Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][C:22]=1[F:23]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:2]([OH:1])[CH2:3][C@H:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CC=O
Reactant: Fc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of (R)-tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate (A. Furstner and J. W. L. Kennedy, Chem.—Eur. J. 2006 12(28):7398-7410) in THF cooled to −78° C. was added (3-chloro-4-fluorophenyl)magnesium bromide (0.720 mL, 0.360 mmol) and the reaction was warmed to RT for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated to afford an oil which was purified by SiO2 chromatography to afford 0.0745 g (72%) of (2R)-tert-butyl 2-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)pyrrolidine-1-carboxylate (301) as a clear oil.
Reaction SMILES: O=[C:2]([CH3:21])[CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH3:20])=[O:5].[NH3:22]>C(O)C>[NH2:22][C:2]([CH3:21])=[CH:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH3:20])=[O:5]
Reactant: N
Reactant: CC(=O)CC(=O)OCCCCn1c(C)nc2cnccc21
Solvent: CCO
Product: CC(N)=CC(=O)OCCCCn1c(C)nc2cnccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-Methylimidazo[4,5-c]pyrid-1-yl)butyl 3-oxobutanoate (1.52 g) (see Preparation 6) was dissolved in ethanol (50 ml) containing dry silica gel (2.5 g) and gaseous ammonia was then bubbled through the mixture for 20 minutes. The mixture was stirred at room temperature for a further 11/2 hours and then filtered and evaporated to dryness leaving the crude title compound (1.54 g) which was used directly.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]([CH:23]=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].OO.[OH:28]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>C(#N)C.O>[C:1]([O:4][C:5]1[C:22]([C:23]([OH:28])=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C=O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)Oc1cc2c(cc1C(=O)O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of 3-acetoxyestra-1,3,5(10)-trien-17-one-2-carboxaldehyde (61, 1.20 g, 3.5 mmol) in acetonitrile (17 mL) and H2O (2.1 mL) were added 30% hydrogen peroxide (0.53 mL) and sodium phosphate monobasic (1.79 g) at room temperature. Sodium chlorite (0.935 g in a H2O (7.0 mL) solution) was added dropwise to the reaction mixture over a 1 h period, and stirring continued for an additional 2 h at room temperature. The reaction mixture was quenched with sodium sulfite, acidified with 10% HCl, and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was washed with Et2O to afford 1.06 g of 62 (85% yield) mp: 180-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.O[CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2>C(O)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:14][CH:15]=1
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)c1ccc(Br)cc1)C1c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
A solution of ethyl 4-bromobenzoylacetate (14.8 g, 0.05 mol) and 9-hydroxyxanthene (10.9 g, 0.06 mol) in ethanol-acetic acid (1:1, 150 ml) was stirred as described in Example 3 (ii) and a white solid collected. The filtrate was stirred a further 3 days and a second crop collected to give ethyl 2-(4-bromobenzoyl)-2-(9H-xanthen-9-yl)acetate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.Cl[Sn:13]([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[CH3:1][N:2]1[C:6]([Sn:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][N:4]=[N:3]1
Reactant: C[Sn](C)(C)Cl
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nncc1[Sn](C)(C)C
Temperature: -30 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a stirred solution of 1-methyl-1H-1,2,3-triazole (0.5 g, 6.0 mmol) in anhydrous tetrahydrofuran (50 mL) at −78° C. under an atmosphere of nitrogen was added n-butyllithium (2.5M solution in hexanes, 2.6 mL, 6.6 mmol) dropwise over ten minutes. On complete addition the reaction was allowed to warm to −30° C. and stirred for 2 h. A solution of chlorotrimethylstannane (1.3 g, 6.6 mmol) in tetrahydrofuran (2 mL) was added dropwise over 10 minutes then the reaction mixture was allowed to warm to room temperature over 2 h. The reaction was quenched by the addition of saturated ammonium chloride solution (5 mL) then diluted with water (20 mL). The solvent was evaporated in vacuo and the aqueous phase extracted with ethyl acetate (2×30 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford a pale yellow oil (1.4 g, 90%). 1H NMR (DMSO-D6, 400 MHz): 7.61 (s, 1H), 4.04 (s, 3H), 0.40 (s, 9H).
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:41][O:42][C:43](=[O:48])[C@H:44]([CH2:46][OH:47])[NH2:45].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:41][O:42][C:43](=[O:48])[C@H:44]([CH2:46][OH:47])[NH:45][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole) as shown in the Japanese patent first publication No. 104863/1981, HOBt (338 mg, 2.5 m mole) and L-serine methylester hydrochloride (467 mg, 3 m mole) were suspended in DMF (10 ml), and WSC (0.5 ml) was added dropwise thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling and next overnight at a room temperature. Ethyl acetate (100 ml) was added to the reaction solution, washed 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-serine methyl ester (1.3 g). The oily product gave a single spot with Rf 0.46 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine and heating). The oily material was dissolved in a mixture (20 ml) of acetone and methanol (1:1) and 1N sodium hydroxide (5 ml) was added thereto under cooling with ice. The mixture was stirred for 1.5 hours at room temperature and neutralized with 1N hydrochloric acid. The organic solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-serine (1.2 g). The oily material gave a single spot with Rf 0.18 by thin layer chromatography (developing solvent: chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying of 25% hydrobromic acid and 0.1% ninhydrine, and heating).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:21]2[CH:20]=[CH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)=[CH:23][CH:22]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: O=C(c1ccc(I)cc1)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
p-Iodobenzoyl chloride was reacted with 4-chlorobiphenyl by the method of Example 6 to give 4' -chloro-4-biphenylyl p-iodophenyl ketone, m.p. 218° C after recrystallisation from benzene.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:31].[OH-].[Na+]>O>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[N:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:31]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(N)=O
Temperature: 70 °C
Yield: 98.2 %

Procedure:
A mixture of crude 5-cyano-4-(2-methylphenyl)-2-(4-methylpiperazinyl) pyridine (16.85 g, 57.6 mmol), 18 mL of toluene, and 27 mL (49.7 g, 507 mmol) of concentrated sulfuric acid was heated at 70° C. for 12 hours. The mixture was cooled and quenched with 200 mL of cold H2O. Ethyl acetate was added followed by a solution of 45.6 g (1.14 mol) of sodium hydroxide in 200 mL of H2O. Water (200 mL) was added and the layers were separated. The aqueous layer was extracted several times with 100 mL of ethyl. The organic layers were combined and concentrated to afford 17.55 g (98.1%) of 4-(2-methylphenyl)-6-(4-methylpiperazinyl)-3-pyridinecarboxamide as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO>[Br:1][C:2]1[S:3][C:4]([CH2:7][NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:5][N:6]=1
Reactant: Nc1nccs1
Reactant: O=Cc1cnc(Br)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ncc(CNc2nccs2)s1
Yield: 51.1 %

Procedure:
A solution of 2-bromothiazole-5-carbaldehyde (150 mg, 0.78 mmol) and 2-amino-thiazole (78 mg, 0.78 mmol) in toluene (7 mL) and 3 Å molecules sieves were stirred at reflux overnight. The strong yellow solution of the corresponding imine was then poured over NaBH4 (147 mg, 3.9 mmol) in hot EtOH (50 mL). The colorless solution was filtered, concentrated and purified by column chromatography (30% AcOEt/PE) yielding N-((2-bromothiazol-5-yl)methyl)thiazol-2-amine (110 mg, 51%) as a solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1>>[O:11]1[CH2:12][CH:13]=[C:14]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:16]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: Cn1ncc([N+](=O)[O-])c1C1=CCOCC1
Yield: 65 %

Procedure:
Following Example 231, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester gave 5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (167 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.99-5.94 (m, 1H), 4.37 (q, J=2.8 Hz, 2H), 3.99 (t, J=5.3 Hz, 2H), 3.84 (s, 3H), 2.40-2.35 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[O-:26][C:27]#[N:28].[K+]>C(O)(=O)C.O>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:27]([NH2:28])=[O:26])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#C[O-]
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a solution of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (200 mg) in acetic acid (2 ml) and water (2 ml) was added solution of potassium cyanate (99 mg) in water (1 ml). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and washed with an aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (4% methanol in chloroform) to afford 2-benzyl-3-oxo-4-(3-ureidophenyl)-3,4-dihydropyrido[2,3-b]pyrazine (78 mg) as solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-methoxyaniline (37 mg, 0.193 mmol) similar to Example 13 and isolated as a white solid (10 mg, 14%). 1H NMR (CDCl3): 9.70 (d, J=1.8 Hz, 1H), 8.77-8.74 (m, 2H), 7.86 (s, 1H), 7.67 (s, 1H), 7.48-7.44 (m, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 6.96 (s, 1H), 6.76 (dd, J=3.0, 9.3 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[N:19]=1)=[O:17]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:24][C:20]2[N:19]=[C:18]([C:16]([OH:17])=[O:15])[CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cccc(CBr)n1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3)cc2)n1

Procedure:
6-(Biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid was prepared using general procedure B from 4-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (Intermediate 2). Yield: 68 mg. Mass spectrum (ES) MH+=306.
Reaction SMILES: [F:1][CH:2]([F:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[F:1][CH:2]([F:9])[C:3]1[CH:8]=[CH:7][N+:6]([O-:18])=[CH:5][CH:4]=1
Reactant: FC(F)c1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(C(F)F)cc1
Reaction time: 20.5 h
Yield: 100.1 %

Procedure:
To a stirring solution of 4-difluoromethylpyridine (5.00 g, 38.7 mmol) in CH2Cl2 (77 mL, 0.5 M) at 0° C. was added 77% meta-chloroperbenzoic acid (10.7 g, 46.5 mmol) and the ice bath was removed and stirring continued for 20.5 hr. The reaction mixture was concentrated to dryness and reaction residue purified by flash column chromatography (100:0-95:5 CH2Cl2/MeOH) to afford 4-difluoromethyl-pyridine-N-oxide as a colorless solid (5.62 g, >99%); 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=6.4 Hz, 2H), 7.40 (d, J=6.4 Hz, 2H), 6.63 (t, J=55.7 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].[N:20]([Si](C)(C)C)=[N+:21]=[N-:22].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[CH:12]([N:9]1[C:10]2[CH:11]=[C:3]([C:1]3[NH:22][N:21]=[N:20][N:2]=3)[CH:4]=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]=2[C:7]([CH3:15])=[CH:8]1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2nnn[nH]2)cc2c1c(C)cn2C(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
To a stirred suspension of methyl 6-cyano-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.951 mmol) in azidotrimethylsilane (1.0 mL, 7.53 mmol) in a small vial was added tetrabutylammonium fluoride trihydrate (300 mg, 0.951 mmol). The reaction was heated to 85° C. and stirred for 18 hr (attached a small reflux condensor). (The reaction became a semi-solid mass.) The reaction was taken up in EtOAc (75 mL), washed with 1N HCl (75 mL) (stirred till dissolved). The organic phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF40-80g, 0 to 3% MeOH/CH2Cl2 with 0.1% HOAc) gave the product methyl 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylate (0.28 g, 0.935 mmol, 48.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=1.3 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 4.86 (quin, J=6.6 Hz, 1H), 3.94 (s, 3H), 2.33 (s, 3H), 1.50 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 300.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[K+]>C(O)(=O)C>[C:17]([O:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:20][C:17](=[O:19])[CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(-c2ccc(COC(C)=O)cc2)cc1
Yield: 68 %

Procedure:
0.1 moles 4,4'bis(chloromethyl)biphenyl (prepared by method A above), 0.25 moles potassium acetate and 100 mls glacial acetic acid were reflux for 17 hours with stirring. The reaction mixture was filtered and the filtrate evaporated to dryness at 80° C. under water pump vaccum. The residue was recrystallised from methanol to yield 0.068 moles product=68 percent of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([C:18](=[O:33])[N:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH:11]([C:18](=[O:33])[N:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:42])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCN(CCc1ccccc1)C(=O)C(CCC(=O)OC)CSc1ccc(Cl)c(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCN(CCc1ccccc1)C(=O)C(CCC(=O)OC)CS(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Yield: 34.6 %

Procedure:
Into a solution of methyl 5-(3,4-dichlorophenylthio)-4-(N-pentyl-N-phenethylcarbamoyl)pentanoate (280 mg) in dry chloroform (10 ml) were added portions of m-chloroperbenzoic acid (70%, 140 mg) with stirring at -78° C. After stirring at -78° C. for 2 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with dichloromethane/diethy ether/hexane (1:1:2) to give 100 mg of methyl 5-(3,4-dichlorophenylsulfinyl)-4-(N-pentyl-N-phenethylcarbamoyl)pentanoate (diastereomer A) in a early fraction and 110 mg of diastereomer B in a later fraction.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21]I>C1COCC1.O>[CH3:21][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cccc(Nc2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccccc1)c1cccc(C(=O)O)c1
Reaction time: 0.17 h
Yield: 30 %

Procedure:
NaH 60% in mineral oil (0.050 g; 1.23 mmol) was added to a solution of ethyl 3-(phenylamino)benzoate (0.198 g; 0.820 mmol) in THF (3 mL). After stirring the resulting solution for 10 minutes, methyl iodide (0.102 mL; 1.1.64 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted in water and extracted with ethyl acetate. The organic layer was washed with brine and dried to yield 0.056 g (30%) of the title compound as a colourless solid which was used without further purifications.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH2:1]([O:8][C:9]1[C:13]([CH:29]=[O:30])=[C:12]([CH:14]([CH3:15])[CH3:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(OCc2ccccc2)nn1C(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1c(C=O)c(OCc2ccccc2)nn1C(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-benzyloxy-1,5-diisopropyl-1H-pyrazole (0.44 g) in N,N-dimethylformamide (3 mL) was added phosphorus oxychloride (0.31 g) at 80° C., and the mixture was stirred at 80° C. for 30 minutes. After the reaction mixture was cooled to room temperature, a sodium hydroxide aqueous solution (1 mol/L) was added to the reaction mixture. The mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.42 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[C:11]=2[CH2:12][CH2:13]O)=[O:6])[CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=3)[C:11]=2[CH:12]=[CH2:13])=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (124 mg, 0.361 mmol) obtained in Example 114 was dissolved in THF (2.5 ml), tributylphosphine (102 mg, 0.469 mmol, 1.3 eq.) and ADDP (120 mg, 0.469 mmol, 1.3 eq.) were added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed with 2% aqueous sodium carbonate solution, 10% aqueous sodium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:1-2:1) on silica gel (manufactured by E. Merck, Art.7734, 10 g). The fraction obtained by elution with ethyl acetate-hexane (3:2-2:1) was concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (101 mg, 0.310 mmol, 86.0%).