH2:2][CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Reactant: CCO
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)Cc1ccc2c(c1)CCc1cccnc1O2
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
A mixture of 20 mg of (5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]oxepin-8-yl)-acetamide, 0.5 ml of hydrazine hydrate and 1.5 ml of ethanol was refluxed for 1 hour. The solvent and excess hydrazine hydrate were removed by distillation to obtain a residue, to which was added ethanol. Thereafter, the solvent was distilled off to obtain a yellow oil, to which were added 0.1 g of sodium hydroxide and 3 ml of dry diethylene glycol. The mixture was stirred at 100° C. for 20 minutes and then at 120° C. for 2.5 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid, which was chromatographed over 1 g of silica gel and eluted with chloroform, thereby yielding 3.5 mg (yield: 18%) of (5,6-dihydrobenzo[b]pyrido[3,2-f]oxepin-8-yl)-acetic acid as white needle crystals having a melting point of 203°-204° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[S:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12]([C:22]3[CH:23]=[CH:24][C:25]([S:26][CH3:27])=[C:20]([CH3:19])[CH:21]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ccc(B(O)O)cc1C
Reactant: COc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O
Product: COc1c(-c2ccc(SC)c(C)c2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 6 starting with 2-(3,4-difluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting 3-methyl-4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 2.0 g, 85%). 1H NMR (300 MHz, CDCl3) δ 2.39 (s, 3H), 2.53 (s, 3H), 4.11 (s, 3H), 7.22-7.32 (m, 2H), 7.34 (s, 1H), 7.42-7.50 (m, 2H), 7.55-7.64 (m, 1H), 7.92 (s, 1H). MS (APCI+) m/z 375 (M+H)+.