Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([O:19][C:20]([C:22]1[C:23]([NH2:27])=[N:24][NH:25][CH:26]=1)=[O:21])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:17]([O:19][C:20]([C:22]1[C:23]([NH2:27])=[N:24][N:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2nccc(-c3ccc(N(C)C)cc3)n2)nc1N
Temperature: 105 °C
Yield: 36.7 %

Procedure:
A mixture of [4-(2-Chloro-pyrimidin-4-yl)-phenyl]-dimethyl-amine (2.0 g, 8.58 mM), 3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (1.32 g, 8.58 mM), Cs2CO3 (4.4 g, 13.58 mM) in DMF (15 ml) was heated 2 hr at 105° C. The reaction was then cooled to room temperature and diluted with water (100 mL) and the yellow precipitate collected via filtration and was washed with water (2×30 ml) then ethyl ether (2×30 ml). The solid was dried under vacuo and comprised a mixture of 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester and 5-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester in a ratio of approximately 6:4. The solid is flushed thru a pad of silica eluting with 5% MeOH/dichloromethane/1% TEA and the material is pooled and evaporated to a solid. Crystallization from dichloromethane/MeOH afforded the slower of the two isomers 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (1.1 g, 36.4% yield) as a bright yellow solid. ES-MS MH+353, 1H NMR (300 MHz, ppm, DMSO-d6): 8.84 (s, 1H), 8.63 (d, 1H), 8.15 (d, 2H), 7.77 (d, 1H), 6.93 (d, 2H), 5.85 (br s, 2H) 4.27 (q, 2H), 3.04 (s, 6H), 1.32 (t, 3H). Chromatography of the filtrate on silica eluting 1% TEA/EtOAc can provide the other faster isomer 5-Amino-1-[4-(4-dimethylamino-phenl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester as an off-white solid. ES-MS MH+ 353, 1H NMR (300 MHz, ppm, DMSO-d6): 8.7 (d, 1H), 8.12 (d, 2H), 7.83 (d, 1H), 7.79 (s, 1H), 7.64 (br S, 2H), 6.84 (d, 2H), 4.28 (q, 2H), 3.04 (s, 6H), 1.28 (t, 3H).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:13][CH:14]=1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 113.3 %

Procedure:
To a solution of 7-methoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (52 mg, 0.20 mmol) in dichloromethane (7 ml) at 0° C. was added dropwise trifluoroacetic acid (0.23 ml, 3.01 mmol) and the reaction mixture was then stirred at room temperature for 24 hours. The mixture was then made basic to pH 9 by dropwise addition of saturated aq. sodium carbonate solution. The mixture was extracted three times with a 1:1 mixture of ethyl acetate and tetrahydrofuran, the phases separated, and the organic phase dried over sodium sulphate and concentrated in vacuo to yield the title compound as a light brown oil (37 mg, 92%); MS (ISP): 164.4 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5](=O)[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO.O>[CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[CH:5]([NH2:33])[CH2:4][CH2:3]1
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(N)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.3 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2 ) in 5 ml of MeOH was added 922 mg (12 mmol) of ammonium acetate and then 188 mg (3 mmol) of sodium cyanoborohydride. The reaction mixture was refluxed for 1 hour, stirred at ambient temperature for 12 hours and then diluted with water (10 ml) and extracted with Et20 (3×30 ml). The organic layer was washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo to an oil. Recrystallization from EtOAc-hexane yielded the title compound as a white solid.
Reaction SMILES: [C:1]([C:6]1([CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[NH:23][NH2:24].C([O-])(=O)C.[Na+]>CO>[CH2:4]([O:3][C:1]([C:6]1([CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]1=[N:24][NH:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[Cl:15])=[O:2])[CH3:5]
Reactant: NNc1cc(Cl)ccc1Cl
Reactant: C=CCC1(C(=O)OCC)CCCC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCC1(C(=O)OCC)CCCC1=NNc1cc(Cl)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-carbethoxy-2-allylcyclopentanone (110 mg, 0.55 mmol) in 1 mL of methanol was added (2,5-dichloro-phenyl)-hydrazine (89 mg, 0.50 mmol) and sodium acetate (62 mg, 0.75 mmol). The reaction mixture was stirred at room temperature over night. The reaction mixture was concentrated and adding 10 mL of ethyl acetate diluted the residue. The organic solution was washed with 5 mL of water and 5 mL of brine. The organic layer was dried over sodium sulfate and concentrated to give the crude product, which was directly used in next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>N1C=CC=CC=1.C(Cl)Cl>[CH2:12]([O:11][C:9]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: Nc1ccncc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
4-Aminopyridine (17.34 grams) (184.3) was dissolved in dry pyridine (217 ml.) and cooled to 0° C. over 30 minutes. Ethyl chloroformate (17.2 ml.) (180.7 mmoles) was added and the solution was stirred at 0° C. for 1 hour and then at 25° C. for 40 hours. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and water. The CH2Cl2 was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2% (10% saturated NH4OH in MeOH)--CH2Cl2 to give the title compound (Yield: 10 grams, 33%, M+ 166).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:16]([CH3:18])[CH3:17])[C@H:9]([CH2:14][CH3:15])[C:10](OC)=[O:11])[C:5]([N+:19]([O-])=O)=[CH:4][N:3]=1.[H][H]>C(O)(=O)C.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:19][C:10](=[O:11])[C@@H:9]([CH2:14][CH3:15])[N:8]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C(C)C
Temperature: 75 °C
Reaction time: 2 h
Yield: 206.5 %

Procedure:
Methyl (2R)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]butanoate 22b (7.30 g, 23 mmol) was dissolved in 100 mL acetic acid followed by the addition of 5 g Raney nickel, repeated filled with hydrogen for three times. The reaction mixture was heated to 75° C., stirred for 2 hours and filtered. The filtrate was concentrated under reduced pressure, added with 30 mL of ice water resulting in the formation of precipitate. The precipitate was filtered. the filter cake was dried by heat to obtain the crude title compound (7R)-2-chloro-7-ethyl-8-isopropyl-5,7-dihydropteridin-6-one 22c (12.10 g, yield: 71.7%) as a gray solid, which was used in the next step without further furification.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CSc1ncnc2ccncc12
Solvent: CCO
Product: c1ccc(CNc2ncnc3ccncc23)cc1
Yield: 16.9 %

Procedure:
4-Methylthiopyrido[4,3-d]pyrimidine (160.4 mg, 0.902 mmol), and benzylamine (106.3 mg, 0.992 mmol) in EtOH (2 mL) are heated at 80° C. for 12 h, and then the solvent is removed under reduced pressure. The resulting solid is suspended in CH2Cl2, filtered, and the resulting solid is purified by preparative tlc on silica, eluting with 5% MeOH in CHCl3. Removal of the solvent under reduced pressure yields 4-benzylaminopyrido[4,3-d]pyrimidine (36 mg, 17%). 1H NMR (DMSO) δ 9.60 (1H, s), 9.37 (1H, t, J=5.8 Hz), 8.72 (1H, d, J=5.8 Hz), 8.57 (1H, s), 7.54 (1H, d, J=5.8 Hz), 7.37 (2H, d, J=7.0 Hz), 7.33 (2H, t, J=7.3 Hz), 7.25 (1H, t, J=7.2 Hz), 4.81 (2H, d, J=5.8 Hz).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl.O=[C:7]([CH3:31])[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]([CH3:30])[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:22]=1[CH:21]=[CH:20][C:19]([Cl:23])=[CH:18]2)=[O:13].C([BH3-])#N.[Na+]>CO>[ClH:23].[CH:1]([NH:4][CH:7]([CH3:31])[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]([CH3:30])[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:22]=1[CH:21]=[CH:20][C:19]([Cl:23])=[CH:18]2)=[O:13])([CH3:3])[CH3:2]
Reactant: CC(=O)CCCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NC(C)CCCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.2 ml. of isopropylamine in 25 ml. of methanol is treated with 4 ml. of 5-N methanolic hydrochloric acid. Thereafter, there are successively added under an atmosphere of argon at 20°-25° C. 3.7 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (4-oxopentyl)amide and 0.4 g. of sodium cyanoborohydride and the mixture is then stirred at room temperature for 48 hours. The mixture is made acidic with concentrated hydrochloric acid while cooling with ice, stirred at room temperature for an additional 0.5 hour and then concentrated to dryness under reduced pressure. The residue is made alkaline with 0.5-N sodium hydroxide with the addition of ice and extracted with 200 ml. of diethyl ether. The extract, dried over sodium sulfate, is concentrated to dryness and the residual oily base crystallized from hot hexane. The thus obtained colorless base, which melts at 102°-105° C. is dissolved in 30 ml. of acetone and treated with excess ethereal hydrochloric acid. The separated hydrochloride is removed by filtration and washed with acetone, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [4-(isopropylamino)pentyl]amide hydrochloride in the form of colorless crystals having a melting point of 216°-218° C. (decomposition). Recrystallization from acetone/methanol does not increase the melting point.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19](=O)C)=[C:14]([F:22])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].CI>CN1CCCC1=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[C:14]([F:22])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SC(C)=O)c(F)c2)C(=O)O1
Solvent: CN1CCCC1=O
Solvent: CI
Product: CSc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reaction time: 8 h

Procedure:
Prepared according to Method A of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-ones from BAL resin immobilized 5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazoli-dine-2-one with methyl iodide (0.05 mL, 0.81 mmol) in N-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t. overnight, and the crude cleaved product purified by TLC (eluent:. 10% methanol in dichloromethane). Yield 6.3 mg (52%). MS: 299 [M+H]+. 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20](O)=[O:21])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)CC)C.Cl.[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH2:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH:42][C:20]([C:18]1[S:19][C:15]([C:12]2[CH2:11][C:10]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=3)([C:26]([F:28])([F:27])[F:29])[O:14][N:13]=2)=[C:16]2[CH2:25][CH2:24][CH2:23][C:17]=12)=[O:21]
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of compound 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid (10.0 g, 21.4 mmol) in dichloromethane (100 mL) is added triethylamine (6.49 g, 64.2 mmol), glycine methyl ester hydrochloride (3.2 g, 25.7 mmol) and HATU (12.2 g, 32.1 mmol), after the addition the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is diluted with dichloromethane, then the solution is washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated and the residue is dried in vacuum to give 11 g crude product, which is used directly in next step.
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[C:9]([F:14])[CH:8]=1.[C:15](=[C:18]1[C:23](=[O:24])[O:22][C:21]([CH3:26])([CH3:25])[O:20][C:19]1=[O:27])([CH3:17])[CH3:16]>C1COCC1.C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:15]([CH:18]2[C:19](=[O:27])[O:20][C:21]([CH3:25])([CH3:26])[O:22][C:23]2=[O:24])([CH3:17])[CH3:16])=[C:9]([F:14])[CH:8]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(C)=C1C(=O)OC(C)(C)OC1=O
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(C)(C)c2ccc(Br)cc2F)C(=O)O1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution (183 mL, 182.79 mmol) of 1M isopropylmagnesium chloride in THF was added dropwise to a solution of 4-bromo-2-fluoro-1-iodobenzene (50.0 g, 166.17 mmol) in anhydrous THF (96 mL) over 20 min at −20° C. under argon atmosphere. The reaction mixture was stirred at −20° C. for 30 min, and added dropwise to a solution of 5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione in anhydrous toluene (84 mL) over 20 min at −20° C., and then the used container was washed with THF (24 mL). The reaction mixture was stirred at 0° C. for 3 hr, 10% aqueous citric acid solution (200 mL) was added thereto at 0° C., and the mixture was extracted with toluene (200 mL). The organic layer was concentrated under reduced pressure to give 5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione as a pale-yellow oil.
Reaction SMILES: [OH-].[Na+].C(N(CC)CC)C.CN1[C:15](=[O:16])/[C:14](=[CH:17]/[CH:18]2[C:22](=[O:23])[CH2:21][CH2:20][C:19]2=O)/[S:13]C1=S.[OH:26]P([O-])(O)=O.[K+]>O>[O:23]=[C:22]1[C:18]2[CH:17]=[C:14]([C:15]([OH:16])=[O:26])[S:13][C:19]=2[CH2:20][CH2:21]1
Reactant: CN1C(=O)/C(=C/C2C(=O)CCC2=O)SC1=S
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1cc2c(s1)CCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
In a 500-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser, was charged with sodium hydroxide (3.34 g, 83.6 mmol) and water (65 mL). The solution was degassed with nitrogen for 15 min. 4 (7.19 g, 20.2 mmol) was added and the mixture was stirred at room temperature for 3 h. After this time, 1 M aqueous potassium phosphate monobasic was added to adjust the pH of the reaction mixture to 8.0, followed by water (200 mL). After heating at 50° C. for 16 h, the water was evaporated to 50 mL under reduced pressure, and 12 N hydrochloric acid was added to adjust the pH to 2.8 (pH meter). The resulting precipitate was collected by vacuum filtration, washed with water (5 mL) and dried for 16 h under vacuum at 50° C. to afford 5 in 37% yield (1.37 g) as a green solid: mp 195-196° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.30 (br s, 1H), 7.64 (s, 1H), 3.23 (t, 2H, J=5.5 Hz), 2.76 (t, 2H, J=5.5 Hz); MS (APCI+) m/z 183.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH2:12]([O:19][C@@H:20]1[CH2:26][CH2:25][C@H:24]2[C@H:22]([O:23]2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C@@H:20]1[CH2:26][CH2:25][C@H:24]([OH:23])[C@@H:22]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1cccn1
Reactant: c1ccc(CO[C@@H]2CC[C@@H]3O[C@@H]3C2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)CC[C@@H]1O
Yield: 36.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-methylpyrazole (650 mg, 7.92 mmol), n-butyl lithium (2.69 M solution in hexane; 3.08 mL, 8.28 mmol), (1R*,3R*,6S*)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (Bioorg. Med. Chem. 2004, 12, 1459; 1.54 g, 7.54 mmol) and THF (45 mL), to yield the title compound (790 mg, 37%) as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[S:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH2:10]1.Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([CH:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C1=Cc2ccccc2SC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C1C=Cc2ccccc2S1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Under a dry nitrogen atmosphere, 7.18 g (0.0914 mole) of acetyl chloride was added to a cold (5° C.), stirred mixture of 11.9 g (0.0893 mole) of aluminum chloride in 100 ml of carbon tetrachloride. To this mixture was added a solution of 10.6 g (0.079 mole) of thianaphthalene in 25 ml of carbon tetrachloride. The reaction mixture was allowed to warm to room temperature and was stirred for two hours. The mixture was heated at reflux for 45 minutes and was cooled. The resultant mixture was poured into ice water, and 100 ml of concentrated hydrochloric acid was added. This mixture was stirred until the ice melted. The organic phase was removed and saved. The aqueous phase was extracted with methylene chloride. The organic phases were combined and dried over anhydrous sodium sulfate. This mixture was filtered, and the filtrate was treated with silica gel and decolorizing charcoal. The resulting mixture was filtered through a pad of silica gel. The filtrate was evaporated under reduced pressure to yield 11.3 g of 2 -acetylthianaphthalene as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Cc1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C

Procedure:
To a solution of 5-methylindazole (901 mg) in DMF (10 mL) was added sodium hydride (327 mg) at 0° C., and the mixture was stirred with heating at 40° C. for 30 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2.28 g), and the mixture was stirred with heating at 90° C. for 19 hours. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:5 as the eluting solvent) to give Compound Q1 (1.04 g).
Reaction SMILES: [N:1]1([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[CH3:20])[CH2:29][CH2:30]3)=[O:16])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(-n4cnc5ccccc54)cc3)CC2)c(C)c1
Yield: 55.6 %

Procedure:
Using methyl 4-(benzimidazol-1-yl)benzoate (126 mg) and 1-(2,4-dimethylphenyl)piperazine (95 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (114 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([F:19])[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)=[O:10])[CH2:5][CH2:4]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=1.[BH4-].[K+]>C1(C)C=CC=CC=1>[Cl:18][C:13]1[CH:12]=[C:11]([C:9]([N:6]2[CH2:7][CH2:8][C:3]([F:19])([CH2:2][NH:1][CH2:31][C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[N:30]=3)[CH2:4][CH2:5]2)=[O:10])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: O=Cc1cccc(-c2ccco2)n1
Reactant: NCC1(F)CCN(C(=O)c2ccc(F)c(Cl)c2)CC1
Agent: [BH4-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)c(Cl)c1)N1CCC(F)(CNCc2cccc(-c3ccco3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.687 g of (4-aminomethyl-4-fluoropiperidin-1-yl)-(3-chloro-4-fluorophenyl)methanone (2.38 mmol) and 0.371 g of 6-furan-2-yl-pyridine-2-carbaldehyde (2.38 mmol) are mixed in 25 ml of toluene. The solution is heated under reflux under a nitrogen atmosphere for 2 hours, removing the water formed continuously. The toluene is evaporated off, the residue is taken up in 25 ml of methanol and then 0.257 g of potassium borohydride (4.51 mmol) is added in portions. The reaction mixture is stirred for 5 hours at room temperature and then the methanol is evaporated off. The residue is taken up in chloroform, the organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform/methanol; 98:2). 0-65 g of a yellow oil is obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]#[CH:36])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:36]#[C:35][CH2:34][CH2:33][N:30]4[CH2:29][CH2:28][CH:27]([CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:32][CH2:31]4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)ccc21
Reactant: C#CCCN1CCC(Cc2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(C#CCCN3CCC(Cc4ccccc4)CC3)ccc21
Yield: 80.3 %

Procedure:
A mixture of 1-benzenesulfonyl-5-bromoindole (1.34 g, 4 mmol), 4-benzyl-1-(3-butynyl)-piperidine (908 mg, 4 mmol) and tetrakis(triphenylphosphine)palladium (0) (600 mg) is stirred in pyrrolidine (50 mL) at 50° C. under N2 overnight. Most of the pyrrolidine is evaporated and the residue purified by medium-pressure column chromatography on silica gel eluting with 50% increasing to 100% EtOAc/hexanes to give the title compound as a pale yellow oil (1.55 g)