Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][C:16]([OH:18])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>ClCCl.O>[CH3:23][O:22][N:21]([CH3:20])[C:16](=[O:18])[CH2:15][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CNOC
Reactant: COc1ccc(C2(CC(=O)O)CCCCC2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2(CC(=O)N(C)OC)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
To a solution of [1-(4-methoxy-phenyl)-cyclohexyl]-acetic acid (1.2 g) in dichloromethane (9.7 ml) was added N,O-dimethylhydroxylamine hydrochloride (577 mg). The mixture was cooled in an ice bath. 1,1′-Carbonyldiimidazole (1.01 g) was added. The mixture was stirred for 5 min at 0° C. and for 2 days at room temperature. A mixture of water and 1 M HCl was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (20 g NH3-modified SiO2, cyclohexane/ethyl acetate 1:0 to 3:2) to give the title compound (1.13 g) as a colorless oil, MS (ESI+): m/z=292.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14](CC(N)=O)[CH:15]=[CH:16][C:3]1=2.C(OC(=O)C(OCC)=O)C.CC(C)([O-])C.[K+]>CN(C)C=O>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: NC(=O)Cc1ccc2c(c1)Sc1ccccc1CC2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(=O)C(=O)OCC
Product: O=C1Cc2ccccc2Sc2ccccc21
Temperature: 25 °C

Procedure:
Stir at room temperature a mixture of 5.118 gm. of the amide of Step 5, 2.939 gm. of diethyloxalate, 4.723 gm. of potassium t-butoxide and 40 ml. of dimethylformamide for 6 hours. Pour the reaction mixture into 300 ml. of ice-water and extract with 300 ml. of ethyl acetate. Acidify with 6N hydrochloric acid and separate the ethyl acetate layer. Wash with saturated sodium chloride solution and dry. Evaporate to dryness and dissolve the residue in warm dioxane. Treat with a slight excess of ammonia and separate the solid by filtration. Wash with dioxane and dry. Suspend the product in water, acidify with 6N hydrochloric acid and extract with ethyl acetate. Wash the extract with saturated sodium chloride solution, dry over magnesium sulfate and evaporate to obtain the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23][CH2:24][CH2:25]O)=[CH:21][C:20]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:25][CH2:24][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 3-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-propan-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give (6-{3-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-propoxy}-indol-1-yl)-acetic acid ethyl ester as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:21][C:22]1[O:23][C:24]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:27][C:25]=2[N:26]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10]([C:29]3[CH:28]=[CH:27][C:25]4[N:26]=[C:22]([CH3:21])[O:23][C:24]=4[CH:30]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Temperature: 85 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (1 equiv), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (0.1 equiv) in a 3:1 mixture of 1,4-dioxane and water (0.2 M) was added sodium carbonate (3 equiv). The reaction was stirred at 85° C. for 15 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then extracted with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (0-50% ethyl acetate in hexane) to give the title compound (72.0% yield) as a brown oil 1H NMR (400 MHz, DMSO-d6) δ ppm −0.06 (s, 9H) 0.83-0.92 (m, 2H) 2.64 (s, 3H) 3.55-3.65 (m, 2H) 5.65 (s, 2H) 7.47 (dd, J=8.00, 1.76 Hz, 1H) 7.72 (d, J=8.20 Hz, 1H) 7.79-7.83 (m, 1H) 8.05 (s, 1H); MS (ESI) m/z 449.5 [M+1]+.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:2]=1.[Na+:32].[Na+].Cl.CC[OH:37]>O>[CH:5]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([N:16]=[C:17]([NH2:19])[NH:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:1][CH:2]=[C:3]([C:20]([NH:22][C@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:4]=1.[OH2:37].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[Na+:32].[Na+:32]
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
Pemetrexed Disodium Heptahydrate was prepared by adjustment of the pH of the Pemetrexed Disodium solution after saponification from pH=13 to pH=8 using HCl followed by addition of EtOH (3 times the volume of water) to achieve crystallization. Precipitated Pemetrexed Disodium Heptahydrate was isolated by filtration, washed with a mixture of EtOH and water (4:1 v/v) followed by EtOH. The wet product was dried in vacuo at 200 mbar at 20° C. to 30° C. until water content of the dried product was 20.1% to 22.1%.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CCOC(C)=O>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[N:4]=[C:5]([O:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 160 °C

Procedure:
A mixture of (S)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (1.61 g, 4.74 mmol) and ethyl hydrazinecarboxylate (1.482 g, 14.23 mmol) in NMP (8 mL) was heated at 160° C. overnight. The reaction mixture was diluted with EtOAc and washed with water (2×). The aqueous layer was back-extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound as a pale oil, which was used without further purification. ESI-MS m/z [M+H-tert-butyl]+ 342.3.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[O:18][C:17](=[O:19])[CH2:16][CH2:15]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[O:18][C:17](=[O:19])[CH2:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(CO)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
p-Toluenesulfonyl chloride (23.65 g, 124.03 mmol) was added portion wise to a solution of (±)-dihydro-5-hydroxymethyl-2(3H)-furanone (example 56) (11.07 g, 95.43 mmol) and pyridine (15.4 mL, 190.86 mmol) in methylene chloride (300 mL) at 0° C. The solution was allowed to warm to rt and stirred overnight. The solution was then washed with water (2×100 mL), 0.5 n HCl until the washings were acidic and finally with saturated NaHCO3. After drying and concentrating, the residue was triturated with toluene to give the title compound as a white solid (19.63 g, 76%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH:35]=[CH2:36])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:49]CC1>>[CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:30])([CH3:32])[CH3:31])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:12]([CH2:34][CH2:35][CH2:36][OH:49])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@H]1C[C@](COCc2ccccc2)(n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C1CCOC1
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 23 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
BH3 (2.7 mL, 1.0M solution in THF) was added to a solution of 18 (1.12 g, 1.8 mmol) in THF (15 ml) followed by stirring for 3 hr at 23° C. The reaction was quenched by the slow addition of MeOH (0.2 mL). A NaOH solution (6 mL, 3M) was added and the reaction mixture concentrated under reduced pressure to a white solid. The solid was suspended in THF (15 mL) and oxidized by the addition of H2O2 (3 mL, 30% aqueous solution) for 3 hr at 23° C. The solvent was evaporated under reduced pressure and the residue purified by silica gel chromatography (CH2Cl2 /AcOEt, 10:1 then 3:1) to give 0.51 g (44.3%) of the title compound as a white foam. 1H NMR (CDCl3) δ 1.10 (s, 9H, Me3C); 1.18-1.54 (m, 4H); 1.65 (s, 3H, 5-CH3); 2.10-2.40 (m, 3H); 2.18 (t, 1H, J=5.7 Hz, OH); 3.62 (m, 2H, CH2CH2 CH2OH); 3.65 (m, 2H, 5'-H); 4.07 (d, 1H, J=9.8 Hz, 4'-H); 4.71 (s, 2H, OCH2Ph), 5.50 (s, 2H, NCH2O); 6.11 (t, 1H, J=5.1 Hz, 1'-H); 7.26-7.51 (m, 12H, 6-H and aromatic-H); and 7.67-7.70 (m, 4H, aromatic-H).
Reaction SMILES: Cl[C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[CH:21]=1.[C:25](=O)([O-])[O-:26].[Cs+].[Cs+].CO.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:7]2[C:6]3[CH:21]=[C:2]([O:26][CH3:25])[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]=3[O:10][C:9]([CH3:12])([CH3:11])[C:8]2=[O:13])=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(Cl)cc2N(c2ccc(F)cc2)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C(=O)N2c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 26 h
Yield: 37.2 %

Procedure:
A mixture of 6-chloro-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 50(2); 400 mg), palladium acetate (5.1 mg), racemic 2-(di-tert-butylphosphino)-1,1′-binaphthyl (11.4 mg), cesium carbonate (557 mg), methanol (1 mL) and toluene (4 mL) was stirred at 70° C. under argon atmosphere for 26 hours. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was suspended in chloroform (4 mL) and thereto was added 1-hydroxybenzotriazole (154 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (208 mg). The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed successively with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel; solvent; n-hexane/ethyl acetate=9/1) to give 4-(4-fluorophenyl)-6-methoxy-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (147 mg) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[O:14][CH2:13]1>>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=3[CH3:1])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: Cc1c(NCc2ccc3c(c2)OCO3)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitroaniline and 1,3-benzodioxole-5-carbaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:6])(=O)C.P([O-])([O-])([O-])=O>C(Cl)(Cl)Cl>[OH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH3:6]
Reactant: CC(=O)OC(C)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Yield: 88.6 %

Procedure:
15 g of benzyl (-)-4'-(1-acetoxyethyl)-4-biphenylcarboxylate, 10 ml of chloroform, 400 ml of 0.2M phosphate buffer and 3 g of Amano swine liver esterase were mixed and reacted at 30°-35° C. for 30 hours. The reaction solution was extracted with chloroform. The chloroform layer was concentrated and the residue was column-chromatographed to give 11.8 g of (-)-benzyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate (V-26).
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][OH:8].[F:9][C:10]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O>O.C(O)C>[F:9][C:10]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[N:7][OH:8]
Reactant: NO
Reactant: COc1cccc(C=O)c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(C=NO)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a stirred solution of sodium hydrogen carbonate (2.73 g, 32.5 mmol) in water (50 mL) was added hydroxylamine hydrochloride (2.30 g, 33.2 mmol) in portions over 30 min. The resultant solution was added to a vigorously stirred suspension of 2-fluoro-3-methoxybenzaldehyde (5.00 g, 32.5 mmol) in ethanol (45 mL) and the reaction mixture stirred at RT for 16 hr. The resultant precipitate was removed by filtration and washed with water (3×100 mL) and then allowed to dry in air to afford 2-fluoro-3-methoxybenzaldehyde oxime (14) (4.69 g, 85%) as a white crystalline solid: m/z 170 (M+H)+ (ES+).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.75 g, 3.5 mmol) and (4-methylsulfonylphenyl)boronic acid (1.0 g, 5.0 mmol) in a manner analogous to Step 2c. The product was isolated as tan solid (0.60 g, 59%). MP=236-239° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.63 (d, J=6.3 Hz, 1H), 8.38 (d, J=7.9 Hz, 2H), 8.03 (d, J=7.9 Hz, 2H), 7.84 (d, J=7.3 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.21 (br s, 2H), 3.28 (s, 3H). MS=289 (MH)+.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:12]1([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: Cn1cccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1

Procedure:
Proceeding in a manner similar to that described in part A of Example 16, 14.8 g (0.1 mole) of phthalic anhydride, 16.2 g (0.2 mole) of N-methylpyrrole and 39.0 g (0.3 mole) of aluminum chloride were interacted in 50 ml of chlorobenzene to obtain 2-[(1-methyl-2-pyrrolyl)carbonyl]benzoic acid (Formula IX: R°=R1 =R2 =R3 =H; R7 =CH3) melting at 165°-167° C. A significant infrared absorption maximum appeared at 1710 cm-1 (C=O; s).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][NH:19][OH:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C.O>C1COCC1>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][N:19]([OH:20])[C:26]([NH2:25])=[O:27])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCCn1cc(Cc2ccccc2)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N(O)CCn1cc(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of product from Step 4 (150 mg, 0.56 mmol) in THF (4 mL) at room temperature there was added 85% trimethyl silyl isocyanate (TMSNCO, 162 mg, 1.2 mmol) and the mixture was stirred for 30 minutes. H2O (5 mL) was added, and after stirring for a further 10 minutes the THF was evaporated, and the residue extracted with Et2O, the extracts washed with H2O, dried over MgSO4 and evaporated to afford the title compound as a thick oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A mixture of methyl 4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}benzoate obtained in Example 33 (608 mg), 1 M sodium hydroxide solution (5 mL), methanol (20 mL), and tetrahydrofuran (5 mL) was stirred at 50° C. for 4 h. 1 M hydrochloric acid solution was added to the reaction solution, and the solvent was evaporated under reduced pressure to afford crystals. Crystals were washed with water, diethyl ether and dried under reduced pressure to provide the title compound (580 mg, 99%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[Cl:22]C1C=C(SSC2C=CC(Cl)=C(Cl)C=2)C=CC=1Cl>>[Cl:22][C:7]1[CH:6]=[C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:19]([OH:21])=[O:20])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccc2c(Sc3ccc(Cl)cc3)c(C(=O)O)[nH]c2c1
Reactant: Clc1ccc(SSc2ccc(Cl)c(Cl)c2)cc1Cl
Product: Cc1ccc2c(Sc3ccc(Cl)c(Cl)c3)c(C(=O)O)[nH]c2c1
Yield: 43.4 %

Procedure:
Following the method used to prepare 1, product 1 (0.15 g, 0.85 mmol) and bis(3,4-dichlorophenyl)disulfide (66) (0.37 g, 1.03 mmol) provided 0.13 g of product 21 (43%) as an off white solid, mp 252-255° C. 1H NMR (300 MHz, DMSO-d6) δ 2.40 (s, 3H), 6.95 (dd, J=2, 9 Hz, 1H), 6.99 (d, J=9 Hz, 1H), 7.23 (d, J=2 Hz, 1H), 7.30-7.34 (m, 2H), 7.46 (d, J=9 Hz, 1H), 12.30 (s, 1H), 13.38 (s, 1H). LC-MS (CI): m/z 350.0, 352.0 [(M−H)− C16H11Cl2NO2S requires 350.99]. Purity (100%). Calcd for C16H11Cl2NO2S.0.04-CH2Cl2: C, 54.17; H, 3.14; N, 3.94; S, 9.02; Cl, 20.74. Found: C, 54.00; H, 2.95; N, 3.93; S, 9.02; Cl, 20.74.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].C([O-])(O)=O.[Na+].Br[CH2:18][C:19](Br)=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)(Cl)Cl.CCOC(C)=O.CN(C=O)C.O>[CH3:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:19](=[O:20])[CH2:18][O:11][C:3]=2[CH:4]=1
Reactant: O=C(Br)CBr
Reactant: COc1cc(N)c(O)cc1C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1C)OCC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-amino-5-methyl-4-(methyloxy)phenol (3.0 g, 19 mmol) in CHCl3 (100 mL) were added saturated NaHCO3 (60 mL) and bromoacetyl bromide (5.78 g, 28.5 mmol) sequentially. The reaction mixture was vigorously stirred for 2 hours at room temperature, diluted with EtOAc (300 mL), washed with H2O, brine, and dried (Na2SO4). The solvent was removed via rotovap to give a brown solid. This brown solid was dissolved in DMF (200 mL), Cs2CO3 (6.19 g, 19 mmol) was added, and the reaction mixture was heated at 80° C. for 3 h. It was then poured into cold water (300 mL) and extracted with EtOAc (3×250 mL). The organic extracts were combined, washed with water, brine, and dried (MgSO4). The solvent was removed via rotovap, and the residue was purified on silica gel, using 50% EtOAc-Hexane, to give the title compound (2.13 g, 58%) as a brown solid. MS (ES) m/e 194 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[CH2:15][O:14]2)=[C:8]([Cl:21])[CH:7]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:21][C:8]1[CH:7]=[C:6]([N:5]=[C:1]=[O:2])[CH:11]=[CH:10][C:9]=1[CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[CH2:15][O:14]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)CON(Cc2ccc(N=C=O)cc2Cl)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of 7.9 grams (0.08 mole) of phosgene in toluene was added dropwise a solution of 5.0 grams (0.02 mole) of 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone in tetrahydrofuran. Upon completion of addition the reaction mixture was warmed to 80° C. where it stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give 5.6 grams of 2-(2-chloro-4-isocyanatophenyl)methyl-4,4-dimethyl-3-isoxazolidinone as a residual solid.