Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:17](OC)(=[O:22])[C:18]([O:20][CH3:21])=[O:19].Cl>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=O)OC
Reactant: Brc1ccccc1C=Cc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1/C=C\c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of the Grignard reagent prepared from part of the mixture of isomers of 1-phenyl-2-(2-bromophenyl)ethylene described above (5.58 g) and magnesium (0.63 g) in dry THF (20 ml) was added dropwise over 30 mins. to a stirred solution of dimethyl oxalate (5.06 g) in dry THF (40 ml) cooled to -15° C. The resulting mixture was stirred at about -15° C. for 30 minutes, then at room temperature for 1 hour, then poured into dilute hydrochloric acid and extracted with ether. The extracts were washed with water, dried, concentrated under reduced pressure, then chromatographed twice [(i) 30% ether in petrol; (ii) 20% hexane in dichloromethane] to give isomerically pure Z-methyl 2-(2'-phenylethenyl)phenylglyoxalate (1.76 g, 31% yield) as a yellow oil, 1H nmr (CDCl3) : delta 3.87 (3H, s), 6.78 (centre of 2 doublets, each 1 H, J 12Hz) p.p.m.
Reaction SMILES: Cl.[CH3:2][C@H:3]([CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:4][NH2:5].[C:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[C:17]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(O)=[O:12].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:35][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:25]=1[CH2:24][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([C:11](=[O:12])[NH:5][CH2:4][C@H:3]([CH3:2])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH:15]=2)[N:19]([CH3:23])[CH:18]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: C[C@@H](CN)CC(F)(F)F
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc23)c(OC)c1
Reaction time: 18 h
Yield: 55.1 %

Procedure:
A mixture of (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride (9.79 g), methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate (20.55 g), 4-dimethylaminopyridine (7.45 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.07 g) and triethylamine (9.3 mL) was dissolved in dry methylene chloride (240 mL) and the solution was stirred under an inert atmosphere for 18 h. The mixture was diluted with methylene chloride (200 mL) and washed twice with 1N hydrochloric acid. The combined acid washes were back extracted with methylene chloride and the combined organic extracts were washed (water, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatography, eluting with 97:3 methylene chloride:ethyl acetate to give methyl (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate (14.48 g, 55%) as a white solid; mp 150°-151° C.; partial NMR (300 MHz, CDCl3): 1.12 (d, 3H, CH3), 1.98-2.08 (m, 1H, CHCH3) 2.12-2.44 (m, 2H, CF3CH2), 3.30-3.58 (m, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.13 (s, 2H, ARCH2Ar'), 6.23 (br t, 1H, NHCO).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)=[O:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[ClH:48].O1CCOCC1>C(Cl)Cl>[ClH:48].[O:32]=[C:31]([N:33]1[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]1)[CH2:30][N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][C@@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:47])([F:46])[F:1])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)no2)cc1C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)N3CCNCC3)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tertiary-butyl 4-{[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetyl}piperazine-1-carboxylate (70.7 mg) in methylene chloride (1 ml) was added dropwise 10 equivalents of 4M HCl/dioxane, followed by stirring at room temperature for 3 hours. After 5 hours, the reaction solution was concentrated. With addition of diisopropyl ether, a white solid was precipitated. The white solid was washed with IPE to obtain 1-(2-oxo-2-piperazin-1-ylethyl)-4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole hydrochloride (58.9 mg) as a pale red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][CH3:24])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:31])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][CH3:24])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COCCN1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COCCN1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(2-methoxyethyl)piperazin-1-yl]quinolin-7-yl}ethanone (22 mg, 0.063 mmol) and ammonium acetate (48.8 mg, 0.632 mmol) in methanol (0.36 mL) and acetonitrile (0.36 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (7.95 mg, 0.126 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (22 mg, 99%). The residue was used directly in the next step. LCMS calculated for C18H26ClN4O(M+H)+: m/z=349.2; found: 349.1.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]1=[O:43]>ClCCl.C(OCC)C>[O:43]=[C:27]1[C:28]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:30][N:26]1[CH2:25][CH:24]=[O:23]
Reactant: O=C1N(CCO)CCC1(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of Dess-Martin periodinane (8.03 g, 18.92 mmol) in dichloromethane (100 mL) was added a solution of the product from Example 67A (4.84 g, 17.20 mmol) in dichloromethane (50 mL) at room temperature. After 30 minutes at room temperature, the reaction is diluted with diethyl ether, filtered and concentrated. Chromatography eluting with a gradient of 50% to 100% ethyl acetate/hexanes using a SF25-40 g (Analogix®, Burlington, Wis.) column gave the title compound. MS (DCI+) m/z 280.1 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6]([NH:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH2:49].C(N(CC)CC)C>ClCCl>[CH3:45][O:46][C:47](=[O:50])[CH2:48][NH:49][C:8]([C:7]1[C:6]([NH:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[N:5][CH:4]=[C:3]([Cl:2])[CH:11]=1)=[O:9]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNc1ncc(Cl)cc1C(=O)O
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1cc(Cl)cnc1NCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.4 %

Procedure:
To a suspension of 5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}-nicotinic acid hydrochloride salt (0.060 g, 0.12 mmol) in dichloromethane (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.034 g, 0.18 mmol). The reaction was stirred at ambient temperature for 5 minutes. This was followed by addition of solution of glycine methyl ester hydrochloride (0.015 g, 0.12 mmol) and triethylamine (0.016 mL, 0.12 mmol) in dichloromethane (0.5 mL). The reaction was then stirred at ambient temperature overnight. The reaction was diluted with dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.030 g).
Reaction SMILES: [CH3:1][O:2][N:3]([CH:7]([CH3:27])[CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:24][CH2:25][CH3:26])[C:4](=[O:6])[CH3:5].CO[N:30](CCCCN1C2C3C=CC=CC=3N=CC=2N=C1CCC)C(=O)C.[OH-].[NH4+]>>[NH2:30][C:15]1[C:14]2[N:13]=[C:12]([CH2:24][CH2:25][CH3:26])[N:11]([CH2:10][CH2:9][CH2:8][CH:7]([N:3]([O:2][CH3:1])[C:4](=[O:6])[CH3:5])[CH3:27])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC)C(C)=O
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(C)N(OC)C(C)=O
Agent: [NH4+]
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(C)N(OC)C(C)=O

Procedure:
A modification to the general procedure of Part G of Example 6 was followed using N-methoxy-N-[1-methyl-4-(2-propyl-1H-imidazo-[4,5-c]quinolin-1-yl)butyl]-acetamide (1.0 g, 2.71 mmol) in lieu of N-methoxy-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]acetamide. The reaction mixture was cooled to 0° C. before addition of the ammonium hydroxide. Recrystallization from hot acetonitrile following flash column chromatography provided 0.059 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-N-methoxyacetamide as a tan crystalline solid, mp 140-142° C. MS (APCI) m/z 384.1 (M+H+); Theor. Mass: 384.240 Da Meas. Mass: 384.2406 Da. Mass Dev. 1.6 ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[K+].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.Cl>O>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:15])=[CH:12][CH:11]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(NC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of L-Alanine (2.67 g, 30.0 mmol) and KOH (3.90 g, 69.5 mmol) in water (50.0 mL) was added 4-chlorobenzoyl chloride (5.25 g, 30.0 mmol). After stirring at RT for 16H, the reaction mixture was cooled to 0° C., acidified to pH=2 with 10 M HCl and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and air dried under vacuum to afford 5.80 g (85% yield) of the title compound as a white solid that was carried forward without further purification: 1H NMR (500 MHz, DMSO-d6) δ 12.62 (1H, br. s.), 8.76 (1H, d, J=7.15 Hz), 7.90 (2H, d, J=8.25 Hz), 7.55 (2H, d, J=8.25 Hz), 4.40 (1H, qd, J=7.33, 7.15 Hz), 1.38 (3H, d, J=7.15 Hz); HPLC retention time: 2.223 min; LCMS (ES): m/z 228 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-])=O)=O.N12CCCN=C1CCCCC2.C1C=CC([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:35][C:36]2[CH:41]=[C:40]([C:42]#[N:43])[CH:39]=[CH:38][CH:37]=2)=CC=1.[Br-]>C1(C)C=CC=CC=1>[NH2:14][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[CH2:1][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:42]#[N:43])[CH:41]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: N#Cc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(CCc2cccc(C#N)c2)c(N)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 136 %

Procedure:
Ethyl 4-formyl-3-nitrobenzoate (5.81 g) was dissolved in 70 ml of toluene, then 2.1 ml of 1,8-diazabicyclo[5.4.0]-undec-7-ene and the mixture was stirred at 80° C. for one hour. To the reaction solution, 2.69 g of 3-[(1,1,1-triphenylphosphonio)methyl]benzonitrile bromide was added, and the mixture was stirred at 80° C. for 24 hours. Insoluble matters were filtered out and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (10:1) as an eluting solvent. The resulting intermediate (3.1 g) was dissolved in a mixed solvent of 50 ml of ethanol and 10 ml of tetrahydrofuran, then 1 g of a palladium oxide-barium sulfate complex was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 3 days. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluting solvent to give 2.35 g of ethyl 3-amino-4-[2-(3-cyanophenyl)ethyl]benzoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[C:6]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)Cc1cc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(Cl)n1
Temperature: -5 °C

Procedure:
A suspension of 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine (10.56 g) in DCM (230 mL) was stirred magnetically (under nitrogen) and cooled to −5° C. Triethylamine (6.78 mL) was added followed by the dropwise addition of a solution of morpholine (3.85 mL) in DCM (30 mL) maintaining the reaction temperature below −5° C. The reaction was stirred at room temperature for 1 hour and then the organic mixture washed with water (300 mL). The organic phase was dried (MgSO4), filtered and evaporated to a brown solid which was chromatographed on silica, eluting with 50% ethyl acetate in DCM, to give the desired material (6.81 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:14]([CH3:16])[NH2:15])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18]>Cl.CO>[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[N:15][N:14]([C:4]2[N:5]=[N:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([CH3:1])[N:3]=2)[CH3:16])=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cc1nc(N(C)N)nnc1-c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1nc(N(C)N=Cc2ccc(C#N)cc2)nnc1-c1ccccc1
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
6N-Hydrochloric acid (1 drop) was added to a stirred solution of 5-methyl-3-(1-methylhydrazino)-6-phenyl-1,2,4-triazine (0.71 g) and 4-cyanobenzaldehyde (0.44 g) in methanol (5 ml) at room temperature and then the stirring was continued for 5 minutes. The mixture was evaporated under reduced pressure, the residue was triturated with diethyl ether, and the precipitates were collected by filtration to give 3-[2-(4-cyanobenzylidene)-1-methylhydrazino]-5-methyl-6phenyl-1,2,4-triazine (0.95 g).
Reaction SMILES: Cl.[C:2]([C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:20]>>[C:2]([C:10]1[CH:11]=[C:12]([C:18]([NH2:19])=[O:20])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1C(=O)c1ccccc1
Reactant: O
Agent: Cl
Product: Cc1[nH]c(=O)c(C(N)=O)cc1C(=O)c1ccccc1

Procedure:
Admix 80 ml 35% hydrochloric acid and 20 g (0.078 mole) of 5-benzoyl-1,2-dihydro-6-methyl-2-oxo-3-pyridine carbonitrile, stir the mixture at 40° C. for 5 hours, cool, and dilute the resulting mixture with 80 ml water. Collect the title compound as a precipitate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]1[O:9][C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1.[OH-].[Na+]>[C:1]([O:5][C:6]([CH2:7][C:8]1[O:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][CH:12]=1)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(CC(=O)OC(C)(C)C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(C(=O)O)o1
Reaction time: 8 h
Yield: 24.2 %

Procedure:
5-Ethoxycarbonylfuran-2-ylacetic acid tert-butyl ester (0.37 g, 1.46 mmol) obtained in step 2 was dissolved in tetrahydrofuran (2 mL), dissolved in 1N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred overnight. 1N Hydrochloric acid (1.5 mL) was added to the reaction mixture, and the mixture was neutralized, purified by high performance liquid chromatography and freeze-dried to give the title compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([C:16]([O:18]CC)=O)=[CH:14][N:13]=[C:12]([S:21][CH3:22])[N:11]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][NH2:33]>FC(F)(F)CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:10]3[N:11]=[C:12]([S:21][CH3:22])[N:13]=[CH:14][C:15]=3[C:16](=[O:18])[N:32]([C:26]3[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])[N:33]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1C(=O)c1cccc(Cl)n1
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: OCC(F)(F)F
Product: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)nc(-c3cccc(Cl)n3)c2n1
Temperature: 108 °C

Procedure:
To a suspension of Example 159A (512 mg, 1.516 mmol) in 2,2,2-trifluoroethanol (15 mL) was added 2,6-dichlorophenylhydrazine hydrochloride (324 mg, 1.516 mmol). This mixture was heated in a sealed tube at 108° C. overnight. The mixture was partitioned between ethyl acetate and brine. The organic phase was concentrated, and the residue was purified by flash chromatography (15-50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 451 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: O=C(O)C(O)Cc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid and 50 ml of ethanol were charged to a pressure reactor to form a solution, and 1.0 g of Raney nickel was added thereto. The atmosphere was displaced with hydrogen, and the mixture was stirred at 70° C. under a hydrogen pressure of 30 kg/cm2 for 0.5 hour. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 8.7 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.
Reaction SMILES: N[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:11][B-](F)(F)F.[H+].N(OCCC(C)C)=O>C(O)C>[F:11][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1cccnc1[N+](=O)[O-]
Agent: CC(C)CCON=O
Agent: [H+]
Solvent: CCO
Product: O=[N+]([O-])c1ncccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a stirred solution of 3-Amino 2-nitro pyridine (2.5 g, 17.97 mmol) in dry ethanol (20 ml) was added 10 ml of tetrafluoroboric acid (48% in water). The reaction mixture was cooled to 0° C. and isoamyl nitrite (2.6 g, 22.4 mmol) was added dropwise at 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was filtered, and the solid obtained was washed with diethyl ether. The filtered solid was added to preheated (150 mL) toluene with stirring and reaction mixture was refluxed for 24 hours. The solvent was evaporated and the residue taken in ethyl acetate (200 ml) and washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude 3-fluoro-2-nitropyridine. This was purified by column over silica gel using 10% ethyl acetate in pet ether as eluant to get 1 g (39%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.CO>O1CCCC1>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(F)c(Br)cc1F
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 2 g (8.44 mmol) of 4-bromo-2,5-difluorobenzoic acid (prepared according to the procedure of Ishikawa et al., Kogyo Kagaku Zasshi, pg 972-979, 1970) in 20 mL of tetrahydrofuran was added 40 mL of a 1M solution of borane-tetrahydrofuran complex. The solution was heated under reflux for 64 h, cooled to ambient temperature and 100 mL of methanol was added. The reaction was then heated for a further 2 h, cooled and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 1.6 g of 4-bromo-2,5-difluorobenzyl alcohol. To a solution of 1.3 g (5.6 mmol) of 4-bromo-2,5-difluorobenzyl alcohol in 20 mL of dichloromethane at 0° C. was added 2.27 g (6.7 mmol) of carbon tetrabromide and 1.8 g (6.7 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) to afford 1.5 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[O:12][CH3:13].F[P-](F)(F)(F)(F)F.[N:21]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2N=N1.ClCCl>C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:21][C@H:25]2[CH2:24][CH2:29][C@@H:28](/[CH:7]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:27][CH2:26]2)=[O:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC/C=C/[C@H]1CC[C@@H](NC(=O)Cc2ccc(O)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a mixture of the above product (2) (2.17 g), 4-hydroxy-3-methoxyphenyacetic acid (1.16 g), benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (3.33 g) and dichloromethane (50 ml) under ice-cooling was added triethylamine (2.68 ml). The reaction mixture was stirred at room temperature for 1 hour, and then washed with saturated aqueous ammonium chloride and then brine. The organic layer was dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) and the recrystallized from hexane-ethyl acetate to give 770 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])=[O:16])[CH:12]=[CH:11][N:10]=1)=[O:8].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH+:6]([O-:31])[C:7]([C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])=[O:16])[CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: COCCCNC(=O)c1ccnc(C(=O)NCCCOC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COCCCNC(=O)c1ccnc(C(=O)[NH+]([O-])CCCOC)c1

Procedure:
From 1 g of N,N'-di-(3-methoxypropyl)pyridine-2,4-dicarboxamide and 1.2 g of MCPBA.