Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[C:16]([F:25])[CH:15]=2)=[CH:8][C:7]=1[CH2:26][N:27]([CH:29]1[CH2:31][CH2:30]1)[CH3:28])([CH3:3])[CH3:2].O1CCCC1.O.O.[OH-].[Li+]>CO>[CH:1]([O:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[CH:8][C:7]=1[CH2:26][N:27]([CH:29]1[CH2:31][CH2:30]1)[CH3:28])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ccc(C#Cc2ccc(CC(=O)O)c(F)c2)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of 2-[(cyclopropyl-methyl-amino)-methyl]-4-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-benzoic acid isopropyl ester (Intermediate 124, 0.04 g, 0.09 mmol) in a mixture of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product as a white solid (0.026 g, 54%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([CH2:8][N:9]=[N+:10]=[N-:11])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.O>[CH2:25]([O:24][C:22]([NH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]=[N+:10]=[N-:11])=[CH:12][CH:13]=1)=[NH:2])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [N-]=[N+]=NCc1ccc(C(=N)N)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
The crystals from (ii) above were dissolved in 500 ml methylene chloride and the resulting solution was dried (K2CO3), filtered and 27 ml (194 mmol) triethyl amine was added. 25 ml Benzyl chloroformate was slowly added to the stirred solution while the reaction mixture was cooled in an ice bath. After 30 minutes an additional 2 ml benzyl chloroformate was added and stirring was continued for another 30 minutes. Subsequently water was added and the aqueous phase was adjusted to pH 7 with 2M HCl. The organic phase was dries (MgSO4) and the solvent was removed in vacuo. 4-(benzyloxycarbonylamidino) benzyl azide was finally isolated as colorless crystals from ether/methylene chloride/hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11].C([Li])CCC>>[F:1][C:2]1[C:3]([F:8])=[C:4]([Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:5]=[CH:6][C:7]=1[Si:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: Fc1ccccc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(F)c1F

Procedure:
4-Alkoxy-2-fluoro-3-phenoxyphenylacetic acid compounds were prepared from o-difluorobenzene. A mixture ortho-difluorobenzene (54a) and trimethylsilylchloride was treated with butyl lithium to produce 2,3-difluoro-1,4-bis-trimethylsilanyl-benzene (54b) which was brominated to afford 54c. Selective monometallation of 54c with iso-propylmagnesium chloride-lithium chloride complex and quenching the organomagnesium compound with DMF afforded 54d. Reaction of 54d with a phenol in the presence of K2CO3 resulted in displacement of the fluorine atom adjacent to the aldehyde to afford 56a. The aldehyde was subjected to a Baeyer-Villiger oxidation with trifluoroperacetic acid which underwent concomitant hydrolysis to the phenol 56b which was alkylated with Cs2CO3 and methyl iodide to afford the methoxy substituted analog 56c. Metallation of the remaining bromine substituent with iso-PrMgCI/LiI/THF and allylation of the resulting Grignard reagent afforded 58a which was oxidatively cleaved with NaIO4/Ru(III)Cl3 to produce the phenylacetic acid 58b.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]([C@@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([NH:33][C@H:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([N:22]3[CH2:21][CH2:20][N:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:24][CH2:23]3)[CH:26]=2)[CH3:32])=[O:10])=[CH:11][CH:12]=1
Reactant: C[C@H](N)c1cccc(N2CCN(c3ccccn3)CC2)c1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C=Cc1ccc(F)cc1)c1cccc(N2CCN(c3ccccn3)CC2)c1
Yield: 60.4 %

Procedure:
A solution of 4-fluorocinnamic acid (17 mg, 0.1 mmol), (S)-1-[3-(4-pyridin-2-yl-piperazin-1-yl)phenyl]ethylamine (24 mg, 0.11 mmol), EDC (28 mg, 0.15 mmol), DMAP (12 mg, 0.1 mmol) and triethylamine (40 mg, 0.4 mmol) in dichloromethane (2 ml) was stirred at room temperature for 14 h. The reaction mixture was purified by flash chromatography over silica gel with ethyl acetate/hexanes (1:1) to give the title compound as a solid (26 mg, 60% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CC(O)C>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH:2]([CH3:3])[CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc2[nH]c(C(=O)OC(C)C)c(Sc3ccc(Cl)cc3)c2c1
Yield: 58 %

Procedure:
Following the method used to prepare 24a, 1b (0.21 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with 2-propanol (2 mL) provided 44 mg (58%) of product 12 as a white solid, mp 172-174° C. 1H NMR (300 MHz, DMSO-d6) δ 1.18-1.24 (m, 6H), 2.35 (s, 3H), 5.09-5.12 (m, 1H), 7.04 (dd, J=2, 9 Hz, 2H), 7.19 (d, J=8, 1H), 7.25-7.30 (m, 3H), 7.46 (dd, J=2, 9 Hz, 1H), 12.34 (s, 1H). LC-MS (CI): m/z 360.0 [(M+H)+ C19H18ClNO2S requires 359.07]. Purity (100%). Calcd for C19H18ClNO2S: C, 63.41; H, 5.04; N, 3.89; S, 8.91; Cl, 9.85. Found: C, 63.59; H, 4.97; N, 3.90; S, 9.04; Cl, 9.85.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=3)[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.IC.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:32][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=3)[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc4[nH]ccc4c3)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc4c(ccn4C)c3)c2)cc1
Yield: 55.4 %

Procedure:
A solution of methyl 3-(4-{[3-(1H-indol-5-yl)benzyl]oxy]phenyl)propanoate (0.40 g, 1.04 mmol), iodomethane (0.18 mL, 2.89 mmol) and potassium carbonate (0.50 g, 3.62 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 4 days. The reaction solution was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-1:3-1:2) to give the title compound (0.23 g, yield 56%) as colorless prism crystals. MS: m/z 400 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:8]=O.[C:10]([N:13]1[CH2:18][CH2:17][N:16]2[CH:19]=[CH:20][CH:21]=[C:15]2[CH2:14]1)(=[O:12])[CH3:11].N>O>[C:10]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([CH2:8][N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:20][CH:21]=[C:15]2[CH2:14]1)(=[O:12])[CH3:11]
Reactant: C=O
Reactant: C1COCCN1
Reactant: CC(=O)N1CCn2cccc2C1
Agent: Cl
Agent: N
Solvent: O
Product: CC(=O)N1CCn2c(CN3CCOCC3)ccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
A mixture of 2.72 g of morpholine hydrochloride, 1.65 g of a 40% solution of formaldehyde, and 3.3 g of 2-acetyl-1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine was stirred for 4 hours at room temperature. 15 ml of water, alkalized with a 25% solution of ammonia, was added to the reaction mass and the product was extracted with benzene. Benzene was removed by distillation and the residue was crystallized from ethanol to give 3.2 g (61%) the title compound, mp 117°-118° C. Nmr (CDCl3): δ2.1 (s) (3H, CH3); 2.2-2.4 (m) (4H, CH2); 3.38 (s) (2H, CH2 -N); 3.5-3.7 (m) (4H, CH2), 3.7-4.1 (m) (4H, 3,4-CH2); 4.6 (s) (2H, 1-CH2); 5.7-5.82 (m) (1H, 7-H); 5.82-6.0 (m) (1H, 8-H). Anal. calculated for C14H21N3O2 : C 63.85%; H 8.04%; N 15.96% and found: C 63.90%; H 8.06%; N 15.76%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1>C1COCC1>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22])[CH2:14][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Pyrrolidine (0.2 g, 2.8 mmol) and triethylamine (0.28 g, 2.8 mmol) were added to a solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 104, 0.22 g, 0.894 mmol) in THF (5 mL). The reaction mixture was stirred for 1 hour at room temperature before being concentrated under reduced pressure and purified by silica gel column chromatography eluting with 10% methanol in ethyl acetate to afford the title compound as a pale yellow powder (0.18 g, 94%). 1H-NMR (500 MHz, CDCl3): δ 1.8 (t, J=6.7 Hz, 4H), 2.51 (t, J=6.7 Hz, 4H), 3.65 (s, 2H), 3.96 (s, 3H), 6.96 (dd, J=9.7 Hz, 1.5 Hz 1H), 7.12 (s, 1H), 7.8 (d, J=8.3 Hz, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](C(O)=O)=[CH:13][N:12]=[C:11]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:25](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([NH2:25])=[CH:13][N:12]=[C:11]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 66 °C
Yield: 40 %

Procedure:
4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 2-e, (200 mg, 0.68 mmol) was dissolved in THF (20 ml) and treated with Et3N (204 mg, 2.02 mmol) and DPPA (204 mg, 0.74 mmol). The mixture was heated at 66° C. for 12 hours. Then water was added and the resulting mixture was continued to stir at reflux for 2 h. After that the mixture was concentrated under vacuum. The residue was diluted with aq. K2CO3 followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel column with the eluent of dichloromethane/methanol=50/1 (Rf=0.7) to provide compound 2-f (72 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1.O.CN(C)[CH:42]=[O:43]>>[OH:16][CH:15]([CH2:17][C:42]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)=[O:43])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: c1c[nH]cn1
Reactant: CN(C)C=O
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CC(=O)n1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and imidazole (18 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (36 mg, yield 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:20])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[CH:6][C:5]=1[Cl:21]>C(OCC)(=O)C.[Pd]>[Cl:21][C:5]1[CH:6]=[C:7]([C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:22].[Cl:21][C:5]1[CH:6]=[C:7]([CH:10]([OH:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:22]
Reactant: COC(=O)c1ccc(C(=O)/C=C/c2cccc(O)c2)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Product: COC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Yield: 64 %
Yield: 26 %

Procedure:
A mixture (E)-2-chloro-4-[3-(3-hydroxyphenyl)-1-oxoprop-2-en-1-yl]benzoic acid methyl ester (Example 91; 250 mg, 0.8 mmol) and 10% palladium-on-charcoal (25 mg) in ethyl acetate (5 mL) was hydrogenated at atmospheric pressure for 90 min. The reaction mixture was filtered through Celite® and the filter cake was washed with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was then chromatographed over silica gel (20-50% ethyl acetate/hexanes) to give 2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoic acid, methyl ester (160 mg, 64% yield) and rac.-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoic acid, methyl ester (65 mg, 26% yield). The alcohol was obtained as a racemic mixture and was not resolved.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(COC)OC.CC(C)([O-])C.[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1>O>[F:37][C:36]([F:38])([F:39])[O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 9.5 °C
Reaction time: 0.5 h

Procedure:
10.00 kg of tert-butyl 4-hydroxypiperidin-1-carboxylate, 40 L of dimethoxyethane and 9.55 kg of sodium tert-butoxide were mixed, and stirred at 2 to 17° C. for 30 min. The mixture was mixed with 13.31 kg of 4-bromomethyl-1-trifluoromethoxybenzene and 10 L of dimethoxyethane at 12 to 14° C., and stirred at 21 to 23° C. for 3 hours. The reaction mixture was diluted with 100 L of water; extracted with 100 L of ethyl acetate; and the organic layer was washed with 100 L of a 1% NaCl aqueous solution twice. The organic layer was concentrated under reduced pressure to quantitatively obtain 19.21 kg of a yellow oily target substance.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[C:9](C)=[CH:8][C:7]([C:11]2C=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[Cl:20]OC(C)(C)C.BrBr.[C:28]([Cl:32])(Cl)(Cl)Cl>C(O)(=O)C>[Cl:20][C:8]1[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:28]=2[Cl:32])=[N:6][N:5]([CH:4]([CH3:17])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[CH:9]=1
Reactant: Cc1cc(-c2ccccc2)nn1C(C)C(=O)N(C)C
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OCl
Agent: BrBr
Solvent: CC(=O)O
Product: CC(C(=O)N(C)C)n1cc(Cl)c(-c2ccccc2Cl)n1

Procedure:
Following the procedure of Example 108, but substituting 3-(o-chlorophenyl)-N,N,α-trimethylpyrazole-1-acetamide for N,N,α,5-tetramethyl-3-phenylpyrazole-1-acetamide, tert-butyl hypochlorite for bromine, and carbon tetrachloride for acetic acid as the reaction solvent, there was obtained 4-chloro-3-(o-chlorophenyl)-N,N,α-trimethylpyrazole-1-acetamide having a melting point of 108°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:30])=[C:14]([NH:19][C:20](=O)[C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:32])[CH3:31])=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[C:13]([CH3:30])=[C:14]([NH:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:32])[CH3:31])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(F)cc2)C(C)(C)O3)cc1
Solvent: CO
Product: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(F)cc2)C(C)(C)O3)cc1
Yield: 52 %

Procedure:
By using N-[3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-4-methoxybenzamide, the title compound was synthesized according to Example 2b. Yield: 52%. Melting point: 114-115° C. (Methanol)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[CH2:43][NH2:44]>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[CH2:43][N:44]1[C:7](=[O:9])[C:6]2[CH:5]=[C:4]([CH2:11][CH2:12][CH3:13])[S:3][C:2]=2[NH:1][C:15]1=[O:17]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution (800 mL) of methyl 2-amino-5-propylthiophene-3-carboxylate (2 g) in methylene chloride were added triphosgene (1.27 g) and triethylamine (3.6 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1-(2,4-dimethoxyphenyl)methanamine (1.95 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (100 mL), sodium methoxide (2.7 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (2.7 g, 75%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:5]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[CH2:29](I)[CH2:30][CH2:31][CH3:32]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:26])[C@:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[N:5]=[C:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[C@@](Cc1ccccc1)(N=C(c1ccccc1)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-methyl-N-(diphenylmethylene)phenylalaninate (0.50 g, 1.4 mmol) (for synthesis see: O'Donnell et al, J. Org. Chem. 1982, 47, 2663-2666) in 6 mL DMF at 0° C. was added 95% NaH (0.14 g, 5.6 mmol). After 30 min, butyl iodide was added via syringe to the dark red reaction. After 30 min at 0° C., the reaction was warmed to rt for 14 h, then quenched by the addition of water. The aqueous layer was extracted with EtOAc (2×), the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (40 g silica, 0->8% EtOAc/hexanes) afforded methyl-α-butyl-N-(diphenylmethylene)phenylalaninate as a viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.57 (m, 2H), 7.37-7.17 (m, 11H), 7.05-7.03 (m, 2H), 3.36 (d, J=11.5 Hz, 1H), 3.32 (d, J=11.5 Hz, 1H), 3.24 (s, 3H), 1.78 (m, 2H), 1.41 (m, 2H), 1.29-1.24 (m, 2H), 0.89 (t, J=7.2 Hz, 3H). LC/MS M+H=400.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].C(N(CC1C=NC=CC=1)C(NC)=S)C1C=CC=CC=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CCO>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][NH:38][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:33][CH:32]=1
Reactant: CSC(=C[N+](=O)[O-])N(C)C
Reactant: NCc1ccc(Cl)nc1
Agent: CNC(=S)N(Cc1ccccc1)Cc1cccnc1
Solvent: CCO
Product: CN(C)C(=C[N+](=O)[O-])NCc1ccc(Cl)nc1

Procedure:
The 1-dimethylamino-1-methylthio-2-nitroethylene (1.0 g) prepared in (1) and 1.0 g of 6-chloro-3-pyridylmethylamine were refluxed in 30 ml of EtOH for 2 hours. The EtOH was then distilled off and the residue was subjected to silica gel column chromatography using CHCl3 --MeOH (10:1) as an eluent. The crystals obtained were recrystallized from EtOH to recover 0.82 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:10](=O)[CH3:11])[CH:7]=[N:8][CH:9]=1)[CH3:3].[NH2:13][OH:14].Cl>CCO.O.[OH-].[Na+]>[CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([C:10](=[N:13][OH:14])[CH3:11])[CH:7]=[N:8][CH:9]=1)[CH3:3]
Reactant: NO
Reactant: C=C(C)c1cncc(C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)c1cncc(C(C)=NO)c1
Yield: 79.4 %

Procedure:
To a stirred solution of 1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanone (460 mg, 2.86 mmol) in 95% EtOH was added a solution of NH2OH.HCl (1.19 g, 17.14 mmol) in a mixture of water (5.8 mL) and 10% NaOH (5.8 mL) and refluxed for 2.5 h. All solvent was removed. The residue was dissolved in CHCl3, washed with water, dried with Na2SO4 and concentrated under reduced pressure to yield 400 mg of crude 1-(5-(prop-1-en-2-yl)pyridin-3-yl)ethanone oxime.