Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10]Cl)[N:6]=1)([CH3:4])[CH3:3].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:2]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)c1ccn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 37.4 %

Procedure:
0.77 g of 3-i-propyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.64 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 8 ml of N,N-dimethylformamide. 1.54 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-ethyl acetate to obtain 0.42 g of [(3-i-propyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (2), hereinafter) shown by below formula.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:18]([NH2:20])[CH3:19])=[C:10]([C:13]3[N:14]=[CH:15][S:16][CH:17]=3)[CH:11]=2)[CH:6]=[CH:5]1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[C:24]([S:31][CH3:32])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][C@H:18]([C:9]2[N:8]=[C:7]3[CH:6]=[CH:5][N:4]([CH3:3])[C:12]3=[CH:11][C:10]=2[C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH3:19])[N:25]=[C:24]([S:31][CH3:32])[N:23]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1cscn1
Reactant: CSc1nc(N)c(C#N)c(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2cscn2)n1
Temperature: 120 °C
Yield: 8.6 %

Procedure:
(S)-1-(1-methyl-6-(thiazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine dihydrochloride (200 mg, 0.604 mmol), 4-amino-6-chloro-2-(methylthio)pyrimidine-5-carbonitrile (182 mg, 0.906 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.315 mL, 1.81 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by column chromatography eluting with 20-80% EtOAc in hexane over 60 minutes. The fractions containing the desired product were collected and concentrated to give the title compound (22 mg, 9%). ESI-MS m/z [M+H]+ calc'd for C19H18N8S2, 423; found 423.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:38]([C@H:34]4[CH2:35][CH2:36][CH2:37][N:33]4[C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])=[O:39])[CH2:24][CH2:25]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCNCC3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a stirred solution of (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(piperazin-1-yl)-1H-indazole (0.051 g, 0.14 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.061 g, 0.28 mmol) in dichloromethane (1 mL) was added HATU (0.11 g, 0.28 mmol) and iPr2NEt (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by the addition of dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% methanol in dichloromethane) to afford the (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.052 g, 0.088 mmol, 63%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:3]1=[O:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Solvent: ClCCl
Product: CC(=O)OC1CCN(CC#CCN2CCCC2)C1=O

Procedure:
A solution of 0.4 of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone and 1.0 ml of acetic anhydride in 20 ml of dichloromethane was stirred overnight. The solvent was removed in vacuo. The residue was basified with potassium bicarbonate solution and extracted with dichloromethane. The dichloromethane solution was washed with water, dried, concentrated in vacuo and the residue was purified by chromatography (alumina), giving the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20].C(=O)(O)[O-].[Na+]>CC#N>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[C:19](=[O:20])[CH2:18][N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:12][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: O=C(CBr)N1CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CN1CCC(c2n[nH]c3cc(F)ccc23)CC1)N1CCc2ccccc2C1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.8 g, 18.9 mmol) in CH3CN (200 ml) was added 2-bromo-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (4.8 g, 18.9 mmol) and sodium bicarbonate (1.9 g, 22.7 mmol) at room temperature. The reaction mixture was warmed to reflux (4 hours), cooled to room temperature and filtered through a pad of celite. The solids were washed with DCM and the combined filtrates were concentrated. The remaining residue was purified via preparative HPLC (silica gel, 5-10% MeOH/DCM) to give 4.1 g of 1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethanone which was used without further purification. To a suspension of the latter (3.7 g, 9.4 mmol) in THF (100 ml) was added (dropwise) lithium aluminum hydride (11.3 ml of 1.0M solution in THF, 11.3 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux (5 hours), cooled to room temperature and carefully quenched with water (10 ml). The precipitated salts were removed via filtration and washed with 1:1 EtOAc/DCM. The combined filtrates were concentrated and the remaining oil was purified via flash column chromatography (silica gel, 10% MeOH/DCM) to give 2.2 g of the product. The dimaleate salt was prepared in methanol (30 ml) with maleic acid (3.0 eq.), m.p. 185°-187° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:18])[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][C:13]=2[NH2:14])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:18])[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][C:13]=2[NH:14][CH2:27][CH3:28])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCC1CC(N)=C(c2cccc(C(F)(F)F)c2)C1=O
Reactant: CCOS(=O)(=O)OCC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCC1CC(NCC)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 25 °C

Procedure:
In this example, a mixture containing 8.0 g of 2-(3-trifluoromethylphenyl)-3-amino-5-propyl-2-cyclopentenone; 3.0 g of aqueous 50 wt % sodium hydroxide; 6.4 g of benzyltriethylammonium chloride; and 5.0 ml of diethyl sulfate in 70 ml of methylene chloride was stirred at room temperature for about 1 hour and then warmed to, and stirred at reflux for about 15 to 20 minutes. The mixture was cooled to room temperature and successively washed three times with water, twice with aqueous 1N hydrochloric acid and then twice with saturated aqueous sodium bicarbonate. The washed mixture was dried over magnesium sulfate and evaporated affording an oil residue. The oil was triturated with a mixture of ethyl ether and petroleum ethers and filtered affording 3.2 g of the title compound as a solid, m.p. 120°-120.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.[Br:21]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=1
Reactant: COc1ccc(-n2ccc3cc(O)ccc3c2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-n2cc(Br)c3cc(O)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methoxyisoquinoline-1-ol was prepared as described above, followed by deprotection of the methoxy group using chlorobenzene and boron tribromide (6 equivalents, neat) added dropwise under argon atmosphere at room temperature, to obtain isoquinoline-1,6-diol (14v). Compound 14v (11.5 mmol) reacted with 4-iodoanisole (4.01 g, 17.13 mmol), copper (I) iodide (0.44 g, 2.28 mmol). L-proline (0.53 g, 4.57 mmol) and anhydrous potassium carbonate (3.16 g, 22.84 mmol) were placed in a dry 250 mL three-necked round-bottomed flask fitted with a stirring bar and reflux condenser. The reaction flask was vacuumed and refilled with dry argon. 50 mL of anhydrous methyl sulfoxide was added via syringe. The reaction mixture was stirred and heated to 130° C. for 20 hours. 50 mL of water was added to quench the reaction, and solid precipitated out. The solid was filtered, washed with water (2×20 mL) and dried in air. This solid was purified by flash column chromatography (silica gel, ethyl acetate) to give 6-hydroxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (14w) a brown solid product. Compound 14w (1.8 mmol) was placed in a dry 250 mL single-necked round-bottomed flask fitted with a stirring bar and septa. Acetonitrile (10 mL) was added via a syringe under argon atmosphere at room temperature. N-Bromosuccinimide or NBS (0.33 g, 1.87 mmol) was added portionwise under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was then added. The mixture was extracted with ethyl acetate (3×10 mL). Organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, hexanes/EtOAc=2/3 v/v) to give white solid of 4-bromo-6-hydroxy-2-(4-methoxyphenyl)isoquinolin-1(2H)-one (14xME)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:16]C.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C:6]=2[CH:5]=[C:4]([C:18](=[O:21])[CH2:19][CH3:20])[C:3]=1[OH:16]
Reactant: CCOC(=O)C1Cc2ccc(OC)c(Cl)c2O1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)C1Cc2cc(C(=O)CC)c(O)c(Cl)c2O1

Procedure:
To 1,2-dichloroethane (50 ml) were added ethyl 7-chloro-2,3-dihydro-6-methoxybenzofuran-2-carboxylate (1b) (4.25 g, 0.01656 mol) and propionyl chloride (2.58 ml, 0.03311 mol). The solution was stirred on an ice bath and treated with anhydrous aluminum chloride (6.62 g, 0.04967 mol) at 0°-5° C. for 45 minutes. An additional portion of aluminum chloride (2.21 g, 0.01656 mol) was added and the mixture left to stir overnight.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-])=O.[H-].[Na+].[CH3:17][O:18][CH2:19][CH2:20][CH2:21]OS(C1C=CC(C)=CC=1)(=O)=O.[I-].[K+]>CC(N(C)C)=O.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:21][CH2:20][CH2:19][O:18][CH3:17])[C:8]=2[CH:14]=1
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Fe]
Agent: [H-]
Agent: [I-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCCCN1C(=O)COc2ccc(N)cc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-nitro-4H-benzo[1,4]oxazin-3-one (5 g, 25.8 mmol) and NaH (˜60% moistened with oil, 911 mg, ˜23 mmol) in DMA (30 ml) is stirred at 5° C. for 30 min. Toluene-4-sulfonic acid 3-methoxy-propyl ester (6.87 g, 28.1 mmol) in DMA (10 ml) is added, followed by potassium iodide (4.67 g, 28.1 mmol). The ice-bath is removed and the mixture stirred for 3 h at 60° C. The solvent is distilled off in vacuo and the residue partitioned between H2O and ethyl acetate. The organic layer is dried (Na2SO4) and the solvent evaporated. Part of the crude product (5 g, 18.8 mmol) is dissolved in a mixture of acetic acid (50 ml) and ethyl acetate (50 ml). The solution is added dropwise to a suspension of Fe powder (6 g, 107 mmol) in 5% aqueous acetic acid (50 ml). The resultant mixture is kept at 70° C. for 5 h. After cooling to RT, the Fe powder is filtered off, and the filtrate diluted with H2O. The aqueous layer is extracted with ethyl acetate. The organic layer is washed with NaHCO3 solution, dried (Na2SO4) and evaporated. The residue is purified by column chromatography (SiO2, CH2Cl2/CH3OH 100:0-80:20) to afford 6-amino-4-(3-methoxy-propyl)-4H-benzo[1,4]oxazin-3-one as a dark brown oil. MS: 237.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 2.66 min. Part of this intermediate (1 g, 4.2 mmol) is diluted with methanol (15 ml). Acetaldehyde (166 μl, 2.94 mmol), acetic acid (480 μl, 8.4 mmol) and NaBH3CN (396 mg, 6.3 mmol) are added. The mixture is stirred for 1.5 h at RT, quenched with 5% KHSO4 solution and extracted with ethyl acetate. The organic layer is washed with NaHCO3 solution and brine, dried over Na2SO4 and evaporated in vacuo. Purification of the product by column chromatography (SiO2, CH2Cl2/CH3OH) affords the title compound as a purple oil. MS: 265.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 3.41 min
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[O:15][CH2:16][C:17](=[O:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.[OH-].[Na+]>C(O)C.Cl>[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28]([CH:35]=[C:16]2[O:15][C:14]([NH:13][C:7]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:25])=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2=[O:24])=[CH:27]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(C)cc2OCCN(C)C)OCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(C)cc2OCCN(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 5.5 %

Procedure:
To a stirred solution of ethyl 2-({2-[2-(dimethylamino)ethoxy]-4-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.011 g, 0.030 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0044 g, 0.030 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.045 mL, 0.091 mmol) was added at ambient temperature. The mixture was refluxed for 9 h. Cooled with ice bath, 2M sodium hydroxide solution (0.041 mL, 0.082 mmol) was added dropwise to neutralize, and ethanol (0.5 mL) was added. The mixture was refluxed for further 16 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.00079 g, y. 5%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[C:21]([CH3:33])[CH:20]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[C:38]([CH3:40])[N:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:33][C:21]1[CH:20]=[C:19]([CH2:18][C:15]2[C:16](=[O:17])[N:11]([CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)[C:12]3[N:13]([N:37]=[C:38]([CH3:40])[N:39]=3)[C:14]=2[CH2:34][CH2:35][CH3:36])[CH:24]=[CH:23][C:22]=1[C:25]1[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Yield: 99.8 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile (1.20 g), 3N hydrochloric acid (15 mL) and tetrahydrofuran (15 mL) was stirred under refluxing for 15 hr. The reaction mixture was neutralized with 1 M aqueous sodium hydroxide solution (45 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (1.10 g, quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2=[CH:21][CH:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:19]2[CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[O:16][CH2:17][CH2:18][C:19]=23)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1cccc2c1CCO2
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3c2CCO3)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 2,3-dihydro-benzofuran-4-carboxylic acid. LC-MS (acidic): tR=1.01 min; [M+H]+=359.1.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21]CC)=O)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][NH2:25]>C(O)C>[C:1]1([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH:24][NH2:25])=[O:21])[CH2:16][CH2:17]2)[C:2]2[C:7](=[CH:8][CH:9]=[CH:4][CH:3]=2)[CH:6]=[CH:5][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2cccc3ccccc23)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2cccc3ccccc23)CC1

Procedure:
Synthesized according to General Procedure C: 6{24} (8.29 g, 26.5 mmol, 1 equiv.), anhydrous hydrazine (2.5 mL, 79.6 mmol, 3 equiv.), ethanol (53.4 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{24} (6.86 g, 87%) as a brown oil. 1H-NMR (500 MHz, CDCl3): δ 8.70 (d, 1H, J=8.0 Hz), 8.19 (br s, 1H), 7.84 (d, 1H, J=7.5 Hz), 7.77 (dd, 1H, J=3.0, 6.5 Hz), 7.52-7.46 (m, 2H), 7.41-7.38 (m, 2H), 3.90 (s, 2H), 3.87 (br s, 2H), 3.06 (s, 2H), 2.51 (br s, 8H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 133.7, 133.7 132.4, 128.3, 127.9, 127.3, 125.6, 125.5, 125.0, 124.6, 60.9, 60.5, 53.6, 53.2.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:13][CH2:12]2)=[N:3]1.[CH3:27][C:28](=[CH2:32])[C:29](Cl)=[O:30]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:29](=[O:30])[C:28]([CH3:32])=[CH2:27])=[C:21]([CH3:26])[CH:20]=3)[CH2:15][CH2:16]2)=[N:3]1
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Product: C=C(C)C(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 72.8 %

Procedure:
Starting with 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine hydrochloride (0.6 g, 1.702 mmol) and 2-methyl-acryloyl chloride (0.206 mL, 1.702 mmol) and following the procedure outlined in Example 512, N-{4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-2-methyl-acrylamide (0.521 g, 1.239 mmole) was obtained. Yield=73%. 100% purity at 254 nM; LCMS (APCI): 421.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 811.17 (bs, 1H), 9.32 (s, 1H), 8.10 d, J=7.88 Hz, 1H), 8.07 (d, J=7.88 Hz, 1H), 7.55 (t, J=7.88 Hz, 1H), 7.43 (t, J=7.88 Hz, 1H), 7.19 (d, J=7.88 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=7.88 Hz, 1H), 5.80 (s, 1H), 5.44 (s, 1H), 4.05 (bd, J=12.08 Hz, 2H), 3.63 (bd, J=12.08 Hz, 2H), 3.51–3.32 (m, 5H), 3.31 (s, H2O), 3.29–3.22 (m, 1H), 3.07–2.98 (m, 2H), 2.12 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:8]([CH2:14][OH:15])[CH2:9][OH:10])[CH:3]=1
Reactant: CCOC(=O)C(Oc1cc(C)on1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(OC(CO)CO)no1
Temperature: 25 °C
Reaction time: 40 h
Yield: 70.5 %

Procedure:
A solution of 23.72 g of diethyl 2-(5-methyl-3-isoxazolyloxy)malonate (prepared as described in Preparation 19) in 120 ml of tetrahydrofuran was added dropwise to a suspension of 14.00 g of lithium aluminum hydride in 140 ml of tetrahydrofuran over a period of 30 minutes, whilst ice-cooling. The mixture was stirred at room temperature for 40 hours, after which 56 ml of a 4% w/v aqueous solution of sodium hydroxide was added dropwise to it over a period of 30 minutes, whilst ice-cooling. An insoluble material was filtered off using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 300 g of silica gel. 11.26 g of the title compound was isolated as a colorless oil from the fractions eluted with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[CH2:19][O:20]C)=[C:14]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][C:18]=1[CH:19]=[O:20])=[C:14]([C:22]1[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=1[F:28])[C:13](=[O:30])[CH:12]=[CH:11]2
Reactant: COCc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: O=Cc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Reaction time: 12 h
Yield: 39.6 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-7-(hydroxymethyl)-2H-quinolizin-2-one (Example 52, 21 mg) was added Dess-Martin periodinane (30 mg) at room temperature and stirred for 12 h. The mixture was concentrated and purified by silica gel (methylene chloride/methanol=20/1) to give the title compound (8 mg).