Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([O:26]CC)=O)[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:30][NH2:31]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:31][CH3:30])=[O:26])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 17 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and methylamine (0.11 mL of a 8M solution in ethanol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-N-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (10 mg, 17% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 9.97 (br s, 1 H), 8.58 (s, 1 H), 7.46 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.32 (m, 2 H), 4.13 (s, 2 H), 3.49 (m, 2 H), 3.21 (m, 1 H), 3.01 (d, J=4.8 Hz, 3 H), 1.83 (m, 2 H); HRMS m/z calcd for C20H21N3O4F: 386.1516. Found: 386.1517.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29])([CH3:24])([CH3:23])[CH3:22].O>C1COCC1>[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:12][CH:13]=1)=[O:29])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: C=CCOC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(NC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
In a round bottom flask, there are introduced 5.92 g (33.4 mmoles) of allyl 4-aminobenzoate, 5.6 ml (40.25 mmoles) of triethylamine and 100 ml of THF. A solution of 8 g (38.4 mmoles) of 3-tert.butyl-4-methoxybenzoyl chloride dissolved in 50 ml of THF are slowly added and the mixture is stirred at ambient temperature for 4 hours. The reaction medium is poured into water and extracted with dichloromethane. The organic phase is decanted, washed with demineralized water up to pH 6, dried on Na2SO4 and filtered. The solvents are evaporated under reduced pressure. The resulting maroon oil is crystallized in hexane. The solid is filtered and recrystallized in absolute ethanol. After filtration on fritted glass and drying for 48 hours at 80° C. 5.1 g (42.5%) of the expected ester are obtained in the form of white crystals whose melting point is 180°-182° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:11]1[CH:18]=[N:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[Cl-].[NH4+]>C1COCC1>[CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][O:5][C:11]1[CH:18]=[N:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[Si](C)(C)CCO
Reactant: N#Cc1ccncc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOc1cnccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A flask was charged with 2-(trimethylsilyl)ethanol (1.02 g, 8.66 mmol) and added THF (20 mL). Sodium hydride (0.219 g, 8.66 mmol) was added and the reaction was stirred at ambient temperature for 1 hour. 3-Chloroisonicotinonitrile (1.00 g, 7.22 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 hour and then at 50° C. overnight. A saturated solution of ammonium chloride was added. The reaction mixture was extracted with ethyl acetate, dried and concentrated to give the desired product (1.30 g, 81.7% yield) as light brown semi solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:5]=[C:6]([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20]C(OC(C)(C)C)=O)[NH:7]2.FC(F)(F)C(O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[N:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])[CH:5]=[C:6]([C:13](=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20])[NH:7]2
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1C(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2[nH]1
Reaction time: 24 h

Procedure:
Combine 5,7-dichloro-2-[2-(t-butoxycarbonylamino) benzoyl]-4-[benzenesulfonylimino]-1,4-dihydroquinoline (1 mmol) and ethyl acetate (50 mL). Add trifluoroacetic acid (1 mL) and stir. After 24 hours, evaporate in vacuo and partition the residue between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the organic layer, dry over MgSO4, filter and evaporate in vacuo. Chromatograph the residue on a column of silica gel to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[C:12]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:12]2[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(C)c1cccc(O)c1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(Oc2ncc([N+](=O)[O-])cn2)c1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 3-(1-methylethyl)phenol (680 mg, 5 mmol, Aldrich) in acetonitrile (50 mL) were added 2-chloro-5-nitropyrimidine (800 mg, 5 mmol) and triethylamine (1.01 g, 10 mmol) and the resulting mixture was heated at reflux and stirred for 3 hours. The reaction mixture was concentrated under vacuum and water was added to the residue (80 mL). It was extracted with ethyl acetate (3 times 50 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by silica gel chromatography (mobile phase: ethyl acetate: petroleum ether=0˜20%) to afford the title compound (900 mg).
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([C@@:14]2([CH3:20])[O:18][C:17](=[O:19])[NH:16][CH2:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])=[C:2]([CH3:4])[CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C@@:14]2([CH3:20])[O:18][C:17](=[O:19])[NH:16][CH2:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc([C@]2(C)CNC(=O)O2)cc1OC=C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc([C@]2(C)CNC(=O)O2)cc1OCC(C)C
Yield: 51.3 %

Procedure:
360 mg of (R)-(-)-5-(3-isobutenyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone is dissolved in 10 ml of ethyl acetate and mixed with 50 mg of palladium/10% carbon. It is hydrogenated until hydrogen absorption is completed. After filtration on diatomaceous earth and concentration by evaporation in a vacuum, an oily residue is obtained. The crude product is purified by chromatography on a silica gel column, with a hexane-acetone mixture as eluant. 186 mg of (R)-(-)-5-(3-isobutyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone, melting point 93.7° C., results. [α]D =-24.7°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[CH:11][C:12]([Br:16])=[C:13]([NH2:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:18]([NH:26][C:27]([NH:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([CH3:17])=[CH:11][C:12]=1[Br:16])=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cc(Br)c(N)cc1OCc1ccccc1
Solvent: CC(C)=O
Product: Cc1cc(Br)c(NC(=S)NC(=O)c2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 5-benzyloxy-2-bromo-4-methyl-phenylamine (0.50 g, 1.71 mmol) in acetone (20 mL) was added benzoylisothiocyanate (0.28 mL, 2.08 mmol) dropwise at room temperature. The resulting reaction mixture was stirred for 30 min. at the same temperature. After completion of reaction (TLC monitoring), acetone was distilled off, the solid residue was stirred in hexane for 5-10 min and then filtered to obtain the desired product as white solid (0.70 g, 88%). 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 5.10 (s, 2H), 7.33 (m, 1H), 7.40 (t, J=7.20 Hz, 2H), 7.48 (d, J=7.60 Hz, 2H), 7.55 (m, 3H), 7.67 (m, 1H), 7.73 (s, 1H), 8.0 (d, J=7.20 Hz, 2H), 11.81 (br s, 1H) and 12.59 (br s, 1H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[H-].[Na+].[CH2:36](Br)[CH:37]=[CH2:38]>CN(C=O)C>[CH2:38]([O:5][C@@H:4]1[C@@H:6]([CH2:7][OH:8])[O:9][C@@H:1]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@@H:2]1[OH:3])[CH:37]=[CH2:36]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=CCBr
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Adenosine (20 g, 74.84 mmol) was dried over P2O5 under high vacuum at 40° C. for two days. It was then suspended in DMF under inert atmosphere. Sodium hydride (2.5 g, 74.84 mmol, 60% dispersion in mineral oil), stirred at room temperature for 10 minutes. Then allyl bromide (7.14 mL, 82.45 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. DMF was removed under vacuum and residue was washed with ethyl acetate (100 mL). Ethyl acetate layer was decanted. Filtrate obtained contained product. It was then placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 109 (15.19 g, 66%). Rf 0.4, 0.4a ((10% MeOH in CH2Cl2)
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]/[CH2:4][OH:5].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[N+](C1C=CC=CC=1C=O)([O-])=O.Cl>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]/[CH:4]=[O:5]
Reactant: CC(C)=CCC/C(C)=C\CO
Agent: CC(C)[O-]
Agent: Cl
Agent: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)=CCC/C(C)=C\C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
(2Z)-3,7-Dimethyl-2,6-octadien-1-ol (310 mg, 2.0 mmol) was dissolved in benzene (1 mL), added with aluminum isopropoxide (40 mg, 0.1 eq, 0.20 mmol) and 2-nitrobenzaldehyde (390 mg, 1.3 eq, 2.6 mmol) and stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was added with ethyl acetate and made acidic with addition of 2 N hydrochloric acid, and then the organic layer was separated. Subsequently, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain 250 mg (yield: 83%, E:Z=9:10) of the title compound as yellow oil.
Reaction SMILES: N1(C2C[CH2:9][N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)CC2)CCC1.[CH:28]1([N:31]2[CH2:36]CN[CH2:33][CH2:32]2)[CH2:30][CH2:29]1>>[Cl:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:19]2[N:20]=[C:12]([CH2:11][N:8]3[CH2:33][CH2:32][N:31]([CH:28]4[CH2:30][CH2:29]4)[CH2:36][CH2:9]3)[S:13][C:14]=2[N:15]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCN(C4CC4)CC3)sc2n1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using 1-cyclopropylpiperazine in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (117 mg, 56%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:8]=1[CH:9]=O)C>C(O)(=O)C>[CH3:18][O:17][C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:7]2[O:6][C:5]([CH:4]=[O:3])=[CH:9][C:8]=2[CH:11]=1
Reactant: CCOC(COc1c(C=O)cc(OC)cc1OC)OCC
Solvent: CC(=O)O
Product: COc1cc(OC)c2oc(C=O)cc2c1
Yield: 27.9 %

Procedure:
A stirred solution of 39 (1.2 g, 4.0 mmol) in acetic acid (35 mL) was refluxed for 16 h. After cooling, the solution was evaporated to dryness. The crude product was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (2:1) to give 40 (230 mg, 28%) as a white solid. 1H NMR (500 MHz, CDCl3): δ: 9.89 (1H, s, CHO), 7.50 (1H, s, H-3), 6.69 (1H, d, J4,6=2.2 Hz, H-6), 6.64 (1H, d, J4,6=2.2 Hz, H-4), 4.01 (3H, s, OMe), 3.87 (3H, s, OMe). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ: 179.91 (CHO), 153.37 (C-2), 116.10 (C-3), 101.80 (C-6), 94.90 (C-4), 56.20 (OMe), 55.88 (OMe).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.I[CH2:16][CH3:17].[H-].[Na+]>>[CH2:16]([N:11]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:14]=[CH:13][C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:12])[CH3:17]
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCN1C(=O)CCCc2ccc(OC)cc21

Procedure:
As shown in Scheme 3, 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) was alkylated using iodoethane as an alkylating reagent and one equivalent of sodium hydride as a base to provide 1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (9A). A bromination in methanol at ambient temperature using bromine as a brominating agent afforded exclusively 7- bromo regioisomer (10A) which was transformed further employing a catalytic cross coupling methodology. This coupling reaction was conveniently carried out by use of 4-methylpiperazine as a reagent, BINAP as a chelating reagent, palladium acetate as a catalyst in the presence of cesium carbonate as a base.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:31](I)[CH3:32].CN(C)C=O>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:31][CH3:32])=[O:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 6.4 g of 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid, 3.1 g of sodium hydrogencarbonate, 8.6 g of ethyl iodide and 20 ml of N,N-dimethylformamide is heated at 100° C. with stirring for 3 hours. Further, 2.9 g of ethyl iodide and 1 g of sodium hydrogencarbonate are added to the reaction solution, followed by heating at 100° C. for 2.5 hours. After cooling, 200 ml of water is added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed with water, 0.1N hydrochloric acid, and dilute aqueous sodium hydrogen-carbonate solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5 g of ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoate as an oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:18]1([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH:22]=[N:21][CH:20]=[N:19]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N:18]4[CH:22]=[N:21][CH:20]=[N:19]4)=[CH:31][CH:30]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: O=C(c1ccc(-n2cncn2)cc1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=3.86 min; Mass spectrum (ESI+): m/z=424 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:9]2[C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3].I[CH3:20]>>[CH3:20][O:1][CH:2]([C:4]1[C:9]2[C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)c1oc2cccc(C(C)O)c2c1C
Reactant: CI
Product: CCOC(=O)c1oc2cccc(C(C)OC)c2c1C
Yield: 100 %

Procedure:
According to the procedure of (Example 100, Step 1), 0.21 g of ethyl 4-(1-hydroxyethyl)-3-methyl-1-benzofuran-2-carboxylate after heating with iodomethane for 8 days provided 0.22 g of ethyl 4-(1-methoxyethyl)-3-methyl-1-benzofuran-2-carboxylate. Yield: ˜100% m.p. 67-69° C.; MS: 263.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[Mg].II.[C:22](OC(=O)C)(=[O:24])[CH3:23].[Cl-].[NH4+]>CCOCC>[C:9]1([CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:22](=[O:24])[CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: BrCCCCCOCc1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(=O)CCCCCOCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[[(5-Bromopentyl)oxy]methyl]naphthalene (9.96 g) in dry ether (40 ml) was added to magnesium turnings (0.94 g) and iodine (one small crystal) under nitrogen with stirring at a rate which maintained a gentle reflux. The mixture was stirred at reflux for 30 min, cooled to ambient temperature and added over 2.5 h to acetic anhydride (7.67 ml) in ether (15 ml) at -78° under nitrogen with vigorous stirring. After 2 h at -78°, the mixture was allowed to warm to -10° and treated with aqueous saturated ammonium chloride (50 ml). Ether (50 ml) was added, the aqueous layer was separated and the ethereal layer was washed with 1M-aqueous sodium hydroxide (100 ml). The combined aqueous washings were extracted with ether (100 ml) and this extract was combined with the ethereal layer above. The dried ethereal solution was evaporated and the residual oil purified FCC. Elution with ether-cyclohexane (1:4) gave, after Kugelrohr distillation, the title compound as a colourless oil (3.39 g), b.p. 190°/0.3 Torr (Kugelrohr).
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:32]=4)[CH:27]4[CH2:29][CH2:28]4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:46](Cl)(=[O:50])[CH:47]([CH3:49])[CH3:48]>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:26]([CH:27]2[CH2:29][CH2:28]2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:46](=[O:50])[CH:47]([CH3:49])[CH3:48])[CH2:20][NH:19][CH2:24]2)=[O:44])=[CH:32][C:33]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43]
Reactant: CC(C)C(=O)Cl
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1Cl
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C(C)C)C2)C2CC2)ccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{[4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 92A.) and isobutyryl chloride. MS: 466.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.04 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CC(NCCc3ccccc3)CCC2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCCC(NCCc3ccccc3)C2)cc1
Reaction time: 3 h

Procedure:
A mixture of (RS)-[3-(4-methoxy-phenyl)-cyclohex-2-enyl]-phenethyl-amine (1.5 g, 4.88 mmol), 10% Pd/C (0.3 g) and MeOH (30 ml) was hydrogenated for 3 h. Removal of the catalyst, evaporation of the solvent and separation of the isomers by flash-chromatography over SiO2 (Biotage 40, 90 g) eluting with AcOEt gave (1RS,3SR)-[3-(4-methoxy-phenyl)-cyclohexyl]-phenethyl-amine (0.57 g, 38%, light yellow oil, MS: m/e=310.2 (M+H+)) and (1RS,3RS)-[3-(4-methoxy-phenyl)-cyclohexyl]-phenethyl-amine (0.25 g, 17%, light yellow oil, MS: m/e=310.2 (M+H+)).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:19][CH:18]=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]12([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH3:16])[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCNCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)CCCCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCCCc1ccncc1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
N,N-Dimethylformamide (8.4 ml) was added to a mixture of 2-(1-adamantyl)-N-propylethylamine (Intermediate No. 1-6) (0.37 g, 1.7 mmol) and 5-(4-pyridyl)valeric acid (Intermediate No. 5-1) (0.30 g, 1.7 mmol), and the whole was stirred at room temperature. N-Methylmorpholine (0.27 ml, 2.5 mmol) and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2.0 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate (20 ml) was added to the residue, and the whole was washed with a saturated aqueous sodium hydrogencarbonate-solution (20 ml) and saturated brine (5 ml) successively. The organic layer was dried over sodium sulfate, and ethyl acetate was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography to give 0.21 g (33%) of the titled compound as a colorless oily matter.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C@@H:16]3[C@@H:12]([CH2:13][O:14][CH2:15]3)[O:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[CH:20]1([CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=2)[CH2:22][CH2:21]1>>[NH2:17][C:10]1[O:11][C@H:12]2[C@@H:16]([C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH:20]5[CH2:22][CH2:21]5)=[CH:30][N:29]=4)=[O:32])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=1)[CH2:15][O:14][CH2:13]2
Reactant: O=C(O)c1ccc(OCC2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC4CC4)cn3)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21

Procedure:
The coupling of (3aS,7S,7aS)-7-(5-amino-2-fluoro-phenyl)-7-methyl-3,3a,7,7a-tetrahydro-1H-2,4-dioxa-6-aza-inden-5-ylamine and 5-cyclopropylmethoxy-pyridine-2-carboxylic acid (prepared as described in Scott, J. et al., WO 2011/044181) following procedure G yielded the title compound as a colorless solid. MS: m/z=441.3 [M+H]+.