Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:17])[CH3:16].O>C(O)C.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:16][CH2:15][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pt]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reaction time: 4 h
Yield: 106.6 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (15 g, 75.28 mmol) was dissolved in ethanol (150 ml) and treated with 70% ethylamine/H2O (6.06 ml, 75.29 mmol), followed by 5% Pt/C JM type 117 (2.25 g, 20 wt %). The reaction mixture was subjected to hydrogenation at 2 bar, 50° C. with stiring for 4 hours. The reaction mixture was purged with nitrogen and filtered through GF/F filter paper. The catalyst was washed with ethanol (2×15 ml). The liquors were combined and evaporated to dryness to give N-(1-tert-butoxycarbonyl-4-piperidinyl)ethylamine as a colourless oil (18.33 g, 107%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].[OH-].[Na+]>CN(C)C=O.C(O)C>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13])[CH2:15][CH3:16]
Reactant: CCCNCCC
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCN(CCC)C(=O)c1ccc(C(=O)O)cn1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
N,N′-carbonyldiimidazole (145 mg, 0.89 mmol) was added to a solution of 5-(methoxycarbonyl)pyridine-2-carboxylic acid (162 mg, 0.89 mmol) in N,N-dimethylformamide (2.5 mL) at 60° C. The reaction mixture was stirred at 60° C. for 10 min. Dipropylamine (90 mg, 0.89 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at ambient temperature over night. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Half the amount of the crude intermediate (83 mg, 0.31 mmol) was dissolved in ethanol (3 mL) and 1 M sodium hydroxide (3 mL, 3 mmol) and heated to 50° C. for 30 min. The solvents were removed in vacuo and the residue was dissolved in water (3 mL) and cooled on ice. A 6 M hydrochloric acid solution was added dropwise and the solvents were removed in vacuo. The residue was added acetonitrile followed by evaporation in vacuo in order to remove trace of water. The procedure was repeated twice. The material was suspended in N,N-dimethylformamide and filtered. The filtrate was concentrated in vacuo to give 80 mg (64% total yield); MS (APPI/APCI) m/z 251[M+H+].
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:19])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:19][CH3:22])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2cc(O)c([N+](=O)[O-])cc2CC1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h

Procedure:
1.30 g (4.27 mmol) of 2,2,2-trifluoro-1-(7-hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone are dissolved in 20 ml DMF. At room temperature 0.59 g (4.27 mmol) potassium carbonate and 0.26 ml (4.27 mmol) methyliodide are added and the mixture is stirred overnight. Then it is filtered and the filtrate is concentrated by evaporation i.vac., the residue is triturated with water and suction filtered and dried in the circulating air dryer at 45° C.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][CH:9]1[CH2:10][CH2:11][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:20]([NH2:23])[C:21]#[CH:22]>C(O)C>[CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][CH:9]1[CH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[N:23][C:12]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2CC1CC(=O)N2Cc1ccccc1
Reactant: C#CCN
Solvent: O
Solvent: CCO
Product: O=C1CC2CC(Cc3cccnc32)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
A flask charged with a stir bar, 2-benzyl-2-aza-bicyclo[3.3.1]nonane-3,6-dione (for preparation see J. Chem. Soc., Perkin Trans. 1, 1999, 1157-1162; 0.80 g), NaAuCl4.2 H2O (30 mg), propargylamine (0.45 mL), and ethanol (5 mL) is heated at 100° C. with microwave irradiation for 10 min. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate/methanol 6:4:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].CCOC(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])[N:3]=1
Reactant: Oc1ccccc1Cl
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2ccccc2Cl)n1
Yield: 89 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 2-chlorophenol (193 μL, 1.86 mmol, d=1.24 g/mL), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (363 mg). Yield: 89%. 1H NMR (250 MHz, DMSO-d6) δ 7.37-7.39 (m, 1H, Harom 4), 7.46-7.47 (m, 2H, Harom 5+6), 7.64 (d, 1H, Harom 3, J=8.2 Hz), 8.55 (s, 1H, HPz 5), 8.65 (s, 1H, HPz 3). m/z: 240.0 [(M)+, calcd for C10H6Cl2N2O 240.0].
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:20]1CCOCC1.[OH-].[Na+]>O>[NH2:3][C:4]1[C:5]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:20])=[O:1]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(S(=O)(=O)c3ccccc3)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1S(=O)(=O)c1ccccc1

Procedure:
A mixture of 2-oxo-7-phenylsulfonylindoline (6.50 g.), dioxane (100 ml.), sodium hydroxide (3.0 g.) water (50 ml.) was refluxed under heating for 16 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water, washed with diethyl ether, adjusted to pH 4 with 1N sulfuric acid and then extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure. The residue was washed with a mixture of ethanol and diethyl ether and cooled. The precipitates were collected by filtration to give white crystals of 2-(2-amino-3-phenylsulfonylphenyl)acetic acid (3.60 g.). mp 218° to 220° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH2:19][N:4]3[C:5](=[O:16])[C:6]4[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=4[N:2]([CH3:1])[C:3]3=[O:17])=[N:24][C:23]=2[CH:25]=1
Reactant: Clc1ccc2sc(CBr)nc2c1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(Cl)ccc3s1)c(=O)n2C
Yield: 96.1 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (297 mg, 1 mmol) was dissolved in N,N-dimethylformamide (8 ml). 2-bromomethyl-5-chloro-1,3-benzothiazole (263 mg, 1 mmol) and potassium carbonate (213 mg, 1.5 mmol) were added to give a reaction mixture. The reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 3b (460 mg, light yellow solid), yield: 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccc(Cl)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 352(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][CH:9]2C#N)=O)=[CH:4][CH:3]=1.F[B-](F)(F)F.[H+].[C:27]([C:33]([O:35][CH3:36])=[O:34])#[C:28][C:29]([O:31][CH3:32])=[O:30]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[N:8]3[C:9]([S:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=43)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:27]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:20]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: N#CC1Sc2ccccc2N1C(=O)c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(4-chlorobenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (9.12 g, 30.0 mmol) in dichloromethane (50 mL) was added dropwise 9 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (12.7 g, 90.0 mmol) in DMF (40 mL) and then warmed at 35° C. for 14 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from methanol to give dimethyl 1-(4-chlorophenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate, 2.5 g (21%); mp 172-173° C. 1H NMR (DMSO-d6) δ 3.64 (3H, s, COOMe), 3.83 (3H, s, COOMe), 6.85-6.87 (1H, m, ArH), 7.30-7.42 (2H, m, ArH), 7.60-7.66 (4H, m, 4×ArH), 8.04-8.06 (1H, m, ArH). Anal. Calcd. for (C20H14ClNO4S.0.5H2O): C, 58.75; H, 3.70; N, 3.43; S, 7.84. Found: C, 58.76; H, 3.45; N, 3.59; S, 7.73.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][CH:6]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O)[C:7](O)=[O:8]>CO>[CH3:4][O:5][CH:6]1[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[N:3][NH:2][C:7]1=[O:8]
Reactant: NN
Reactant: COC(CC(=O)c1ccc(C)cc1)C(=O)O
Solvent: CO
Solvent: O
Product: COC1CC(c2ccc(C)cc2)=NNC1=O
Reaction time: 8 h
Yield: 61.9 %

Procedure:
0.5 g of hydrazine hydrate (100%) was added, at room temperature, to a solution of 2.22 g of 2-methoxy-4-(4-methylphenyl)-4-oxobutyric acid (prepared as described in Preparation 2) in 20 ml of methanol, and the mixture was allowed to stand at room temperature overnight. The crystals which precipitated were collected by filtration and washed with methanol, to give 1.35 g of the title compound. The filtrate was concentrated by evaporation at 50° C. and the resulting residue was washed with methanol, giving a further 0.5 g of the pure title compound, melting at 167°-169.5° C. The total yield was 85%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:37]=[CH:36][C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20]2)=[CH:36][CH:37]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 17.6 %

Procedure:
Acetic anhydride (68 mg, 0.67 mmol) was added dropwise to a stirred solution of 1-(4-aminophenethyl)-4-(diphenylmethoxymethyl)piperidine (180 mg, 0.45 mmol) (see Example 21) and triethylamine (55 mg, 0.54 mmol) in acetonitrile (5 ml) and the mixture heated under reflux for 2 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate and the layers separated. The aqueous layer was extracted into ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ethyl acetate and dried to give the title compound (35 mg) as an off-white solid which was characterised containing 0.25 equivalents of water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCCC(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)CCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (212 mg, 0.75 mmole), dimethylformamide (5 mL), and 4-aminobutanoic acid (78 mg, 0.75 mmole) is stirred at room temperature for 1 hour. The reaction mixture is diluted with ether, filtered, washed with fresh ether and dried to give a salmon solid, 164 mg, (61%), mp 260-2° C. dec; MS (ES+): m/z 353.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1)([CH3:3])=[CH2:2].[H][H]>CCO.C1COCC1.[Pd]>[CH:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(OC)cc2cc(-c3ccc(OC)cc3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)C)c3o2)cc1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
7-Isopropenyl-5-methoxy-2-(4-methoxy-phenyl)-benzofuran 116 (0.28, 0.95 mmol) was hydrogenated over an atmosphere of hydrogen with 10% Pd/C (0.05 g) in EtOH/THF (10 ml). After 2 hr, the reaction was filtered through celite and concentrated to give 117 as a solid (0.27 g, 95%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:12]2[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH:16](Cl)[CH3:17])[O:15][C:11]=2[C:10]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[C:9]([F:37])[CH:8]=1.[C-:38]#[N:39].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:12]2[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH:16]([C:38]#[N:39])[CH3:17])[O:15][C:11]=2[C:10]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[C:9]([F:37])[CH:8]=1
Reactant: CCOC(=O)c1c(C(C)Cl)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(C)C#N)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
20 ml of N,N-dimethylformamide was added to 0.8 g (1.6 mmol) of 3-[4-chloro-2-(1-chloroethyl)-3-ethoxycarbonyl-6-fluorobenzofuran-7-yl]-1-methyl-6-trifluoromethyluracil, 0.16 g (2.5 mmol) of potassium cyanide and 0.40 g (2.9 mmol) of potassium carbonate, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.58 g (yield: 74%) of the desired product as a yellow glassy substance. Refractive index: 1.5348 (20° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 10 mL was added 2-fluoro-5-(trifluoromethyl)benzaldehyde 75 (77.7 mg, 0404 mmol). PTSA (153.8 mg, 0809 mmol) was added and the reaction mixture stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 76 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(2-fluoro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 76 was eluted at 34% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1)=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:24](O)(=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCCCNC(=O)C1CCCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCC(=O)N1CCCC[C@H]1C(=O)NCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
(S)-(6-{[1-(1-Tridecanoyl-piperidin-2-yl)-methanoyl]-amino}-hexyl)-carbamic acid tert-butyl ester was obtained by treating a solution of {6-[(1-piperidin-2-yl-methanoyl)-amino]hexyl}-carbamic acid tert-butyl ester in DCM (100 mL) with tridecanoic acid (2.36 g, 1.1 equiv.) in the presence of HATU (5.0 g, 1.3 equiv.) and DIEA (4.2 mL, 2.4 equiv.). After 2 hours of stirring at rt the reaction was judged to be complete by tlc monitoring. DCM was added (50 mL) and the reaction mixture was washed 3 times with citric acid (0.5 M). 3 times with an aqueous saturated solution of NaHCO3 and with brine. Drying over Na2SO4, evaporation in vacuo gave a residue which was purified via flash chromatography (SiO2) using EtOAc:chexanes (6:4) as eluant. (S)-(6-{[1-(1-Tridecanoyl-piperidin-2-yl)-methanoyl]-amino}-hexyl)-carbamic acid tert-butyl ester (4.6 g) was obtained as a yellow oil in a 87% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25]OS(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:25][N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Product: COC(=O)CCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (150.3 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(1H-imidazol-1-yl)propanamide (46.8 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:14][CH:15]=O)[C:4](=[O:17])[CH:3]=1.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:15][CH2:14][N:5]4[C:6]5[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][C:4]4=[O:17])[CH2:39][CH2:38]3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COc1ccc2c(c1)c(C)cc(=O)n2CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)c(C)cc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To 25 mL of a chloroform solution containing 71 mg of (4-methyl-6-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde and 108 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 18 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 121 mg of sodium triacetoxyborohydride was added, and stirred for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 140 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-6-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.