Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>C(#N)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:15]1[CH2:14][CH2:13][CH:12]([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[O:11])[CH2:17][CH2:16]1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc2c(c1)CCO2)C1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C(=O)c2ccc3c(c2)CCO3)CC1
Temperature: 85 °C
Yield: 41.5 %

Procedure:
To a solution of (2,3-dihydro-benzofuran-5-yl)-piperidin-4-yl-methanone (0.30 g, 1.30 mmol) in acetonitrile (10 mL) was added ethyl 2-bromoacetate (0.26 g, 1.6 mmol) and triethylamine (0.66 g, 6.5 mmol). The mixture was heated at 85° C. overnight, the solvent was evaporated under reduced pressure and purified via flash column chromatography (ethyl acetate:heptane) to provide desired product as a white solid (0.18 g, 0.54 mmol). MS (ESI) m/z 317.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.22 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1>C(Cl)Cl>[CH:2]12[CH2:7][CH2:6][CH:5]([CH2:4][CH2:3]1)[C:8](=[O:10])[NH:1]2
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Solvent: ClCCl
Product: O=C1NC2CCC1CC2
Yield: 85.6 %

Procedure:
cis-4-Aminocyclohexyl carboxylic acid (1.60 g, 11.2 mmol) was heated to 290° C. for 15 min. After completion of the reaction, the reaction mixture was suspended in DCM and filtered. The organic layer was evaporated to dryness to afford 1.20 g (86.3%) of 2-azabicyclo[2.2.2]octan-3-one as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>ClCCl>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([NH:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.06 g) in dichloromethane (80 ml) is added o-methylphenyl isocyanate (0.66 g) under ice-cooling. The mixture is stirred at room temperature for 4 hours. After completion of the reaction, the solvent is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1), and recrystallized from ethyl acetate to give 1-[4-(2-methylanilinocarbonylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.97 g) as white powder, m.p. 182°-182.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:12]2[CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1)C1C=CC=CC=1.Br>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:24]=[CH:23][C:12]2[CH:13]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C1=Cc2ccc(OCc3ccccc3)cc2OCC1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=Cc2ccc(O)cc2OCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 21.6 %

Procedure:
Ethyl 8-(benzyloxy)-2,3-dihydro-1-benzoxepine-4-carboxylate (2.5 g) was dissolved in trifluoroacetic acid (10 mL), and 42% hydrobromic acid (0.5 mL) was added, and the mixture was heated at 60° C. for 30 min. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and back-extracted with 1 M aqueous sodium hydroxide solution. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated. The residue was dissolved in ethanol (100 mL), and thionyl chloride (1 mL) was added dropwise under ice-cooling. The mixture was stirred overnight at room temperature, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give crude crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.39 g) as crystals.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:15])[NH2:14])=[CH:8][C:7]=1[CH3:16].[Li+].[OH-]>C1COCC1>[C:21]([O:20][C:18]([NH:17][C@@H:4]([CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:15])[NH2:14])=[CH:8][C:7]=1[CH3:16])[C:3]([OH:25])=[O:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@H](Cc1c(C)cc(C(N)=O)cc1C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) and stirred at 0° C. Upon consumption of the starting materials, the organic solvents were removed and the aqueous phase was neutralized with cooled 1N HCl at 0° C., and extracted with EtOAc, and dried over Na2SO4 overnight. Filtration and evaporation to dryness led to the title acid (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid (2.51 g, 87%); 1H NMR (300 MHz, DMSO-d6): δ 1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS (ES+) (relative intensity): 236.9 (6) (M-Boc)+.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CN(OC)[C:17](=[O:19])[CH3:18]>O1CCCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:17](=[O:19])[CH3:18]
Reactant: CON(C)C(C)=O
Reactant: c1cc2sccc2cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2cnccc2s1
Temperature: -45 °C
Reaction time: 0.75 h

Procedure:
A solution of thieno[3,2-c]pyridine (5.0 g) in 75 mL THF (tetrahydrofuran) was cooled to −45° C. in a CH3CN/dry ice bath. n-Butyllithium (1.6M in hexanes) (35.0 ml) was added dropwise maintaining the internal temperature at or below −40° C. The addition took about 45 minutes. The reaction was stirred for 1 hour at −45° C. N-methyl-N-methoxyacetamide in 5 mL THF was added and as a result the reaction warmed to −30° C. The reaction was stirred at −45° C. for 1.5 hours. The reaction was quenched with saturated NH4Cl. The aqueous layer had a pH of about 8. The aqueous layer was extracted three times into EtOAc. The combined organic extracts were washed with brine and dried over MgSO4. The material was filtered, concentrated on a rotary evaporator and subjected to column chromatography (Biotage Horizon system, 120 g Analogix column, equilibrate with hexanes, elute with 50% EtOAc/hexanes). The most pure fractions were concentrated on a rotary evaporator and then triturated with Et2O to remove some color and collect a pale orange solid by filtration (2.667 g).
Reaction SMILES: C1(C)C=CC=CC=1.C(C(C)=O)=C.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([CH:23]3[CH2:28][CH2:27][C:26](N4CCCC4)=CC3)[CH2:19][CH2:18]2)OCC1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[CH:22]1[C:17](=[O:13])[CH2:18][CH2:19][CH:20]2[C:21]=1[CH2:26][CH2:27][CH2:28][CH2:23]2
Reactant: C1=C(N2CCCC2)CCC(C2CCC3(CC2)OCCO3)C1
Agent: C=CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C2CCCCC2CC1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Toluene (300 ml) and methyl vinyl ketone (42 ml) were added to 1-(4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohex-1-enyl)pyrrolidine (105.8 g) obtained in the first step in a reaction vessel at room temperature under an atmosphere of nitrogen, and the mixture was refluxed for 6 hours. After the reaction mixture had been cooled to room temperature, sodium acetate (18 g), acetic acid (36 ml) and water (60 ml) were added, and the mixture was refluxed for 4 hours. After the reaction mixture had been cooled to room temperature, water (200 ml) was added, and then the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The methanol was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-heptane=1/5 by volume) and then by recrystallization (solvent: Solmix/n-heptane=1/9 by volume) to give 6-(1,4-dioxaspiro[4.5]decan-8-yl))-4,4a,5,6,7,8-hexahydronaphthalene-2(3H)-one (43.3 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](O)=[O:18])=[C:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH:50][CH2:51][C:52]2[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=2[CH3:58])=[O:18])=[C:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(Cc3ccccc3)c3ccccc23)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To a solution of 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (212 mg, 0.8 mmol) in dichloromethane (20 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (135 mg, 1 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 1 mmol) and triethylamine (252 mg, 2.5 mmol), and stirred at room temperature for 0.5 hour, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added and stirred for 4 hours. To the reaction mixture was added water (20 mL), which was extracted with dichloromethane (2×20 mL), combined and the organic layers were concentrated, the residue was purified by column chromatography (dichloromethane/methanol=20:1) to afford 1-benzyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (200 mg, 63%). LRMS (M+H+) m/z: calcd 399.19. found 399. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.61 (s, 1H), 7.80-7.69 (m, 2H), 7.46-7.42 (m, 1H), 7.30-7.22 (m, 3H), 7.11-7.07 (m, 2H), 6.98 (d, J=7.5 Hz, 2H), 5.89 (s, 1H), 5.46 (s, 2H), 4.33 (d, J=4.5 Hz, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=2)[CH:12]=1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH:12]=1
Reactant: CCOC(=O)c1cn2cc(-c3ccccn3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3ccccn3)ccc2n1
Yield: 98.7 %

Procedure:
317 mg of ethyl 6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 280 mg of 6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in the form of a pasty pink solid.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1.[S]>CC(C)=O>[C:1]1([CH:16]=[CH:16][C:1]2[CH:2]=[CH:3][C:4]([C:7]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:8])=[CH:5][CH:6]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Oc2ccccc2)cc1
Agent: [S]
Solvent: CC(C)=O
Product: O=C(Oc1ccccc1)c1ccc(C=Cc2ccc(C(=O)Oc3ccccc3)cc2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 5.9 %

Procedure:
Sixty five g (0.306 mole) of neat phenyl p-toluate were maintained in the temperature range of 280°-310° C. (boiling point) while a slow stream of nitrogen was bubbled in from below the surface (sparged). Sulfur (1.92 g, 0.060 mole) dissolved in more phenyl p-toluate (20 g, 0.099 mole) at 100° C. was added slowly with stirring over a period of 2-3 hours. The heating, stirring and nitrogen sparging were continued an additional four hours and then the mixture was allowed to cool near 80° C. and 100 mL of boiling acetone was added. The suspension was transferred to a larger flask and an additional 400 mL of acetone was added. The suspension was filtered at the boil to yield 3.8 g of diphenyl 4,4'-stilbenedicarboxylate.
Reaction SMILES: Br[C:2]1([N+]([O-])=O)[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH2:3]1.BrC1C=CC(C)=C([N+]([O-])=O)C=1.[O-][Mn](=O)(=O)=O.[K+]>O=[Mn]=O.O>[C:6]([OH:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)C1=CCC(Br)([N+](=O)[O-])C=C1
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=[Mn]=O
Agent: Cc1ccc(Br)cc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1ccccc1
Yield: 22 %

Procedure:
4-Bromo-4-nitrobenzoic acid. A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of Celite®. The filter cake was washed with water. The basic filtrate was acidified to pH˜1 with concentrated HCl and extracted with EtOAc (3×300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide pure benzoic acid (1.22 g, 22%). 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). MS (ESI): neg. ion m/z 244 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14](O)=[O:15])=[C:12]([S:17][C:18]3[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=3)[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[H-].[Na+].[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44].C(=C1N=CC=N1)=O.C(O)(=O)C1C=CC=NC=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]([NH:46][S:43]([CH3:42])(=[O:45])=[O:44])=[O:15])=[C:12]([S:17][C:18]3[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=3)[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(Sc2nccc(-c3cccc(Cl)c3)c2C(=O)O)n1
Reactant: CS(N)(=O)=O
Agent: O=C(O)c1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=C1N=CC=N1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Sc2nccc(-c3cccc(Cl)c3)c2C(=O)NS(C)(=O)=O)n1
Yield: 328.3 %

Procedure:
To a solution of 3.0 g (0.0074 mol) of 4-(3-chlorophenyl)-2-(4,6-dimethoxypyrimidin-2-ylthio)nicotinic acid in 30 ml of N,N-dimethylformamide was added 1.50 g (0.0093 mol) of carbonyldiimidazole with stirring, and the mixture was stirred at room temperature for 24 hours. To a suspension of 0.60 g (0.0015 mol) of 60% sodium hydride in 30 ml of N,N-dimethylformamide was added 1.8 g (0.0019 mol) of methanesulfonamide and stirred at 80° C. for 2 hours. Thereafter, the above prepared N,N-dimethylformamide solution of carbonylimidazole of nicotinic acid was added thereto at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was then poured into water, and washed with 50 ml of ethyl acetate. Thereafter, the aqueous layer was acidified with 10% HCl, and extracted with 100 ml of ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, filtrated and concentrated. The concentrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=1/1) to obtain 3.0 g of a light-yellowish glass-like aimed product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=1[C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[CH3:36][N:35]([CH3:37])[C:33]([C:32]1[CH:38]=[CH:39][CH:40]=[CH:41][C:31]=1[NH:30][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1)=[O:34]
Reactant: CN(C)C(=O)c1ccccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N(C)C)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-amino-N,N-dimethylbenzamide. MS (ES+): m/z 582.40 (100) [MH+]; HPLC: tR=1.01 min (UPLC, purity).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:7]=1[F:22])[CH3:2].C(N(CC)CC)C.[CH2:40]([O:42][C:43](=[O:46])[CH2:44]Br)[CH3:41]>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:46])[CH2:20][CH2:21]2)[C:7]=1[F:22])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCNCC2)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(Oc2cc(OCC)cc(C(Nc3ccc(C#N)cc3)C(=O)OCC)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 300 mg (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester in 10 ml THF was cooled to 0° C. and treated with 0.14 ml triethylamine and 0.90 ml bromoacetic acid ethyl ester. The reaction mixture was stirred at r.t. overnight, then evaporated. The residue was taken up in water and extracted with EtOAc. The organic layer was dried over MgSO4. The crude product was purified by chromatography on silica with cyclohexane/EtOAc 1:2 to give 215 mg (RS)-(4-cyano-phenylamino)-[5-ethoxy-3-(1-ethoxycarbonylmethyl-piperidin-4-yloxy)-2-fluoro-phenyl]-acetic acid ethyl ester as a colorless foam. MS: 528.3 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2.C(O)(=O)C>O>[F:16][C:3]1[C:2]([N:1]2[C:20](=[O:21])[C:19]3[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=3[C:17]2=[O:22])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21

Procedure:
A mixture of 6-amino-7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine (0.31 g), 3,4,5,6-tetrahydrophthalic anhydride (0.28 g) and acetic acid (3 ml) is heated under reflux for 2 hours. After being allowed to cool, water is added to the mixture, which is then extracted with ethyl acetate. The organic layer is washed with water, neutralized with sodium bicarbonate solution, dried and concentrated. The residue is purified by silica gel thin layer chromatography using a (1:2) mixture of ethyl acetate and hexane as the eluent to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(=O)(O)(O)O.[H][H]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCCc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 12.3 gm (42.7 millimols) of 4-(4'-chloro-4-biphenylyl)-4-oxo-butyric acid in 150 ml of acetic acid was admixed with 4 ml of orthophosphoric acid of 89% and hydrogenated in the presence of 4 gm of palladium/barium sulfate (5%) at a hydrogen pressure of 5 atmospheres and at room temperature. The catalyst was vacuum-filtered off, and the solvent was evaporated. The residue was dissolved in ether, the organic phase was washed with water and evaporated to dryness. The free acid thus obtained was dissolved again in ethyl acetate, the solution was filtered and mixed with a small excess of cyclohexylamine. Yield: 9.5 gm (62.5% of theory); m.p. 187°-190° C. (cyclohexylamine salt). Melting point of the free acid: 136°-137° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Ni]>[CH:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CN(C2CCCCC2)CN1c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(N2CN(C3CCCCC3)CC2=O)cc1

Procedure:
1-Cyclohexyl-3-(4-nitrophenyl)-imidazolidin-4-one (2.9g) was dissolved in ethanol (500 ml) and 200 mg Raney nickel added. The mixture was then hydrogenated.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:20])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([C:3]1[S:4][C:5]2[N+:11]([O-:20])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2cccnc2s1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2ccc[n+]([O-])c2s1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 83.1 %

Procedure:
2-Ethyl-7-azabenzothiazole (2.95 g) was dissolved in dichloromethane (30 ml), and meta-chloroperbenzoic acid (4.7 g) was added to the solution at room temperature. After 3.5 hours, meta-chloroperbenzoic acid (2.3 g). was further added. After completion of a reaction, the reaction mixture was treated with an aqueous solution of sodium sulfite while chilling with ice water. The thus-treated reaction mixture was diluted with dichloromethane, and the resultant organic layer was washed with aqueous sodium hydrogencarbonate, water and saline in that order, and dried. The solvent was distilled out to obtain 2-ethyl-7-azabenzothiazole-7-oxide (2.69 g). This compound was added to dichloromethane (27 ml), and dimethylaminocarbamoyl chloride (4.16 g), trimethylsilyl cyanide (5.69 ml) and triethylamine (6.3 ml) were successively added to conduct a reaction for 8 hours at room temperature. Trimethylsilyl cyanide (2.5 ml) and dimethylaminocarbamoyl chloride (2.5 ml) were further added. After the reaction was conducted for 2 days at room temperature, aqueous sodium hydrogencarbonate was added to the reaction mixture, followed by stirring for 1 hour. The reaction mixture was subjected to extraction with ethyl acetate, and the resultant organic layer was washed with water, dried and evaporated. After purifying the residue through a silica gel column (eluthion with dichloromethane: methanol=200:1), recrystallization from dichloromethaneisopropyl ether was conducted to form 2-ethyl=6-cyano-7-azabenzothiazole (1.37 g). The intended compound was obtained in accordance with the same procedure as that of Example 106 except that the above compound was used in place of 2-ethyl-6-chlorobenzothiazole. Physical properties of this compound are described below.