Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][C:32]1[O:33][C:34]([CH:38]=[O:39])=[C:35]([CH3:37])[N:36]=1>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:38]([C:34]3[O:33][C:32]([CH3:31])=[N:36][C:35]=3[CH3:37])[OH:39])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cc1nc(C)c(C=O)o1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.5 g, 3.48 mmol, Intermediate 5: step d) was added THF (65 mL) and the solution was cooled to −70° C. n-BuLi (2.5 M in hexanes, 1.62 mL, 4.04 mmol) was then added dropwise. After 2 minutes, 2,4-dimethyloxazole-5-carbaldehyde (520 mg, 4.16 mmol in 3 mL THF) was introduced. After 25 minutes the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (10% CH3CN-DCM increasing to 30% CH3CN+1% MeOH) provided the title compound as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH3:17][N:18]=[C:19]=[O:20]>O1CCCC1>[CH3:17][NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and poly(4-vinyl pyridine) (50 mg, 0.400 mmol, 2% cross-linked) in tetrahydrofuran (2 mL) were allowed to stand 10 min. Methyl isocyanate (20 μL, 0.344 mmol) was added and the reaction mixture was mixed for 96 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was purified by silica gel chromatography (5% 2M ammonia in methanol:methylene chloride). The solvent was evaporated to give 28.1 mg (89%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].CCO.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](B(O)O)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[N:37][CH:38]=1)[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Reactant: OB(O)c1cncc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cncc2ccccc12
Temperature: 97.5 °C

Procedure:
To a solution of methyl [3,5-bis(trifluoromethyl)benzyl](2-iodo-5-trifluoromethyl-benzyl)carbamate (41 mg, 0.070 mmol) (Example 5) in 3:2 EtOH:toluene, 4-isoquinolineboronic acid (18.2 mg, 0.105 mmol) and 2.5 M sodium carbonate (0.175 mmol) were added. The solution was degassed, followed by the addition of a catalytic amount of tetrakis(triphenylphosphine)palladium. The solution was stirred at 95-100° C. until completion of the reaction. Upon cooling, the solvent was removed in vacuo. The desired product was obtained by preparative thin layer chromatography using 25% acetone/hexane. 1H NMR (CDCl3, 500 MHz) δ 9.36 (s, 1H), 8.38 (s, 1H), 8.10-8.13 (m, 1H), 7.68-7.80 (m, 4H), 7.26-7.64 (m, 5H), 4.22-4.48 (m, 4H), 3.64-3.78 (m, 3H). LC-MS (M+1) 587.2 (3.48 min).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][C:15]#[CH:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][C:15]#[CH:16])=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: C#CCC(N)c1ccccc1N1CCCCC1
Product: C#CCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 47 from 1-(2-piperidino-phenyl)-3-butyn-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([N:9]2[C:13]3=[C:14]4[CH:20]=[CH:19][NH:18][C:15]4=[N:16][CH:17]=[C:12]3[NH:11][C:10]2=[O:21])[CH2:4]1.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC(Cl)C>[O:21]=[C:10]1[N:9]([C@H:5]2[CH2:6][CH2:7][CH2:8][C@H:3]([CH:2]=[O:1])[CH2:4]2)[C:13]2=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=[C:12]2[NH:11]1
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1[C@H]1CCC[C@H](CO)C1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C[C@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 1-[trans-3-(hydroxymethyl)cyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (180 mg) in dichloroethane (2 ml) was added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (293 mg) at 4° C. The mixture was stirred at ambient temperature for 2 hours. To the mixture were added chloroform, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium thiosulfate. The organic layer was separated and extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform:methanol=100:0-85:15 to give trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (50 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[C:8]([NH:15][C@H:16]([CH:24]1[CH2:26][O:25]1)[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O>C1COCC1>[C:8]([NH:15][C@@H:16]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH:24]([OH:25])[CH2:26][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9]
Reactant: Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C1CO1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(O)CCc1ccccn1
Reaction time: 1 h

Procedure:
220 μl of 2-picoline (2 eq) are deprotonated in analogy to Example (6c). Then 300 mg of Boc-2-cyclohexyl-1(S)-oxiran-2(R,S)-ylethylamine in THF are added dropwise at -60° C. After 1 h, H2O is added, and the mixture is extracted 3 times with EA. The organic phases are dried with Na2 so4 and then concentrated, and the title compound is isolated by chromatography on SiO2 with EA/H 2:1 as eluent.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[C:44]1([O:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:49][CH2:48][CH2:47][CH2:46]C1)CCC.C(N(CC)CC)C>C(Cl)Cl>[CH2:51]([O:50][C:44]1([O:1][CH2:2][C:3]2[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=2)[CH2:46][CH2:47][CH2:48][CH2:49]1)[CH2:52][CH2:53][CH3:54]
Reactant: CCCCOC1(OCCCC)CCCCC1
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC1(OCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
To a solution of 2-hydroxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-ethyl-1H-imidazole (19) (345 mg, 1 mmol) prepared in accordance with the method as described in WO 96/10019 (EXAMPLE 25) and p-toluenesulfonic acid pyridinium (264 mg, 1.05 mmol) in methylene chloride (5 ml) was added 1,1-dibutoxycyclohexane (2.14 g, 10.0 mmol), and stirred at room temperature for 20 hours. A drop of triethylamine was added to the reaction mixture , and the mixture was filtered to remove the precipitated insoluble matter. The filtrate was concentrated under reduced pressure. Hexane was added to the residue, and the mixture was filtered to remove the insoluble matter. The filtrate was purified by chromatography on an alumina column (eluate: toluene) to give the compound 20 (165 mg, 34%). Rf 0.41 (Al2O3 60, Type E, toluene).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:39][C@@H:40]([NH2:51])[C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1>O.CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C@@H:10]([C:14]([NH:51][C@@H:40]([C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=[CH:43][CH:42]=2)[CH3:39])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H]1CC(=O)N(Cc2ccccc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A 20 ml DMF solution of 1.16 g of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid was mixed with 2.0 g of WSC hydrochloride and 859 mg of HOBt and stirred at room temperature for 30 minutes. 1.1 g of (1R)-1-naphthylethylamine was added thereto successively and stirred at 60° C. After completion of the reaction, this was mixed with 100 ml of water, extracted with ethyl acetate and washed with 1 M hydrochloric acid. The organic layer was concentrated, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) and then recrystallized from ethyl acetate-hexane to obtain 856 mg and 831 mg of (3R)-1-benzyl-N-[(1R)-1-(1-naphthyl)ethyl]5-oxopyrrolidine-3-carboxamide and (3S)-1-benzyl-N-[(1R)-1-(1-naphthyl)ethyl]5-oxopyrrolidine-3-carboxamide (stereoisomers un-verified). Both of the thus obtained compounds were respectively subjected to reduction in the same manner as in Example 84, made into salt with fumaric acid and recrystallized from ethanol-ethyl acetate to obtain (1R)—N-{[(3S)-1-benzylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine fumarate and (1R)—N-{[(3R)-1-benzylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine fumarate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2.[Br:16]Br>C(O)(=O)C.C(Cl)Cl>[Br:16][C:6]1[C:5]2[C:9](=[C:10]([CH:12]=[O:13])[CH:11]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[NH:8][N:7]=1
Reactant: O=Cc1cc(C(F)(F)F)cc2cn[nH]c12
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=Cc1cc(C(F)(F)F)cc2c(Br)n[nH]c12
Reaction time: 1 h

Procedure:
To a mixture of 5-(trifluoromethyl)-1H-indazole-7-carbaldehyde (270 mg, 1.26 mmol) in acetic acid (5 mL) was added bromine (97 μL, 1.89 mmol) slowly over 5 min. After 1 h, the reaction mixture was diluted with methylene chloride, washed with water (2×), saturated sodium thiosulfate (2×), saturated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated to afford 340 mg (92%) as a yellow powder. 1H-NMR (CDCl3, 300 MHz) δ 10.18 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H). Mass spec.: 294.81 (MH)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:24])([F:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:3][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([F:24])([F:23])[F:5])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 3.78 ml of thionyl chloride in 30 ml of dichloromethane were slowly added dropwise to a solution of 9.69 g (34.57 mmol) of (4-{2-[4-(trifluoromethyl)phenyl]ethyl}phenyl)methanol in 100 ml of dichloromethane. After the addition had ended, the reaction mixture was warmed to room temperature and stirred at this temperature for two hours. The reaction mixture was then once more cooled to 0° C., and 100 ml of saturated aqueous sodium bicarbonate solution were added slowly and carefully with vigorous stirring until a pH of 6 had been reached. The phases were then separated, and the organic phase was dried over magnesium sulphate, filtered and concentrated to dryness. This gave 8.64 g (28.92 mmol, 84% of theory) of the title compound.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:25])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][C@H:15]1[CH3:21])[C:10](=[CH2:23])[C@H:9]3[CH3:24].[OH-:26].[Na+]>CO>[F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:25])[C@:16]1([CH3:17])[C:11]2([O:26][CH:12]2[C:13](=[O:22])[CH2:14][C@H:15]1[CH3:21])[C:10](=[CH2:23])[C@H:9]3[CH3:24]
Reactant: C=C1C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: C=C1[C@@H](C)[C@@H]2[C@H](CC[C@]3(C)C(=O)[C@H](F)C[C@@H]23)[C@@]2(C)[C@H](C)CC(=O)C3OC132
Temperature: 0 °C
Reaction time: 24 h

Procedure:
344 mg of 16α-fluoro-1β,7α-dimethyl-6-methylenandrost-4-ene-3,17-dione (which can be prepared as described in Example 1) are dissolved in methanol (20 ml) and the solution cooled to 0°-5° C. Ice cold 36% hydrogen peroxide (2 ml) and 2% sodium hydroxide (1 ml) are added and the mixture stirred for further 24 hrs at 0°-5° C. Then the mixture is poured into ice water, the product filtered off, washed with water and dried to yield 16α-fluoro-4,5-epoxy-1β,7α-dimethyl-6-methylenandrostane-3,17-dione (306 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])=[CH:10][CH:9]=1)=[O:6].[H-].[Na+].[CH3:33]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[C:5]([N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])=[CH:10][CH:9]=1)[CH3:33])=[O:6]
Reactant: CI
Reactant: COc1ccc(C(=O)Nc2ccc(N3C(=O)CCc4ccccc43)cc2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(C)c2ccc(N3C(=O)CCc4ccccc43)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 1-[4-(2,4-dimethoxybenzoylamino)phenyl]-3,4-dihydrocarbostyril (0.19 g) in dimethylformamide (8 ml) is added with stirring 60% sodium hydride (0.02 g) under ice cooling. The mixture is stirred at room temperature for 0.5 hour and thereto is added a solution of methyl iodide (0.08 g) in dimethylformamide (6 ml). The mixture is stirred at room temperature for 3 hours. The solvent is distilled off under reduced pressure and water is added to the residue. The mixture is extracted with dichloromethane, washed with water and dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography to give 1-{4-[N-(2,4-dimethoxybenzoyl)-N-methylamino]phenyl}-3,4-dihydrocarbostyril (70 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1Br)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:42]1([CH:47]=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43]1>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:47]([CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)[OH:48])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Reactant: O=CC1CCCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCC2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (117.4 mg, 0.21 mmol) in THF (0.5 mL) at 0° C. was added iPrMgCl/LiCl in THF (0.35 mL, 0.7 mmol). The mixture was stirred at 0° C. for 3 hours. Cyclopentanecarboxaldehyde (41 mg, 0.42 mmol) was added. The mixture was stirred at 0° C. for 3 hours, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford the title compound as a colorless oil (55.5 mg, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 0.97-1.10 (m, 1H) 1.33-1.42 (m, 1H) 1.43-1.70 (m, 5H) 1.76-1.86 (m, 1H) 2.17-2.32 (m, 1H) 2.56 (s, 1H) 4.17-4.20 (m, 3H) 4.69-4.79 (m, 3H) 4.81 (s, 1H) 4.90 (d, J=15.77 Hz, 1H) 7.34 (s, 1H) 7.52 (d, J=8.71 Hz, 1H) 7.58 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 581.2, Found: 582.4 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][O:1][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NCCO)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of benzyl N-(2-hydroxyethyl)carbamate (5.9 g, 30 mmol), N-hydroxyphthalimide (4.9 g, 30 mmol), and triphenylphosphine (7.9 g, 30 mmol) in tetrahydrofuran (100 mL) was added diethyl azodicarboxylate (5.2 g, 30 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, the solution washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (9.3 g, 91%). 1H-NMR (300 MHz, CDCl3) δ 7.84 (m, 2H), 7.78 (m, 2H), 7.37 (m, 5H), 5.97 (br s, 1H), 5.14 (s, 2H), 4.27 (t, J=4.9 Hz, 2H), 3.51 (q, J=5.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.[CH:20](=[NH:24])OCC>C1COCC1>[NH:24]=[CH:20][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: CCOC=N
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(NC=N)cc2)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
N-{4-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (150 mg) was dissolved in THF (2 ml) and pH=7 buffer (2 ml). Then, ethyl imidoformate hydrochloride (1.26 g) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CH3CN/water (7:3) as an eluent. The oil was purified again by preparative silica gel chromatography with CHCl3/MeOH (5:1) as an eluent to give N-[4-(2-{4-[(iminomethyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (110 mg) as pale brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH:14]C(=O)OC(C)(C)C)=[CH:6][CH:5]=1)[CH3:2].Cl>O1CCOCC1.C(OCC)C>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH2:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOc1ccc2cccc(N)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.7 %

Procedure:
To a solution of the product of Example 1C (14.47 g, 50.4 mmol) in dioxane (30 mL) at 0° C. was added 4N HCl in dioxane (60 mL, 240 mmol). The reaction mixture was stirred at room temperature for 3.5 hours, diluted with 3 volumes of diethyl ether. The resulting dark brown precipitate was collected by filtration. It was then treated with saturated NaHCO3 solution and was extracted with ethyl acetate. The solution was dried over MgSO4, filtered and evaporated in vacuo to yield the title compound (4.88 g, 52%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH:10]([CH3:12])[CH3:11].[OH-].[K+].O>CS(C)=O>[CH3:11][CH:10]([CH3:12])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]#[N:8]
Reactant: CC(C)Br
Reactant: N#CCc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C(C#N)c1cccs1
Yield: 71.8 %

Procedure:
47.6 g (0.39 mol) of 2-thiopheneacetonitrile and 57.0 g (0.46 mol) of 2-bromopropane were dissolved in 100 ml of DMSO, and a 50% KOH aqueous solution was added dropwise to the solution. After completion of the reaction, water was added, and the mixture was extracted with toluene. After washing with brine and an aqueous saturated ammonium chloride, the mixture was dried over magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to distillation under a reduced pressure (2 to 3 mmHg: 132 to 137 deg), to give 46.4 g (0.28 mol, 72.7%) of the title compound as a colorless oil. The physico-chemical data of the compound was as below.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.O>CN(C=O)C>[CH:22]1([CH2:21][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
To a solution of 4-(difluoromethoxy)-3-hydroxybenzaldehyde (18.4 g, 98 mmol) in DMF (200 ml), potassium carbonate (29.7 g, 215 mmol) and KI (16.3 g, 98 mmol) were added followed by (bromomethyl)cyclopropane (14.28 ml, 148 mmol), and the resulting suspension was stirred at RT for 24 hours. The mixture was poured into water (800 ml) and extracted with diethyl ether (3×300 ml); the combined organic layers were dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (22.5 g, 93 mmol, 94.8% yield, MS/ESI+ 243.1 [MH]+). This product was used without purification.