Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:53]2[C:52]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[N:46]=[C:45]([NH2:54])[C:44]=2[N:43]=[C:42]1[CH2:55][CH2:56][O:57][CH3:58]>ClCCl.N1C=CC=CC=1>[NH2:54][C:45]1[C:44]2[N:43]=[C:42]([CH2:55][CH2:56][O:57][CH3:58])[N:41]([CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:53]=2[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[N:46]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cc2ccccc2cn1
Temperature: 0 °C
Yield: 29.6 %

Procedure:
Under a nitrogen atmosphere isoquinoline-3-carboxylic acid (1.32 g, 7.63 mmol), 1-hydroxybenzotriazole (1.12 g, 8.27 mmol), and dichloromethane (60 mL) were combined, allowed to stir for several minutes and then cooled to 0° C. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added. Pyridine (1.8 mL) was added and the resulting mixture was allowed to stir for at least 60 minutes. A solution of 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.37 mmol) in dichloromethane (250 mL) was added dropwise. The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was washed with sodium bicarbonate, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (40 g silica gel eluting with dichloromethane/methanol 9/1) followed by recrystallization from methanol to provide 882 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}isoquinoline-3-carboxamide as a yellow crystalline solid, m.p. 199-200° C. Analysis: Calculated for C27H28N6O2: % C, 69.21; % H, 6.02; % N, 17.94. Found: % C, 69.03; % H, 5.99; % N, 18.11.
Reaction SMILES: [N:1]1([C:6]2[N:10]=[C:9]([CH:11]=O)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[C:28]([CH2:30][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:29]=[C:22]2[N:21]=1.N1CCCN2CCCCCC=12>O1CCCC1>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[C:28]([CH:30]=[CH:11][C:9]3[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:7]=[C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:10]=3)[N:29]=[C:22]2[N:21]=1
Reactant: O=Cc1nc(N2CCCC2)nn1CC(F)(F)F
Reactant: Cc1cc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C)n2nc(C=Cc3nc(N4CCCC4)nn3CC(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
A mixture of 3-(pyrrolidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole-5-carbaldehyde (54 mg, 218 μmol, Eq: 1.00), ((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (99.8 mg, 218 μmol, Eq: 1.00) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (82.8 mg, 544 μmol, Eq: 2.5) in tetrahydrofuran (3.36 ml) was stirred for 18 hours at 25° C. under argon atmosphere. Chromatography afforded 5,7-dimethyl-2-{2-[5-pyrrolidin-1-yl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-a]pyrimidine (20 mg/23.4%) as a light yellow viscous oil. MS: m/z=393.4 (M+H+).
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.P(Cl)(Cl)[Cl:25]>ClCCl>[Cl:25][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: ClP(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Cl)c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (0.89 g) and phosphorous trichloride (0.57 g) in dichloromethane (50 ml) were stirred at 0° C. for 2 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate), filtered and evaporated to dryness. The crude product was purified by column chromatography on silica eluted with a mixture of petroleum ether/ethyl acetate to give 4-[chloro-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 298, 0.79 g) as a yellow oil: NMR: (CDCl3) 1.1 (4H,m) 1.9(1H,m) 6.9(1H,s) 7.9(1H,m) 8.0(1H,s) 8.25(2H,m).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([O:9][C:10]1[C:11]([CH3:27])=[N:12][N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:16]([CH3:26])[O:15][C:14]=12)[CH2:6][CH2:7][CH3:8])C.CC(C[AlH]CC(C)C)C.[Cl-].[NH4+]>C1COCC1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:17]1[N:13]2[N:12]=[C:11]([CH3:27])[C:10]([O:9][CH:5]([CH2:6][CH2:7][CH3:8])[CH2:4][OH:3])=[C:14]2[O:15][C:16]=1[CH3:26]
Reactant: CCCC(Oc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12)C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(CO)Oc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.), stirring solution of 2-[3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-yloxy]-pentanoic acid ethyl ester (85 mg, 0.200 mmol) in THF (2.0 ml) at is added DIBAL-H (0.400 ml, 0.400 mmol). The reaction mixture is warmed to RT and stirred for 2 hours. The mixture is added to sat. ammonium chloride (50 ml) and the product is extracted into EtOAc (2×50 ml). The combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 12 g SiO2-column to yield the title compound as a white solid; MS: m/z 385.13 [M+H]+.
Reaction SMILES: C(O)(=O)C.C([Si](C)(C)[O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2(O)[C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[CH:13][C:12]=1[O:34][CH3:35])(C)(C)C.C([O-])(O)=O.[Na+]>O>[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH:17]=[C:18]2[C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[CH:13][C:12]=1[O:34][CH3:35]
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(O)(c1cc(OC)c(OC)c(OC)c1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)C(c1cc(OC)c(OC)c(OC)c1)=CCC2
Temperature: 25 °C
Yield: 86.2 %

Procedure:
To a solution of acetic acid (10 mL) in H2O (60 mL), was added 7-[(tertbutyldimethylsilyl)oxy]-1-hydroxy-6-methoxy-1-(3′,4′,5′-trimethoxyphenyl)-tetralin (137 mg, 0.29 mmol). The solution was heated to reflux for 8 hour, and then cooled down to rt. NaHCO3 (20 mL, saturated solution) was added, and the mixture was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 7-Hydroxy-6-methoxy-1-(3′,4′,5′-trimethoxyphenyl)-3,4-dihydronaphthalene (84.3 mg, 0.25 mmol, 86%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 2.37 (m, 2H), 2.78 (t, J=7.7 Hz, 2H), 3.84 (s, 6H), 3.88 (s, 3H), 3.91 (s, 3H), 5.41 (s, 1H), 5.98 (t, J=4.6 Hz, 1H), 6.54 (s, 2H), 6.68 (s, 1H), 6.81 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35][C:36](=[O:50])[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][C@H:47]([NH2:49])[CH3:48])[CH:41]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:31]([O:35][C:36](=[O:50])[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][C@H:47]([NH:49][CH2:21][C@@H:20]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:19])[NH:17]3)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:48])[CH:41]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: C[C@@H](N)Cc1cccc(CCNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Cc1cccc(CCNC(=O)OC(C)(C)C)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 63.5 %

Procedure:
A stirred solution of 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethyl-silanyloxy)ethyl]-1H-quinolin-2-one (3.14 g, 6.43 mmol); {2-[3-((R)-2-aminopropyl)-phenyl]ethyl}carbamic acid tert-butyl ester (1.79 g, 6.43 mmol) and triethylamine (1.08 mL, 7.72 mmol) in DMF (21.0 mL) was microwaved (300 watts) at 80° C. for 15 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give the title compound (2.8 g, 63% yield) as an off-white solid.
Reaction SMILES: C[Al](C)C.CCCCCC.Cl.[CH3:12][NH:13][CH3:14].[C:15]([C:17]1[C:22]2[N:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[O:25][C:21]=2[C:20]([CH2:29][C:30]([O:32]C)=O)=[C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:18]=1[CH3:40])#[N:16].Cl>C1(C)C=CC=CC=1>[C:15]([C:17]1[C:22]2[N:23]=[C:24]([CH:26]3[CH2:27][CH2:28]3)[O:25][C:21]=2[C:20]([CH2:29][C:30]([N:13]([CH3:14])[CH3:12])=[O:32])=[C:19]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:18]=1[CH3:40])#[N:16]
Reactant: COC(=O)Cc1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)c(CC(=O)N(C)C)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
At room temperature, trimethylaluminium/n-hexane solution (1.03 mol/l) (547 μl, 0.563 mmol) was added to a toluene (2 ml) suspension of dimethylamine hydrochloride (38.3 mg, 0.469 mmol), followed by stirring at room temperature for 30 minutes. Methyl (4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)acetate (I-295) (65.0 mg, 0.188 mmol) was added to the reaction liquid, followed by heating under reflux in an oil bath at 120° C. for 15 hours. With cooling with ice, 1 N hydrochloric acid was added to the reaction liquid. After extraction with ethyl acetate, the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (56.0 mg, 83%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:13][O:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]3[C:3]([C:14](=[O:16])[N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=3)=[CH:4][NH:5][C:6]=2[CH:7]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Product: COc1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c2c1

Procedure:
The title compound was prepared following the procedure described in Step 3 using 3e and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 3.86 (3H, s), 7.10 (3H, m), 7.38 (2H, dd, J=8.24, 7.42 Hz), 8.09 (3H, m), 8.65 (1H, d, J=6.04 Hz). m/z 292.3 (MH+).
Reaction SMILES: [C:1]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18]C1CCOC(=O)CCCCCCCCCC1>>[CH3:18][CH:13]1[CH2:14][CH2:15][O:16][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C1CCCCCCCCCCCCCCO1
Reactant: CC1CCCCCCCCCCC(=O)OCC1
Product: CC1CCCCCCCCCCCC(=O)OCC1

Procedure:
Fragrance; In quality, it has an elegance like that of 15-pentadecanolide and a nitromusk-like characteristic similar to that of 12-methyl-14-tetradecanolide.
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH3:23])\[CH2:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([O:17]C)[C:13]([CH3:19])=[C:12]([CH3:20])[C:11]=1[O:21]C)(=[O:3])[CH3:2]>C(#N)C.O>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](/[CH3:23])\[CH2:8][CH2:9][C:10]1[C:11](=[O:21])[C:12]([CH3:20])=[C:13]([CH3:19])[C:14](=[O:17])[C:15]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C\COC(C)=O)c1C
Solvent: O
Solvent: CC#N
Product: CC(=O)OC/C=C(/C)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A solution of (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate (0.98 g) in acetonitrile (15 ml) was treated dropwise at -20° C. with a solution of ceric ammonium nitrate (4.1 g) in water (15 ml). After 15 minutes the mixture was warmed to -10° C and left at this temperature for 1 hour. The mixture was diluted with ice-water and extracted twice with methylene chloride. The extracts were washed with water, dried and chromatographed on silica gel with hexane/ethyl acetate 95:5, yielding 0.67 g of (Z)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadienyl)-2-pentenyl acetate as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[NH:9][C:10]([C:12]3[C:16]([NH:17][C:18](=[O:27])[C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])=[CH:15][NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].O.Cl>[OH-].[Na+].CO>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:18]([NH:17][C:16]1[C:12]([C:10]2[NH:9][C:8]3[CH:28]=[CH:29][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[N:13][NH:14][CH:15]=1)=[O:27]
Reactant: COC(=O)c1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.2 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-5-carboxylic acid methyl ester (12.0 mg, 0.03 mmol) in 2 M aqueous NaOH/MeOH (1:1, 4 ml) was stirred at ambient temperature for 14 h. The mixture was reduced in vacuo, water (5 ml) added and the mixture taken to pH 4 using 1 M aqueous HCl. The precipitate formed was collected by filtration and dried under vacuum to give 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-5-carboxylic acid as a pale coloured solid (6 mg, 52%). (LC/MS: Rt 2.88, [M+H]+ 383.97).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][C:31](O)=[O:32])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][C:31]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:32])[CH2:27]2
Reactant: O=C(O)CC1C2CC3CC(C2)CC1C3
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC(C3)CC1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.69 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.78 g (4.1 mill), and stirred at 0° C. for 30 min. 2-adamantyl acetic acid 0.80 g (4.1 mill) and WSC 1.11 g (5.79 mill) were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 23 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(2-adamantylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 50 ml solution of lithium aluminum hydride 0.47 g (12 mill) and refluxed for 2 hours. The reaction mixture was cooled, added water and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1-5:1) to obtain the product.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:20]3[CH:21]=[CH:22][C:23]([CH2:24][NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)=[CH:26][CH:27]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccc(O)cc1
Reactant: O=Cc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1ccc(CNCc2ccc(-c3nc4ccn5cnnc5c4cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-2 (0.05 g, 0.14 mMol) and 4-(aminomethyl)phenol (0.04, 0.35 mMol) in DMF (0.5 mL) was added acetic acid (0.04 mL, 0.7 mMol). After stirring for 2 hours at room temperature, sodium triacetoxyborohydride (0.06 g, 0.3 mMol) was added. After stirring overnight, the reaction was filtered through a syringe filter and purified on a C18 reverse phase HPLC to yield 19-1 as a solid. LC/MS (M+1) calculated: 458.5; observed: 458.3.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:35])=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])C>CO>[OH:35][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:34][CH:33]=[C:32]2[C:26]=1[C:27](=[O:28])[N:29]([CH3:31])[CH2:30]2
Reactant: CCOc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3ccc4c(c3O)C(=O)N(C)C4)c(=O)c2=O)C2(C)COC2)o1
Temperature: 55 °C
Yield: 4 %

Procedure:
287 mg (1.58 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 3 ml of methanol were added to a suspension of 235 mg (0.78 mmol) of 3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide in 20 ml of methanol at 55° C. The reaction medium was heated at 55° C. for 24 hours and then concentrated to dryness. The residue was chromatographed on silica gel (40 g prepacked column, 30 ml/min, 100% dichloromethane then 4% of methanol). A residue of 130 mg was obtained and was purified by preparative TLC (eluent: 50/50/1 ethyl acetate/acetone/water). 52 mg were obtained and then precipitated from dimethyl sulfoxide and filtered off 15 mg of product were obtained in the form of a white solid. Yield=4%, HPLC=98.56%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[C:24](=O)[C:23]([CH3:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:21]3[CH2:20][CH2:19][CH2:24][C:23]([CH3:32])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: CC1(c2ccccc2)CCCC(Br)C1=O
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4(C)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (90 mg, 0.36 mmol) and crude 6-bromo-2-methyl-2-phenyl-cyclohexanone (0.29 g, ca. 1.1 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown solid (65 mg, 43%). MS (ISP) 419.3 [(M+H)+]. mp 160-164° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccncc2)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
4-Aminopyridine (100 mg, 1.06 mmol) and 4-methoxyphenyl isocyanate (158.5 mg, 1.06 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14]C(=O)OC(C)(C)C)=[N:12][CH:13]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCOCC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl 5-(morpholinomethyl)pyridin-2-ylcarbamate (107; 1.40 g, 4.77 mmol) in dichloromethane (10 mL) was added TFA (10.0 mL). The mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Enough saturated aqueous Na2CO3 was added to the resulting residue to adjust the pH=9. The mixture was extracted with dichloromethane (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford 5-(morpholinomethyl)pyridin-2-amine 108 (0.85 g, 92%).
Reaction SMILES: Cl.[CH:2]([NH2:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10](O)=[O:11]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[F:16])[C:10]([NH:5][CH:2]([CH3:4])[CH3:3])=[O:11]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)N
Agent: Cl
Product: CC(C)NC(=O)c1ccc(F)c(Cl)c1

Procedure:
Using isopropylamine hydrochloride and 3-chloro-4-fluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained as a white solid (81% yield). ESI-MS: m/z 216 (M+H)+.
Reaction SMILES: C([Li])CCC.[I:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>O1CCCC1.CCCCCC>[CH2:19]([O:18][C:15](=[O:17])[CH:16]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([I:6])=[CH:8][CH:9]=1)[CH3:20]
Reactant: O=Cc1ccc(I)cc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred, cooled (−78° C.) solution of triethylphosphonoacetate (11.1 mL, 56 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a 1.6M solution of n-butyl lithium in hexanes (27 mL, 43.75 mmol). After 10 min, the reaction mixture was cannulated into a cooled (−78° C.) solution of 4-iodo-benzaldehyde (6.5 g, 28 mmol) in tetrahydrofuran (20 mL). The reaction mixture was allowed to warm to 0° C. over 1 h. It was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 6-8% ethyl acetate in hexane as the eluent to afford the title compound (2.7 g pure, 3.2 g ˜95% pure, 69%).