Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:4]2[N:5]([CH:15]=1)[C:6]([CH2:13]O)=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=2.S(Cl)([Cl:27])=O>ClCCl>[Cl:1][C:2]1[N:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:4]2[N:5]([C:6]([CH2:13][Cl:27])=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=2)[CH:15]=1
Reactant: Cc1cc(C)c(-n2c(Cl)cn3c(CO)c(C(F)(F)F)nc23)c(C)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)c(-n2c(Cl)cn3c(CCl)c(C(F)(F)F)nc23)c(C)c1
Yield: 100 %

Procedure:
A solution of [6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-yl]-methanol (614.8 mg, 1.718 mmol) and thionyl chloride (1.25 mL) in dichloromethane was stirred at 0° C. for 15 min. Thionyl chloride and the solvent were removed in vacuo and the residue was dried under high vacuum to yield the desired product as a yellow solid (646.3 mg, 100%). LC/MS: tR=1.46 min., MS: [MH−Cl+OMe]=373.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:24])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].[CH2:25](N)[CH2:26][CH2:27][CH3:28].S>C(O)C>[CH2:25]([NH:23][C:22]([C:19]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:6]([CH3:7])[CH2:5][N:3]([CH2:1][CH3:2])[CH3:4])[C:21]=2[CH:20]=1)=[S:24])[CH2:26][CH2:27][CH3:28]
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCCCN
Agent: S
Solvent: CCO
Product: CCCCNC(=S)c1ccc2c(c1)N(C(C)CN(C)CC)c1ccccc1S2
Temperature: 100 °C

Procedure:
A mixture of 10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (2.1 g) and butylamine (8.5 cc) in absolute ethanol (30 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After being cooled, the orange solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil is purified by chromatography on a column (height: 4 cm; diameter: 3 cm) of silica gel (0.2-0.063 mm), eluting successively with methylene chloride (2 liters) and with a mixture (90:10 by volume) (1 liter) of methylene chloride and methanol and collecting 60-cc fractions. Fractions 36 to 39 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (1.8 g) is again purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 cm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (75:25 by volume) (1 liter) of ethyl acetate and cyclohexane and collecting 60-cc fractions. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Butyl-10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (1.25 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1.[H-].[Na+].[CH3:23]I.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13])([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1)[CH3:23]
Reactant: CI
Reactant: COC(=O)C(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 31 %

Procedure:
To a stirred solution of 2.4 g (8.1 mmol) of benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester in 15 mL of DMF at 0° C., 389 mg (8.9 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 1.72 g (12.1 mmol, 1.5 eq) of methyliodide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc (from 2:1 to 2:1) yielded 0.78 g (31%) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid methyl ester as a white solid, MS: 311 (MH+) and 0.53 g (21%) of (RR,SS)-2-benzenesulfonyl-2-(3-oxo-cyclopentyl)-propionic acid methyl ester as a white solid, MS: 311 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[N+:13]([O-])=O.[OH-].[Na+]>>[NH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([Cl:9])=[C:6]([NH2:10])[CH:5]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(N)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 399 gm. (1.77 mole) of stannous chloride dihydrate in 975 ml. of concentrated hydrochloric acid is added 60 gm. (0.258 mole) of 1,5-dichloro-2,4-dinitrobenzene. The temperature rises to 72° and a solution occurs. The mixture is allowed to cool to room temperature and then cooled in an ice-bath (to 5°). A cold 50% solution of sodium hydroxide is added, with cooling, until the mixture is strongly basic. The mixture is filtered and the precipitate on the funnel washed four times with 500 ml. portions of ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous M9SO4 and the solvent removed. The residue is recrystallized from 50% ethanol-water. There is obtained 31.9 gm. (70%) of colorless needles melting at 142-3°.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=NO)=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH2:33][CH3:34])=[C:16]([F:35])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:37].C.O>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:37])=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH2:33][CH3:34])=[C:16]([F:35])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Reactant: O=S(=O)(O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate (18c) (7.4 g, 15.0 mmol) was dissolved in EtOAc (200 mL), followed by the addition of sulfuric acid (1.50 mL). 10% Pd/C, Degussa type, wet 50% (0.05:0.45:0.5, palladium:carbon black:water, 16.0 g) was then added and the mixture was degassed with nitrogen and then stirred at room temperature under hydrogen for 2 hours. The mixture was then degassed with nitrogen, the palladium was filtered off under nitrogen and the resulting material was concentrated to obtain the title compound as a pale yellow oil (6.5 g). Anal. HPLC retention time=3.2 minutes. Gradient conditions: 10% solvent B/90% solvent A to 90% solvent B/10% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H34FN3O3, 468.27; found 468.4. 1H-NMR (DMSO-d6) 7.67 (1H, d), 7.54 (1H, t), 7.33 (1H, t) 7.10 (1H, d), 7.03 (2H, d), 6.87 (1H, s), 5.08 (1H, s), 4.12 (2H, m), 4.00 (2H, s), 3.99 (2H, s), 3.48 (2H, s), 2.32 (2H, m), 1.62 (3H, m), 1.14 (9H, s), 0.85 (3H, t).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:5]1[C:4]([CH2:3][CH2:2][O:1][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)=[CH:12][N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: OCCc1cn2ccccc2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.80 g of 2-(2-hydroxyethyl)imidazo[1,2-a]pyridine (prepared as described in Preparation 26), 2.79 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.7 ml of tributylphosphine, 1.51 g of 1,1'-(azodicarbonyl)dipiperidine and 30 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:4 to 0:1 by volume as the eluent, to give 0.97 g of the title compound, melting at 135.5-142.4° C. (with decomposition).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:13][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=[O:12]
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c2c(ccc1=O)C(=O)CCC2

Procedure:
3.36 g (0.0206 mol) of 7,8-dihydro-2,5(1H,6H)-quinolinedione are stirred with 5.69 g (2×0.0206 mol) of powdered anhydrous potassium carbonate and 1.92 ml (1.5×0.0206 mol) of methyl iodide in 35 ml of dimethylformamide for 16 hours at ambient temperature. The mixture is then suction filtered, the solvent is evaporated off in vacuo and the residue is recrystallised from chloroform/ethyl acetate. Melting point: 203°-205° C., Yield: 3.1 g (84.9% of theory).
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7](=O)[C:6]=2[C:5]([C:16]([OH:18])=O)=[CH:4][CH:3]=1.[NH2:19][NH2:20]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16](=[O:18])[NH:20][N:19]=[C:7]3[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[NH:10][C:11]=1[C:6]=23
Reactant: NN
Reactant: O=C(O)c1cc(=O)c2c(C(=O)O)ccc(F)c2[nH]1
Solvent: CCO
Product: O=C(O)C1=Cc2n[nH]c(=O)c3ccc(F)c(c23)N1
Temperature: 90 °C

Procedure:
To a solution of 35 (0.600 g, 2.39 mmol) in EtOH (5 mL) was added hydrazine (0.0840 g, 2.63 mmol). The resulting mixture was heated at 90° C. for 24 hand then cooled to room temperature. The resulting precipitate was filtered, washed with Et2O (25 mL), and dried in vacuum at 60° C. for 6 h to give a white solid (36, 0.484 g, 74.5%). 1H NMR (DMSO-d6, 300 MHz) δ ?8.25-8.30 (m, 1H), 7.51-7.57 (m, 1H), 7.06 (s, 1H); Anal. Calcd for C11H6N3O3F (2H2O): C, 46.65; H 3.56; N 14.84. Found: C, 46.80; H, 3.59; N, 14.86.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([C:20]1([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:22][CH2:21]1)[CH:18]=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]3[N:10]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:14]=3)[CH:9]=2)=[CH:4][C:3]=1[F:15]
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)cn1
Solvent: CCO
Product: Fc1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)ccc1Br
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(4-bromo-3-fluorophenyl)pyrimidin-2-amine (0.50 g, 1.9 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.463 g, 1.88 mol) in ethanol (20 mL) was stirred at 100° C. overnight. The solution was concentrated and the residue was purified by chromatography on silica gel with MeOH in CH2Cl2 (0-6%) to afford the desired compound. LCMS: (M+H)=458.9.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1.[CH3:16]O>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cc1
Yield: 100 %

Procedure:
Thionyl chloride (18 mL, 0.25 mol) was added dropwise to a solution of 4-bromo-phenylacetic acid (50 g; 0.23 mol) in methanol (250 mL). The resulting mixture was stirred at room temperature for 1 hour before the methanol was removed in vacuo. Ethyl acetate (300 mL) was added and the resulting solution was washed with water (3×150 mL) and 1M aqueous NaHCO3 (1×150 mL), dried (MgSO4) and evaporated to give the ester (52.8 g; 100%) as an orange oil which was used without further purification.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.N1CC[O:27][CH2:26][CH2:25]1.C(Cl)(=O)C>C(Cl)Cl>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:26](=[O:27])[CH3:25])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 3 h

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone [Enantiomer C] (CC-039) (0.150 g, 0.45 mmol) in DCM (2 mL) was added polymer supported morpholine (2.5 equivalents) and acetyl chloride (0.51 mmol). The reaction mixture was stirred for 3 hours, filtered and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.095 g). LCMS m/z 375.27 [M+H]+ RT=9.71 min (Analytical Method 2).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:12])=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:11][C:8]1[C:5]([C:6]#[N:7])=[C:4]([CH3:12])[C:3]([CH:1]2[CH2:2][O:21]2)=[CH:10][CH:9]=1
Reactant: C=Cc1ccc(F)c(C#N)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 3-ethenyl-6-fluoro-2-methylbenzonitrile (6.05 g, 37.6 mmol) in 200 mL of DCM was added m-CPBA (15.30 g, 85% purity, 75.16 mmol). Then the mixture was stirred at r.t. for 12 hrs and diluted with DCM (300 mL), washed with saturated Na2SO3 (4×300 mL) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to obtain 6-fluoro-2-methyl-3-oxiran-2-ylbenzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.41˜7.44 (m, 1H), 7.02 (t, J=8.6 Hz, 1H), 3.95 (t, J=3.1 Hz, 1H), 3.16˜3.19 (m, 1H), 2.60˜2.62 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(Cl)cncc1Cl
Temperature: 50 °C

Procedure:
3,5-Dichloropyridine-4-carboxylic acid (0.5 g, 2.6 mmol; Reference Example 1) was dissolved in CH2Cl2 (1.75 mL) and DMF (50 μL). Thionyl chloride (0.21 mL, 2.86 mL) was added and the reaction mixture was heated at 50° C. for 20 h. The residue was concentrated in vacuo. The formation of the acid chloride was observed by TLC (50% EtOAc/hexane) and the crude 3,5-dichloropyridine-4-carboxylic acid chloride was used in Step E without further purification.
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1Cl)[CH2:2][CH2:3][CH3:4].[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.CCOCC>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC/N=C/c1c(F)cccc1CC

Procedure:
Prepared as described in Example 58(a) as by-product of reaction between butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine and ethylmagnesium bromide in tetrahydrofuran and ether. MS (ISP): 208.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)c2ccccc2)c1Cl

Procedure:
57 g (0.4 mol) of 2-chloro-3-methyl-aniline [CA 89, 30772h) were dissolved in 1.5 1 of toluene, 55 g of potassium carbonate were added and 62 g (0.4 mol) of benzoyl chloride were added dropwise at 80° C. After reaction is complete, the solid was filtered off in the cold and washed with water, and the filtrate was dried. After concentrating and triturating with petroleum ether 98 g of product (100%) crystallized.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15]>C(O)(C)C>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][NH:11][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCC(O)CO
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnccc1NCC(O)CO
Yield: 33.8 %

Procedure:
A solution of 4-chloro-3-nitropyridine (1.1 g, 6.94 mmol) and 3-amino-1,2-propanediol (1.22 g, 13.4 mmol) in isopropanol (50 ml) was stirred at 20°-25° C. for 20 hours and then concentrated under reduced pressure. Flash chromatography of the residue over silica gel and elution with 10% MeOH-90% CHCl3 gave pure 4-(2,3-dihydroxy-1-propylamino)-3-nitropyridine (500 mg, 33.8%). An analytically pure sample, m.p. 131°-35° C., was obtained upon recrystallization from MeOH-EtOAc-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([S:18][C:19]([F:22])([F:21])[F:20])[N:15]=[C:14]1[Cl:23].[OH:24]O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([S:18]([C:19]([F:22])([F:21])[F:20])=[O:24])[N:15]=[C:14]1[Cl:23]
Reactant: FC(F)(F)Sc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)n1
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: O=S(c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 36.02 %

Procedure:
To a solution of 800 mg (1.93 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-chloro-4-trifluoromethylsulfenylimidazole in trifluoroacetic acid was added 0.20 ml of 30% hydrogen peroxide at 0° C. The resulting mixture was stirred at 0° C. for 4 h and then at RT for 50 h. The mixture was evaporated at RT and the residue was partitioned between methylene chloride and a saturated aqueous sodium bisulfite solution. The organic layer was washed with an aqueous sodium bicarbonate solution and the organic layer was evaporated. The residue was purified by flash column chromatography on silica gel using 5% ethyl acetate in hexane. After the solvent was removed there was obtained 300 mg (36.02% yield) of the desired product as a white solid, mp 147.5° C.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH2:5]([C:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])([CH2:10]O)[CH2:8][OH:9])[CH3:6]>CCCCCC>[CH2:2]([CH:1]1[O:9][CH2:8][C:7]([CH2:5][CH3:6])([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:10][O:4]1)[CH3:3]
Reactant: CCC(CO)(CO)OCc1ccccc1F
Reactant: CCC=O
Solvent: CCCCCC
Product: CCC1OCC(CC)(OCc2ccccc2F)CO1

Procedure:
Using the procedure of Example 51, propionaldehyde and 2-ethyl-2-(2-fluorobenzyloxy)-1,3-propanediol were reacted, using hexane as solvent, to give, after separation by column chromatography, r-2-ethyl-5-ethyl-t-5-(2-fluorobenzyloxy)-1,3-dioxane, b.p. 89°-90°/0.01 mm, nD26 1.4895; and r-2-ethyl-5-ethyl-c-51 -(2-fluorobenzyloxy)-1,3-dioxane, b.p. 93°-95°/0.01 mm, nD26 1.4902. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: Nc1ncccn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ncccn1
Temperature: 25 °C

Procedure:
A solution of 2 amino-pyrimidine (2.0 g) in dry dichloromethane (17 mL) under nitrogen at 0° C. was treated with triethylamine (2.6 mL) followed by slow addition of chloroacetyl chloride (1.5 mL 18.4 mmol). The reaction mixture was allowed to warm up to room temperature. After 2h, the mixture was partitioned between dichioromethane and water.
Reaction SMILES: [N:1]1([NH:7][C:8](=O)OC(C)(C)C)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27](C=O)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[N:1]1([N:7]=[CH:8][C:27]2[CH:30]=[CH:31][C:24]([C:23]([F:33])([F:32])[F:22])=[CH:25][CH:26]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(C=NN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Tert-butyl piperazin-1-yl-carbamate (403 mg, 2.0 mmol) was suspended in methylene chloride (4 ml), to which trifluoroacetic acid (1.6 ml) was added, and the mixture was stirred at room temperature for 5 minutes. To which 4-(trifluoromethyl)benzaldehyde (0.3 ml, 2.2 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into sodium hydrogencarbonate aqueous solution, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=9/1) to afford piperazin-1-yl-(4-trifluoromethylbenzylidene)-amine (432 mg, yield 84%) as a colorless crystalline powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:6]1[CH:8]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:12]#[N:13]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of 5-chloro-2-nitro-aniline (6.902 g, 40 mmol), Zn(CN)2 (2.818 g, 24 mmol), and Pd(PPh3)4 (2.311 g, 2 mmol) in DMF (40 mL) was heated to 120° C. for 4 days. Cooled to room temperature. Partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide 1.49 g (23%) of 3-amino-4-nitro-benzonitrile.