Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14](OCC)=[O:15])=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[OH:15][CH2:14][C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:10]=[N:11][CH:12]=1
Reactant: CCOC(=O)c1cncn1-c1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2cncc2CO)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a stirred solution of ethyl 1-(4-cyanophenyl)-1H-imidazole-5-carboxylate (50 mg, 0.21 mmol, 1.00 equiv) in anhydrous tetrahydrofuran (10 mL) maintained under nitrogen at −40° C. was added LiAlH4 (24 mg, 0.63 mmol, 3.05 equiv) in portions. The reaction was stirred at −40° C. for 1 h and then quenched by the addition of 2 mL of saturated aqueous NH4Cl solution. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified on a silica gel column eluted with 3.0-6.7% of methanol in dichloromethane to yield 36 mg (87%) of 4-(5-(hydroxymethyl)-1H-imidazol-1-yl)benzonitrile as a white solid. 1H-NMR (300 MHz, CDCl3): δ 10.11 (s, 1H), 8.07 (d, J=6.3 Hz, 2H), 7.85 (d, J=6.3 Hz, 2H), 7.77-7.72 (m, 4H), 7.24 (s, 1H), 4.63 (d, J=7.5 Hz, 2H) ppm. LCMS (method C, ESI): RT=0.25 min, m/z=200.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol- 1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14](=O)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH2:19][CH2:18]1.B.[Na].O>CO>[ClH:29].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH2:21][CH2:22]1
Reactant: Cc1c(C(=O)CCN2CCN(c3ccccc3Cl)CC2)cnn1-c1ncccn1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1c(/C=C/CN2CCN(c3ccccc3Cl)CC2)cnn1-c1ncccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
3.7 g of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-chlorophenyl)-1-piperazinyl]-1-propanone hydrochloride was dissolved in 300 ml of methanol. After adding 1.25 g of sodium boron hydride, the obtained mixture was stirred at room temperature for 2 hours. To the reaction mixture was further added 0.6 g of sodium boron hydride followed by stirring for 2 hours. Under ice cooling, water was added to the reaction mixture and the methanol was removed by evaporation. The residue was extracted with chloroform and the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography and developed with a solvent mixture (chloroform/methanol, 30:1) to thereby give 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-chlorophenyl-)1-piperazinyl]-1-propanol. Next, 16 ml of a 1N hydrochloric acid/ethanol solution was added to the product. After dissolving by heating, ether was further added thereto. The crystals thus precipitated were collected by filtration to thereby give 1.26 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([C:16]3[N:17]=[C:18]([C:19]4[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]4[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=3)[CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 19.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (150 mg, 0.30 mmol) in DCM (10 mL) was added 1,4′-bipiperidine (152 mg, 0.90 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (35 mg, 19%). LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.37 (m, 2H), 1.51 (m, 2H), 1.65 (m, 4H), 1.81 (m, 2H), 2.33 (s, 3H), 2.63 (m, 5H), 2.70 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 4.50 (m, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:7][O:8][C:9]=1[NH2:10])=[O:4].[OH-].[Na+]>CO>[NH2:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2cccc(F)c2)noc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Yield: 54.6 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylate (6.0 g, 25.40 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (3.08 g, 13.86 mmol, 55%) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)[CH:2]=1.S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21].[OH-].[NH4+]>>[N+:20]([C:10]1[C:11](=[O:14])[NH:12][CH:13]=[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:9]=1)([O-:22])=[O:21]
Reactant: O=c1ccc(Cc2cccnc2)c[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=c1[nH]cc(Cc2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-(Pyrid-3-ylmethyl)-2-pyridone (10 g) was added to concentrated sulphuric acid (20 ml) with cooling and stirring. Fuming nitric acid (4.5 ml) was then added over 10 mins. with cooling (ice-bath), allowed to warm to room temperature overnight and then poured on to ice (200 ml). Concentrated ammonium hydroxide solution was added to bring the pH to 8, when the product precipitated from solution. The solid was filtered off and recrystallised from methanol to give the title compound (7.04 g), m.p. 216°-7° C.
Reaction SMILES: O.NN.[CH2:4]([N:11]1[CH2:15][CH2:14][C:13]([CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)([CH2:16][O:17][CH3:18])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(O)C>[CH2:4]([N:11]1[CH2:15][CH2:14][C:13]([CH2:19][NH2:20])([CH2:16][O:17][CH3:18])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COCC1(CN2C(=O)c3ccccc3C2=O)CCN(Cc2ccccc2)C1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: COCC1(CN)CCN(Cc2ccccc2)C1
Yield: 89.5 %

Procedure:
Hydrazine hydrate (85% solution in water, 0.372 g, 6.32 mmol) is added to a solution of 2-(1-benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)isoindole-1,3-dione (Example A20, 1.581 g, 4.34 mmol) in ethanol (50 mL). The resulting mixture is refluxed for 4.5 hours, cooled and acidified with concentrated hydrochloric acid. The precipitate is removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in ethanol/water (2:1) and the insoluble material is removed by filtration. The filtrate is basified to pH 10 with 1N sodium hydroxide solution and extracted with dichloromethane. The combined organic extracts are dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (0.910 g). 1H NMR (200 MHz, CDCl3): δ 7.41–7.15 (m, 5H), 3.57 (s, 2H), 3.33 (s, 3H), 3.30 (s, 2H), 2.71 (s, 2H), 2.64–2.51 (m, 2H), 2.42–2.24 (m, 2H), 1.68–1.52 (m, 2H), 1.38–1.10 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)c1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C(=O)O)c1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
To a solution of ethyl 2-[2-(4-fluorophenyl)-5-(3-thienyl)-oxazol-4-yl]-2-methylpropionate (54 mg) in methylene chloride (3 ml) was added boron tribromide (0.45 ml, 1.0M methylene chloride solution) under ice-cooling, and the mixture was allowed to warm to room temperature. To the mixture, another portion of boron tribromide (1.05 ml, 1.0M methylene chloride solution) was added to the mixture, and the resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture were added water and ethyl acetate, the organic layer was collected, washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=15:1) to obtain 2-[2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl]-2-methylpropionic acid (32 mg). The product was dissolved in methanol, sodium methoxide (0.19 ml, 0.5M methanol solution) was added to the solution and after the mixture was stirred for 10 minutes, the solvent was removed under reduced pressure. The resulting residue was triturated with acetone to obtain sodium 2-[2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl]-2-methyl-propionate (30 mg) as pale brownish powder.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)C>[C:6]([C:5]1[C:8](=[NH:9])[N:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]2=[N:10][CH:4]=1)#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1cccnc1N
Solvent: CCO
Product: Cc1cccn2c(=N)c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To 200 ml of ethanol were added 11.8 g (97 mmoles) of ethoxymethylenemalononitrile and 10.5 g (97 mmoles) of 2-amino-3-methylpyridine, and the reaction was carried out with stirring at room temperature for 2 hours. After completion of the reaction, the crystals precipitated were collected by filtration to obtain 13.5 g of 3-cyano-4-imino-9-methyl-4H-pyrido[1,2-a]pyrimidine. Yield: 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH3:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]([NH:24][S@@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH3:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCCC(F)(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCCC(F)(F)F)c(Cl)c1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (2.96 g, white solid) from 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (2.80 g, 10.5 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.90 g, 15.7 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:9]1=[O:26])(C)(C)C>C(OCC)(=O)C>[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][N:10]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:9]1=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CN(CC(F)(F)F)C1=O
Solvent: CCOC(C)=O
Product: N[C@H]1C[C@@H](c2ccccc2F)CN(CC(F)(F)F)C1=O
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl[(3S,5S)-5-(2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate (126 mg, 0.32 mmol) in ethyl acetate (10 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to 23° C. as stirring was continued for 2 h. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=291.1 (M+1).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)C=CC=CC=1.[CH3:22][O:23][C:24](=[O:31])[N:25]([CH2:27][CH2:28][CH2:29]Cl)[CH3:26]>>[CH3:22][O:23][C:24](=[O:31])[N:25]([CH3:26])[CH2:27][CH2:28][CH2:29][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:7]=[N:8][C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]1=2
Reactant: c1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Reactant: COC(=O)N(C)CCCCl
Product: COC(=O)N(C)CCCN1c2ccccc2C=Nc2cccnc21

Procedure:
The title compound is prepared by reacting 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine and (3-chloropropyl)methylcarbamic acid methyl ester.
Reaction SMILES: [O:1]1CC[O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4O[C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)C.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(=CC(=O)[C@@H]5O[C@@H]53)C=C4)CC2)C)OC1>>[O:3]1[C:6]2([O:1][CH:2]12)[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C12OC1O2
Yield: 75 %

Procedure:
The procedure of Example 7 was repeated except that 0.295 g (0.769 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one was used in lieu of 0.328 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one to give 0.231 g of 20-(1,3-dioxolan-2-yl)-1α,2α;6α,760 -diepoxypregn-4-en-3-one (yield: 75%).
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[CH3:8][C:9]1[C:10]([C:28](OC)=O)=[C:11]([NH:14][C:15](=[O:27])[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[S:12][CH:13]=1>C1COCC1>[CH3:8][C:9]1[C:10]([C:28]2[O:7][N:6]=[C:3]([CH3:4])[N:5]=2)=[C:11]([NH:14][C:15](=[O:27])[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[S:12][CH:13]=1
Reactant: COC(=O)c1c(C)csc1NC(=O)Cc1cccc2ccccc12
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2c(C)csc2NC(=O)Cc2cccc3ccccc23)n1
Reaction time: 72 h
Yield: 10.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 106 mg, 2.65 mmol) was added to a solution of acetamide oxime (218 mg, 2.94 mmol) in dry THF (5 mL) at rt. Methyl 4-methyl-2-(2-(naphthalen-1-yl)acetamido)thiophene-3-carboxylate (Aldrich, 500 mg, 1.47 mmol) was added, and the reaction mixture was allowed to stir over 3 days. The mixture was concentrated under reduced pressure, then partitioned between ethyl acetate and water. The organic layer was separated, and washed with saturated NaCl solution. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes elution), and then triturated from acetonitrile to afford the desired product (58 mg) as a white solid. Method [7]: rt=9.42 min; 1H NMR (CDCl3) δ11.3 (s, 1H), 8.02-7.89 (m, 3H), 7.63-7.50 (m, 4H), 6.48 (s, 1H), 4.35 (s, 2H), 2.42 (s, 3H), 2.08 (s, 3H); 13C NMR (CDCl3) δ172.1, 168.9, 165.2, 146.4, 134.0, 133.4, 132.4, 129.4, 129.1, 129.0, 128.8, 127.2, 126.4, 125.7, 123.7, 114.0, 106.9, 42.1, 16.9, 11.4; MH+ 364.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:11]([O:18][C:19]([N:21]1[C@H:23]([CH3:24])[C@@H:22]1[C:25]([O:27][CH3:28])=[O:26])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[C@@H:22]([C@H:23]([CH3:24])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[NH:21][C:19]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: Cn1ccc2ccccc21
Reactant: COC(=O)[C@H]1[C@@H](C)N1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.3 %

Procedure:
To a mixture of 1-methylindole (4.26 g) and methyl (2R,3R)-N-benzyloxycarbonyl-3-methyl-2-aziridinecarboxylate (2.70 g) in dry methylene chloride (50 ml) was added boron trifluoride etherate (1.33 ml) under ice-bath cooling. The mixture was stirred for five minutes at ambient temperature and the solvent was evaporated off. The residue was chromatographed on silica gel (chloroform and a 1:1 mixture of hexane and ether as eluent) to give (αR,βR)-N-benzyloxycarbonyl-1,β-dimethyltryptophane methyl ester (1.62 g) as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 29,123 mg (0.40 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 72 mg (0.60 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.22 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 170 mg of crude imine are cyclized in the same way as in Example 29 at −30° C. with 2.8 ml (2.8 mmol) of 1 M boron tribromide solution to give the desired product. Purification by chromatography on silica gel (dichloromethane/ethyl acetate 0-40%) gives 21 mg of product.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12].C1CCN2C(=NCCC2)CC1>C1COCC1>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:10][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=1[C:16]#[N:17]
Reactant: OCCCCCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: N#Cc1c(OCCCCCCCCO)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
To a solution of 1,8-octanediol (3.87 mmol, 566 mg) in THF (dry, 10 mL) was added 2,6-dinitrobenzonitrile (1.29 mmol, 250 mg) and DBU (1.30 mmol, 194 μL). The reaction mixture was stirred for 24 hours at room temperature an evaporated. The oily residue was triturated with 10% citric acid/water and solid NaCl added. The precipitate was collected, washed with water, dried in vacuo and purified on silica gel (40% to 100% EtOAc in hexanes) to give the desired product (235 mg, 62.3%) as a pinkish solid. MS 293 (MH+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[CH:27][C:28]([CH2:31][OH:32])=[N:29][CH:30]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[F:33][C:24]([F:23])([F:34])[C:25]1[CH:26]=[CH:27][C:28]([CH:31]=[O:32])=[N:29][CH:30]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dess-Martin periodinane (CAS number 87413-09-0; 13.17 g, 31.10 mmol) was added to a solution of [5-(trifluoromethyl)pyridin-2-yl]methanol (CAS number 31181-84-7; 5.00 g, 28.2 mmol) in DCM (60 ml). The reaction was stirred at room temperature for 18 hours and then a saturated solution of sodium thiosulfate (aq, 100 ml) was added. The reaction was stirred for 45 min at room temperature and then phases separated. The aqueous phase was further extracted with DCM (60 ml) and the combined organics were washed with a saturated solution of sodium bicarbonate (aq, 60 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C(O[CH:5]1[CH:12]2[CH2:13][CH:9]3[CH2:10][CH:11]2[CH:7]([CH2:8]3)[O:6]1)(=O)C.[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=[CH2:16]>C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)C1C(O)=C(C(C)(C)C)C=C(C)C=1>[C:14]([O:19][CH:5]1[CH:12]2[CH2:13][CH:9]3[CH2:10][CH:11]2[CH:7]([CH2:8]3)[O:6]1)(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)O
Reactant: CC(=O)OC1OC2CC3CC2C1C3
Agent: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Product: C=C(C)C(=O)OC1OC2CC3CC2C1C3
Temperature: 50 °C
Yield: 93 %

Procedure:
A mixture of 16 g of 4-oxatricyclo[4.2.1.03,7]non-5-yl acetate, 40 g of methacrylic acid, and 16 mg of 2,2′-methylenebis(6-t-butyl-p-cresol) was heated at 50° C. under atmospheric pressure for 30 minutes, after which under a reduced pressure of 0.20 kPa, the reaction mixture was heated for 18 hours for distilling off the acetic acid formed. The reaction mixture was purified by distillation, obtaining 17 g (yield 91%) of the target compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][S:4][C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:19])([F:18])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH:20]([F:22])[F:21].ClC1C=CC=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:24][C:2]([F:1])([F:23])[CH2:3][S:4]([C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:18])([F:19])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH:20]([F:22])[F:21])=[O:33]
Reactant: FC(F)c1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(CC(F)(F)F)c1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(F)F
Yield: 96.9 %

Procedure:
To 0.37 g (1.0 mmol) of [2-difluoromethyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (Compound No. V-295 of the present invention) in 5 ml of chloroform, 0.25 g (1.5 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction solution was stirred for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.38 g of [2-difluoromethyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfoxide (yield 97.4%) as a yellow dough (nD20 1.4909).