Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=2)=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cn2)cs1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47 %

Procedure:
2-[(4-{2-[(5-Bromopyridin-2-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (12.5 g) obtained in Example 242-1 was dissolved in tetrahydrofuran (20 mL), 1 mol/L-borane/tetrahydrofuran complex (100 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (100 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, 2-aminoethanol (40 mL) was added, and the mixture was stirred at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1) to give the title compound (5.7 g) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=[O:7])#[N:2].[C:13](Cl)(=O)C>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([F:12])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)c(C#N)c1
Yield: 78.1 %

Procedure:
To a stirred suspension of 16.0 g (96.9 mmol) 2a and 161 ml methanol were added 30.4 g (387.6 mmol) acetyl chloride drop wisely at 0° C. The reaction mixture was stirred over night, filtered and concentrated. The residue was diluted with dichloromethane, washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (hexane:ethylacetate). The desired product 2b was obtained in 78.1% yield (13.5 g; 75.7 mmol)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.[C:18](=[NH:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:18](=[N:31][C:2]2[N:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:3]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(-c2cnnc(Cl)c2)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cnnc(N=C(c3ccccc3)c3ccccc3)c2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of methyl 3-(6-chloropyridazin-4-yl)benzoate (0.21 g, 0.84 mmol), benzophenone imine (260 μL, 1.5 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (26 mg, 0.042 mmol), cesium carbonate (0.55 g, 1.7 mmol) and palladium acetate (9.5 mg, 0.042 mmol) in 1,4-dioxane (3 mL) was vacuum and refilled with nitrogen for 3 times. The reaction was stirred at 110° C. overnight. After cooling it was diluted with ethyl acetate. The organic solution was washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in methylene chloride (0-20%) to afford the desired product (0.23 g). LCMS (M+H)+: m/z=394.2
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.CO.C(#N)C.C([O-])(=O)C.[Ca+2:42].C([O-])(=O)C>CCCCCCC.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:42]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Solvent: CCCCCCC
Solvent: CO
Solvent: CC#N
Product: [Ca]
Temperature: 67.5 °C
Reaction time: 6 h

Procedure:
Raltegravir (10 gm), methanol (60 ml), acetonitrile (40 ml), water (2 ml) and calcium acetate (4 gm) were added at 25 to 30° C. The contents were heated to 65 to 70° C. and distilled off solvent completely under vacuum at 45° C. to obtain residue. To the residue was added n-heptane (50 ml) and again distilled to obtain residue. n-Heptane (100 ml) was added to the residue and stirred for 6 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 9.8 gm of raltegravir calcium.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[CH:25]([CH:27]=O)=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:27][CH:25]=[O:26]
Reactant: O=CC=O
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Product: CSc1ccc(/C=C2/C(C)=C(CCON=CC=O)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with glyoxal by the method of Example 1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([OH:15])[CH:6]=1.[OH-].[Na+]>O>[N+:1]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]([OH:15])[CH:6]=[N:5]2)([O-:4])=[O:2]
Reactant: Oc1cnc2ccccc2c1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cccc2ncc(O)cc12
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of concentrated sulfic acid is added concentrated nitric acid dropwise at −30° C. Quinolin-3-ol is added to the mixture at −30° C., and then stirred at 30° C. for 2 hours. After cooled to ambient temperature, the mixture is poured into water and then neutralized with aqueous 4N sodium hydroxide solution. After extracted with ethyl acetate, the organic layer is dried, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to provide 5-nitroquinolin-3-ol.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH:9]=O.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH:9]=[N:26][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:17]
Reactant: NCCc1ccccc1
Reactant: COc1ccc(OCCCN(C)C)c(C=O)c1
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN(C)C)c(C=NCCc2ccccc2)c1
Yield: 83 %

Procedure:
2-[3-(Dimethylamino)propoxy]-5-methoxybenzaldehyde (33.5 g) and 17.4 g of phenethylamine are reacted in 140 ml. of toluene following the procedure described in Example 1B yielding 39.9 g of the title compound, boiling point 197°-202° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]([CH3:27])[C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([O:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[Cl:67])[CH2:56][CH2:55]1)=[O:53]>CN(C=O)C.O>[Cl:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[O:60][CH:57]1[CH2:56][CH2:55][N:54]([C:52](=[O:53])[CH2:51][NH:50][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([CH3:10])[CH3:27])[CH:13]=3)=[CH:23][CH:22]=2)=[O:26])[CH2:59][CH2:58]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: CN(C)c1cccc(-c2ccc(C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cccc(-c2ccc(C(=O)NCC(=O)N3CCC(Oc4ccccc4Cl)CC3)cc2)c1
Reaction time: 0.03 h
Yield: 22.2 %

Procedure:
DIPEA (170 mg, 1.3 mmol) was added to a stirred solution of to a stirred solution of 3′-dimethylamino-biphenyl-4-carboxylic acid (80 mg, 0.33 mmol) (generated from methyl 3′-amino(1,1′-biphenyl)-4-carboxylate) in DMF (2 mL) followed by HOBt (49 mg, 0.36 mmol) and EDCI (126 mg, 0.66 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (110 mg, 0.36 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure The residue was purified by preparative HPLC to afford 36 mg (22% Yield) of 3′-dimethylamino-biphenyl-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 492, 86.69%. 1H NMR (300 MHz, DMSO-d6): δ 8.6 (t, 1H), 8.0-7.9 (d, 2H), 7.8-7.7 (d, 3H), 7.5-7.4 (d, 1H), 7.36-7.24 (m, 3H), 7.1-7.0 (m, 2H), 7.0-6.94 (m, 1H), 6.88-6.8 (d, 1H), 4.8 (q, 1H), 4.2 (d, 2H), 4.0-3.7 (m, 4H), 3.5 (m, 3H), 3.0 (s, 6H), 2.0-1.8 (m, 3H), 1.8-1.6 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH:19][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](NS(=O)(=O)c2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 98.9 %

Procedure:
A solution of 39 (0.08 g, 0.21 mmol), benzenesulfonyl chloride (0.07 g, 0.42 mmol), triethylamine (0.06 g, 0.63 mmol), and a catalytic amount of DMAP in CH2Cl2 (40 mL) was stirred at room temperature for 18 h. Absolute MeOH was then added and the solution was washed with 10% HCl (3×25 mL) and saturated NaCl (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield a crude solid. The solid was purified by flash column chromatography (eluent: n-hexanes/EtOAc, 1:1). Removal of the solvent under reduced pressure gave 0.11 g (97%) of 43 as a white solid, mp 271-273° C. (EtOAc/n-hexanes): 1H NMR (acetone-d6): δ 0.98 (3H, s); 1.29 (3H, s); 1.52 (2H, m); 1.65 (1H, m); 1.70 (1H, ddd, J=3.0, 3.0, 12.6); 1.82 (1H, ddd, J=1.8, 5.1, 13.5); 1.95 (1H, ddd, J=6.3, 6.3, 10.2); 2.09 (1H, d, J=13.2); 2.22 (1H, dd, J=2.7, 11.7); 2.29 (1H, ddd, J=3.3, 6.9, 13.5); 2.62 (1H, s); 2.96 (1H, dd, J=3.5, 13.4); 3.66 (3H, s); 4.19 (1H, m); 5.47 (1H, dd, J=5.4, 12.0); 6.53 (1H, dd, J=0.9, 1.5); 6.69 (1H, d, J=8.4); 7.38 (1H, m); 7.40 (1H, d, J=6.9); 7.44 (1H, dd, J=2.1, 3.0); 7.60 (2H, m); 7.80 (2H, m); 13C NMR (acetone-d6): δ 15.7, 16.8, 19.4, 35.5, 36.4, 39.1, 43.4, 44.3, 51.5, 52.2, 54.8, 61.2, 64.7, 72.4, 110.0, 127.5, 128.2, 130.1, 133.5, 141.2, 142.4, 145.1, 171.7, 173.0, 205.3.
Reaction SMILES: [C:1]1([C:7]2[NH:12][CH2:11][C:10](=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(OCC)(=O)C>[C:1]1([C:7]2[N:12]=[CH:11][C:10](=[O:13])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CNC(c2ccccc2)=NN1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Product: O=c1cnc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To 0.60 g. 3-phenyl-4,5-dihydro-1,2,4-triazin-6(1H)-one dissolved in 40 ml ethyl acetate was added 0.80 g. DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). The solution immediately became green and was stirred at about 25° C. for 16 hours. The reaction mixture was then refluxed for 3 hours and cooled in an ice bath. The solid was collected and washed with three 50 ml portions of hexane. Yield 0.37 g. 64% Yield.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:28]\O)/[C:24]([O:26][CH3:27])=[O:25])[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:28]\[O:6][CH3:7])/[C:24]([O:26][CH3:27])=[O:25])[CH:12]=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)/C(=C/O)c1ccccc1COc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
Dimethyl sulphate (0.4 ml, 4.2 mmol) was added dropwise to a mixture of (E)-methyl 2-[2-(6-chloropyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (1.04 g, 2.9 mmol) and anhydrous potassium carbonate (0.78 g, 5.6 mmol) in dry DMF (10 ml). After stirring at room temperature for 3 hours, the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried and concentrated to give an oil which was purified by column chromatography (silica eluted with 20% ethyl acetate in hexane) to give (E)-methyl 2-[2-(6-chloropyrid-2-yloxymethyl)phenyl]-3-methoxyacrylate (Compound No.244 in Table I of EP-A-0278595) (0.72 g, 74%) as a cream solid; mp 91-92° C.; 1H NMR (270 MHz)δ: 3.69(3H,s), 3.83(3H,s), 5.26(2H,s), 6.63(1H,d), 6.90(1H,s), 7.15-7.55(5H,m), 7.56(1H,s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[CH2:11]([NH:18][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccccc1)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A solution of 2-chloroisonicotinic acid (5.00 g, 31.7 mmol) in thionyl chloride (25 mL) was refluxed for 30 minutes and concentrated in vacuo to dryness. The residue was dissolved in dichloromethane (100 mL) and added to a mixture of benzylamine (3.40 g, 31.7 mmol) and triethylamine (6.64 mL, 47.6 mmol) in dichloromethane (40 mL). The resulting solution was stirred at ambient temperature for 16 hours, washed with saturated sodium bicarbonate solution (30 mL), water (30 mL) and brine (30 mL). The separated organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with 60-80% ethyl acetate in hexanes to give N-benzyl-2-chloroisonicotinamide as a colorless solid (5.35 g, 49%): 1H NMR (300 MHz, DMSO-d6) δ 9.44-9.40 (m, 1H), 8.56 (d, J=5.1 Hz, 1H), 7.91 (s, 1H), 7.82-7.80 (m, 1H), 7.34-7.25 (m, 5H), 4.49 (d, J=5.1 Hz, 2H), MS (ES+) m/z 247.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH3:30])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH3:30])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 83.2 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (125b) (0.27 g, 0.59 mmol), 2 N lithium hydroxide (5 mL, 10 mmol), methanol (5 mL) and THF (5 mL), to obtain 0.21 g of the title compound as a colorless solid (83%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:26])[C:4]([C:7]1[N:12]=[C:11]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:14])[C:10]([OH:24])=[C:9]([OH:25])[N:8]=1)([CH3:6])[CH3:5].N1C[CH2:31][O:30][CH2:29]C1.CC#N.O>CN1C(=O)CCC1>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13]([C:11]2[C:10]([OH:24])=[C:9]([OH:25])[N:8]=[C:7]([C:4]([CH3:6])([N:3]3[CH2:2][CH2:31][O:30][CH2:29][CH2:26]3)[CH3:5])[N:12]=2)=[O:14])=[CH:22][CH:21]=1
Reactant: CN(C)C(C)(C)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Reactant: C1COCCN1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1)N1CCOCC1
Temperature: 100 °C

Procedure:
To a stirred solution of 2-[1-(dimethylamino)-1-methylethyl]-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide hydrochloride (prepared as described in example 4) in NMP an excess of morpholine (10 eq.) was added and mixture was stirred over night at 100° C. After cooling to room temperature, title product was isolated by RP HPLC (MeCN/H2O containing 0.1% TFA as eluant).
Reaction SMILES: [NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-:30]>C1COCC1.O.C(OCC)(=O)C>[NH:1]([C:8](=[O:28])[C:9]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1)([C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(O)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
To a solution of 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoic acid in THF (5 mL) at room temperature was added a solution of LiOH (28 mg, 1.2 mmol) in water (2 mL). The reaction mixture was stirred open to air for 20 h then heated to 40° C. for 8 h. Additional LiOH (20 mg, 0.83 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate, washed with 1 M HCl (1×), brine (1×), dried over MgSO4, and concentrated. Purification by reverse phase HPLC (30% to 100% MeCN in water) gave 4-[2-anilino-1-(anilinocarbonyl)-1-hydroxy-2-oxoethyl]benzoic acid (31 mg, 25%) as a white solid: ESIMS calcd 391.1 (M++H), found 391.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)([OH:17])[CH2:13]2>[Ni].C(O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[NH:23][CH2:22][CH2:21][CH2:20][N:19]=1)([OH:17])[CH2:13]2
Reactant: OC1(c2ncccn2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Agent: [Ni]
Solvent: CCO
Product: OC1(C2=NCCCN2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Add Raney nickel to a solution of Example 1 (160 mg) in ethanol (10 ml) at RT. Heat to 80° C. and stir for 20 h, filter and concentrate. Purify the residue by column chromatography to produce the title compound. 1H NMR (CDCl3) 7.85 (d, 2H), 7.25 (m, 4H), 7.15 (t, 2H), 5.55 (s, 1H), 3.40 (dd, 4H), 3.10 (s, br, 2H), 2.05-2.35 (m, 6H), 2.75(q, 2H), 1.55 (d, 2H).
Reaction SMILES: CC1N(C(C(Cl)Cl)=O)[C:10]2C=CC=[CH:6][C:5]=2[O:4]C1.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([O-:19])=[O:18].ClCC(=O)C>>[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:10][C:5](=[O:4])[CH3:6])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC1COc2ccccc2N1C(=O)C(Cl)Cl
Agent: CC(=O)CCl
Product: CC(=O)COc1ccccc1[N+](=O)[O-]

Procedure:
The preparation of benoxacor, a safener in the use of herbicides, is a three-stage process: in the first stage, o-nitrophenol is reacted with chloroacetone to give o-nitrophenoxyacetone; in the second stage, the compound is hydrogenated so as to obtain a benzoxazine, which is then acylated. This process is described in EP1283829.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].BrBr.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.CC(C)=O.O>[C:13]([CH:15]([CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10])[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1C
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 189.3 %

Procedure:
2′-Methylacetophenone (13.42 g) was dissolved in diethyl ether (100 mL), and bromine (16.0 g) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After dropwise addition, the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 1-bromo-1-(2-methylphenyl)ethanone (21.3 g) as an oil. To ethyl cyanoacetate (79.20 g) was added potassium carbonate (27.64 g), and the mixture was stirred at 43-45° C. for 45 min. A solution (150 mL) of crude 1-bromo-1-(2-methylphenyl)ethanone (21.3 g) in acetone was added dropwise over 30 min. After completion of the dropwise addition, the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. An excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=10:1→8:1) to give the title compound as a pale-yellow oil (yield 46.44 g, about 100%).