Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)[CH:2]=[CH2:3].[CH2:9]([NH2:12])[CH2:10][CH3:11]>C(O)C>[CH2:1]([O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:12][CH2:9][CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCOCC1CO1
Reactant: CCCN
Solvent: CCO
Product: C=CCOCC(O)CNCCC

Procedure:
Allylglycidyl ether (94.7 g.) is added with stirring to a solution of n-propylamine (98 g., 137 ml.) in ethanol (200 ml.). The mixture is heated under reflux for 18 hours and the solvent in excess of n-propylamine are distilled off. The residual oil is distilled and the fraction b.p. 79°-85° C. at 1 m.m. is collected to give 1-allyloxy-3-n-propylamino-2-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>CCOC(C)=O>[CH3:19][N:20](/[CH:22]=[C:10]1\[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2](/[N:1]=[CH:19]\[N:20]([CH3:22])[CH3:21])=[CH:7][CH:6]=2)[C:17]2[C:12]([C:11]\1=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:21]
Reactant: Nc1ccc(C2CCC(=O)c3ccccc32)cc1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)/C=N\c1ccc(C2C/C(=C\N(C)C)C(=O)c3ccccc32)cc1
Yield: 98 %

Procedure:
A mixture of 4-(4-aminophenyl)-3,4-dihydronaphthalen-1(2H)-one (6.0 g, 25.3 mmol) and DMF-DMA (60 mls, 10 vols) was heated at 100 C for 12 h. The reaction mixture was stripped and residue stirred in EtOAc at rt for 1 h. The resulting solids were then filtered and rinsed on the filter with water. After drying, the product was afforded as a yellow solid (8.6 g, 98%). LCMS m/e 348 [M+H].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[N:1]1([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1-n1ccc2ccccc21
Reaction time: 3.5 h
Yield: 47 %

Procedure:
A mixture of indole (4.16 g; 35.53 mmol), methyl 2-bromobenzoate (2.64 g; 35.53 mmol), potassium carbonate (5.50 g) and CuO (2.0 g) in 40 mL of DMF was refiuxed uncler an argon atmosphere for 3.5 hrs. The crude material obtained upon extraction into ethyl acetate and removal of the solvent was purified on a silica gel column (10% ethyl acetate/hexane) to obtain 4.20 g (47%) of methyl 2-(1-indolyl)benzoate, 1H NMR (CDCl3): δ 3.45 (s, 3H); 6.43 (d, 1H); 6.99-7.20 (m, 4H); 7.35-7.42 (m, 2H); 7.60 (m, 2H); 7.88 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cn1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.2) (1.50 g, 4.38 mmol) and commercially available 3-bromo-benzene-boronic acid (1.01 g, 5.03 mmol) according to the general procedure IIb. Obtained as a white solid (1.15 g, 56%). MS (EI) 448.0, 450.0 [(M)+]; mp 160° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH3:13])[C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.CCN(CC)CC.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](Cl)=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH3:13])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[C:11]=3[N:12]=2)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cn1c(=O)c(N)c(N)c2ccccc21
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.1 %

Procedure:
To a suspension of 3,4-diamino-1-methyl-1H-quinolin-2-one (0.60 g, 1.59 mmol) in CH2Cl2 (10 mL) were added Et3N (0.177 g, 1.74 mmol) and 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (0.45 g, 1.60 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h, and then excess acid chloride was quenched by addition of MeOH. The mixture was concentrated in vacuo, and the amide intermediate was taken up in 5 mL of HOAc and heated at reflux for 7 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The cyclized product was purified by flash chromatography, to give 4-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester (0.12 g, 18% yield). 1H-NMR (DMSO): δ 8.08 (m, 1H), 7.60 (m, 1H), 7.43 (m, 1H), 7.32 (m, 6H), 5.02 (s, 2H), 3.91 (m, 2H), 3.34 (s, 3H), 2.81 (m, 3H), 1.78 (m, 2H), 1.39 (m, 2H). MS: calculated for C24H24N4O3+H 417.2; found: 417.4.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.O=[C:20]([CH2:28][CH3:29])[CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:28]([CH3:29])=[C:20]2[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CCC(=O)CCCC(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1c(CCCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-fluorophenyl)hydrazine hydrochloride and methyl 5-oxoheptanoate as the starting materials and tert-butanol as the solvent, the title compound was prepared.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([O:20][CH3:21])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:21][O:20][CH:6]1[CH2:7][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:9][CH2:10][CH:4]([NH2:1])[CH2:5]1
Reactant: COC1CC(N=[N+]=[N-])CCN(c2c([N+](=O)[O-])cnn2C)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC1CC(N)CCN(c2c([N+](=O)[O-])cnn2C)C1
Temperature: 65 °C

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol, Intermediate 18 (0.85 g, 3.0 mmol) in DMF (5 mL) cooled to 0° C. under nitrogen, was added sodium hydride (60% in mineral oil, 133 mg, 3.3 mmol) and the resulting mixture was stirred for 10 min. Iodomethane (0.37 mL, 6.0 mmol) was added and the mixture stirred at room temperature for 16 hr. Water (200 mL) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave 5-azido-3-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as an oil (0.76 g). This azide (0.76 g, 2.6 mmol) in THF (15 mL) and water (3 mL) was treated with triphenylphosphine (0.71 g, 2.7 mmol). The mixture was heated at 65° C. for 16 hr and the solvents were removed under reduced pressure to afford 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was suspended in DCM (40 mL) and di-tert-butyl dicarbonate (1.13 g, 5.2 mmol) and DIPEA (1.36 mL, 7.8 mmol) were added. After stirring at room temperature for 16 hr the solvent was removed under reduced pressure and the residue dissolved in DCM (40 mL). Water (20 ml) was added and the organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave tert-butyl 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.84 g, 74% over three steps) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=4.3 Hz, 1H), 5.39 (d, J=7.9 Hz, 1H), 4.21-3.94 (m, 1H), 3.84 (s, 3H), 3.56-3.42 (m, 2H), 3.35-3.03 (m, 6H), 2.28-1.89 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:14](=[O:16])[CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCC(=O)N1
Reactant: Fc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)pyrrolidin-2-one with commercially available 1-(bromomethyl)-4-fluorobenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.71 min.; [M+H]+: 330.24 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H][H]>[Pd]>[C:4]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Product: CCOC(=O)C1CCC(=O)CC1

Procedure:
Into a 1-liter magnetically stirred autoclave is placed 489 grams of ethyl-p-hydroxybenzoate having the structure: ##STR138## and 5% palladium on carbon catalyst (4 grams). The autoclave is sealed and hydrogenated at 125°-140° C. and 50 psig hydrogen pressure until the uptake of hydrogen is approximately 70% of theory. GLC analysis indicates that the reaction product at this point contains 71% ketone having the structure: ##STR139## 7.6% alcohol having the structure: ##STR140## and 20% starting material having the structure: ##STR141##
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[CH3:19])O)=[CH:7][CH:6]=1)C.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)c1ccc(C(O)c2cnccc2C)cc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1ccncc1Cc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A mixture of 400 mg of the hydroxymethyl compound (prepared as described in Reference Example 4), 5 ml of benzene and 196 μl of thionyl chloride was stirred at 40° C. for one hour, and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and the mixture extracted with chloroform. The extract was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. To the residue was added 5 ml of acetic acid and 175 mg of zinc powder, and the mixture stirred at room temperature for one hour, and then concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and concentrated under reduced pressure to give 166 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.OS(O)(=O)=O>C(O)(C)(C)C>[CH:5]1([C:10]([O:12][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C=C(C)C
Reactant: O=C(O)C1CCCC1
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C1CCCC1
Reaction time: 72 h
Yield: 95 %

Procedure:
Cool a metal bomb in a CO2 -acetone bath and charge with isobutylene (150 ml), cyclopentanecarboxylic acid (29.4 g, 0.26 mol), t-butanol (4 ml) and H2SO4 (1 ml). Remove the bomb from the cold-bath, seal and stir for 3 days. Cool the bomb in a CO2 -acetone bath, open to the atmosphere and evaporate isobutylene under a stream of N2 while allowing the reaction mixture to attain R.T. Add Et2O (300 ml) and wash the mixture with sat'd NaHCO3 (300 ml) and sat'd NaCl, then dry (MgSO4), filter and concentrate to obtain a colorless oil (41.5 g, 95%) which is used without further purification. 1H Nmr (CDCl3) δ2.58 (1H, m), 1.90-1.35 (8H, m), 1.39 (9H, s).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][O:14][C:15]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:16]=1[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:28]>ClCCl>[C:1]([CH2:3][C:4]([N:18]([CH2:17][C:16]1[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:15]=1[O:14][CH3:13])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:5])#[N:2]
Reactant: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)CC#N)c2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1

Procedure:
To a solution of cyanoacetic acid (43.0 mg, 0.511 mmol) in 1 mL of dichloromethane at room temperature was added PCl5 (106 mg, 0.511 mmol). The mixture was heated to reflux for 10 minutes. A solution of {2-[(2,4-dimethoxybenzyl)amino]-5-methoxyphenyl}(3-fluorophenyl)methanone (101 mg, 0.255 mmol) in 1 mL dichloromethane was added, and the reaction was refluxed for an additional 1.5 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a yellow foam (117 mg, 99% yield) which was used in the next step without further purification. Proton NMR for the product was consistent with the titled compound. ESI+MS: 463.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=1[C:28]([F:31])([F:30])[F:29].CCN(C(C)C)C(C)C>C(O)CCC>[NH2:27][C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:22]=1[C:28]([F:31])([F:30])[F:29]
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Reactant: Nc1ncnc(Cl)c1C(F)(F)F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C(F)(F)F)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 42 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]-imidazole-7-carboxamide (Prepared in Example 20, 150 mg, 0.581 mmol), 6-chloro-5-(trifluoromethyl)pyrimidin-4-amine (172 mg, 0.871 mmol) and 1,1′-dimethyltriethylamine (202 μL, 1.161 mmol) in n-butanol (2 mL) was stirred at 120° C. After 42 h, the mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent to give 2-((1S)-1-((6-amino-5-(trifluoromethyl)-4-pyrimidinyl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.50-8.41 (m, 1H), 8.05 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.28-7.18 (m, 2H), 6.90-6.78 (m, 2H), 5.89-5.81 (m, 1H), 3.40-3.33 (m, 1H), 2.82 (d, J=4 Hz, 3H), 1.60 (d, J=8 Hz, 3H), 1.16-1.03 (m, 2H), 0.95-0.75 (m, 2H); LC-MS (ESI) m/z 420.1 [M+H]+.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:21][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH:11][C:1]12[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
A mixture of 4-(3-adamantan-1-yl-ureido)butyric acid 822 (0.15 g, 0.54 mmol), K2CO3 (0.09 g, 0.64 mmol), and iodomethane (0.04 mL, 0.59 mmol) in DMF (20 mL) was stirred at room temperature for 20 h. Then the product was extracted with ether (20 mL), and the ether was washed with 1 N NaOH aqueous solution (20 mL) and brine (20 mL), dried over Na2SO4, and evaporated to afford 0.15 g (95%) of 883: 1H NMR (CDCl3) 1.66-1.68 (6H, m), 1.81 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.37 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 3.68 (3H, s), 4.09 (1H, s), 4.25 (1H, s); LC-MS (ESI) m/z calcd for C16H26N2O3 [M+H]+ 295.19. found [M+H]+ 295.24; mp 114 C. Anal. (C16H26N2O3) C, H, N.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:4]([OH:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.O.[C:32]1(C)[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(C)=O>[CH3:33][C:32]1([CH3:37])[O:14][C@H:4](/[CH:5]=[CH:6]/[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:3]([N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:2][O:1]1
Reactant: Cc1ccc(/C=C/[C@@H](O)C(CO)N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(/C=C/[C@H]2OC(C)(C)OCC2N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 94 %

Procedure:
A mixture of 1,3-diol, 2-hydrazino (7B) (59 mg, 0.14 mmol) and p-toluene sulfonic acid monohydrate (2.7 mg, 0.014 mmol) in 5.0 mL anhydrous acetone was stirred at rt for 42 h. The reaction mixture was quenched with 5% NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, and removed in vacuo. Purification by flash chromatography on silica gel afforded the desired product as a white solid (94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH3:8]
Reactant: CC(O)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1ccccn1
Reaction time: 1.17 h
Yield: 105.3 %

Procedure:
To a stirred solution of 1-pyridin-2-yl-ethanol (156 mg, 1.27 mmol) (Mandal, S. K. et al. J. Org. Chem. 2003, 68, 4600-4603) and Et3N (0.27 mL, 1.94 mmol) in CH2Cl2 (5 mL) was added methanesulphonyl chloride (0.11 mL, 1.29 mmol) and the solution was stirred for 70 minutes. The solution was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (2×15 mL) and brine (1×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give crude methanesulphonic acid 1-pyridin-2-yl-ethyl ester as a yellow oil (269 mg, 100%). 1H NMR (CDCl3) δ 1.77 (d, 3H, J=6.6 Hz), 2.94 (s, 3H), 5.79 (q, 1H, J=6.6 Hz), 7.28 (ddd, 1H, J=7.4, 7.1, 1.3 Hz), 7.47 (d, 1H, J=7.9 Hz), 7.76 (td, 1H, J=7.6, 1.7 Hz), 8.61 (d, 1H, J=4.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:17]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccsc1C(=O)OC
Temperature: 0 °C

Procedure:
To a flame dried flask equipped with stir bar was added methyl 3-aminothiophene-2-carboxylate (2.06 g, 13.1 mmol) and anhydrous methylene chloride (10.0 mL). The resulting solution was cooled to 0° C., and treated successively with pyridine (1.11 mL, 13.7 mmol) and butyryl chloride (1.44 mL, 13.7 mmol) while stirring under N2. The ice bath was removed, and the reaction warmed to 25° C. and stirred 3 h. The reaction was then poured into 1N HCl and extracted with methylene chloride. The combined organics were dried over magnesium sulfate, filtered and concentrated to provide methyl 3-(butyrylamino)thiophene-2-carboxylate (1-2). MS 228 found, 227.3 required.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]4)[CH:14]=3)[C:9]2=[O:25])=CC=1.CO>C(O)(C(F)(F)F)=O>[NH2:24][C@H:21]1[CH2:22][CH2:23][C@H:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:25])[NH:8][CH:17]=[CH:16]3)[CH2:20]1
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@H](N)C4)ccc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)C1
Temperature: 150 °C
Yield: 50.6 %

Procedure:
125 mg (0.34 mmol) of 2-(4-methoxy-benzyl)-6-((1S,3S)-3-amino-cyclopentyloxy)-2H-isoquinolin-1-one (39) were dissolved in 1 mL of TFA and heated in a microwave oven at 150° C. for 3 h. Methanol was added and the reaction mixture was evaporated. The solution was taken up in 1N HCl and extracted three times with dichloromethane. The combined dichloromethane layers were extracted with 1N HCl twice and the combined HCl layers were lyophilized. The residue was dissolved in water and lyophilized again to yield 42 mg of 6-((1S,3S)-3-amino-cyclopentyloxy)-2H-isoquinolin-1-one (43) as hydrochloride. Rt=0.86 min (Method E). Detected mass: 245.1 (M+H+).