Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]([C:20]2[C:21]([NH2:27])=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=2)=O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)Cl>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:15][C:18]([C:20]3[C:21]([NH2:27])=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=3)=[N:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)c2cc(Br)cnc2N)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[N′-(2-amino-5-bromo-pyridine-3-carbonyl)-hydrazinocarbonyl]-piperidine-1-carboxylic acid tert-butyl ester (1.3 g, 2.939 mmol) in ACN (50 mL) were added DBU (1.68 g, 11.035 mmol), PPh3 (1.95 g, 7.434 mmol) and CCl4 (4 mL, 41.558 mmol) at RT. The reaction mixture was stirred for 18 h at RT. The reaction mixture was poured into ice-water (30 mL), extracted with ethyl acetate (3×50 mL), organic layer was washed with brine dried over anhydrous sodium sulphate concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 40% EtOAc in petroleum ether to afford the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:9])#[CH:2].[CH3:11][CH2:12][NH:13][C:14]([C@H:16]1[O:20][C@@H:19]([N:21]2[C:25]3[N:26]=[C:27](I)[N:28]=[C:29]([NH2:30])[C:24]=3[N:23]=[CH:22]2)[CH:18]([OH:32])[C@H:17]1[OH:33])=[O:15]>>[CH2:12]([NH:13][C:14]([CH:16]1[CH:17]([OH:33])[CH:18]([OH:32])[CH:19]([N:21]2[CH:22]=[N:23][C:24]3[C:25]2=[N:26][C:27]([C:2]#[C:1][C:3]2([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH3:9])=[N:28][C:29]=3[NH2:30])[O:20]1)=[O:15])[CH3:11]
Reactant: C#CC1(O)CCCCC1C
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)C(O)[C@H]1O
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CC4(O)CCCCC4C)nc32)C(O)C1O
Yield: 65 %

Procedure:
The reaction of 1-Ethynyl-2-methyl-cyclohexanol (JR3169B) (100 mg, 0.72 mmol) with 2-iodo-NECA (25 mg, 0.06 mmol) under the general coupling conditions gave JR3177A (8.0 mg) and JR3177B (8.2 mg) (overall yield 65%) as white solids after purification by a silica plug and RP-HPLC. JR3177A: 1H NMR (CD3OD-d4) δ 8.47 (s, 1H), 6.05 (d, J=6.9 Hz, 1H), 4.77 (dd, J=6.9 Hz, J=4.9 Hz, 1H), 4.45 (d, J=1.9 Hz, 1H), 4.34 (dd, J=4.6 Hz, J=2.1 Hz, 1H), 3.41 (m, 2H), 2.13 (d, J=12.7 Hz, 2H), 1.65 (m, 5H), 1.32 (m, 2H), 1.14 (t, J=7.0 Hz, 3H), 1.13 (d, J=6.6 Hz, 3H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.3 (MH+, 100), 427.4 (80), 254.4 (14). 1H NMR (CD3OD-d4) δ 8.49 (s, 1H), 6.05 (d, J=6.9 Hz, 1H), 4.78 (dd, J=6.4 Hz, J=4.9 Hz, 1H), 4.45 (d, J=1.9 Hz, 1H), 4.34 (dd, J=4.6 Hz, J=1.6 Hz, 1H), 3.42 (m, 2H), 2.12 (d, J=12.3 Hz, 2H), 1.65 (m, 4H), 1.35 (m, 4H), 1.14 (t, J=7.3 Hz, 3H), 1.12 (d, J=6.6 Hz, 3H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.7 (MH+, 100), 427.3 (35), 254.4 (3.5).
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[P:14]([O:19]C)([O:17][CH3:18])[O:15][CH3:16].BrCCN1C(=O)C2=CC=CC=C2C1=O.P(OCC)(OCC)OCC>>[C:7]1(=[O:8])[N:3]([CH2:2][P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: COP(OC)OC
Agent: CCOP(OCC)OCC
Agent: O=C1c2ccccc2C(=O)N1CCBr
Product: COP(=O)(CN1C(=O)c2ccccc2C1=O)OC

Procedure:
Reaction of N-bromomethylphthalimide with trimethyl phosphite as described in Example 18 for N-(2-bromoethyl)phthalimide and triethyl phosphite gives dimethyl phthalimidomethylphosphonate.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]([O:16]C)(OC)[C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1.Cl>C1COCC1>[OH:18][C:3]1([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=2)[C:4](=[O:16])[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)=[C:2]1[CH3:1]
Reactant: COc1cccc(C2=C(C)C(=O)C2(OC)OC)c1
Reactant: COc1cccc([Mg]Br)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(C2=C(C)C(O)(c3cccc(OC)c3)C2=O)c1
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A THF solution (12 mL) of 2-methyl-4,4-bis(methyloxy)-3-[3-(methyloxy)phenyl]-2-cyclobuten-1-one (245) (0.500 g, 2.02 mmol, 1 equiv) was cooled to ca. −78° C. 3-Methoxyphenylmagnesium bromide (3.02 mL, 1.0 M, 1.5 equiv) was added. After 5 min, aqueous HCl (3 N, 20 mL) was added. Extraction with EtOAc (3×20 mL) was followed by washing with 50% aqueous NaHCO3, drying (Na2SO4), filtration, and concentration to a bright yellow oil. Radial chromatography (SiO2, 4 mm plate, 80:20; hexanes/EtOAc) afforded the title compound (246) as a bright yellow oil (0.515 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.29 (m, 4H), 7.10-6.88 (m, 4H), 3.88 (s, 3H), 3.85 (s, 3H), 2.47 (s, 3H); TLC (60:40; hexanes/EtOAc): Rf=0.23.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8].[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1.B>CO>[C:34]1([CH2:33][NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]2[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[N:22]=2)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:20]=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)=[O:8])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(N(CCCN)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Agent: B
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(N(CCCNCc2ccccc2)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Reaction time: 0.25 h

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide (50 mg, 0.11 mmol) (a compound of formula (Yc6)) in methanol (2 mL) was added benzaldehyde (0.2 M in methanol, 68 μL, 0.14 mmol). After stirring for 15 minutes, borane-pyridine complex (0.2 M in methanol, 0.14 mmol) was added. After 2 hours, the solution was evaporated. The residue was partitioned into water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (2:1 ethyl acetate/hexanes) to provide 2-[[3-(phenylmethylamino)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Yc8); as a white solid; NMR (CDCl3) 8.65 (s, 1), 7.7 (s, 1), 7.2 (br, 5), 7.1 (s, 1), 6.6 (d, 1), 6.55 (s, 1), 6.5 (d, 1), 6.1 (br, 2), 5.9 (s, 2), 3.95 (br, 6), 2.7 (m, 3), 2.35 (s, 6) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:18](=O)[CH3:19])[C:11]([O:13][CH:14]1[CH2:17][O:16][CH2:15]1)=[O:12].[NH2:21][C:22]([CH2:28][F:29])=[CH:23][C:24]([O:26][CH3:27])=[O:25]>C(O)(C)(C)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH:14]2[CH2:17][O:16][CH2:15]2)=[O:12])=[C:18]([CH3:19])[NH:21][C:22]([CH2:28][F:29])=[C:23]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C=C(N)CF
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1COC1
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC2COC2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of the product of step (a) (2.9 g, 7.6 mmoles) and methyl 3-amino-4-fluoro-2-butenoate (1 g, 7.6 mmoles) in dry tert-butanol (20 ml) was heated to 60° (oil bath temperature) for 16 hours. The solution was allowed to cool to room temperature and the solvent removed in vacuo. Chromatography on silica, eluting with dichloromethane/ethyl acetate mixtures afforded the title compound as an oil which crystallised on addition of petroleum ether (60°-80° ). The solid was recrystallised from petroleum ether (60°-80° )/acetone to afford the title compound 1.03 g, mp 155°-6°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CCOc1ccc(F)cc1
Yield: 82.7 %

Procedure:
A mixture of 4-fluorophenol (22.4 g, 200 mmol), chloroacetonitrile (17.1 g, 220 mmol) and excess powdered potassium carbonate was refluxed for 7 h then the mixture was concentrated under reduced pressure. The residue was mixed with H2O and was extracted with Et2O. The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was Kugelrohr distilled to provide 2-(4-Fluorophenoxy)acetonitrile (25 g, 84%). The 2-(4-Fluorophenoxy)acetonitrile (25 g, 185 mmol) was reduced with alane [generated from lithium aluminum hydride (19.6 g, 516 mmol) and sulfuric acid (25.3 g, 258 mmol) according to the procedure in Example 1]. The crude product was purified by Kugelrohr distillation to provide the titled compound (12 g).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]([O:40][C:41](=[O:47])[NH:42][CH:43]([CH3:46])[CH2:44]O)([CH3:39])([CH3:38])[CH3:37].[CH2:48]([O:50][C:51]([C:53]1[NH:54][N:55]=[C:56]([CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:57]=1)=[O:52])[CH3:49]>C1COCC1>[CH2:48]([O:50][C:51]([C:53]1[N:54]([CH2:44][CH:43]([NH:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:47])[CH3:46])[N:55]=[C:56]([CH2:58][O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:57]=1)=[O:52])[CH3:49]
Reactant: CC(CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 227.1 %

Procedure:
Di-tert-butyl azodicarboxylate (2.52 g, 10.96 mmol) was added to a stirred solution of triphenylphosphine (2.87 g, 10.96 mmol), 2-hydroxy-rac-1-methyl-ethyl-carbamic acid tert-butyl ester (2.13 g, 12.18 mmol) and 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.5 g, 6.09 mmol) in THF (45 mL). The mixture was stirred at 120° C. for 20 minutes under microwave irradiation and the solvents evaporated in vacuo. The crude product was purified by open column chromatography (silica; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (5.58 g, 91% yield, 40% pure) as a colorless oil that crystallized upon standing in white crystals.
Reaction SMILES: [CH:1]1C[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:13]=[O+][O-].O=O.O=[O+][O-].[CH3:21][OH:22]>>[CH:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:21]=[O:22]
Reactant: O=[O+][O-]
Reactant: CO
Reactant: C1=CC=CCCCCCCC=C1
Agent: O=O
Product: O=CCCCCCCCCCCC=O
Temperature: -20 °C

Procedure:
162.3 g (1 mol) of cyclododecatriene (purity 95%) were dissolved in 1500 ml of methanol, the solution was cooled to -20° C., and an O3 /O2 mixture containing 4% by weight of O3 was passed in until 0.33 mol of ozone had been introduced into the solution. The hydrogenation solution obtained as in Example 1 contained dodecanedial and its acetals. Cyclododecane formed was extracted from the acetic acid solution using petroleum ether prior to the oxidation.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccncc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-pyridin-4-ylethanol (Arch. Pharm. Ber. Deut. Pharm. Ges. 1972, 305, 248-53) (58 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5.0 mL) was stirred for 48 hours at room temperature. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (83 mg) as a white solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([CH3:33])[CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[NH:24][C:25]([CH2:27][C:28]([O:30]CC)=O)=[N:26][C:21]3=[CH:20][CH:19]=2)[CH2:14]1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]#[N:42]>C1COCC1>[NH2:42][C:41]1[C:36]2[C:35](=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:34][C:28](=[O:30])[C:27]=1[C:25]1[NH:24][C:22]2=[N:23][C:18]([N:15]3[CH2:16][CH2:17][CH:13]([N:12]([CH3:11])[CH3:33])[CH2:14]3)=[CH:19][CH:20]=[C:21]2[N:26]=1
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)Cc1nc2ccc(N3CCC(N(C)C)C3)nc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C1CCN(c2ccc3nc(-c4c(N)c5ccccc5[nH]c4=O)[nH]c3n2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
LiHMDS (3.5 equivalents) was added to ethyl {5-[3-(dimethylamino)pyrrolidin-1-yl]-3H-imidazo[4,5-b]pyridin-2-yl}acetate (1.0 equivalent) in THF at −40° C. After 10 minutes, a solution of 2-aminobenzenecarbonitrile (1.1 equivalents) in THF was added. The resulting mixture was allowed to warm to room temperature, stirred for 1 hour, and then heated to 60° C. overnight. The mixture was cooled to room temperature and quenched with NH4Cl (aqueous saturated). The aqueous phase was extracted with CH2Cl2 (5 times). The product crashed out of the organic solution during the extractions. Evaporation of the solvent under reduced pressure afforded a brown solid that was triturated repeatedly with MeOH and acetone to obtain a yellow greenish powder. LC/MS m/z 390.2 (MH+), Rt 1.48 minutes.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.CN(C=O)C>O>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Reaction time: 4 h
Yield: 3.9 %

Procedure:
A mixture of 1.0 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.11 g of potassium carbonate, 760 mg of 4-methoxybenzyl chloride and 20 ml of DMF was stirred at 70°-80° C. for 4 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography. Recrystallization from methanol gave 60 mg of 5-[4-(4-methoxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 194°-196° C., colorless needles.
Reaction SMILES: C1(C)C=CC=C(C)C=1.C(C1OC1)Cl.[CH2:14]([O:18][CH2:19][CH:20](CC)[CH2:21][CH2:22]CC)[CH:15]1[O:17][CH2:16]1.C1(CN)C=CC=C(CN)C=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>>[CH2:14]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]1[O:17][CH2:16]1
Reactant: CCCCC(CC)COCC1CO1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: NCc1cccc(CN)c1
Solvent: Cc1cccc(C)c1
Solvent: ClCC1CO1
Product: CCCCOCC1CO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 203.4 %

Procedure:
In the same reaction vessel as in Example 1 was fed 275 g of the modified polyamine synthesized in Production Example 2 (corresponding to the modified polyamine based on 1 mol of metaxylene, 0.125 mol of polyethylene glycol, and 0.28 mol of epichlorohydrin), and then 163 g (0.88 mol) of 2-ethylhexyl glycidyl ether (epoxy equivalent of 186, produced by NOF Corporation, the trademark "Epiol EH") was added dropwise thereto over one hour at 80° C. in an atmosphere of nitrogen under stirring. After the completion of the dropwise addition, the reaction was carried out for one hour at a reaction temperature raised 100° C. Then, the vessel interior was cooled to 80° C., and then 200 g (1.47 mol) of metaxylylenediamine was added thereto. Then, a mixture of 282 g (0.743 mol) of epoxy resin in a liquid form of bisphenol A type (epoxy equivalent 190, produced by Yuka Shell Epoxy Co., Ltd., the trademark "Epicoat 828") with 236 g (1.79 mol) of butyl glycidyl ether (epoxy equivalent of 132, produced by NOF Corporation, the trademark Epiol B") was added dropwise thereto over one hour at 80° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:12](=[O:14])[CH3:13])[C:5]([O:7]C(C)(C)C)=[O:6].[Br:15]Br.[Cl-].[Na+].ClCCCl>O1CCOCC1>[Br:15][CH2:13][C:12](=[O:14])[C:4](=[N:3][O:2][CH3:1])[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)OC(C)(C)C
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CON=C(C(=O)O)C(=O)CBr
Temperature: 20 °C
Reaction time: 20 h
Yield: 41.1 %

Procedure:
In 50 ml of 1,4-dioxane was dissolved 20.1 g (0.1 mole) of tert-butyl 2-methoxyimino-3-oxobutyrate, and 32.0 g (0.2 mole) of bromine was added dropwise at 0° to 5° C. over a period of 1 hour and 30 minutes and stirred at 20° C. for 20 hours. After completion of the reaction, 25 ml of a saturated aqueous sodium chloride solution and 50 ml of 1,2-dichloroethane were added and then stirred, and the resulting mixture was allowed to stand and then separated and the aqueous layer was removed. The organic layer was further washed with 25 ml of water and dried over anhydrous magnesium sulfate, after which the 1,2-dichloroethane was distilled off under reduced pressure, and the residue was crystallized from 50 ml of xylene to obtain 9.2 g (yield 41.1%) of 4-bromo-2-methoxyimino-3-oxobutyric acid as white crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:32][C:33](=O)[CH3:34])[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=O)=[CH:19][CH:18]=1>C(O)C.C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:32]=[C:33]([CH3:34])[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:24]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:21][CH:22]=1
Reactant: CC(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)cc(-c2ccc(F)cc2)c1-c1ccccc1
Temperature: 100 °C
Yield: 42.9 %

Procedure:
Ethyl 2-aminoacetate hydrochloride (0.775 g, 5.55 mmol) was diluted with ethanol (5 ml) then triethylamine was added (1.160 ml, 8.32 mmol), followed by 2-(4-fluorophenyl)-1-phenylpentane-1,4-dione (1.5 g, 5.55 mmol), added as a solution in DCM. The reaction was heated at 100° C. overnight, after which TLC showed a new spot (less polar, Rf˜0.9 in 20% EtOAc/hexanes). The reaction was diluted with 10 mL DCM and washed with water (10 mL) and the aqueous layer was back-extracted with DCM (10 mL×2). The organics were combined, dried, filtered, and concentrated under vacuum to yield a crude orange oil. This oil was loaded onto a SiO2 column and purified using a 0-20% gradient of EtOAc in hexanes, affording the desired product ethyl 2-(3-(4-fluorophenyl)-5-methyl-2-phenyl-1H-pyrrol-1-yl)acetate (0.804 g, 2.383 mmol, 42.9% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.36-7.34 (m, 3H), 7.26-7.22 (m, 2H), 7.11-7.07 (m, 2H), 6.85-6.81 (m, 2H), 6.20 (b, 1H), 4.42 (s, 2H), 4.21 (q, 2H), 2.26 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:20](=O)[CH2:21][CH2:22][C:23]#[CH:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH2:24]([NH:1][C:2]1([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[CH2:23][CH2:22][C:21]#[CH:20]
Reactant: C#CCCC=O
Reactant: NC1(CNC(=O)OCc2ccccc2)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: C#CCCCNC1(CNC(=O)OCc2ccccc2)CCOCC1
Reaction time: 2 h

Procedure:
To a solution of benzyl ((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (G17, 106 mg) and 4-pentynal (34 mg) in methylene chloride (4 mL), sodium triacetoxyborohydride (205 mg) and acetic acid (22 μL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 0% hexane in ethyl acetate) to obtain benzyl ((4-((4-pentyn-1-yl)amino)tetrahydro-2H-pyran-4-yl)methyl)carbamate (G18, 74 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1.FC(F)(F)S(O[CH2:26][CH:27]([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][N:17]([CH2:26][CH:27]([F:29])[F:28])[CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COc1ccc2c(Cl)ncc(N3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)ncc(N3CCN(CC(F)F)CC3)c2c1
Yield: 16.3 %

Procedure:
To a solution of 1-chloro-6-methoxy-4-(piperazin-1-yl)isoquinoline (0.2 g, 0.720 mmol) in DMF (5 ml) was added 2,2-Difluoroethyl trifluoromethanesulfonate (0.154 g, 0.720 mmol) followed by sodium carbonate (0.114 g, 1.080 mmol). The reaction mass was stirred until judged complete. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.04 g, 15.93%) as semi solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.18-8.15 (d, J=12 Hz, 1H), 7.93 (s, 1H), 7.45-7.42 (d, J=12 Hz, 1H), 7.37 (s, 1H), 6.36-5.76 (tf, 1H), 3.97 (s, 3H), 3.10 (m, 4H), 2.84 (m, 4H); 19F NMR: δ ppm −118.59 (1F); MS: MS m/z 342.19 (M++1).