Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[N:9](CC3C=CC(OC)=CC=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.O.CCOC(C)=O>CC#N>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:22])([CH3:21])[NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)c3ccc(Cl)nc3C2(C)C)cc1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)c2ccc(Cl)nc21
Yield: 62.8 %

Procedure:
To solution of 2-chloro-6-(4-methoxy-benzyl)-7,7-dimethyl-6,7-dihydro-pyrrolo[3,4-b]pyridin-5-one (1.58 g, 5.0 mmol) in CH3CN (20 mL) was added ceric ammonium nitrate (8.2 g, 15.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours before water and EtOAc was added into the mixture. The organic layer was separated, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel column chromatography to give title compound (617 mg, 63%) as a solid. MS: 197.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[S:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:43])[CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:43])[CH2:31][S:17][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: S=c1[nH]c2ccccc2cc1-c1ccccc1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CSc1nc2ccccc2cc1-c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Phenylquinolin-2-thione (2.5 g.) was added to a suspension of sodium hydride (0.55 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (16 ml.) at 0°-5°. When all the hydrogen had evolved, (S)-2-t-butoxycarbonylamino-1-p-toluenesulphonyloxypropane (3.5 g.) was added and the mixture was stirred at ambient temperature for 16 hr. The mixture was then poured into ice-water (160 ml.) and extracted with ethyl acetate (3×50 ml.). The ethyl acetate extract was washed with brine (50 ml.) and then dried (MgSO4). The solvent was evaporated and the residue was crystallised from petroleum ether to give (S)-2-(2-t-butoxycarbonylaminopropylthio)-3-phenylquinoline, m.p. 86°-7°.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[NH:20][C:19]2=[O:28])[CH:12]=1.CO.[Li+].[OH-].Cl>O>[F:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:28])[C:18]2=[CH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29]
Reactant: COC(=O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
6-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid methyl ester (410 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (289 mg, 73% yield) as a brown solid. LC-MS (m/z) 397 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:28]([NH:29][C:30](=[O:37])[CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:27](=[O:38])[N:9]2[C:10]=1[C:11]([O:13]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12])#[N:2].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:1]([CH2:3][CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:28]([NH:29][C:30](=[O:37])[CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:27](=[O:38])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])#[N:2]
Reactant: N#CCCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#CCCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
A solution of diphenylmethyl 3-(2-cyanoethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (1g.) in anisole (1 ml.) was treated with trifluoroacetic acid (4 ml.). After 5 minutes at 23° the solvents were removed in vacuo and the residue was partitioned between ethyl acetate and dilute aqueous sodium bicarbonate solution. The alkaline phase was washed thoroughly with ethyl acetate, then taken to pH2 with 2N-hydrochloric acid. The acidic mixture was extracted with ethyl acetate and the organic extracts washed with brine, and dried and evaporated in vacuo. The residual gum was dissolved in ethyl acetate and the solution run into petroleum ether to give, after filtration and drying, the title acid (567 mg., 82%) as an amorphous solid, m.p. ca 105° (decomp.) [α]D22 + 102° (C 0.75, 1% NaHCO3), λinflex. (0.1 M-pH 6 phosphate buffer) 260 nm. (ε 7,290), νmax. (Nujol) 3300 (NH), 3675 to 2400 (bonded OH), 2210 and 2250 (CN), 1775 (β-lactam), 1715 (CO2H), and 1665 and 1530 cm.-1 (CONH), τ (D2O with NaHCO3) 4.43 (C(7) --H, d, J 4.5 Hz), 4.95 (C(6) --H, d, J 4.5 Hz.), 6.13 (CH2CONH), 6.42 and 6.82 (C(2), AB-q, J 18 Hz.), and 7.1 to 7.6 (CH2CH2CN, ABCD-complex) (Found: C, 50.7; H, 4.0; N, 10.7; S, 16.0; C16H15N3O4S2 requires C, 50.9; H, 4.0; N, 11.1; S, 17.0%), Rf 0.28 (System C) and Rf 0.6 (System B).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C@@H:12]([N:19]2[CH2:23][C:22]([O:24][CH3:25])=[CH:21][C:20]2=[O:26])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>O1CCCC1.O.ClCCl>[CH:14]1([CH2:13][C@H:12]([N:19]2[CH2:23][C:22]([O:24][CH3:25])=[CH:21][C:20]2=[O:26])[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=2)=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)N2CC(OC)=CC2=O)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccc(C(=O)O)cn2)C1
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A solution of 6-[(S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 10, 62 mg, 0.16 mmol) in tetrahydrofuran (2 mL) was treated with a solution of lithium hydroxide monohydrate (8 mg, 0.18 mmol) in water (1 mL). The mixture was stirred for 1 h. It was then acidified with 2N aqueous hydrochloric acid and diluted with dichloromethane, washed with saturated sodium chloride solution and dried to afford 6-[(S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-nicotinic acid, (23 mg, 39%) as a white powder: LR-ES-MS m/z calculated for C19H23N3O5 [M]+ 373, observed [M+H]+ 374; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.97 (m, 11H) 3.79 (s, 3H) 4.01 (d, J=17.9 Hz, 1H) 4.33 (d, J=17.7 Hz, 1H) 4.93 (dd, J=10.9, 4.5 Hz, 1H) 5.18 (s, 1H) 8.12 (d, J=8.5 Hz, 1H) 8.24 (dd, J=8.7, 2.3 Hz, 1H) 8.83 (d, J=2.3 Hz, 1H) 11.18 (s, 1H) 12.81 (br. s., 1H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: C1COCCN1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCOCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3.1 g), morpholine (2 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 4-[(2-phenylquinazolin-4-yl)-carbonyl]-morpholine (3 g), melting at 148° C., is obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1.CCOC(C)=O>COCCOC.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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:49]3[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=3)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (200 mg, 0.364 mmol), sodium carbonate (77 mg, 0.729 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (91 mg, 0.437 mmol) and bis(triphenylphosphine)palladium chloride (25.6 mg, 0.036 mmol) in DME (2 mL) and H2O (0.667 mL) was stirred at 85° C. for 2 h. To the resulting mixture was added EtOAc. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2(Hexane/EtOAc=2/3) to give the title compound as a yellow oil (88 mg, 40.6%). 1H NMR (500 MHz, CDCl3) δ ppm 1.28-2.01 (m, 17 H), 3.80 (d, J=2.93 Hz, 3 H), 3.85 (s, 3 H), 3.91-4.01 (m, 4 H), 4.23 (br s, 2 H), 4.41 (br s, 1 H), 4.68 (d, J=1.95 Hz, 2 H), 5.36 (br s, 1 H), 6.36-6.54 (m, 2 H), 7.15-7.21 (m, 1 H), 8.26 (br s, 1 H), 9.02 (br s, 1 H). [M+H] calc'd for C31H39FN6O5, 595; found, 595.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13]O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>ClCCl>[ClH:17].[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][Cl:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cnn(Cc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.88 g of (1-benzyl-1H-pyrazol-4-yl)methanol was dissolved in 30 ml of dichloromethane, and 2.1 ml of thionyl chloride was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain 2.39 g of 1-benzyl-4-(chloromethyl)-1H-pyrazole hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10][N:9]2CC=C)=[CH:4][CH:3]=1.C(O)C>[Rh](Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[NH:9][CH2:10][CH2:11][N:12]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13]2)=[CH:6][CH:7]=1
Reactant: C=CCN1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: Cl
Product: Clc1ccc([C@@H]2CN(Cc3ccccc3)CCN2)cc1
Temperature: 95 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
To (R)-2-(4-chlorophenyl)-4-(phenylmethyl)-1-(2-propenyl)hexahydropyrazine (357 mg, 1.1 mmol) produced in Example 15, ethanol (3 mL), distilled water (0.2 mL) and tris(triphenylphosphine) rhodium chloride (30 mg, 0.05 equivalent) were added. The mixture was stirred at 95° C. for 18 hours, and was concentrated. To the concentrate, 1 N hydrochloric acid (5 mL) and toluene (5 mL) were added; and formed insolubles were removed by filtration. After the organic layer and aqueous layer was separated, the obtained aqueous layer (yield: 63%, chemical purity: 77.5 area %, optical purity: 97.7% e.e.) was concentrated. To the concentrate, acetone (10 mL) was added to precipitate crystals. The mixture was stirred at 25° C. for 1 hour, then cooled to 5° C., and further stirred for 1 hour. The crystals were separated by filtration under reduced pressure, then washed with acetone (5 mL), and dried under vacuum, to obtain 134 mg of the title compound as white crystals (yield: 44%, chemical purity: 99.1 area %, optical purity: 99.9% e.e.). The retention time in the chemical purity analysis method was 3.1 min.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13](O)([CH3:15])[CH3:14])[CH:10]=[N:11][CH:12]=1)([CH3:3])[CH3:2].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][C:13]([C:9]1[CH:10]=[N:11][CH:12]=[C:7]([CH2:6][O:5][Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:1]([CH3:3])[CH3:2])[CH:8]=1)([CH3:15])[CH3:14]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)[Si](OCc1cncc(C(C)(C)O)c1)(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OCc1cncc(C(C)(C)F)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To 2-(5-((triisopropylsilyloxy)methyl)pyridin-3-yl)propan-2-ol (1.1 g, 3.4 mmol) in DCM (30 mL) at −78° C. was added diethylaminosulfur trifluoride (DAST) (0.67 mL, 5.1 mmol) and stirred at the same temperature for 1 hr, then warmed to 0° C. for 3 hrs. The resulting mixture was quenched with MeOH and saturated aqueous NaHCO3. The mixture was extracted with EtOAc three times and dried with anhydrous NaSO4, filtered and concentrated to dryness. Careful purification by flash chromatography (silica gel, hexanes/EtOAc) gave the desired fluoride (3-(2-fluoropropan-2-yl)-5-((triisopropylsilyloxy)methyl)pyridine) as a light yellow solid (0.43 g). 1H NMR (CDCl3): d: 1.127 (d, J=6.3 Hz, 18H), 1.204 (m, 3H), 1.712 (s, 3H), 1.786 (s, 3H), 4.922 (s, 2H), 7.781 (s, 1H), 8.566 (s, 2H). 3-(2-fluoropropan-2-yl)-5-((triisopropylsilyloxy)methyl)pyridine was deprotected with excess aqueous HF in THF to provide (5-(2-fluoropropan-2-yl)pyridin-3-yl)methanol as a white solid. (5-(2-fluoropropan-2-yl)pyridin-3-yl)methanol was then oxidized to 5-(2-fluoropropan-2-yl)nicotinaldehyde using standard Swern Oxidation conditions.
Reaction SMILES: Br.Br[CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1.C([O:26]C)(C)(C)C.ClCCl>O>[OH:26][CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1
Reactant: COC(C)(C)C
Reactant: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Agent: Br
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1

Procedure:
first isolating the compound (VI) as a solid by stirring the reaction solution into a suitable organic solvent, methyl tert-butyl ether, dichloromethane etc., and subsequently reacting the resulting product with water and by stirring at 50°-100° C., preferably at 60°-80° C., to give 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.[CH3:10][S:11]SC.N(OC(C)(C)C)=O.O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([S:11][CH3:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1F
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: ClCCCl
Product: CSc1ccc(C)c(F)c1
Reaction time: 2 h
Yield: 525.5 %

Procedure:
A mixture of 3-fluoro-4-methylaniline (25 g), dimethyl disulphide (375 g) and t-butyl nitrite (30 ml) in 1,2-dichloroethane was warmed to start the reaction. A solution of 3-fluoro-4-methylaniline (225 g) in 1,2-dichloroethane was added dropwise, simultaneously with t-butyl nitrite (241 ml) at such a rate as to maintain the temperature below 60° C. The mixture was stirred for 2 hours, then water was added. The organic layer was washed with water, hydrochloric acid, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 2-fluoro-4-(methylsulphenyl)toluene (164 g) as a yellow oil; NMR (acetone-d6); 2.2 (3H,d), 2.5 (3H,s), 7.05 (3H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[ClH:1].[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: COc1ccccc1COc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1COc1cncc(N2CCNCC2)n1
Product: Cl

Procedure:
The title compound was prepared according to the procedure of example 4, step 2 starting from the product of step 1 above (0.49 g), piperazine (0.86 g, 10 mmol) and K2CO3 (1.00 g, 7.2 mmol). This gave the free base of the title compound as an oil. Yield 0.43 g (73%). The free base was dissolved in ethyl ether and a solution of HCl in diethyl ether was added until no more precipitate was formed. The precipitate was collected, washed with diethyl ether, and dried in vaccum to give 0.41 g (56%) of the title compound: mp 171-173° C.). HRMS m/z calcd for C16H20N4O2 (M)+ 300.1586, found 300.1586. Anal. (C16H20N4O2.2HCl) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[NH:6][C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[C:13]([O:12][C:11]([N:10]([CH2:9][C:7]1[N:6]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]2[CH:19]=[C:20]([Cl:21])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)[CH3:18])=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl [(5,6-dichloro-1H-benzimidazol-2-yl)methyl]methylcarbamate (400 mg) and DMF (4 mL) were added ethyl bromoacetate (201 μL) and K2CO3 (335 mg), followed by heating and stirring at 70° C. for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=50/50-0/100) to obtain ethyl (2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-5,6-dichloro-1H-benzimidazol-1-yl)acetate (393 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][N:10]=1)C1C=CC=CC=1>CCO.[Pd]>[CH3:18][O:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[N:10][CH:11]=1
Reactant: COCOc1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(O)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 0.1 %

Procedure:
To 2-(benzyloxy)-5-(methoxymethoxy)pyridine (1.8 g, 8.71 mol) in EtOH was added Pd/C (1.0 g). The mixture was charged with H2 (15 psi), stirred at rt for 45 min, filtered, and concentrated to give 5-(methoxymethoxy)pyridin-2-ol (1.35 g, quantitative yield) as a pale yellow solid. LRMS (M+H+) m/z 156.1
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5](/[CH:23]=[C:24](\[F:35])/[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[CH:6]=[N:7][C:8]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:11]1.CCOC(C)=O>CCO>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:4]=[C:5](/[CH:23]=[C:24](\[F:35])/[C:25]([NH:27][OH:28])=[O:26])[CH:6]=[N:7][C:8]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:11]1
Reactant: O=C(NOC1CCCCO1)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NO)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2M ethanolic hydrogen chloride (2.0 mL) was added to the solution of (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.5 g) in EtOH (5 ml) and the mixture was stirred at ambient temperature for 3 hrs. To the reaction mixture was added AcOEt and isolated precipitate was collected by filtration to give (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (0.28 g),
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:35])[C:8]1=[O:36]
Reactant: CC(C)CCc1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCc1c(Oc2cccc(OC(F)(F)F)c2)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of 3-(5-isopentyl-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenoxy)-1,2-dihydro pyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.098 mmol) in THF (2 mL) and water (2 mL was added LiOH.H2O (8.2 mg, 0.196 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-1-methyl-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 20.0% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.57 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.98-6.95 (m, 2H), 4.51 (t, J=5.6 Hz, 1H), 4.02-3.97 (m, 2H), 3.58 (s, 3H), 3.50-3.45 (m, 2H), 3.15-3.10 (m, 2H), 1.77-1.70 (m, 2H), 1.54-1.50 (m, 1H), 1.32-1.23 (m, 2H), 0.79 (d, J=6.8 Hz, 6H). LCMS: MH+ 482 and TR=3.447 min.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].CC1C=C(C(C)(C)C)[C:21]([OH:28])=[C:20](C(C)(C)C)C=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.Cl>C(O)(=O)C>[C:21]([C:10]1([OH:16])[CH:9]=[CH:8][C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:11]1[C:12]([OH:14])=[O:13])(=[O:28])[CH3:20]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=C(C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-methacrylamidosalicylic acid (30 millimole, 6.7 g) was mixed with butylhydroxytoluene (20 mg), acetic anhydride (10.0 g), and acetic acid (15.0 g). After sealing the solution, its temperatures was raised to 60° C., and the solution was kept at 60° C. for 30 min while stirring. Then, a mixture (1.0 g) of concentrated sulfuric acid (1 part) with hydrochloric acid (10 parts) was added to the solution, followed by raising its temperature to 90° C., and kept at 90° C. for one hour to proceed the reaction. After the reaction was over, the solution was stood to cool to room temperature to give brown crystal. The crystal was filtrated, and recrystallized by a solution of 0.5% hydroquinone in methanol. Dried under a reduced pressure, 2-acetyl-5-methacrylamidosalicylic acid was obtained as pale reddish brown crystal having a needle shape: mp. 192.4° C., yield 2.54 g, 64.1%.