Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(NC(C)C)(C)C.[F:20][C:21]([F:64])([F:63])[C:22]1[CH:23]=[C:24]([C@H:32]2[O:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[C:44]([N:45]([CH2:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:51][CH2:50]4)[CH2:46][CH3:47])=[CH:43][CH:42]=[CH:41][N+:40]=3[O-])[C@H:33]2[CH3:62])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:20][C:21]([F:64])([F:63])[C:22]1[CH:23]=[C:24]([C@H:32]2[O:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[C:44]([N:45]([CH2:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:51][CH2:50]4)[CH2:46][CH3:47])=[CH:43][CH:42]=[C:41]([Cl:1])[N:40]=3)[C@H:33]2[CH3:62])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc[n+]([O-])c2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(Cl)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphosgene (360 mg, 1.21 mmol) and diisopropylamine (123 mg, 170 μL, 1.21 mol) were added successively to a stirred solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-1-oxidopyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate (156.6 mg, 0.243 mmol) in dry CH2Cl2 (9 mL) at −20° C. under N2. The reaction was stirred at room temperature for 6 h. Additional triphosgene (360 mg, 1.21 mmol) and diisopropylamine (123 mg, 170 μL, 1.21 mmol) were added successively and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-60% EtOAc in hexanes gradient) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. Rf=0.32 (20% EtOAc/hexanes). LCMS calc.=664.2; found=664.4 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 7.87 (s, 1 H); 7.81 (s, 2 H); 7.41 (d, J=8.4 Hz, 1 H); 7.19 (d, J=8.4 Hz, 1 H); 5.83 (d, J=8.4 Hz, 1 H); 4.97 (d, J=16.9 Hz, 1 H); 4.47-4.43 (m, 1 H); 4.29 (d, J=16.9 Hz, 1 H); 4.12-4.06 (m, 2 H); 2.98-2.88 (m, 2 H); 2.81-2.74 (m, 2H); 2.13 (d, J=6.8 Hz, 2 H); 1.84-1.68 (m, 5 H); 1.36-1.24 (m, 1 H); 1.22 (t, J=7.1 Hz, 3 H); 0.99 (t, J=7.0 Hz, 3 H); 0.95-0.81 (m, 4 H); 0.73 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]=[O:25])[C:21]([OH:26])=[C:20]([C:27]([O:29][CH3:30])=[O:28])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].B.[Na]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][OH:25])[C:21]([OH:26])=[C:20]([C:27]([O:29][CH3:30])=[O:28])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cc(C=O)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Agent: B
Agent: [Na]
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CO)c(O)c(C(=O)OC)c3)cs2)cc1OCC
Yield: 99.5 %

Procedure:
In 20 ml of methanol was suspended 300 mg of 2-(3,4- diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylphenyl)thiazole with stirring. Threto was added 26.5 mg of sodium boron hydride at 0° C. The mixture was stirred at room temperature for 1 hour. 26.5 mg of sodium boron hydride was further added, and the resulting mixture was stirred at the same temperature for 1 hour. The solvent was removed from the reaction mixture by distillation. To the residue were added 30 ml of dichloromethane and 15 ml of water, and phase separation was conducted. The organic layer was washed with 10 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent to obtain 300 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-hydroxymethylphenyl)-thiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.C([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25]([OH:27])[CH:26]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1(SC)C=CC=CC=1>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:27][C:25]1[CH:26]=[C:21]([OH:20])[CH:22]=[CH:23][C:24]=1[CH3:28]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CSc1ccccc1
Solvent: CC#N
Product: Cc1ccc(O)cc1Oc1ccnc2ccc(Br)cc12
Temperature: 150 °C
Yield: 47 %

Procedure:
141 mg (0.58 mmol) of 6-bromo-4-chloroquinoline and 150 mg (0.7 mmol) 5-(benzyloxy)-2-methylphenol in 5 ml acetonitrile are mixed with 97 mg (0.7 mmol) of potassium carbonate and heated in the microwave oven to 150° C. for 3 h. The mixture is diluted with water and then extracted with ethyl acetate. The organic layers are washed with brine and dried over sodium sulfate. The solvent is evaporated and the resulting residue is dissolved in 5 ml TFA. 54 mg (0.44 mmol) thioanisole is added and the mixture is stirred over night. The solvent is evaporated, the resulting residue is dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layers are dried over sodium sulfate, the solvent is evaporated and the resulting residue is purified by preparative HPLC. 90 mg (46%) of the desired product are obtained
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:7](=O)[CH:8]([CH3:10])[CH3:9].C1CCCCC1>O>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][NH:6][CH:7]1[CH:8]([CH3:10])[CH3:9]
Reactant: CNCCCN
Reactant: CC(C)C=O
Solvent: C1CCCCC1
Solvent: O
Product: CC(C)C1NCCCN1C

Procedure:
530 g of N-methyl-1,3-diaminopropane are slowly added dropwise to a mixture of 650 ml of isobutyraldehyde and 400 ml of cyclohexane cooled with ice. When the exothermic reaction has died down, the reaction mixture is boiled under reflux on a water separator until approximately 108 ml of water have been separated. Cyclohexane and isobutyraldehyde are distilled off at reduced pressure. Fractional distillation of the residue (b.p.15 : 68° to 75° C.) yields 680 g of 1-methyl-2-isopropylhexahydropyrimidine.
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:21])[CH2:11][N:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:13][CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O([CH2:30][CH3:31])S(C(F)(F)F)(=O)=O.[Cl-:32].FF>C(Cl)Cl.CO.O>[Cl-:32].[C:1]([O:9][CH:10]([CH3:21])[CH2:11][N+:12]([CH2:30][CH3:31])([CH2:13][CH3:14])[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC(C)OC(=O)c1ccccc1)C1CCCCC1
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: FF
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC[N+](CC)(CC(C)OC(=O)c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(cyclohexyl(ethyl)amino)propan-2-yl benzoate (0.427 g, 1.47 mmol) in dry DCM (20 mL) was added ethyl triflate (0.25 mL, 1.92 mmol) dropwise at ice-cold conditions. The resulting mixture was stirred at rt for 16 hours in a sealed tube. The reaction mixture was concentrated and the crude material was purified by Combiflash chromatography eluting with 3-4% methanol/DCM to provide a sticky liquid. Amberlite® IRA-400 (Cl) chloride form resin (3.0 g) was added to a solution of the liquid compound in methanol (15 mL) and stirred for 6 hours. The solution was then filtered, concentrated and lyophilized to provide a solid. Because the fluorine NMR spectrum showed incomplete counter ion exchange, the solid was again treated with Amberlite® IRA-400 (Cl) chloride form resin in water and filtered. The filtrate was concentrated and the crude material was lyophilized to provide N-[2-(benzoyloxy)propyl]-N,N-diethylcyclohexanaminium chloride as an off white solid. Yield: 0.05 g (9.62%). 1H NMR (DMSO-d6) δ 7.98 (d, J=8 Hz, 2 H), 7.68 (t, J=7 Hz, 1 H), 7.54 (t, J=8 Hz, 2 H), 5.52-5.49 (m, 1 H), 3.95-3.89 (m, 1 H), 3.55 (d, J=15 Hz, 1 H), 3.44-3.35 (m, 5 H), 2.19-2.17 (m, 1 H), 2.09-2.06 (m, 1 H), 1.80-1.78 (m, 2 H), 1.54-1.51 (m, 3 H), 1.36 (d, J=6 Hz, 3 H), 1.25-1.07 (m, 9 H). LCMS: m/z=318.0 [M+], RT=2.88 min, (Column: Y, Program: P1). UPLC: 98.70% (200 nm), RT=3.59 min, (Mobile Phase A. 0.05% TFA in water, B. Acetonitrile; Column: Zorbax® SB-C18 (4.6×50 mm) 1.8μ)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20].[H][H]>C(#N)C.[Ni]>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH2:15][CH2:14][O:13][CH3:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: COCCNCCOC
Agent: [Ni]
Solvent: CC#N
Product: COCCN(CCOC)c1ccc(Cl)cc1N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene (35.1 mg, 0.2 mmol) and N,N-bis(2-methoxyethyl)amine (0.266 g, 2.4 mmol) in acetonitrile (10 mL) in a capped 20-mL-vial was shaken at 80° C. overnight and concentrated. The concentrate was dissolved in methanol (10 mL), treated with Raney nickel (50% water suspension, 0.40 g, 6.8 mmol), filled with excess hydrogen, shaken at 50° C. for 1 hour, and filtered. The filtrate was concentrate and the concentrate was purified by HPLC with acetonitrile/water containing 0.1% TFA to provide the desired product. MS (APCI(+)) m/z 260 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+].C(OP([CH:31]=[C:32]1[NH:38][CH2:37][CH2:36][N:35]([CH3:39])[C:34]2[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:33]1=2)(=O)OCC)C.[H-].[Na+]>CN(C)C=O>[ClH:10].[ClH:10].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[CH:31][C:32]2=[N:38][CH2:37][CH2:36][N:35]([CH3:39])[C:34]3[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:33]2=3)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=Cc1ccccc1F
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(F)ccc21)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN=C(C=Cc2ccccc2Oc2ccc(Cl)cc2)c2ccc(F)cc21
Product: Cl
Temperature: 95 °C
Reaction time: 2 h
Yield: 9.8 %

Procedure:
To a mixture of 56 mg (0.45 mmol) of 2-fluorobenzaldehyde and 64 mg (50 mmol) of 4-chlorophenol in 2.5 ml of dimethylformamide was added 75 mg (0.54 mmol) of sodium hydrogen carbonate. The mixture was heated at 95° C. for 18 hours. To the mixture at ambient temperature was added 118 mg (0.36 mmol) of (8-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester followed by 25 mg (0.63 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 2 hours. The mixture was partitioned between 12 ml of water and 3×4 ml of dichloromethane. The combined organic portions were dried (magnesium sulphate), filtered and evaporated. The product was purified by column chromatography (20 g IST pre-packed column) eluting with ethyl acetate and treated with 0.15 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated to leave a red gum which was recrystallised from acetone/ethyl acetate/diethyl ether to give 17 mg of (E)-5-[2-(4-chlorophenoxy)styryl]-8-fluoro-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine dihydrochloride as a red solid; MS: m/e 452 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:31])[NH:29][NH2:30])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:30][NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:14]
Reactant: COC(=O)CCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.81 g (50 mmol) of sebacic acid monomethyl ester is dissolved in tetrahydrofuran and successively mixed with 8.32 ml (60 mmol) of triethylamine and 5.28 ml (55 mmol) of chloroformic acid ethyl ester [ethyl chloroformate] at -5° C.. After 15 minutes 6.61 g (50 mmol) of tert-butylcarbazate in tetrahydrofuran is instilled at this temperature and then stirred at room temperature for 2 hours. The precipitate is suctioned off, the filtrate is concentrated by evaporation and taken up in ethyl acetate. The organic phase is successively washed with NaHCO3 solution, citric acid and water and dried on Na2SO4. The oil obtained after concentration by evaporation of the ethyl acetate is chromatographed on silica gel in diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])O[C:8](=[O:9])[C:7]=12.[CH:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([NH2:23])[CH:17]=1>CN1CCCC1=O>[C:18]1([N:23]2[C:8](=[O:9])[C:7]3=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]3[C:11]2=[O:12])[CH:19]=[CH:20][C:21]([N:22]2[C:11](=[O:12])[C:6]3=[C:5]([Cl:13])[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]3[C:8]2=[O:9])=[CH:16][CH:17]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: CN1CCCC1=O
Product: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1c1ccc(N2C(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c3C2=O)cc1
Temperature: 200 °C
Yield: 52.9 %

Procedure:
In a 5 liter round-bottom flask equipped with a heating mantle, a stirrer, a thermometer, a condenser and a nitrogen purge, there were reacted 457.5 gms (1.6 mole) of tetrachlorophthalic anhydride and 86.5 gms (0.8 mole) of p-phenylenediamine in 2000 ml. of N-methyl-2-pyrrolidone (NMP), the reactants going into solution as the mixture was heated with stirring. At 170° C., precipitation began and continued as the temperature was raised to 200° C. where it was maintained for 90 minutes. The reaction mixture was then allowed to cool overnight. The cooled mixture was filtered and the yellow precipitate was recovered. The precipitate was washed with NMP, thoroughly stirred in acetone, filtered and washed with more acetone. The product was dried under vacuum at 150° C. for 16 hours. 272.7 gms (yield=53%) of an ivory-yellow material was obtained, having a melting point in excess of 500° C., with one sublimation at about 425° C. The IR spectrum had the characteristics of an imide with the absorption bands at 1710s and 1770w cm-1. The product was insoluble in water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+].CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of 3,5-dibromopyridine (134a, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and then 21.3 mL of sodium methoxide (25% by wt. in methanol (92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under N2. The reaction was cooled to RT and quenched with water (200 mL) and extracted with Et2O (2×200 mL). The combined organic extracts was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude 3-bromo-5-methoxypyridine (134b 14.8 g, 93% theory) afforded a colorless oil after purification by flash chromatography on silica gel (EtOAc:hexane 1:10).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:34]3[S:30][C:31](=[O:36])[NH:32][C:33]3=[O:35])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCc1ccc(C(COc2ccc(C=O)cc2)S(=O)(=O)c2ccc(C)cc2)nc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCc1ccc(C(COc2ccc(C=C3SC(=O)NC3=O)cc2)S(=O)(=O)c2ccc(C)cc2)nc1
Temperature: 125 °C

Procedure:
To 1 g (0.0023 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-tosyl-ethoxy]-benzaldehyde dissolved in 15 mL toluene was added 0.27 g (0.0023 mol) thiazolidin-2,4-dione. To this 0.21 g (0.0035 mol) acetic acid and 0.3 g (0.0035 mol) piperidine were added. Reaction mixture was refluxed at 120-130° C. for 4 hr. After completion of reaction on TLC, substantial work-up gave the titled product. Yield of the product was 0.36 g (30%).
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH3:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].O.NN.C(O)COCCO.[OH-].[K+]>C(O)C>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)[CH2:19][CH3:20]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(C(=O)CC)cc2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: OCCOCCO
Solvent: O
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(CCC)cc2)CC1
Temperature: 200 °C
Reaction time: 2 h

Procedure:
A mixture of 235 mg of p-[trans-4-(trans-1-pentenyl)cyclohexyl]propiophenone (prepared according to Example 1), 0.161 ml of hydrazine hydrate, 5 ml of diethylene glycol and 5 ml of ethanol was heated to reflux for 30 minutes under an argon atmosphere in a round flask provided with a reflux condenser. The mixture was then treated with 195 mg of solid potassium hydroxide and subsequently gradually heated to 200° C., while distilling off the ethanol, and held at this temperature for 2 hours. The cooled mixture was poured into 50 ml of water and extracted three times with 50 ml of petroleum ether each time. The organic phases were washed three times with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue with hexane on a short column of silica gel gave 185 mg (83%) of 4-propyl-1-[trans-4-(trans-1-pentenyl)cyclohexyl]benzene as a colourless liquid; purity 98.6%, m.p. (C-I) 7.0° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH:21]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH2:24]1)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])(=O)C.[OH-].[Na+]>CO.O1CCCC1.O>[CH2:32]([O:31][C:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH:21]([N:7]([CH2:6][CH2:5][OH:4])[S:8]([C:11]2[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:9])=[O:10])[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH2:28][CH2:27]1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(CC(CN2CCN(C(=O)OCc3ccccc3)CC2)N(CCOC(C)=O)S(=O)(=O)c2cccc3cnccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(CN2CCN(C(=O)OCc3ccccc3)CC2)N(CCO)S(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
600 mg of the amorphous compound obtained in Example 138 was dissolved in 6 ml of methanol and 3 ml of tetrahydrofuran, to the solution was added 6 ml of 1N sodium hydroxide aqueous solution, and the mixture was stirred at a room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with 50 ml of chloroform, and the extract was washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. Resulting oil was applied to a silica gel column and eluted with chloroform/methanol (100:1 to 50:1) to obtain 403 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1.CO>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3Cl)n2)CC1
Yield: 85.2 %

Procedure:
Mix 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.223 g) and 2-chlorobenzoyl chloride (0.175 g) in 1,4-dioxane (10 mL) and heat at reflux for 1 hour. Dilute with methanol (10 mL) and load on a SCX column (10 g). Wash the column with methanol, elute the product with 2 M NH3 in methanol, evaporate and purify the product on a silica gel column (CH2Cl2 with 2 M NH3 in methanol) to obtain 0.305 g (84%) of the title compound: mass spectrum (electric spray) m/z=358 (M+1) and 360 (M+2+1); 1H NMR (CDCl3): 8.60 (br s, 1H), 8.54 (d, 1H), 7.90 (dd, 1H), 7.81 (d, 1H), 7.76 (dd, 1H), 7.45 (m, 3H), 3.63 (m, 1H), 2.90 (m, 2H), 2.29 (s, 3H), 2.07 (m 2H), 1.85 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]([CH2:19][CH3:20])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C1COCC1.C(O)(=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([N:17]([CH2:19][CH3:20])[CH3:18])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CCN(C)c1nc(Cl)nc2c1CCC2c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(C)c1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
2-Chloro-N-ethyl-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (160 mg, 0.556 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (124 mg, 0.556 mmol) in THF (1.5 mL) and acetic acid (1.5 mL). The reaction mixture was stirred overnight at 80° C. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (85.3 mg, 0.171 mmol, 30.7% yield). LC-MS (M+H)+=475.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.49-7.61 (1H, m), 7.38 (1H, br. s.), 7.23-7.34 (6H, m), 7.13 (1H, d, J=8.5 Hz), 7.05 (1H, s), 4.35 (1H, dd, J=9.3, 4.1 Hz), 3.69-3.82 (4H, m), 3.47 (2H, br. s.), 3.27-3.38 (4H, m), 3.11-3.23 (1H, m), 2.56-2.72 (1H, m), 2.24 (1H, ddd, J=9.0, 4.4, 4.3 Hz), 1.31 (3H, t, J=7.2 Hz).