Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[BH4-].[Na+]>CO>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a mixture of 7-butyl-4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.08 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added sodium borohydride (0.007 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained 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 colorless amorphous solid (0.04 g, 48%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][C:5]([CH2:8][CH2:9]O)=[CH:6][N:7]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Cl:13][CH2:9][CH2:8][C:5]1[S:4][C:3]([NH2:2])=[N:7][CH:6]=1.[ClH:1]
Reactant: Nc1ncc(CCO)s1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(CCCl)s1
Temperature: 25 °C

Procedure:
To a suspension of 14.73 g of 2-amino-5-thiazoleethanol, monohydrochloride (Example B) in 200 ml of chloroform is added rapidly 50 ml of thionyl chloride. The mixture is refluxed for 30 minutes, cooled to room temperature, filtered through a pad of Celite, concentrated to a brown oily solid, and crystallized from ethanol-diethyl ether to give 5-(2-chloroethyl)-2-thiazolamine as the monohydrochloride salt; mp 145°-147° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3]1=[O:14])[CH:7]=[CH:8][CH:9]=2>[Ni].C(O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[CH2:11][CH2:12][CH2:13][CH:4]([C:5]=23)[C:3]1=[O:14]
Reactant: CN1C(=O)c2cccc3cccc1c23
Agent: [Ni]
Solvent: CCO
Product: CN1C(=O)C2CCCc3cccc1c32
Yield: 80 %

Procedure:
Ethanol and Raney nickel slurry (Aldrich) were added to 1-methyl-benz[cd]indole-2(1H)-one (4.5 g, 25 mmol) to carry out catalytic reduction under ordinary pressure. The reaction was terminated when 1.15 L of hydrogen absorption was observed, Raney nickel was removed by filtration, the resulting filtrate was concentrated and then the thus obtained colorless oil was purified by a silica gel column chromatography to obtain 3.8 g of the title compound (20 mmol, 80% in yield).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18]C=[C:16]3[C:11]=2C=CC=[N:15]3)=[CH:4][CH:3]=1.[CH:25]1[C:37]2[CH:36]([C:38](O)=[O:39])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:21]([N:20]=[C:8]([NH:9][C:10]1[CH:11]=[CH:16][N:15]=[CH:18][CH:19]=1)[NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:38]([CH:36]2[C:37]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:39])=[CH:24][CH:23]=1)#[N:22]
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CN=C(NCc1ccc(NC(=O)C2c3ccccc3-c3ccccc32)cc1)Nc1ccncc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (133 mg, 0.50 mmol) and 9H-fluorene-9-carboxylic acid (105 mg, 0.50 mmol) were suspended in N,N-dimethylformamide(1.0 mL). Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (232 mg, 0.52 mmol) was added followed by N,N-diisopropylethylamine (0.20 mL, 1.15 mmol). The reaction mixture was stirred at room temperature for 24 hours and then diluted with ethyl acetate (30 mL). This solution was washed with water (30 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the desired product (102 mg, 44.5%). 1H NMR (DMSO-d6, ppm): 10.72 (s, 1H), 9.59 (bs, 1H), 8.37 (d, 2H), 8.27 (bs, 1H), 7.90 (d, 2H), 7.60 (t, 4H), 7.43 (t, 2H), 7.31 (m, 4H), 7.18 (m, 2H), 5.03 (s, 1H), 4.43 (d, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[C:15]([CH3:29])([OH:28])[CH2:14]1.[C:30]([O:34][C:35]([N:37]([CH:50]([CH3:52])[CH3:51])[CH2:38][CH:39]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)[C:40](O)=[O:41])=[O:36])([CH3:33])([CH3:32])[CH3:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH:39]([C:40]([N:25]2[CH2:24][CH2:23][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[CH2:14][C:15]([OH:28])([CH3:29])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:27][CH2:26]2)=[O:41])[CH2:38][N:37]([CH:50]([CH3:51])[CH3:52])[C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:44][CH:45]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1CC(C)(O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3(C)O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (28 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperature for 4 hours. A 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol) from a different bottle was added. The resulting mixture was stirred for 18 hours. The solvents were removed in vacuo to give (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride. DIPEA (41.5 mg, 0.321 mmol) was added to a suspension of this (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (25.8 mg, 0.0803 mmol), 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (32.9 mg, 0.0964 mmol), and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (36.6 mg, 0.0964 mmol) in CH2Cl2 (6 mL) at room temperature. The resulting mixture was stirred for 1 hour. The solvent was removed in vacuo. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (46 mg, 100%) as a gel. LCMS (APCI+) [M−Boc+H] +472.2; Rt: 3.51 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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:20]1([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=3[CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccccc3)cc2C1
Yield: 81.3 %

Procedure:
A mixture of tert-butyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of phenylboronic acid (111 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (160 mg, 77.3%) as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH:35](O)=[O:36].C(N)=O>C(O)C>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]1[CH:33]=[CH:34][C:16]([CH2:15][N:7]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[CH:17][CH:18]=1)[CH:35]=[O:36])[CH2:31][CH3:32]
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: O=CO
Solvent: NC=O
Solvent: CCO
Product: CCCN(CCC)CCCCN(C=O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
The compound (82.9 mg) obtained in Example 52-3 was dissolved in ethanol (1.0 ml) and added with formic acid (50 μl) and formamide (50 μl). The whole was stirred at an outside temperature of 10° C. for 3 hours. The solution was added with additional formic acid (60 μl) and the whole was stirred for 15 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution to adjust the pH to 11. The aqueous layer was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (27.0 mg) of the subject compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[CH:3]=1.[S-:17][C:18]#[N:19].[K+].N1C=CC=CC=1.BrBr>CN(C)C=O>[NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][C:18]#[N:19]
Reactant: Nc1cc(=O)nc(SCc2ccccc2)[nH]1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
6-Amino-2-[(phenylmethyl)thio]-4(1H)-pyrimidinone (10.5 g)[preparation as described in WO 9635678] and potassium thiocyanate (25 g) in N,N-dimethylformamide (200 ml) were heated together at 65° C. Pyridine (6.3 ml) was added and the solution-cooled to 5° C. Bromine (2.2 ml) was added slowly and the reaction mixture stirred for 2 hours at 5-10° C. The reaction mixture was poured onto ice water, stirred for 1 hour and the solid was isolated by filtration. After washing with water and ether, a pure sample was obtained after trituration with hot methanol.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][CH:6]1[CH2:8][CH2:7]1.[O:14]=[C:15]1[O:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16]1>>[CH2:23]([O:22][C:21](=[O:30])[NH:20][C@@H:17]([CH2:16][C:15]([N:5]([CH:6]1[CH2:7][CH2:8]1)[CH2:4][C:3]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:2]=1[Cl:1])=[O:14])[CH2:18][OH:19])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1cccc(CNC2CC2)c1Cl
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)CO1
Product: O=C(N[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)OCc1ccccc1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
Into a 100 mL round bottom flask fitted with a reflux condenser and a nitrogen inlet, N-(2,3-dichlorobenzyl)cyclopropanamine (30.3 g, 140.3 mmol) (Example 1A) and (S)-benzyl 5-oxotetrahydrofuran-3-ylcarbamate (22.0 g, 93.5 mmol) were added. The mixture was heated without solvent at 100° C. for 24 hours. Purification by column chromatography (5%->10% MeOH/dichloromethane) gave 22.0 g (52%) of 4A. ESI-MS:m/z 451.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][OH:10].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Br)[N:13]=1>C1COCC1.O.C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:10][CH2:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][O:3]2)[N:13]=1
Reactant: BrCc1cccc(Br)n1
Reactant: OCC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc(COCC2CCCCO2)n1
Temperature: 25 °C

Procedure:
To a suspension of NaH (63.8 mg, 1.59 mmol) in THF (4 mL) at 0° C. under argon was added tetrahydro-2H-pyran-2-ylmethanol (92.5 mg, 0.80 mmol). The mixture was maintained at 0° C. for 20 minutes, at which time 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (200 mg, 0.80 mmol) was added. The reaction allowed to warm to room temperature and then heated to 55° C. overnight. The reaction was then cooled to ambient temperature and quenched by the addition of water. The quenched reaction mixture was diluted with water (10 mL) and DCM (10 mL) and shaken. The suspensions were passed through disposable phase separators and the DCM eluent was captured and evaporated to dryness to afford the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(C2CCOC2)cc(=O)[nH]1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)cc(C2CCOC2)n1
Temperature: 110 °C
Yield: 41.1 %

Procedure:
A suspension of 2-amino-6-(tetrahydro-furan-3-yl)-3H-pyrimidin-4-one (1.5 g, 8.28 mmol), tetraethyl ammonium chloride (2.7 g 16.3 mmol) and dimethylaniline (1.4 mL, 11.1 mmol) in acetonitrile (15 mL) was treated with phosphorous oxychloride (2.4 mL, 26.2 mmol) and heated at 110° C. for 20 min. The resulting solution was cooled to rt and concentrated to minimum volume and pipetted onto ice chips. The aqueous portion was extracted with EtOAc (3×50 mL). The combined organic layers were basified with satd. aq. NaHCO3 solution to pH ˜7. The organic portion was separated, dried, and concentrated. The crude material was chromatographed (MeOH/CH2Cl2) to yield 680 mg (42%) of product as a light orange foam. 1H NMR (CDCl3): 6.59 (s, 1H), 5.16 (br s, 2H), 4.00-4.10 (m, 2H), 3.85-3.91 (m, 2H), 3.28-3.35 (m, 1H), 2.25-2.34 (m, 1H), 2.08-2.18 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13](Cl)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[N:24]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C:29]([OH:31])([CH3:30])[CH3:32])[N:24]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)Cl)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionyl chloride in methylene chloride (0.036 M solution, 5 mL, 0.18 mmol) was slowly added to a cooled to 0° C. solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 31 mg, 0.20 mmol) and 2,6-lutidine (31 μl, 0.27 mmol) in methylene chloride (6 ml). The reaction continued to stir at 0° C. for 15 min and then at 25° C. for 4 h. After concentration in vacuo it was purified on an AnaLogix Intelliflash system (40 g column, 100% ethyl acetate) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamide (54 mg, 63%) as an off-white solid: [α]30589=−6.60° (c=5.9, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03, 1.04 (2×s, 6H, 2×CH3), 1.93-2.40 (m, 3H, CH and CH2), 2.66-2.85 (m, 2H, 2×CH or 2×CH2), 2.98-3.12 (m, 2H, 2×CH or 2×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.85-3.91 (m, 1H, ArCHCO2), 6.46 (d, J=2.3 Hz, 1H, Ar), 7.52 (d, J=2.3 Hz, 1H, Ar), 7.61 (dd, Jm=1.6 Hz, Jo=8.3 Hz, 1H, Ar), 7.73 (d, Jm=1.6 Hz, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]2[C:13]=1[CH3:14].[F:15][C:16]([F:33])([F:32])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20]4[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:32])[F:33])=[CH:18][CH:19]=4)=[CH:28][CH:27]=3)=[O:30])=[CH:6][N:5]2[C:13]=1[CH3:14]
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: Cc1nc2ccc([N+](=O)[O-])cn2c1C
Product: Cc1nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn2c1C

Procedure:
Conducting the operations similar to those of Example 1 using 2,3-dimethyl-6-nitroimidazo[1,2-a]pyridine and 4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:23])=O)=[CH:15][CH:14]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]#[N:23])=[CH:15][CH:14]=1
Reactant: NC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: N#Cc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Temperature: 0 °C

Procedure:
3-(4-(2-Quinolinylmethyloxy)benzyl)benzamide (0.03 mol) in pyridine (150 ml) with methane sulfonyl chloride (0.06 mol) is heated at 70° C. for several hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate extract is dried (magnesium sulfate) then applied to a silica gel column. The product is isolated by elution with the appropriate mixture of ethyl acetate and petroleum ether to obtain 3-(4-(2-quinolinylmethyloxy)benzyl)benzonitrile.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH2:10]([N:12]1[C:16]([CH:17]=[O:18])=[CH:15][C:14]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:13]1)[CH3:11].[OH-].[K+].O.[CH3:31]O>>[CH2:10]([N:12]1[C:16]([CH:17]([O:18][CH3:31])[C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:15][C:14]([NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[N:13]1)[CH3:11]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(OC)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (1, 54.0 mg, 0.46 mmol) in methanol (15.0 mL) were added 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 110.0 mg, 0.44 mmol) and potassium hydroxide (0.60 g, 0.011 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give a white solid (531, 0.12 g, 71.1%). MS (ESI) [M−H+]−=378.2.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]([CH2:11][CH3:12])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][NH2:6].[C:14](O)(=[O:17])[CH:15]=[CH2:16]>C1C=CC(NC2C=CC(NC3C=CC=CC=3)=CC=2)=CC=1>[CH3:13][N:2]([CH3:1])[CH2:3][C:4]([CH2:11][CH3:12])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][NH:6][C:14](=[O:17])[CH:15]=[CH2:16]
Reactant: CCCCC(CC)(CN)CN(C)C
Reactant: C=CC(=O)O
Agent: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Product: C=CC(=O)NCC(CC)(CCCC)CN(C)C
Yield: 54.6 %

Procedure:
Proceeding as in Example 1, 173.5 g 3-dimethylamino-2-ethyl-2-butylpropylamine; 67 g acrylic acid; 2 g N,N'-diphenyl-p-phenylenediamine; and 2 g calcium tert-butylate were mixed. 122 g (55%) N-(3-dimethylamino-2-ethyl-2-butylpropyl)-acrylamide, boiling point 129° C. at 66.5 Pa, was isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:16][CH3:17])([CH2:13][CH2:14][OH:15])[C:9]([NH:11][NH2:12])=O)=[CH:4][CH:3]=1.Cl.Cl.[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:34]=[CH:35]/[C:36](=[NH:40])OCC)[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1.C(OCC)(=O)C.O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:16][CH3:17])([C:9]2[NH:11][N:12]=[C:36](/[CH:35]=[CH:34]/[C:24]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:22]([O:21][CH3:20])[CH:23]=3)[N:40]=2)[CH2:13][CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Reactant: COC(CCO)(C(=O)NN)c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(/C=C/c2n[nH]c(C(CCO)(OC)c3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 75 °C
Reaction time: 48 h
Yield: 49.7 %

Procedure:
A solution of 2-(4-fluorophenyl)-4-hydroxy-2-methoxybutyric acid hydrazide (40 mg) in ethanol (1.6 mL) was added to a solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (65 mg) and TEA (0.12 mL) in ethanol (0.7 mL), and the reaction solution was stirred at 75° C. for two days. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate-methanol system) to obtain 38 mg of the title compound. The property value of the compound is as follows.