Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CO.[CH3:19][NH2:20]>CO>[CH3:19][NH:20][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Reactant: CN
Solvent: CO
Product: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 98 %

Procedure:
Tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (3.13 g, 12.58 mmol) was dissolved in methanol (20 ml), to which 40% methylamine methanol solution (30 ml) was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The mixture was washed with saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(2-methylaminoethyl)piperazine-1-carboxylate (3.0 g, yield 98%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:10][C:5]1[CH:6]=[C:7]([C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(N)cc1C#N
Reaction time: 1 h

Procedure:
A suspension of 8.11 g (50 mmol) of 6-methyl-3-nitro-benzonitrile and 0.81 g of 10% of palladium-on-charcoal in 50 ml of ethanol and 50 ml of ethyl acetate is hydrogenated under 2.9 bar for 1 hour. The catalyst is filtered off, the filtrate is concentrated and the residue is crystallised from ether/petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:17]N1C(=O)CCC1=O.C([O-])(=O)C.[K+]>CN(C)C=O>[Br:17][C:9]1[O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncnc2occ(-c3ccccc3)c12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2oc(Br)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To 4-amino-5-phenylfuro-[2,3-d]pyrimidine (2.3 g, 10.8 mmol) dissolved in dimethylformamide (100 mL) was added N-bromosuccinimide (2.0 g, 11.2 mmol) and potassium acetate (1.1 g, 11.2 mmol). The resulting solution was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (25% acetone/hexane) to give the product as a pale solid (2.0 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].CCOC(C)=O>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 5-bromo-3-iodopyridin-2-amine (B-7-1) (20 g, 66.9 mmol) in Et3N (200 mL) was added CuI (1.27 g, 6.69 mmol), and the resulting mixture was degassed with N2 for 2 minutes. Then Pd(PPh3)2Cl2 (1.4 g, 20.1 mmol) was added and the mixture was degassed again. Then ethynyl-trimethyl-silane (7.2 g, 73.6 mmol) was added dropwise into the mixture at 0° C. The mixture was stirred at room temperature for 4 hours. TLC (Petroleum ether: EtOAc=5:1) showed that the reaction was complete. The mixture was evaporated under reduced pressure to give crude mixture which was purified via a silica gel column eluted with petroleum ether/EtOAc (20:1) to afford 5-bromo-3-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (B-7-2) (10 g, 55.6%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([CH3:17])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc(C)cc2)c1
Yield: 79.3 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (2.0 g, 7.23 mmol) in dioxane (10 ml) was added to a mixture of 4-methylaniline (0.77 g, 7.23 mmol) in dioxane (20 ml) and NaHCO3 (1.2 g, 14.5 mmol) in water (20 ml), and the resultant solution was stirred at room temperature for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with dichloromethane-ethyl acetate (20:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (1.9 g, 79%). 1H NMR (DMSO-d6, HMDSO), δ: 2.16 (3H, s); 3.69 (3H, s); 6.65 (1H, d, J=16.0 Hz); 7.00 (4H, s); 7.49–8.11 (5H, m); 10.14 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH2:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1ccc(C(=O)Nc2ccc3c(c2)CCCC3=O)cc1
Yield: 90 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (100 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-4-propyl-benzamide (140 mg, 0.45 mmol, 90% yield) as a white powder after purification by flash chromatography on silica gel (eluent :EtOAc/hexane 2/8 to 4/6).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[Na+]>[CH:1]1([CH2:7][N:8]2[C:13]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:18][CH2:17]3)=[N:12][NH:11][C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(CCC(=O)NNC(=O)NCC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1N1CCN(CCc2n[nH]c(=O)n2CC2CCCCC2)CC1
Yield: 57.4 %

Procedure:
A suspension of N-(cyclohexylmethyl)-2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-1-hydrazinecarboxamide D4 (0.40 g, 0.96 mmol) in 2M NaOH aqueous solution (10 mL) was heated at reflux for 7 hrs. The resulting precipitate was filtered, washed with water and diethyl ether to afford 0.22 g (57%) 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one E17 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[B-](F)(F)(F)[F:24].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([F:24])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(C(=O)OC(C)(C)C)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To a solution of 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)malonate 45A (86.5 g, 288 mmol) in THF (2400 mL) was added NaH (12.65 g, 316 mmol). The reaction was stirred at 0° C. for 15 min. A cloudy solution of Selectfluor (112 g, 316 mmol) in DMF (dry, 800 mL) was added drop-wise at 0° C. and then the reaction was allowed to warm to ambient temperature over a 2 hrs. The reaction was then quenched with saturated NH4Cl (250 mL) and reduced in volume to about 1500 mL. To this mixture, Et2O (300 mL) and water (50 mL) were added. Layers were separated, and the aqueous layer was extracted with Et2O (3×300 mL). The combined organic layers were then washed with saturated NaHCO3 solution (3×150 mL), dried with MgSO4, filtered, and concentrated to dryness via rotary evaporation. The residue was purified via MPLC (Hex:EtOAc, 8:2) to provide 1-tert-butyl 3-ethyl 2-(6-chloropyridazin-3-yl)-2-fluoromalonate 45B (70.2 g, 220 mmol, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.20 Hz, 3 H) 1.46 (s, 9 H) 4.28-4.43 (m, 2 H) 8.14 (s, 2 H). ESI-MS:m/z 319.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[CH2:21][C:22]1[N:26]=[C:25](S(C2C=CC(C)=CC=2)(=O)=O)[S:24][N:23]=1>C(#N)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[CH2:21][C:22]1[N:26]=[C:25]([O:9][C:7]2[C:6]([CH3:10])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=2)[S:24][N:23]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Cc1ccc(S(=O)(=O)c2nc(Cc3cccc(Cl)c3)ns2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Oc2nc(Cc3cccc(Cl)c3)ns2)c(C)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
3.86 g (28.1 mmol) of 2,5-dimethyl-4-hydroxyaniline are placed in 50 ml of acetonitrile, 4.66 g (33.8 mmol) of potassium carbonate are added at ambient temperature and the mixture is stirred for 30 min at ambient temperature. Subsequently, 11.0 g (28.1 mmol) of 3-(3-chlorobenzyl)-5-[(4-methylphenyl)sulphonyl]-1,2,4-thiadiazole are added and the reaction mixture is stirred at 50° C. for 12 h. After cooling, the mixture is concentrated using a rotary evaporator and the residue is taken in dichloromethane, extracted twice with water, dried over Na2SO4 and freed from the solvent under vacuum. 6.86 g of product are obtained (96.4% purity, 68.0% yield, log P (pH 2.3)=3.68).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1Br)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[Br-].[CH:20]1([Zn+])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:5]([OH:7])=[O:6]
Reactant: [Zn+]C1CCCC1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.45 g (1.45 mmol) of benzyl 3-fluoro-4-bromobenzoate (0.45 g, 1.45 mmol) in 4.4 mL of 0.5 M cyclopentylzinc bromide solution in THF was treated with ˜5 mg of bis(tri-t-butylphosphine)palladium(0) and the resulting mixture was stirred at rt for 24 h. The reaction mixture was directly purified on a Biotage 40S cartridge using 1:1 hexanes/EtOAc as the eluant. A mixture of the resulting solid (0.27 g, 0.91 mmol) and 10% Pd/C in 5 mL of MeOH was stirred under 1 atm of H2 for 3 h. The reaction was filtered and concentrated. Purification by HPLC B afforded the title compound: 1H NMR δ 1.58-1.90 (m, 6H), 2.05-2.14 (m, 2H), 3.30 (m, 1H), 7.36 (t, J=7.7, 1H), 7.72 (dd, J=1.6, 10.5, 1H), 7.83 (dd, J=1.6, 8.0, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.[Br-]>CN(C=O)C.O>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:29][CH:28]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)OCC
Temperature: 0 °C
Yield: 84.8 %

Procedure:
60% mineral oil suspension of sodium hydride (1.454 g; 36.3 mmol) was added into anhydrous DMF (50 mL) under nitrogen at 0° C. Diethyl malonate (5.82 g; 36.3 mmol) was added to the stirred suspension over 10 min and the mixture was then stirred rapidly at 0° C. until a clear pale yellow solution was obtained. 4-(bromomethyl)benzophenone (5.00 g; 18.2 mmol) in DMF (15 mL) was added dropwise over 5 min and the reaction mixture was stirred for 16 h at ambient temperature. Complete conversion of the starting bromide was confirmed by TLC. The reaction was diluted with water (400 mL) and extracted with dichloromethane (3×50 mL). The organic phase was separated, dried and evaporated to an oily residue. Chromatography on silicagel (eluent hexane/2-butanone 10:1→5:1) provided the desired 1,3-diethyl 2-[(4-benzoylphenyl)methyl]propanedioate (5.47 g; 86%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[NH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=2)=O)=[CH:7][CH:6]=1)=[O:4].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([C:10]2[S:41][C:13]([C:15]3[NH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)[nH]2)[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(-c3ccc(C(=O)OC)[nH]3)s2)[nH]1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A mixture of compound 4 (1.73 g, 5.2 mmol), dry toluene (75 mL), and Lawesson's reagent (1.50 g, 3.7 mmol) was refluxed under an argon atmosphere for 12 hours. The solution was cooled to room temperature and concentrated to one-third its original volume in vacuo. Methanol was added slowly to the toluene until a precipitate appeared. Column chromatography was performed using pure CH2Cl2 (silica gel; 230-400 mesh) as the initial eluant to remove impurities. Conversion to a 50:50 hexanes:EtOAc eluant system yielded 0.86 g (2.6 mmol, 50%) of a yellow solid. 1H-NMR (CDCl3): δ 7.70 (s, 1H), 6.96 (dd, 1H), 6.52 (dd, 1H), 3.93 (s, 3H). 13C-NMR: δ 161.8, 134.0, 132.4, 125.7, 124.0, 117.8, 109.2, 52.2.
Reaction SMILES: [F:1][C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2.[Br:20]Br>C(OCC)(=O)C>[Br:20][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH2:3][C:2]([F:19])([F:1])[C:15]([F:16])([F:17])[F:18])[CH:6]=2)[C:10]1=[O:14]
Reactant: O=C1CCc2cc(OCC(F)(F)C(F)(F)F)ccc21
Reactant: BrBr
Solvent: CCOC(C)=O
Product: O=C1c2ccc(OCC(F)(F)C(F)(F)F)cc2CC1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.9 g of 5-(2,2,3,3,3-pentafluoropropoxy)-1-indanone are dissolved in 100 ml of ethyl acetate, and a solution of 3.9 g of bromine in 15 ml of ethyl acetate is added dropwise. The solution is briefly heated to reflux before the remainder of the bromine solution is added dropwise. It is then stirred at room temperature for 2 h. The reaction solution is concentrated in vacuo and affords 2-bromo-5-(2,2,3,3,3-pentafluoropropoxy)-1-indanone as an oil which is employed without further purification in the next stage.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10]Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br-:12].[Li+]>C(#N)C>[N:1]1([C:7]([O:9][CH2:10][Br:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(OCCl)N1CCOCC1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: O=C(OCBr)N1CCOCC1
Temperature: 90 °C
Yield: 80.2 %

Procedure:
Chloromethyl morpholine-4-carboxylate [6316] (0.3 g, 1.67 mmol, 1.0 eq) and lithium bromide (0.72 g, 8.3 mmol, 5.0 eq) was taken in acetonitrile (10 ml). The reaction was refluxed at 90° C. for 30 h. Reaction progress was monitored by TLC/1H NMR. The reaction was filtered off and filtrate was evaporated to dryness under reduced pressure to yield light brown gel, bromomethyl morpholine-4-carboxylate [6327](0.30 g, 80%)
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([O:18]CC)=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>O>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([OH:18])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Yield: 68.6 %

Procedure:
Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (2.8 g.) and a solution of sodium hydroxide (0.54 g.) in water (20 ml.) were treated according to a similar manner to that of Preparation (6-5) to give brown powder of 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (1.75 g.).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[CH2:3]1.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C@@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:15])[F:16])[CH2:5][CH2:6][N:7]1[S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:18](=[O:20])[CH3:19])=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: C[C@@H]1CN(c2ccccc2C(F)(F)F)CCN1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ccccc3C(F)(F)F)C[C@H]2C)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a stirred solution of (R)-3-methyl-1-(2-trifluoromethyl-phenyl)-piperazine (500 mg, 2.05 mmol) and 4-acetylbenzenesulfonyl chloride (448.23 mg, 2.05 mmol) in anhydrous dichloromethane (6 mL) was added diisopropylethylamine (0.71 mL, 4.1 mmol). The mixture was stirred at room temperature for over night. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to yield (R)-1-{4-[2-methyl-4-(2-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-phenyl}-ethanone in 74.0% yield (646.7 mg) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.20 (d, J=6.57 Hz, 3H) 2.67 (s, 3H) 2.75-2.83 (m, 2H) 2.98 (d, J=10.11 Hz, 1H) 3.06 (d, J=10.11 Hz, 1H) 3.33-3.43 (m, 1H) 3.76 (d, J=10.61 Hz, 1H) 4.26 (d, J=6.82 Hz, 1H) 7.23-7.30 (m, 2H) 7.52 (t, J=7.71 Hz, 1H) 7.62 (d, J=8.08 Hz, 1H) 7.89-7.99 (m, 2H) 8.07-8.14 (m, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1ccc(CBr)cc1
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)OCC
Yield: 41.8 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (13.6 g) and 4-chlorobenzyl bromide (17.5 g). This was purified by silica gel column chromatography to give the title compound (10.1 g) as an oil.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[OH:12].[CH2:13]=[C:14]1[O:18][C:16](=[O:17])[CH2:15]1>C(O)C>[CH3:1][N:2]([C@@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[OH:12])[C:16](=[O:17])[CH2:15][C:14]([CH3:13])=[O:18]
Reactant: C=C1CC(=O)O1
Reactant: CN[C@@H]1Cc2ccccc2[C@H]1O
Solvent: CCO
Product: CC(=O)CC(=O)N(C)[C@@H]1Cc2ccccc2[C@H]1O
Reaction time: 1 h

Procedure:
To a solution of trans-2-methylamino-1-indanol (4.9 g, 0.03 m) in 100 ml of ethanol was added 2.8 g (0.033 m) of diketene. After stirring about 1 hour the mixture was concentrated to dryness in vacuo. The residue was dissolved in acetonitrile and the solvent was evaporated in vacuo to 6.3 g (85%) of an oily residue which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34]O)[CH2:30][CH2:29]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1>>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][O:14][C:13]([C:7]4[CH:8]=[N:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)=[O:15])[CH2:30][CH2:29]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: OC[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)cc2c1

Procedure:
The title compound is prepared as an off-white semisolid (24 mg, 26% yield) following Scheme 2 and in analogy to Example 28 using 6-methoxy-quinoline-3-carboxylic acid (40 mg, 0.19 mmol, 1.0 eq) and {trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanol (55 mg, 0.19 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[NH:5][CH:4]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:3]=1[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]1[O:47][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:45][CH:44]=1>CN(C)C=O.CO>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:4]2[N:5]([CH2:42][C:43]3[O:47][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:45][CH:44]=3)[C:6](=[O:18])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=3)[C:2]([CH3:1])=[C:3]2[C:27]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:28])=[CH:20][CH:21]=1)#[N:24]
Reactant: CC1=C(C(=O)c2cccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)c3cccnc3)C2c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred suspension of (4-{6-methyl-2-oxo-5-(pyridin-3-ylcarbonyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 21A) (100 mg, 0.22 mmol) and potassium carbonate (60 mg, 0.43 mmol) in dimethylformamide (3 ml) is added methyl 5-(chloromethyl)-2-furoate (57 mg, 0.32 mmol). The suspension is stirred at room temperature for 72 hours. The mixture is diluted with methanol (5 ml) and purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/water 10:90→90:10).