Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C1C2C(COC([CH2:18][C:19]([N:21]3[CH2:25][C@H:24]([F:26])[CH2:23][C@@H:22]3[C:27]([O:29]C)=O)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:31]1CCCCC1>CO>[F:26][C@H:24]1[CH2:25][N:21]2[C:19](=[O:20])[CH2:18][NH:31][C:27](=[O:29])[CH:22]2[CH2:23]1
Reactant: COC(=O)[C@H]1C[C@@H](F)CN1C(=O)CC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C1CCNCC1
Solvent: CO
Product: O=C1NCC(=O)N2C[C@H](F)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A scintillation vial was charged with (2S,4R), (2R,4R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4-fluoropyrrolidine-2-carboxylate (815 mg, 1911 μmol), 19 mL MeOH and piperidine (946 μl, 9556 μmol). The mixture was stirred at RT overnight The mixture was concentrated, dissolved in DCM/MeOH and purified by silica gel chromatography, 50-100% 90/10/1 DCM/MeOH/NH4OH in DCM. (7R)-7-fluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione was isolated as a white solid, and confirmed by 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]2[S:32][C:31]([C:33]3([O:37][CH2:38][O:39][CH3:40])[CH2:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:8]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:5]2=[N:6][CH:7]=1.[O:41]1[CH2:45][CH2:44][CH:43](O)[CH2:42]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:28]2[S:32][C:31]([C:33]3([O:37][CH2:38][O:39][CH3:40])[CH2:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:43]4[CH2:44][CH2:45][O:41][CH2:42]4)=[CH:13][CH:12]=3)[N:8]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: OC1CCOC1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(O)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(OC5CCOC5)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol (Example 69A) (60 mg, 0.101 mmol), tetrahydrofuran-3-ol (12 mg, 0.131 mmol), and triphenylphosphine (34.3 mg, 0.131 mmol) in anhydrous tetrahydrofuran (1 mL) was treated with diisopropyl azodicarboxylate (0.025 mL, 0.131 mmol). The reaction was stirred for 16 hours at ambient temperature. The reaction treated with more tetrahydrofuran-3-ol (12 mg, 0.131 mmol), diisopropyl azodicarboxylate (0.025 mL, 0.131 mmol) and triphenylphosphine (34.3 mg, 0.131 mmol), and the reaction was warmed to 70° C. for 5 hours. The reaction was cooled, diluted with ethyl acetate, and washed with water and brine. The organic layer dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 30 to 40% ethyl acetate in hexanes, to give the title compound. MS ESI(+) m/z 666.1 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:22][O:23][C:24]1[N:29]=[N:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>CN(C=O)C.O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([C:27]3[N:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:31][CH2:32]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COc1ccc(N2CCC(N)CC2)nn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)nn1
Temperature: 120 °C
Yield: 49.2 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.300 g, 1.00 mmol), 1-(6-methoxypyridazin-3-yl)piperidin-4-amine dihydrochloride (0.349 g, 1.24 mmol) and TEA (0.405 g, 4.00 mmol) was dissolved in dry DMF (10 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (200 ml). The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography using a 55:45 mixture of heptane and EtOAc as eluant, to give the title compound (0.232 g, 49%). 1H NMR (500 MHz, CDCl3): δ 7.54-7.49 (m, 2H), 7.46-7.41 (m, 3H), 6.92 (d, 1H), 6.79 (d, 1H), 5.2 (d, 1H), 4.00 (s, 3H), 3.93-3.87 (m, 2H), 3.17-3.08 (m, 1H), 2.53-2.45 (m, 2H), 1.77-1.71 (m, 2H), 1.72 (s, 9H), 1.44-1.35 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 160.1, 159.6, 157.3, 133.8, 131.6, 129.9, 128.7, 125, 119.4, 119.1, 107, 61.6, 54.3, 50.1, 45.1, 31.6, 27.6; Mass Spectrum: M−H+ 472.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[OH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>C(N(CC)CC)C.C1COCC1>[C:31]([C:30]1[CH:34]=[CH:35][C:27]([O:26][C:18]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[CH:8]/[C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])/[C:10]2=[O:25])=[O:19])=[CH:28][CH:29]=1)([OH:33])=[O:32]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Oc3ccc(C(=O)O)cc3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one (332 mg, 1.0 mmol), 4-hydroxybenzoic acid (138 mg, 1.0 mmol), and 2 drops of triethylamine in 3.0 mL of THF was stirred at room temperature overnight and concentrated. The residue was then purified on a silica gel column eluting with ethyl acetate-hexane (1:3) and 0.5% of acetic acid in ethyl acetate-dichloromethane (2:1) to afford 150 mg (37%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-carboxy-phenyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, vbr, 1H, COOH), 12.60 (s, br, 1H, NH-1′), 8.12 (d, J=7.39 Hz, 2H), 7.86–7.88 (m, 1H), 7.64 (s, vbr, 1H), 7.51 (s, 1H, H-vinyl), 7.43 (d, J=7.39 Hz, 2H), 7.21–7.23 (m, 2H), 6.09 (s, br, 1H, H-4′), 2.40 (s, 3H, CH3), and 2.38 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[C:13](O)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>O>[C:13]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12])(=[O:15])[CH3:14]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1NC(C)=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
504 g (3 mol) of 2-amino-4-nitro-1-methoxybenzene are introduced into 860 ml of acetic acid and 600 ml of water (or the combined main filtrate and first wash filtrate of a previous batch) and the mixture is heated to 80° C. 358 g (3.2 mol) of acetic anhydride are added dropwise in the course of 10 minutes. The mixture is subsequently stirred at 80° C. for 4 hours, and then cooled to room temperature, while stirring, by removing the heating bath and finally to 15° C. The pale yellow needles which have precipitated are filtered off with suction, washed with 300 ml of 60% strength acetic acid and 1500 ml of water in several portions and dried.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][O:10][C:11]2[C:20]3[CH2:19][O:18]C(=O)[N:16]([CH2:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[C:15]=3[CH:14]=[N:13][C:12]=2[CH3:31])=[CH:7][CH:6]=1)#[N:4]>CO.ClCCl>[OH:18][CH2:19][C:20]1[C:11]([O:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:33][CH:32]=2)=[C:12]([CH3:31])[N:13]=[CH:14][C:15]=1[NH:16][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=1
Reactant: Cc1ncc2c(c1OCc1ccc(C#N)cc1)COC(=O)N2Cc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ncc(NCc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
Sodium borohydride (2.6 g, 69 mmol) was added to a solution of 4-[5-(4-cyano-benzyloxy)-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1 ylmethyl]-benzonitrile (83) (587 mg, 1.4 mmol) in a mixture of methyl alcohol and dichloromethane (1:1, 20 mL) at 0° C. The resulting solution was warmed to room temperature and stirred for 24 hours. The solvent was evaporated, residue was diluted with water and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified by column chromatography on silica gel using a gradient mixture of dichloromethane:methyl alcohol (1:0 to 40:1) as eluant to give 4-{[4-hydroxymethyl-6-methyl-5-(4-cyano-benzyloxy)-pyridin-3-ylamino]-methyl}-benzonitrile (87) (175 mg, 32% yield) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10][N:11]([CH3:26])[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22](Cl)(=[O:24])=[O:23].Cl>C([O-])(O)=O.[Na+].CC(C)=O.C(N(CC)CC)C>[CH3:10][N:11]([CH3:26])[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:24])=[O:23]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCCCC(=O)O)cccc12
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a stirred solution of 6-aminohexanoic acid (1.5 g, 11.4 mmol) in 1 M NaHCO3 (45 as added 5-(dimethylamino)naphthalene-1-sulfonyl chloride (0.63 g, 2.33 mmol) in acetone (10 mL) and triethylamine (2 mL). The solution was stirred for 1 h, acidified to pH 3 with 2 N HCl, extracted with ethyl acetate (3×15 mL). The organic layer was washed with water (15 mL) and brine (15 mL), dried over Na2SO4. The solvent was evaporated and purified by flash chromatography using CH2Cl2-MeOH to afford 6-(5-dimethylaminonaphthalene-1-sulfonamido)hexanoic acid as a green sticky oil (0.76 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 10.66 (br, 1H), 8.46 (d, 1H, J=8.4 Hz), 8.33 (d, 1H, J=8.4 Hz), 8.19 (d, 1H, J=7.2 Hz), 7.44 (m, 2H), 7.09 (d, 1H, J=7.6 Hz), 5.66 (br, 1H), 2.85 (m, 2H), 2.79 (s, 6H), 2.08 (t, 2H, J=8.8, 7.6 Hz), 1.32 (m, 4H), 1.12 (m, 2H); 13C NMR (100 MHz) δ 179.29, 151.67, 135.03, 130.18, 129.72, 129.58, 129.25, 128.26, 123.16, 119.01, 115.20, 45.30, 42.88, 33.98, 29.07, 25.74, 24.01.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[N:8]=[CH:7][C:6]([C:23]#[N:24])=[C:5]2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=2)=[C:28]([Cl:39])[CH:27]=1.C=O.[C:42]([BH3-])#N.[Na+]>C(O)(=O)C.C(O)C>[Cl:39][C:28]1[CH:27]=[C:26]([NH:25][C:5]2[C:4]3[C:9](=[CH:10][C:11]([N:12]4[CH2:13][CH2:14][CH:15]([N:18]5[CH2:19][CH2:20][CH2:21][CH2:22]5)[CH2:16][CH2:17]4)=[C:2]([NH:1][CH3:42])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:23]#[N:24])[CH:31]=[CH:30][C:29]=1[S:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1
Reactant: [BH3-]C#N
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(N)cc23)cc1Cl
Agent: C=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A mixture of 130 mg (0.23 mmol) of 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile, 12.0 mg (0.4 mmol) of paraformaldehyde, 25.0 mg (0.39 mmol) of sodium cyanoborohydride and 2 drops of acetic acid in 15 mL of ethanol is heated under reflux for 8 hours. The mixture is cooled to room temperature and solvent removed in vacuo. A 12 mL solution of 1N sodium hydroxide is added to the residue, and the mixture is stirred. A crude solid is collected by filtration, washed with water and dried. Purification by silica gel chromatography (gradient 95:5 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 66.0 mg of the 4-({3-Chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-(methylamino)-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as an yellow solid, mp 242-250° C.
Reaction SMILES: [CH2:1]([C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([C:9]1[S:13][C:12]([CH:14]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCc1ccc(C=O)s1
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(C=CC(=O)OCC)s1

Procedure:
A solution of 75.4 g. 5-octyl-2-thiophenecarboxaldehyde and 117.6 g. ethyl (triphenylphosphoranylidene)acetate in 400 ml. tetrahydrofuran is refluxed for 20 hours. The solution is concentrated, the semi-solid residue is slurried with ether and filtered. Concentration followed by distillation of the resultant oil yields ethyl 5-octylthiophene-2-acrylate as an oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].Cl.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:1][CH2:2][OH:3])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 78.6 %

Procedure:
Ethylene bromohydrin (5.4 g) was added dropwise to a mixture of 1-(3-chlorophenyl)piperazine hydrochloride (5 g), potassium carbonate powder (12 g) and N,N-dimethylformamide (35 ml) with stirring. The mixture was further stirred at room temperature overnight, then diluted with 100 ml of water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous sodium chloride and dried over Na2SO4. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: ethyl acetate-methanol (4:1)] to give 4.06 g (78.6%) of 4-(3-chlorophenyl)-1-piperazineethanol as an oil.
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12]>>[CH3:1][CH:2]([NH:6][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([F:7])[CH:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Reactant: CCCC(C)N
Product: C#CCOc1ccc(C(=O)NC(C)CCC)cc1F

Procedure:
According to the same method as that of Production Example 1, 1-methylbutylamine was used in place of 2,2-dimethylpropylamine, 3-fluoro-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1-methylbutyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 57 of the present invention) represented by the formula:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>O.CN(C)C=O>[C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:14][CH2:13]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC1
Reaction time: 3 h

Procedure:
The apparatus described in Example 1 was successively charged with 320 g diethyl malonate (2.0 mols), 1000 ml dimethylformamide, 1308 g of 1,2-dichloroethane (13.2 mols) and 664 g (4.8 mols) of finely comminuted potassium carbonate. While thoroughly stirring, the mixture was heated to 115° C., whereupon release of carbon dioxide and separation of water commenced. Over a period of 3 hours, another 320 g of diethyl malonate (2.0 mols) were metered into the reaction vessel through a dropping funnel. After 6 hours, when no more water separated out, the reaction was complete.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7]Cl.[I-:16].[Na+]>CC(C)=O>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][I:16]
Reactant: CON=C(CCCCl)c1ccc(F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CON=C(CCCI)c1ccc(F)cc1
Yield: 99.8 %

Procedure:
4-Chloro-1-(4-fluorophenyl)butan-1-one O-methyl oxime (0.78 g, 3.40 mmol) and sodium iodide (0.76 g, 5.09 mmol) in acetone (10 mL) were heated at reflux overnight. The mixture was evaporated, the residue diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (gradient to 10% ethyl acetate/hexanes) to give product as an oil (1.09 g, quant.); MS for C11H13FNO m/z 322 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][NH:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[C:29]([NH2:34])[N:28]=1>C(O)C>[Cl:26][C:27]1[CH:32]=[C:31]([N:11]2[CH2:12][CH2:13][O:14][CH:9]([C:7]3[NH:6][C:5]4[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=4[N:8]=3)[CH2:10]2)[N:30]=[C:29]([NH2:34])[N:28]=1
Reactant: Clc1ccc2[nH]c(C3CNCCO3)nc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4cc(Cl)ccc4[nH]3)C2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 5-chloro-2-(2-morpholinyl)-1H-benzimidazole (200 mg, 0.841 mmol) and Hunig's base (109 mg, 0.841 mmol) in ethanol (10 mL) stirred at room temperature was added 4,6-dichloro-2-pyrimidinamine (138 mg, 0.841 mmol), and the reaction mixture was stirred overnight at 85° C. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The solvent was evaporated in vacuo to give the crude product. The residue was triturated with EtOAc (1×5 mL). The resulting solid was filtered, and collected to afford the title compound (300 mg). LC-MS (ES) m/z=365, 367 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:13])[N:4]([CH2:11][CH3:12])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[OH:8].[CH:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:13])[N:4]([CH2:11][CH3:12])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[O:8][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:21][CH:22]=1
Reactant: CCn1c(SC)nc(O)c(Br)c1=O
Reactant: ClCc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(SC)nc(OCc2ccc(C3CCCCC3)cc2)c(Br)c1=O
Yield: 100 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1 g of 5-bromo-3-ethyl-6-hydroxy-2-methylthio-4(3H)-pyrimidinone and 0.8 g of 4-cyclohexylbenzyl chloride, and then 1 g of anhydrous potassium carbonate was added thereto. The mixture was subjected to a reaction at 80° C. for 3 hours. After allowing to cool in air, the resulting solution was poured into 50 ml of water and extracted twice with 30 ml of ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to give 1.65 g of a crude product.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.O.CCOCC.[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:16]#[N:17])[C:7]=1[F:8]
Reactant: Fc1c(Cl)ccnc1Br
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Product: N#Cc1nccc(Cl)c1F
Temperature: 100 °C

Procedure:
To a degassed solution of 2-bromo-4-chloro-3-fluoropyridine (7.3 g, 34.7 mmol) in DMF (50 mL) was added palladium tetrakistriphenylphosphine (4.01 g, 3.47 mmol) and zinc cyanide (4.07 g, 34.7 mmol) and heated to 100° C. for 20 minutes. After this time, more palladium tetrakis triphenylphosphine (4.01 g, 3.47 mmol) was added and heated to 100° C. for 90 minutes. The mixture was allowed to cool to room temperature and treated with water (200 mL) and ether (400 mL). The resulting mixture was filtered to remove insoluble solids, the filtrate was partitioned, and the aqueous layer was extracted with ether (400 mL). The combined ether extracts were washed with water (200 mL), dried (MgSO4), filtered, and the solvent removed in vacuo. This residue was purified by chromatography using silica gel column (330 g) eluting with a gradient of 10-100% CH2Cl2 in hexanes to provide the title compound. 1H NMR (CDCl3) δ=8.45 (d, 1H, J=5 Hz) and 7.65 (dd, 1H, J=5 Hz) ppm.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)(=O)=O.[CH3:23]O.C[O-].[Na+]>CO>[CH3:23][O:5][CH2:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCOS(C)(=O)=O)CC1
Agent: C[O-]
Agent: [Na+]
Product: COCCCOC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 4-[3-(methanesulfonyloxy)propyloxy]-N-t-butyloxycarbonylpiperidine (3.76 g) in methanol (20 ml) was added 28% sodium methoxide methanol solution (22.7 ml), and the mixture was stirred under refluxing for 1.5 hours. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (200 ml). The solution was washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give 4-(3-methoxypropyloxy)-N-t-butyloxycarbonylpiperidine (2.66 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[C:20]([CH3:26])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[C:20]([CH3:26])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: Cc1ccc(C(CN)CC2CC2)c(C)n1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)CC2CC2)c(C)n1

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(2,6-dimethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=377.1, tR (minutes, Method G)=1.68