Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:30]=1[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:29]=1[Cl:28])=[O:32]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Reaction time: 72 h
Yield: 75.3 %

Procedure:
To a suspension of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt (100 mg, 0.25 mmol), 2-chloro-6-methylbenzoic acid (60 mg, 0.35 mmol) and HBTU (132 mg, 0.35 mmol) in DMF (2 mL) was added DIEA (174 μL, 1.0 mmol) at room temperature. The resulting mixture was stirred for 72 h. Then, the mixture was poured into water (25 mL) and was extracted with ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed successively with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (25 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 98 mg (75% yield) of N-[(2-chloro-6-methylphenyl)carbonyl] -4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C26H24ClF3N2O4 (M+Na) 543.1268, found 543.1275.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH2:17]O.BrC1C(C)=CC(C)=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O1CCCC1>[C:1]1([CH:7]2[CH2:8][C:9]3[NH:15][CH:16]=[CH:17][C:10]=3[C:11](=[O:13])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: NCCO
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 0.7 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (15.0 g), 2-aminoethanol (6.3 g), molecular sieves 4A (100 g) and tetrahydrofuran (200 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated to give oil, which was dissolved in dimethylformamide (5 ml). To the solution were added 2-bromomesitylene (0.20 g), tetrakistriphenylphosphine palladium (30 mg) and potassium carbonate (0.28 g), and the mixture was stirred at 150° C. for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.11 g).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:14][C:15](=[O:34])[CH:16]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH:11]([CH3:13])[CH3:12].[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:14][C:15](=[O:34])[CH:16]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:21][CH:20]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)C(COC1=CCC(c2ccccc2)C=C1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
A solution of 2 M Na2CO3 (4 mL) was added at room temperature under an atmosphere of Argon to a mixture of the compound obtained in Example 22, step f (401 mg, 0.848 mmol), Pd(PPh3)2Cl2 (154 mg, 0.22 mmol) and phenylboronic acid (145 mg, 1.1872 mmol) in toluene (10 mL) and the reaction was heated to reflux. After 5 h, the reaction was cooled to room temperature. The mixture was diluted with EtOAc, and washed with brine. The combined organic layers were dried over anhydrous NaSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography which gave the title compound as a white solid (255 mg, 64%).
Reaction SMILES: [OH:1][C:2](=[C:5]1[C:10](=[O:11])[O:9][C:8]([CH3:13])(C)OC1=O)[CH2:3][CH3:4].[CH2:15](O)C#C>C1C=CC=CC=1>[O:1]=[C:2]([CH2:3][CH3:4])[CH2:5][C:10]([O:9][CH2:8][C:13]#[CH:15])=[O:11]
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: C#CCO
Solvent: c1ccccc1
Product: C#CCOC(=O)CC(=O)CC
Temperature: 25 °C
Yield: 95.4 %

Procedure:
Method A. A solution of 5-(1-hydroxypropylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (2) (2.00 g, 10.0 mmol) and 2-propynol (1.10 g, 20.0 mmol) in benzene (20 mL) is stirred at 93° C. for 3.25 h and then cooled to room temperature. After solvent removal at reduced pressure, the residue is purified on silica gel (12.5% to 14.3% ethyl acetate/hexane) to give 1.47 g (95%) of 4 as a colorless liquid.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:23])[NH:10]2.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].[Br-].[Li+]>CN(C)C=O>[C:17]1([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:24]3[CH2:25][CH2:26][CH:27]([NH:30][C:31]([O:32][CH2:33][CH:34]4[CH2:35][CH2:36]4)=[O:37])[CH2:28][CH2:29]3)=[C:6]3[C:11]=2[NH:10][C:9](=[O:23])[CH2:8][CH2:7]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NC1CCNCC1)OCC1CC1
Reactant: O=C1CCc2c(OCCCl)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(OCCN3CCC(NC(=O)OCC4CC4)CC3)ccc(OCc3ccccc3)c2N1
Temperature: 110 °C
Yield: 96 %

Procedure:
5-(2-chloroethoxy)-8-phenylmethoxy-3,4-dihydrocarbostyril (0.7 g), from Preparation 6, and cyclopropylmethyl 4-piperidylcarbamate (0.5 g) were dissolved in dimethylformamide (35 mL) containing potassium carbonate (0.3 g) and lithium bromide (0.3 g). The reaction medium was heated for 34 hours at 110° C., and the solvent was then removed by evaporation under reduced pressure. The residue was dissolved in chloroform (70 mL), and the solution was washed with water (2×40 mL), dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Flash chromatography of the residue, using dichloromethane/methanol (90:10) as eluent, afforded 1 g of the title compound 8-phenylmethoxy-3,4-dihydro-5-[2-(4-((cyclopropylmethoxy)carbonylamino)-1-piperidyl)ethoxy]carbostyril as a yellow oil (ca. 95%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17](O)=[O:18].O=S(Cl)Cl.Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29]>CCN(CC)CC>[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH:29][C:2]([C:3]1[C:17](=[O:18])[C:16]2[C:11]([C:4]=1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:1]
Reactant: COC(=O)CN
Reactant: O=C(O)C1=C(c2ccccc2)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(=O)CNC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
A mixture of 1-oxo-3-phenyl-1H-indene-2-carboxylic acid (2.13 g, 8.5 mmol; can be obtained according to M. R. Barvian et al. in Bioorg. Med. Chem. Lett. 1997, 7, 2903-2908) and SOCl2 (17 ml) was refluxed with stirring for 15 min. Excess SOCl2 was then evaporated in vacuo. The residue was dissolved in anhydrous CH2Cl2 (20 ml), and subsequently the solution was concentrated in vacuo again to remove last traces of SOCl2. The residue was dissolved in anhydrous CH2Cl2 (20 ml). The solution was cooled with an ice bath before glycine methyl ester hydrochloride (1.27 g, 10 mmol) and subsequently NEt3 (3.52 ml, 25 mmol, dropwise addition) were added with stirring. The ice bath was then removed and stirring was continued at ambient temperature for 45 min before the mixture was concentrated in vacuo. To the residue was added water (10 ml) and aqueous 2N HCl (15 ml) and the mixture was extracted with ethyl acetate (1×70 ml). The organic phase was dried over MgSO4 and evaporated in vacuo to give an orange solid (2.77 g). Purification by flash column chromatography on silca gel using hexanes:EtOAc=2:1 as the eluent gave the title compound as an orange solid (2.11 g); MS-(+)-ion: M+1=322.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][B:30]([O:32][CH3:33])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][B:30]([O:32][CH3:33])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COB1O[C@H](CCN)C[C@H](CC(=O)OC(C)(C)C)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: COB1O[C@H](CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)C[C@H](CC(=O)OC(C)(C)C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-methoxy-1,3,2-dioxaborinan-4-yl)acetate.
Reaction SMILES: N[C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1.[ClH:11].N([O-])=O.[Na+]>O.[Cu]>[Cl:11][C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1
Reactant: Cl
Reactant: COC(=O)c1nsc(N)n1
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1nsc(Cl)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 5-amino-1,2,4-thiadiazole-3-carboxylate (26 g), conc.hydrochloric acid (490 ml) and a small amount of copper was added dropwise over 40 minutes a solution of sodium nitrite (22.5 g) in water (28 ml) at -10° to -15° C. The mixture was stirred for 1.5 hours at the same temperature and for 30 minutes at 50° C. The reaction mixture was poured into ice-water (500 ml) and extracted with ethyl acetate. The extract was washed, dried and concentrated to give white powder of methyl 5-chloro-1,2,4-thiadiazole-3-carboxylate (8.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN.C(O)C>C(Cl)Cl>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A mixture of 2.62 g (6.35 mmole) of N-[[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl]phthalimide, 1.21 ml (1.25 g, 25 mmole) of 100% hydrazine hydrate, and 35 ml of absolute ethanol was stirred at room temperature for 7.5 hours. During this time all of the solid gradually dissolved, followed by precipitation. Glacial acetic acid (3.7 ml) was added, and stirring was continued overnight. The white solid was then removed by filtration, and the filtrate was concentrated at room temperature. The residual oil was taken up in 100 ml of ether and washed with 2×50 ml of saturated aqueous Na2CO3 solution. Next, the product was extracted by shaking the ethereal solution with 50 ml of 0.5 N HCl. The aqueous layer was separated and basified by addition of excess saturated Na2CO3. The product, which oiled out, was extracted with 100 ml of ether. The ether phase was dried (Na2SO4), filtered, and concentrated at 30° C. to give 1.58 g (88%) of a very pale yellow, viscous oil, homogeneous by TLC in 95:5:0.5 CH2Cl2 --MeOH-concd NH40H.
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].O1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:3]1[C:1](=[O:2])[N:8]=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:6][C:7]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Product: O=C1N=c2ccccc2=N1

Procedure:
In Scheme I, 2-fluoro-nitrobenzene is reacted with a primary amine, intermediate (h), wherein R1 is as described herein, to provide intermediate (i), which is reduced to a diaminophenyl, intermediate (j). The diaminophenyl is reacted with carbonyldiimidazole in the presence of an inert diluent, such as tetrahydrofuran, at a temperature range of from about 20° C. to about 40° C. for between about 12 and about 30 hours, to provide a benzoimidazolone compound of intermediate (d). A representative synthesis of a compound of intermediate (d) is described herein in Example 1, steps (a)-(c).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH3:21]>>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:21])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CNCCOC
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N(C)CCOC

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid 1.2 was reacted with 2-methoxy-N-methylethanamine Ac following the procedure described in Example 1A to provide 1.3.Ac. MS analysis (m−1)=301.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13].C(O)(=O)C.C(O)(=O)C.CO>CO>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 92 %

Procedure:
To a solution of 3.24 g of methyl 2-(2,6-dichloroanilino)-phenylglyoxylate in 50 ml of a 0.1 N acetic acid solution in methanol (hereinafter often referred to as "0.1 N acetic acid/methanol") was added 0.6 g of 5% Pt-carbon, and vigorous stirring was effected at room temperature under a hydrogen pressure of 2 atmospheres for 10 hours. The catalyst was filtered off and the filtrate was concentrated at room temperature under a reduced pressure of 10 mmHg. The crystalline substance thus deposited was recovered by filtration and recrystallized from ethanol to give 3.0 g of methyl 2-(2,6-dichloroanilino)phenylglycolate. m.p. 123°-124.5° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)=[O:17].Cl>CC(OC)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CSc1ccc(C(C)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COC(C)(C)C
Product: CSc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of ethyl trifluoroacetate (7.95 ml, 1.1 eq) in MTBE (125 ml) was added dropwise 25% sodium methoxide in methanol (16 ml, 1.2 eq). 4-Methylthioacetophenone (Aldrich, 10 g, 0.06 mol) was added portionwise and the mixture stirred at ambient temperature overnight. 2N Hydrochloric acid (40 ml) was added cautiously and the organic phase separated, washed with brine and dried (Na2SO4) to give an orange solid. The orange solid was recrystallised from hot isopropanol to give the title compound as a yellow crystalline solid (11.25 g, 71%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:31][CH2:32][C:33](Cl)=O>ClCCl>[Cl:31][CH2:32][C:33]1[N:19]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Triethylamine (20.4 g, 202 mmol) was added to a solution of tert-butyl 3-[(3-aminoquinolin-4-yl)amino]propylcarbamate (42.52 g, 134.4 mmol) in dichloromethane (500 mnL). Chloroacetyl chloride (16.7 g, 148 mmol) was added dropwise, and the reaction was stirred overnight at ambient temperature. The reaction mixture was filtered to remove a solid; the filtrate was concentrated under reduced pressure and mixed with ethyl acetate. The resulting mixture was filtered to remove a solid, washed sequentially with brine (3×) and dilute aqueous sodium bicarbonate, concentrated under reduced pressure, and dried under high vacuum to provide 41.9 g of tert-butyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1>>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:8])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccncc1
Product: COc1ccc(NC(=O)c2ccncc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from isonicotinoyl chloride and 4-methoxy-2-nitroaniline and was obtained as an orange yellow solid as described in Example 1. 1H NMR (CDCl3): 10.79 (s, 1H), 8.83-8.81 (m, 2H), 7.85-7.83 (m, 2H), 7.61-7.55 (m, 2H), 7.40-7.36 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.[Na].CCCCCCC.[C:17]([C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:24])[C:20](OC)=[O:21])#[CH:18]>CO>[C:17]([C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:24])[C:20]([O:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[O:21])#[CH:18]
Reactant: CN1CCCC(O)C1
Reactant: C#CC(O)(C(=O)OC)c1ccccc1
Agent: [Na]
Solvent: CO
Solvent: CCCCCCC
Product: C#CC(O)(C(=O)OC1CCCN(C)C1)c1ccccc1

Procedure:
1-Methyl-3-piperidinol (3.5 g., 0.03 mole) and a small piece of sodium (~0.05 g.) were refluxed in 150 ml. of n-heptane for about 1 hour in a flask equipped with a small distilling head. Methyl α-ethynyl-α-phenylglycolate (4.0 g., 0.02 mole) was then added intermittently over a one hour period with the temperature of the reaction mixture maintained at 90°. The reaction mixture was heated at 90°-95° for three hours during which time very little methanol was collected. The reaction mixture was subsequently refluxed for 11 hours and the azeotrope collected periodically. During this time sodium methoxide (0.075 g.) was added and 50 ml. of fresh n-heptane was added as an equal volume of distillate was collected simultaneously. These operations were carried out twice. Heating was stopped and a total of 0.3 ml. (38% of theory) of methanol was obtained. As the reaction mixture cooled, an oil settled out. The n-heptane was decanted and the residue was washed with ice water (3×10 ml.). Ether and ice were added to the oil and the mixture worked up as described in Example 12, to yield 1.9 g. (35%) of the product as a yellow oil. Crystallization was effected by dissolving the material in ether, adding 30°-60° petroleum ether to produce turbidity and refrigerating the solution for several days. The product melted at 92°-95° after recrystallization from hexane.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][C:11]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[C:23](O)(=O)[CH3:24]>>[CH2:23]([NH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][C:11]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14])[CH3:24]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N[C@@H]1CCCC[C@H]1N
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN[C@@H]1CCCC[C@H]1Nc1cc(C(F)(F)F)ccc1C#N
Temperature: 60 °C

Procedure:
Under ice-cooling, sodium borohydride was slowly added in small portions to an acetic acid solution of 2-{[(1R,2R)-2-aminocyclohexyl]amino}-4-(trifluoromethyl)benzonitrile, followed by heating at 60° C. for 6 hours. By post-treating the reaction liquid, 2-{[(1R,2R)-2-(ethylamino)cyclohexyl]amino}-4-(trifluoromethyl)benzonitrile was obtained. A formalin aqueous solution and sodium triacetoxyborohydride were added to a THF solution of this, followed by stirring. By post-treating the reaction liquid, 2-({(1R,2R)-2-[ethyl(methyl)amino]cyclohexyl}amino)-4-(trifluoromethyl)benzonitrile was obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH2:25]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:16]=[N:17][C:18]=1[Cl:22])[CH:24]=[CH2:23]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 110.3 %

Procedure:
3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (2.0 g, 5.14 mmol) in toluene (15 mL) was added tetrakis(triphenylphosphine)palladium (15 mg) and allyltributyltin (3.2 mL, 10.2 mmol). The mixture was stirred and refluxed for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (2.0 g, 100%): 1H NMR (CDCl3, 300 MHz) δ 1.24-1.40 (m, 2H), 1.46 (s, 9H), 1.62 (m, 1H), 1.88 (m, 1H), 2.02 (m, 1H), 3.38 (m, 1H), 3.45 (d, 2H, J=7.0 Hz), 3.90 (m, 1H), 4.16 (m, 2H), 5.10-5.20 (m, 2H), 5.94 (m, 1H), 7.14 (m, 1H), 7.96 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/e 352 (M+H)+.