Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CO.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NN=Cc1ccc2ccccc2n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NNCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.5 g 10% Pd/C are added to a solution of 15.00 g tert-butyl N′-(quinolin-2-yl)methylene-hydrazinecarboxylate in 200 ml of methanol. The resulting mixture is then shaken for 6 h at ambient temperature under 1 atm H2 pressure. Then the precipitate and the catalyst are separated from the solvent, the precipitate is dissolved in tetrahydrofuran, filtered again and in this way the catalyst is separated off. The THF solution is evaporated down and the residue is triturated with tert-butylmethylether, separated off and dried at 50° C. The tert-butylmethylether phase is evaporated down again and the residue is triturated this time with diethyl ether, separated off and dried at 50° C. The two solid fractions from the purification with tert-butylmethylether and diethyl ether are combined.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[CH3:11][C:12]1[C:13]([OH:19])=[N:14][C:15]([SH:18])=[N:16][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:9])[C:3]=1[CH2:2][S:18][C:15]1[N:14]=[C:13]([OH:19])[C:12]([CH3:11])=[CH:17][N:16]=1
Reactant: Cc1cnc(S)nc1O
Reactant: Clc1cncc(Cl)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnc(SCc2c(Cl)cncc2Cl)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a mixture of 4-(bromomethyl)-3,5-dichloropyridine (1.0 g, 4.15 mmol) and 5-methyl-2-sulfanylpyrimidin-4-ol (0.38 g, 2.69 mmol) in anhydrous ethanol (25 mL) at 0° C. was added triethylamine (1.67 g, 16.6 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, water was added, and the mixture was sonicated and then filtered. The solid was washed with water and hexane to provide 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5-methylpyrimidin-4-ol (0.817 g, 65% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.90 (s, 3H), 4.66 (s, 2H), 7.99 (s 1H), 8.66 (s, 2H); M+302.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:27][C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: Nc1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Sc2ccc(N)cc2)c2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 0.98 mmol) was treated with 4-aminobenzenethiol (130 mg, 1.04 mmol), copper(I) iodide (400 mg, 2.1 mmol), potassium carbonate (300 mg, 2.17 mmol) in N,N-dimethylformamide (8 ml) according to Preparation 86 but stirring at 100° C. for 2 h. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 350 mg (75% yield) of the title compound. Purity 85%.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([NH2:25])=[N:22][C:21]=2[CH3:26])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:22][C:21]=2[CH3:26])=[O:19])=[CH:27][CH:28]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCc1ccc(Cl)cc1
Yield: 99 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use isonicotinoyl chloride hydrochloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid 4-chlorobenzylamide, the title compound was obtained as a white solid in 99% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.75-8.73 (m, 2H), 7.95-7.93 (m, 2H), 7.34 (s, 2H), 7.31 (s; 2H), 4.86 (s, 2H), 2.54 (s, 3H); MS (ES+) m/z 387.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[CH:12][C:13]=2[Cl:14])=[O:7])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=2[Cl:14])[CH2:15][Br:18])=[O:7])=[CH:16][CH:17]=1
Reactant: Cc1ccc(Cl)c(C(=O)c2ccc(Cl)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1cc(CBr)ccc1Cl
Yield: 50.5 %

Procedure:
A refluxing solution of 3-(4-chlorobenzoyl)-4-chlorotoluene (5.3 g, 20. mmol) and dibenzoylperoxide (200 mg, 0.83 mmol) in benzene (200 ml) was treated in portions with N-bromosuccinimide (4.4 g, 25. mmol) over 20 minutes. The mixture was refluxed 15 hours, cooled and filtered. The filtrate was evaporated under vacuum, triturated with diethyl ether (150 ml), filtered, and evaporated under vacuum. The residue was chromatographed on silica gel (500 g) eluted with 97:3 (v/v) n-hexane-ethyl acetate using a preparative high-performance liquid chromatograph to provide 3.47 g (50%) of 3-(4-chlorobenzoyl)-4-chlorobenzyl bromide, m.p. 81°-83° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH2:21][C:22]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]>CN(C=O)C.C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:22]([NH:21][C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[O:12])=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)N1CCC(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A slurry of 1-isopropylpiperidine-4-carboxylic acid (501.0 mg, 2.92 mmol) and 50% DMF/THF (6.3 mL) was cooled in an ice bath, and a solution of iso-butyl chloroformate (0.34 mL, 2.63 mmol) and 50% DMF/THF (0.7 mL) was added over 10 min via syringe. The ice bath was removed at addition's end, and the mixture was allowed to warm to ambient temperature. After 1 h, 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (414.8 mg, 1.47 mmol) was added in one portion, and the slurry was heated to 70° C. in an oil bath. Analysis by HPLC after 17 h showed only 2.5% of unacylated amine remained, so the volatiles were removed under reduced pressure, and EtOAc (25 mL) and water (20 mL) were added. The organic layer was extracted with saturated NaHCO3 (2×20 mL), and the combined aqueous layers were back-extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to 0.97 g of yellow solid which was found to be contaminated with 45 wt % DMF. Corrected yield was 0.53 g (83% yield), and no further purification was performed:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:8][C:7]=2[CH:31]=1)#[N:2].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[C:56]([O:60][CH2:61][CH3:62])(=[O:59])[CH:57]=[CH2:58].[Cl-].[NH4+]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:58][CH2:57][C:56]([O:60][CH2:61][CH3:62])=[O:59])=[N:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2o1
Reactant: C=CC(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-A) (189 mg, 0.453 mmol) in THF (1.7 mL) was added to a solution of potassium tert-butoxide (50.8 mg, 0.453 mmol) in THF (1.7 mL) under nitrogen at −78° C. After stirring for 15 min a solution 18-crown-6 (11.97 mg, 0.045 mmol) in THF (566 μl) was added to the mixture at the same temperature and the reaction was then stirred for another 15 min. At this point ethyl acrylate (61.5 μl, 0.679 mmol) in THF (566 μl) was added dropwise. After 25 minutes, the reaction mixture was poured into a solution of saturated ammonium chloride, extracted with EtOAc (2×), passed through a phase separator and concentrated and purified via FCC with Heptane/AcOEt (100/0 to 70/30) to afford the title compound. MS (ESI+) m/z 418.4 (M+H-Boc).
Reaction SMILES: Cl.[C:2]([OH:10])(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:32][C:33]1[S:34][CH:35]=[C:36]([C:38]2[C:43]([CH3:44])=[CH:42][C:41]([OH:45])=[CH:40][C:39]=2[CH3:46])[N:37]=1>CN(C=O)C>[OH:45][C:41]1[CH:40]=[C:39]([CH3:46])[C:38]([C:36]2[N:37]=[C:33]([NH:32][C:2](=[O:10])[C:3]3[CH:4]=[CH:5][N:6]=[CH:7][CH:8]=3)[S:34][CH:35]=2)=[C:43]([CH3:44])[CH:42]=1
Reactant: O=C(O)c1ccncc1
Reactant: Cc1cc(O)cc(C)c1-c1csc(N)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of isonicotinic acid hydrochloride (1.48 g, 10.0 mmol, 1.2 equiv) in DMF was added EDC (3.90 g, 2.0 equiv), HOBt (2.7 g, 2.0 equiv) and NEt3 (3.03 g, 3.0 equiv). After being stirred at room temperature for 1.0 h, the solution was added with 4-(2-aminothiazol-4-yl)-3,5-dimethylphenol (5-2, 2.2 g, 1.0 equiv). The reaction mixture was stirred at room temperature overnight. The solution was concentrated and the residue was re-dissolved in EtOAc. The solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give brown solid. The brown solid was washed with 50% EtOAc in hexanes to give 5-3 (2.08 g) as white solids in 64% yield: 1H NMR (500 MHz, CDCl3) δ 9.29 (s, 1 H), 8.80 (d, 2 H), 7.98 (d, 2 H), 7.06 (s, 1 H), 6.51 (s, 2 H), 2.01 (s, 6H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1O[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].NC(N)=[S:13]>O.C(O)C>[C:1]([O:6][CH2:7][CH:8]1[S:13][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: NC(N)=S
Reactant: C=C(C)C(=O)OCC1CO1
Solvent: O
Solvent: CCO
Product: C=C(C)C(=O)OCC1CS1

Procedure:
Glycidyl methacrylate corresponding to the formula: ##STR10## is reacted with thiourea corresponding to the formula: ##STR11## at ambient temperature in a mixture of water and ethanol. The reaction gives 2,3-epithiopropyl methacrylate corresponding to the formula: ##STR12##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]([CH3:34])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1Cl

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (2-chloro-phenyl)-methyl-amine (50 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2-chloro-phenyl)-methyl-amide: MS m/z: (M+H) 537.4.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH:4]([OH:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH2:21]([N:23]([CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH3:22].FC1C=CC(C(C2C=CC=CC=2)C(=O)C)=CC=1>ClCCl>[CH2:30]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH3:31].[CH3:19][N:2]([CH3:1])[CH2:3][CH:4]([OH:18])[CH:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)CCCC(=O)O
Agent: CC(=O)C(c1ccccc1)c1ccc(F)cc1
Agent: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCCC(=O)[O-]

Procedure:
A solution of 3-dimethylamino-1,1-diphenyl-propan-2-ol (2 55g), 4-diethylaminobutyric acid hydrochloride (1 95g) and dicyclohexylcarbodiimide (2 1g) in dichloromethane (50 ml) was stirred at room temperature for 5 days. Dicyclohexylurea was filtered off and the filtrate concentrated. The residue was dissolved in dilute hydrochloric acid and ether. The acid extract was basified; isolation through ether in the normal manner gave an oil which was chromatographed as alumina (200g.). Elution with progressively graded mixtures of light petroleum and ether gave the 4-diethylaminobutyrate of 3-dimethylamino-1,1-diphenyl-propan-2-ol isolated as the dihydrochloride (41%) as a glass.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:17][F:18])[CH2:8][C:7](=O)[C:6]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4]1.C[Si]([C:23]#[N:24])(C)C.P(Cl)(Cl)(Cl)=O.Cl>[I-].[Zn+2].[I-].N1C=CC=CC=1.C1C=CC=CC=1>[C:23]([C:7]1[C:6]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][C:3]([CH2:17][F:18])([CH2:2][F:1])[CH:8]=1)#[N:24]
Reactant: O=C1CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: N#CC1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
To a mixture of 4.05 g of 2,2-bis(fluoromethyl)-3,4-dihydro-6-nitro-2H-1-benzopyran-4-one and 10 ml of dried benzene was added 2.52 ml of trimethylsilyl cyanide with stirring under ice-cooling. 0.82 g of zinc iodide was added therein and the mixture was stirred at room temperature for 12 hours. Further, 8 ml of pyridine and 4.41 ml of phosphorus oxychloride were added therein and the resultant mixture was refluxed with heating for 6 hours. Ice water was added to the residue and it was acidified to be hydrochloric acid and it was extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The obtained residue was purified according to silica gel column chromatography (developing solution, CH2Cl2 :hexane=7:3) to obtain 0.99 g of 4-cyano-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran with a melting point of 136°-137° C.
Reaction SMILES: C(O)(=O)C.OO.[CH:7]1([C:10]2[N:11]=[C:12](S)[N:13]([C:15]3[C:16]([CH3:24])=[CH:17][C:18]([F:23])=[C:19]([CH:22]=3)[C:20]#[N:21])[CH:14]=2)[CH2:9][CH2:8]1.S([O-])([O-])=O.[Na+].[Na+]>O>[CH:7]1([C:10]2[N:11]=[CH:12][N:13]([C:15]3[C:16]([CH3:24])=[CH:17][C:18]([F:23])=[C:19]([CH:22]=3)[C:20]#[N:21])[CH:14]=2)[CH2:8][CH2:9]1
Reactant: Cc1cc(F)c(C#N)cc1-n1cc(C2CC2)nc1S
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)c(C#N)cc1-n1cnc(C2CC2)c1
Temperature: 45 °C

Procedure:
In a 500 mL three neck round bottom flask was placed acetic acid (96 mL), water (19 mL) and hydrogen peroxide (30%, 7.47 mL, 65.88 mmol). The mixture was heated to 45° C. with stirring under nitrogen while monitoring the internal temperature. 5-(4-Cyclopropyl-2-mercapto-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile (6.00 g, 21.96 mmol) was then added as a solid in small portions over 30 minutes while maintaining an internal temperature below 55° C. When addition of the thioimidazole was complete the reaction was stirred for 30 minutes at a temperature of 45° C., and then cooled to room temperature, and a solution of 20% wt/wt sodium sulfite in water (6 mL) was slowly added. The mixture was stirred for 30 minutes and solvents were removed under reduced pressure. The residue was suspended in 250 mL of water and 4N aqueous ammonium hydroxide was added to bring the pH to ˜10. The mixture was extracted with dichloromethane (3×200 ml), the organics combined, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 20 mL EA, and 80 mL of hexanes were added with stirring. The solvents were decanted off and an oily residue was left behind. This process was repeated and the product, 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile was obtained as a viscous oil (5.14 g, 21.33 mmol) Anal. LC/MS (m/z: 242, M+1)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([CH3:14])[CH2:8]2)[OH:4].[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>O1CCCC1>[F:16][C:15]([F:18])([F:17])[C:3]([C:2]([F:1])([F:19])[F:20])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:24](=[O:25])[CH2:23][C:22](=[O:26])[CH3:21])[CH:9]([CH3:14])[CH2:8]2)[OH:4]
Reactant: CC1Cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
To a stirred solution of 6.0 g (0.02 mole) of α,α-bis(trifluoromethyl)-2,3-dihydro-2-methyl-1H-indole-5-methanol in 50 ml of anhydrous tetrahydrofuran is added 1.9 g (0.022 mole) of diketene. After 16 hours at room temperature, the solution is refluxed for one hour. The solvent is evaporated, and the residue is recrystallized from dibutyl ether to give 5.7 g (74%) of α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-2,3-dihydro-2-methyl-1H-indole-5-methanol, m.p. 118°-119°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1CCN(CCCCl)CC1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([O:28][C:29]([N:31]1[CH2:4][CH2:5][N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:2][CH2:3]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCl)CC1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3(C#N)CCOCC3)cc2)CC1
Yield: 83.3 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.99 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (203 mg, 0.76 mmol), DMF (4 ml) and K2CO3 (553 g, 4.00 mmol) was heated to 70° C. and work up according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrate in vacuo at 35° C. to provided the title compound (272 mg, 64%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.50-3.37 (m, 4H), 2.53 (t, 2H), 2.45-2.34 (m, 4H), 2.15-2.00 (m, 4H), 1.97 (p, 2H), 1.46 (s, 9H).
Reaction SMILES: [H-].[Na+].[Cl:3][CH2:4][CH2:5][OH:6].[CH2:7]([O:14][C:15](=[O:21])[CH2:16][C:17]([CH2:19]Br)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1>[CH2:7]([O:14][C:15](=[O:21])[CH2:16][C:17]([CH2:19][O:6][CH2:5][CH2:4][Cl:3])=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CBr)CC(=O)OCc1ccccc1
Reactant: OCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCCl)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.00 g (21.0 mmol) of acetoacetic acid benzyl ester was dissolved in 40 ml of ether. 1.1 ml (21.0 mmol) of bromine was dropped at 0° C. After stirring at 0° C. for 30 minutes and then at room temperature for 5 hours, about 4 g of ice and sodium carbonate were added so that pH showed 7 or more. The organic layer extracted with ether was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated and dried in vacuo to obtain 4-bromoacetoacetic acid benzyl ester. 1.68 g (24.0 mmol) of sodium hydride (60% oily substance) was susptended in 20 ml of THF and 11.7 g (21.0 mmol) of 2-chloroethanol was added at −40° C. 4-bromoacetoacetic acid benzyl ester was dropped at −40° C., gradually heated and stirred at room temperature for 16 hours. After adding 1 N hydrochloric acid and extracting with ethyl acetate, the obtained mixture was washed with water and saturated aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=7/3) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:37])[CH2:34][NH:35][CH3:36])[CH:30]=[CH:31][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:37])[CH2:34][N:35]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:36])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1cccc(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2cccc(N)c2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 65.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (90 mg, 0.23 mmol), 1-(3-aminophenyl)-2-(methylamino)ethanol (Khim.-Farm. Zh 1983, 17, 1093)(69 mg, 0.42 mmol) and diisopropylethylamine (60 μL, 0.34 mmol) in dry DMF (4.6 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with ice (6 g). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the tide compound (79 mg) as a white solid.