Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[CH2:3]([N:2]([CH3:1])[S:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:35]2[CH:34]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:38]=[CH:37][N:36]=2)[CH:40]=1)(=[O:46])=[O:47])[CH:4]([CH3:6])[CH3:5]
Reactant: CNCC(C)C
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methylisobutylamine (0.26 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.45 g, 80%). MS (ISP) 594.7 [(M+H)+]; mp 144° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([S:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CCOC(C)=O>CS(O)(=O)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][CH2:7][CH2:8][C:9](=[O:11])[C:12]=2[CH:13]=1
Reactant: O=C(O)CCSc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCSc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A solution of 3.63 g (13.9 mmol) of 3-(4-bromothiophenoxy)propionic acid in 60 ml methanesulfonic acid was heated to 75° C. for 1.5 hours. After cooling to room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with 2N aqueous NaOH, H2O, and saturated aqueous NaCl and then dried over MgSO4. Removal of the solvent under reduced pressure afforded a yellow solid from which the product was isolated by column chromatography (3% EtOAc--hexanes) as a pale-yellow solid. 1H NMR (CDCl3): δ 8.22 (1H, d, J=2.1 Hz), 7.48 1H, dd, J=2.1,8.3 Hz), 7.17 (1H, d, J=8.5 Hz), 3.24 (2H, t, J=6.4 Hz), 2.98 (2H, t, J=6.7 Hz).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([SH:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].BrBr.O>C(O)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([S:33][S:17][C:6]2[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:3]([CH:2]([F:1])[F:22])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(S)c1CC(C)C
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(SSc2ccc(C(C)(C)C)cc2)c1CC(C)C
Reaction time: 1 h

Procedure:
To a mixture of 100 mg of compound 7 and 48.6 mg of 4-t-butylbenzenethiol in 5 ml of acetic acid was added 23 mg of bromine. The reaction mixture was stirred for 1 h, poured into water and extracted with ether. The ether extract was washed with saturated sodium bicarbonate, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (9:1 Hexane: EtOAc) on silica gel to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:25][N:26]=[C:27]=[O:28].[N-]=C=O>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:25][NH:26][C:27](=[O:28])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: [N-]=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 160 °C

Procedure:
The commercial starting material ethyl 2-aminothiazole-4-carboxylate (2 mmol) was dissolved in NMP and DIEA (1 equivalent) was added followed by addition of the 3,4-dichloro-benzyl isocyanate (1 equivalent). Add 5% DMAP. Heat at 160° C. under microwave irradiation for 30 min Added additional isocyanate reagent (1.0 eq) and microwave for another 30 minutes at 160° C. to obtain ethyl 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylate in >90% conversion.
Reaction SMILES: [CH2:1]([O:8][C:9]1([CH3:25])[CH2:18][CH2:17][C:16]2[N:15]=[CH:14][C:13]([C:19]([O:21]CC)=O)=[C:12](Cl)[C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>C(O)CCC>[CH2:1]([O:8][C:9]1([CH3:25])[CH2:10][CH2:11][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:21])[N:33]([C:30]4[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=4)[N:34]=[C:12]3[C:17]=2[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(C)(OCc1ccccc1)CC2
Reactant: NNc1ccc(Cl)cc1
Solvent: CCCCO
Product: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
A solution of ethyl 6-benzyloxy-4-chloro-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate (5.0 g) and p-chlorophenylhydrazine (2.0 g) in 75 mL of n-butanol is stirred at room temperature for 4 hours, then refluxed overnight. The reaction mixture is evaporated and the residue is treated with Et2O and 2N NaOH. The alkaline layer is separated, the pH is adjusted at 8 with dilute HCl, and the resulting precipitate is collected. This material is washed with EtH/Et2O and air-dried to obtain 8-benzyloxy-2-p-chlorophenyl-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12](Cl)=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[Cl:34]C1C=C2C(C=C(OS(C(F)(F)F)(=O)=O)N=C2)=CC=1>>[ClH:4].[ClH:34].[ClH:1].[Cl:34][C:13]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:16]3[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:26]=4)[CH:21]=3)[N:9]=[CH:10]2)=[CH:5][CH:14]=1
Reactant: O=S(=O)(Oc1cc2ccc(Cl)cc2cn1)C(F)(F)F
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccc(Cl)cc2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 7-chloroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.29-2.46 (m, 4H), 3.24-3.31 (m, 2H), 3.59-3.67 (m, 2H), 4.61-4.72 (m, 1H), 7.91 (dd, J=8.8, 2.0 Hz 1H), 8.10 (s, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.43 (s, 1H), 8.73 (s, 1H), 8.90 (d, J=2.3 Hz, 1H), 9.43 (s, 1H). MS (ES+): m/z=405.09/407.03 [MH+]. HPLC: tR=1.95 min (ZQ3, polar—5 min).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[C:9]([F:15])[CH:8]=1>C(#N)C>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([F:15])[CH:8]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: C1CCNC1
Solvent: CC#N
Product: Fc1cc(Br)ccc1CN1CCCC1
Temperature: 10 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A 4-L RB flask, equipped a magnetic stirring bar was charged with pyrrolidine (363 g, 426 mL, 5.1 mol) and acetonitrile (2750 mL). The mixture was cooled with an ice bath to 10° C., then solid 4-bromo-2-fluorobenzylbromide (MATRIX, Cat. #: 1707, 375 g, 1.4 mol) was added in 6 portions, keeping temperature below 20° C. The mixture was stirred at RT for 4 h. The solvent was removed under vacuum. Then 2 L of sat. Na2CO3 aq. and 500 mL of water was added, and the mixture was extracted with DCM (3×700 mL). The extract was dried over Na2SO4 and evaporated. The resulting light yellow oil was distilled under vacuum (˜1 mm, bp. 125° C.) to give 324.5 g (90%) of the product as a colorless oil. LCMS (M+H): 258.5.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH:15][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C=O)o1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Product: Cc1ccc(CNCC(C)Oc2ccc3ccccc3c2Cl)o1
Yield: 70 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and 5-methylfuran-2-carbaldehyde in 70% yield as a yellow oil.
Reaction SMILES: [CH2:1]([NH:10][C@@H:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[C:24]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([N:10]([C@@H:11]([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][C:24]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@H](NCC=Cc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccccc1
Agent: [Li]CCCC
Product: C[C@@H](c1ccccc1)N(CC=Cc1ccccc1)[C@H](CC(=O)OC(C)(C)C)c1ccccc1
Yield: 93.8 %

Procedure:
(S)-N-cinnamyl-α-methylbenzylamine (4) (0.100 g, 0.42 mmol), 1.6M butyllithium (0.242 ml, 0.39 mmol) and t-butyl cinnamate (7) (0.072 g, 0.35 mmol) were reacted according to the procedure of Example 1. Flash chromatography of the product on silica gel [ethyl acetate/petroleum ether (1:49)] afforded the title compound (Rf 0.3) as a colourless oil (0.145 g, 78%). δH (300 MHz; CDCl3) 7.50-7.18 (15H, m, Ph), 6.42 (1H, d, J=16.0, PhCH=CH), 6.11 (1H, dt, J=16.0 and 6.2; CH=CHPh), 4.53 (1H, dd, J=8.7 and 6.4, PhCHCH2), 4.07 (1H, q, J=6.7, PhCHCH3), 3.32 (2H, dd, J=6.2 and 1.1, NCH2), 2.83 (1H, dd, J=14.6 and 6.4, CH2CO2), 2.62 (1H, dd, J=14.6 and 8.7, CH2CO2), 1.31 (9H, s, (CH3)3C), 1.27 (3H, d, J=6.7, PhCHCH3).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH2:7]O)[CH2:5][OH:6].[CH3:10][O:11][CH2:12][CH:13]=[O:14].C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:10][O:11][CH2:12][CH:13]1[O:6][CH2:5][C:4]([CH2:3][O:2][CH3:1])([CH3:9])[CH2:7][O:14]1
Reactant: COCC(C)(CO)CO
Reactant: COCC=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCC1OCC(C)(COC)CO1
Yield: 91 %

Procedure:
A mixture of 670 g (5 moles) of 2-methoxymethyl2-methyl-1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 250 ml of chloroform was heated with 10 g of pyridinium p-toluenesulfonate under a water separator until water no longer separated off. The solution was deionized using a mixed-bed ion exchanger, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 864 g (91% yield) of 2,5-dimethoxymethyl-5-methyl-1,3-dioxane of boiling point 95° C./10 mbar were obtained.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:47][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:16])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Temperature: -15 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of Boc-Asp(OBzl), 5.0 g (15.5 mmol) and N-methyl morpholine (15.5 mmol) in 50 mL of dry THF under an Ar atmosphere was added isobutylchloroformate (15.5 mmol) at -15° C. After a few minutes, phenethylamine 2.0 mL (15.5 mmol) in 15 mL of dry THF was added. The mixture was maintained at -15° C. for 15 min. and allowed to warm to room temperature. After stirring for an additional 2 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to dryness. The resulting residue was dissolved in ethyl acetate (100 mL) and washed successively with 1M HCl (2×50 mL), water (50 mL), 10% sodium carbonate (2×50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 5.59 gm (85%) of an amorphous white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/B(O)O)=[CH:5][CH:4]=1.Br[C:17]1[C:18]([NH:26][C:27](=[O:35])[CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12>>[CH:30]1([CH2:29][CH2:28][C:27]([NH:26][C:18]2[C:17](/[CH:10]=[CH:9]/[C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=3)=[C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:20]3[N:19]=2)=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(CCC1CCCC1)Nc1nn2cccnc2c1Br
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: O=C(CCC1CCCC1)Nc1nn2cccnc2c1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
Trans-2-[4-(trifluoromethyl)phenyl]vinylboronic acid and the product from Example 153A were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.32-10.34 (bs, 1H), 9.10 (dd, J=6.9, 1.7 Hz, 1H), 8.69 (dd, J=4.1, 1.7 Hz, 1H), 7.70 (s, 4H), 7.64 (d, J=16.3 Hz, 1H), 7.34 (d, J=16.2 Hz, 1H), 7.14 (dd, J=6.9, 4.1 Hz, 1H), 2.49 (t, J=7.9 Hz, 2H), 1.76-1.86 (m, 3H), 1.45-1.70 (m, 6H), 1.07-1.18 (m, 2H); MS (ESI) m/z 429 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([NH:15][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(F)cn1
Product: CC(C)(C)NC(=O)c1ccc(F)cn1

Procedure:
The title compound was prepared by the same method as that described in Example 39-3), using 5-fluoro-2-pyridinecarboxylic acid and t-butylamine.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:16]([CH3:17])[CH2:15][N:14]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([CH3:28])[CH2:12]2)=[CH:7][C:6]=1[C:29]([F:32])([F:31])[F:30])#[N:4].[CH3:33]I.O>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:16]([CH3:17])[CH2:15][N:14]([C:18]([N:20]([CH3:33])[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([CH3:28])[CH2:12]2)=[CH:7][C:6]=1[C:29]([F:31])([F:32])[F:30])#[N:4]
Reactant: C[C@@H]1CN(C(=O)Nc2ccc(F)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)N(C)c2ccc(F)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A 69 mg portion of 60% sodium hydride was suspended in 6 ml of DMF, 660 mg of trans-4-(4-cyano-3-trifluoromethylphenyl)-4′-fluoro-2,5-dimethylpiperazine-1-carboxanilide synthesized in Example 1-1 was added to the suspension under ice-cooling, and then the mixture was stirred at 50° C. for 10 minutes. The reaction solution was ice-cooled, 0.11 ml of methyl iodide was added dropwise thereto, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with water, extracted with ethyl acetate, washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by a silica gel column chromatography to obtain 620 mg of the title compound from ethyl acetate-hexane eluate.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8](=[O:9])[CH2:7][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)CCl
Product: CCCCNCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To 36.5 g of butylamine was added with stirring 15.05 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature of 30°-70° C. The reaction mixture was held at 70° C for an additional one hour. At the end of this period, the excess butyl amine was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 17.0 g (90.0 percent) of N-butylglycine tert-butyl ester, B.P. 76° C/4 mmHg.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]C2C=CC([N+]([O-])=O)=CC=2)=[CH:23][CH:22]=1>CC#N>[N:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Solvent: CC#N
Product: O=C(Nc1ccncc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 55 °C

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.721 mmol) in MeCN (3 mL) was added 4-nitrophenyl pyridin-4-ylcarbamate (561 mg, 2.164 mmol). The resulting mixture was heated to 55° C. overnight. After cooling down to RT the white precipitated obtained was filtered off and washed with DCM (2×1 mL). The combined filtrates were then concentrated and the residue purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 398 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[CH2:9][C:10](N(OC)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Mg]Cl)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([N:8]([CH3:16])[CH2:9][C:10](=[O:11])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CON(C)C(=O)CN(C)Cc1ccccc1
Solvent: C1CCOC1
Product: CN(CC(=O)CCc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
2-(Benzyl-methyl-amino)-N-methoxy-N-methyl-acetamide (2.0 g, 9.0 mmol, 1.0 equiv) was dissolved in 30 mL of dry THF under argon. The solution was cooled to −78° C. and a 1 M solution of phenethyl magnesium chloride (12.6 mL, 12.6 mmol, 1.4 equiv) was added dropwise of a period of 1 min. The resulting mixture was stirred at −78° C. for 3 h, warmed to 0° C. for 20 min and recooled to −78° C. at which time the reaction was quenched by the addition of 5 mL of saturated sodium bicarbonate. The reaction solution was diluted with 200 mL of EtOAc and 200 mL of water. The layers were separated and the organic layer was dried over Na2SO4, decanted and concentrated to an oil (2.4 g, ˜100%) which was used without further purification; MS, m/z 268=M+1.
Reaction SMILES: C([NH:11][C:12]([CH3:33])([C:14]([NH:16][CH2:17][CH:18]1[O:32][C:21]2=[C:22]3[C:27](=[C:28]([CH3:30])[CH:29]=[C:20]2[CH2:19]1)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]3)=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[H][H]>CN(C)C=O.CO.[Pd]>[CH3:30][C:28]1[CH:29]=[C:20]2[CH2:19][CH:18]([CH2:17][NH:16][C:14](=[O:15])[C:12]([CH3:13])([CH3:33])[NH2:11])[O:32][C:21]2=[C:22]2[C:27]=1[NH:26][C:25](=[O:31])[CH:24]=[CH:23]2
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)N)C2
Yield: 95.5 %

Procedure:
2-(N-Carbobenzyloxy-α-methylalanyl]aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.46 g, 5.48 mmol) was dissolved in dimethylformamide (190 ml). To the obtained solution, 10% palladium-on-carbon (2.46 g) was added, followed by stirring at room temperature for 3 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed. The resultant residue was dissolved in methanol (70 ml). To the obtained solution, 1.37 N-HCl--methanol (4.39 ml) was added at room temperature, followed by condensing under reduced pressure. The resultant residue was submitted to a recrystallizing procedure using methanol to obtain 1.65 g of the title compound as pale yellow powdery crystals (85.6%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>C(Cl)Cl>[C:15](=[O:16])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:17][CH2:18][Cl:19]
Reactant: O=C(Cl)OCCl
Reactant: OC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCl)OC1CCCCC1

Procedure:
A solution of 3.0 g of cyclohexanol and 2.4 ml of pyridine in 30 ml of methylene chloride is cooled to -78° C. and, with stirring, 2.4 ml of chloromethyl chloroformate is added dropwise to the solution. After completion of addition, a cold bath is removed. The mixture is stirred at room temperature for 16 hours, washed with three 30-ml portions of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 4.5 g of colorless oil, which is crystallized from ligroine giving the title compound as colorless crystals melting at 36°-37° C.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:20][C:19]([N:28]=[C:29]=[O:30])=[C:18]([F:31])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[C:21]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:20][C:19]([N:28]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:29]2=[O:30])=[C:18]([F:31])[CH:17]=1
Reactant: Cc1nnc(-c2cc(N=C=O)c(F)cc2Cl)o1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nnc(-c2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1.04 g of sodium hydride (oil, purity: 55%) in 75 ml of dimethylformamide, a solution of 4.3 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 58 ml of toluene was added dropwise at 0° C. over a period of 15 minutes. Thereafter, the solution was stirred at 0° C. for 15 minutes and then cooled to -30° C., followed by dropwise addition of a solution of 5.7 g of 4-chloro-2-fluoro-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl isocyanate in 60 ml of toluene. The resulting mixed solution was stirred at room temperature for 3 hours.