Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([N:14]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[NH:17][C:16]3[C:26]([CH2:30][OH:31])=[CH:27][CH:28]=[N:29][C:15]2=3)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.C(Cl)Cl.O>[CH:11]1([N:14]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[NH:17][C:16]3[C:26]([CH:30]=[O:31])=[CH:27][CH:28]=[N:29][C:15]2=3)[CH2:13][CH2:12]1
Reactant: O=C1Nc2c(CO)ccnc2N(C2CC2)c2ncccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (0.08 g, 0.6 mmol) in methylene chloride (5 mL) cooled under Argon to -60° C. was added dropwise dimethyl sulfoxide (0.093 g, 1.2 mmol). After 2 minutes 11-cyclopropyl-5,11-dihydro-4-hydroxymethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.15 g, 0.53 mmol) in dimethyl sulfoxide/methylene chloride (5 mL) was added dropwise and stirring was continued for an additional 15 minutes. Triethylamine (0.267 g, 2.6 mmol) was added and after 5 minutes the mixture was allowed to warm to room temperature. Water (5 mL) was added and the aqueous phase was separated and extracted with methylene chloride. The combined organic phase was dried and evaporated. Column chromatography over silica gel with 30% ethyl acetate/hexane gave the title compound, which crystallized from ethyl acetate/hexane. Yield 0.045 g, m.p. 220°-222° C.
Reaction SMILES: [CH:1]([OH:3])=O.[N:4]1[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH2:16])[C:10]=3[S:9][C:8]=12.[BH4-].[Na+].[OH-].[NH4+]>O>[N:4]1[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:1]=[O:3])[C:10]=3[S:9][C:8]=12
Reactant: O=CO
Reactant: Nc1cccc2c1SC1=NCCN12
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=CNc1cccc2c1SC1=NCCN12
Reaction time: 8 h

Procedure:
To a stirred mixture of 360 parts of formic acid and 7.5 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-8-amine are added portionwise, during a 2 hours-period, 14.7 parts of sodium borohydride while nitrogen gas is introduced and the temperature is kept at about 30° C. Upon completion, stirring is continued first for 1 hour at about 60° C. and further overnight at room temperature. 200 Parts of water are added to the reaction mixture and the whole is alkalized with ammonium hydroxide at a temperature below 10° C. The product is extracted with warm trichloromethane. The extract is filtered over Hyflo and the filtrate is evaporated. The residue is boiled in 1,1'-oxybisethane. The product is filtered off (the filtrate is set aside) and dried, yielding 1 part of N-(2,3-dihydroimidazo[2,1-b]benzothiazol-8-yl)formamide; mp. 217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15](F)([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].Cl>>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:23])[CH:32]=[CH:33][CH:34]=1)(=[O:27])=[O:28]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 511.3 [(M+H)+]; mp 262° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2([CH3:10])[C:7]([CH2:9][CH:3]1[CH2:4][CH2:5]2)=[O:8].[NH2-].[Na+].Br[CH2:15][CH2:16][CH2:17]Br>C1(C)C=CC=CC=1>[CH3:10][C@:6]12[C:2]([CH3:11])([CH3:1])[C@H:3]([CH2:4][CH2:5]1)[C:9]1([CH2:17][CH2:16][CH2:15]1)[C:7]2=[O:8]
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: BrCCCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C21CCC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
A mixture of D-(+)-camphor (4.40 g, 28.9 mmol) and sodium amide (2.50 g, 61.5 mmol) in toluene (100 mL) was stirred at 100° C. for 30 min. A solution of 1,3-dibromopropane (31.8 mmol, 3.24 mL, 6.42 g) in toluene (20 mL) was added, and the reaction was heated at reflux for 3 h. The reaction was cooled to ambient temperature, washed with water (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in 5% methanol in dichloromethane (80 mL) and cooled to −78°C. Ozone was passed through the solution until the blue color persisted (˜10 minutes). Dimethyl sulfide (2 mL) was then added, and the reaction was warmed slowly to ambient temperature. The reaction mixture was concentrated, and the residue was purified on a silica gel column (40 g), eluting with 0-20% ether in hexanes, to obtain (1S,4R)-4,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-one (1.66 g, 29.9% yield) as oil. 1H NMR (CDCl3, 400 MHz): δ 2.26 (m, 1H), 2.10-1.97 (m, 5H), 1.85-1.1.66 (m, 2H), 1.62-1.53 (m, 1H), 1.47-1.40 (m, 1H), 1.28-1.19 (m, 1H), 0.94 (s, 3H), 0.88 (s, 3H), 0.75 (s, 3H); LCMS (m/z): 193 (M+1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[OH:16][C:17]([CH3:27])([CH3:26])[CH2:18][NH:19][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[OH:16][C:17]([CH3:27])([CH3:26])[CH2:18][NH:19][C:20]1=[N:21][C:22](=[O:25])[S:23]/[C:24]/1=[CH:1]\[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(O)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.70 g) in 2-propanol (30 mL) were added 4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one (3.00 g), and piperidinium acetate (1.18 g). The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.72 g).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C[Al](C)C.[N:13]1([CH2:22][C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=2)[C:26]([O:28]CC)=O)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>>[CH:3]1([N:2]([CH3:1])[C:26](=[O:28])[C:25]2[CH:31]=[CH:32][CH:33]=[C:23]([CH2:22][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:24]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)c1cccc(Cn2cnc3ccccc32)c1
Reactant: CNC1CCCCC1
Agent: C[Al](C)C
Product: CN(C(=O)c1cccc(Cn2cnc3ccccc32)c1)C1CCCCC1

Procedure:
N-Cyclohexyl-N-methyl 3-(1H-benzimidazylmethyl)benzamide was prepared by the method of Example 9 starting with N-methylcyclohexylamine and reacting with trimethylaluminium and ethyl 3-(1H-benzimidazylmethyl)benzoate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH3:11][C:12]([CH3:14])=[O:13]>CCOCC>[OH:13][C:12]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([CH3:14])[CH3:11]
Reactant: CC(C)=O
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(O)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of thiazole in ether (1 mL/mmol) at −78° C. was added 2.2M n-butyllithium in hexanes (1.1 eq) and the resulting mixture was stirred for 30 minutes. Acetone (1.2 eq) was added and the mixture was stirred at −78° C. for a further 30 minutes. The mixture was quenched in the cold with saturated aqueous ammonium chloride solution and warmed to room temperature, then partitioned between ether and water. The organic phase was dried and evaporated to yield the crude product as an orange-brown oil which was used as such in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>CC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 84.9 %

Procedure:
To a mixture of 4-nitrobenzene (3.0 g, 14.8 mmol) and 3-methylphenylboronic acid (2.06 g, 15.1 mmol) in 35 mL of acetone and 40 mL of water was added K2CO3.1.5H2O (5.93 g, 37.5 mmol) and Pd(OAc)2 (101 mg, 0.50 mmol). The deep black mixture was refluxed for 6 hr and then cooled. The mixture was extracted with ether and the organic layer was passed through a layer of celite. The pale yellow solution was dried over Na2SO4 and evaporated to dryness. The residue was recrystallized from hot methanol to give pale yellow crystals (2.68 g, 85%). m.p.59-60° C.1H NMR (CDCl3) δ 8.26 (d, 8.7 Hz, 2H), 7.70 (d, 8.7 Hz, 2H), 7.41 (m, 3H), 7.26 (d, 7.1 Hz, 1H), 2.43 (s, 1H). 13C NMR (CDCl3) δ 147.6, 146.8, 138.8, 138.6, 129.6, 128.9, 128.0, 127.6, 124.4, 123.9, 21.4. LRMS (EI) for C13H11NO2 213 (M+, intensity 100); HRMS (EI) calcd 213.0789, obsd 213.0778.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36].N1C=CC=CC=1.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([NH:26][C:35](=[O:37])[CH3:36])[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(N)ccn4c3-c3ccccc3)cc2)CCC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
A solution of {1-[4-(7-amino-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [prepared in a manner analogous to that described in Int-21-0] (225 mg, 0.50 mmol), acetic anhydride (0.061 mL, 6.4 mmol, 1.3 equiv) and pyridine (0.10 mL, 1.24 mmol, 2.5 equiv) in CH2Cl2 (7 mL) was stirred at room temperature for 48 h. The resulting mixture was added to water (10 mL). The resulting mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried (Na2SO4 anh) and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 2 min., gradient to 95% CH2Cl2: 5% MeOH over 1 min.; 95% CH2Cl2: 5% MeOH for 4.5 min., gradient to 90% CH2Cl2: 10% MeOH over 4 min., 90% CH2Cl2: 10% MeOH for 3 min., gradient to 80% CH2Cl2: 20% MeOH over 5 min., 80% CH2Cl2: 20% MeOH for 4.8 min.) to give {1-[4-(7-acetylamino-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (151 mg, 61%):
Reaction SMILES: C1CO[CH:3]([CH2:4][CH2:5][CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[O:2]1.O1CCCC1.Cl>O>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(CCCC2OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCCC=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.5 %

Procedure:
A mixture of 2.8 g of p-(4,4-ethylenedioxybutyl)benzonitrile, 56 ml of tetrahydrofuran and 56 ml of 10 percent hydrochloric acid was stirred for 3 hours at room temperature and then left to stand overnight. Thereafter, the reaction mixture was diluted with water and extracted three times with diethyl ether. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and concentrated. There were obtained 2.6 g of 4-(p-cyanophenyl)butyraldehyde which was processed without additional purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23]#[N:24])=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[Cl:22])[C:8]=1N)(=[O:3])[CH3:2].C(ON=O)(C)(C)C>O1CCCC1>[C:1]([C:4]1[C:5]([C:23]#[N:24])=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([O:17][C:18]([F:19])([F:21])[F:20])=[CH:12][C:11]=2[Cl:22])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CC(=O)c1cn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)nc1C#N

Procedure:
To a stirred solution of 4-acetyl-5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)pyrazole (0.302 g) in tetrahydrofuran (10 ml) at 2° C. was added t-butylnitrite (0.66 ml). The mixture was heated under reflux for 1.5 hours and then evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane. Combination and evaporation of suitable fractions provided the title compound as a white solid, m.p. 105.7-106.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][S:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:26]N(C)C=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][S:23][CH2:24][C:18]=3[N:17]([CH3:26])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CSC3)c(F)cc1Cl
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CSC3)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{1,2,5,7-tetrahydro-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-{1,2,5,7-tetrahydro-1-methyl-2,4-dioxo-thieno[3,4-d]pyrimidin-3(4H)-yl}-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.35 ppm (d, 1H), 5.23 ppm (m, 1H), 4.24 ppm (m, 2H), 4.09 ppm (m, 2H), 3.45 ppm (s, 3H), 1.36 ppm (d, 6H),
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH2:46][C:47](OC)=[O:48])[S:36]([C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[C:47](=[O:48])[CH2:46][N:35]([CH3:34])[S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc(NCc2ccc(Br)cc2)cc1OCc1ccccc1
Reactant: COC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 90 %

Procedure:
Secondary aniline 2 was coupled to carboxylic acid 6 on a 0.2 mmol scale via General Procedure B to furnish 9 (167 mg, 90%): δH (400 MHz, CDCl3) 2.33 (s, 3H, CH3Ar), 2.73 (s, 3H, CH3Ar), 3.54 (s, 2H, CH2CO), 4.64 (s, 2H, CH2Ar), 4.99 (s, 2H, CH2Ar), 5.28 (s, 2H, CH2Ar), 6.50 (br s, 1H, CH (Ar)), 6.55 (dd, J=8.3 and 1.8 Hz, 1H, CH (Ar)), 6.88 (d, J=8.3 Hz, 2H, 2 CH (Ar)), 7.16-7.34 (m, 14H, 14 CH (Ar)), 7.51 (d, J=8.3 Hz, 2H, 2 CH (Ar)), 7.75 (d, J=8.3 Hz, 1H, CH (Ar)); δC (100 MHz, CDCl3) 21.4, 29.6, 36.0, 51.2, 52.4, 53.3, 66.9, 70.7, 113.9, 119.8, 120.9, 121.7, 126.9, 127.3, 127.9, 128.2, 128.5, 129.4, 130.5, 131.6, 133.1, 135.2, 135.5, 135.6, 135.7, 143.3, 144.7, 158.7, 165.2, 167.0; LRMS (ES+) Calcd for [C38H35BrN2O6S+H] 727.15 found 726.83.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCCCCl)Cc1ccc(C(F)(F)F)cc1
Yield: 64.8 %

Procedure:
Using 0.22 g of (4-(trifluoromethyl)benzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-4-chlorobutane, and according to the process described in the Production Example 1, there was obtained 0.20 g of 2-(4-chlorobutyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (87)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([SiH](CC)CC)C>C(Cl)Cl.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1
Reactant: COC1(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: OC[C@H]1OC(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
The crude (3R,4S,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (6.5 g) and triethyl silane (4.03 g, 34.7 mmol) were dissolved in a mixed solvent of methylene chloride (100 mL) and acetonitrile (100 mL). To the resulting mixture was added dropwise boron trifluoride-diethyl etherate complex (5.6 g, 39.5 mmol) at 0° C. After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and stirred for 16 hr. The mixture was quenched with a saturated sodium bicarbonate solution, and extracted with ethyl acetate (250 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (methanol:methylene chloride=0-1:15) to produce 3.8 g of a product in a yield of 46% (three steps in total).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClC(Cl)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (3.70 g) was dissolved in dichloroethane (20 ml). Benzoyl chloride (0.64 ml) and triethylamine (2.8 ml) were added to the solution under ice-cooling, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (developing solvent:chloroform-methanol), and recrystallized from ethyl acetate to give 1.50 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)benzamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.C1(=O)[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C(Cl)Cl>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2nc(CCNCCC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Yield: 56.2 %

Procedure:
1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.03 g, 0.08 mmol) and succinic anhydride (0.02 g, 0.16 mmol) in 10 mL DCM were refluxed for 2 h. Reaction was concentrated and purified on silica gel using 5% MeOH/EtOAc to yield the pure product (20 mg, 53%).
Reaction SMILES: O.[CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]([O:13]O)=[O:12])=[CH:4][CH:3]=1>CO>[C:11]1(=[O:12])[O:13][C:8](=[O:10])[C:6]2=[CH:7][CH:2]=[CH:3][CH:4]=[C:5]12
Reactant: O=C(O)c1ccccc1C(=O)OO
Solvent: CO
Solvent: O
Product: O=C1OC(=O)c2ccccc21

Procedure:
0.81 g of 20-formamido-Δ4,17(20) -pregnadien-11β, 21-diol-3-one, 6.4 ml of water and 6.4 ml of methanol were mixed together under an inert gas atmosphere and 0.8 ml of 50% perphthalic acid (obtained from 2 g of phthalic anhydride solubilized at 40° C. over 15 minutes in a mixture of 1 ml of 50% hydrogen peroxide and 2 ml of methanol) were added with stirring at 22°-23° C. Then after 90 minutes of stirring, another 0.8 ml of perphthalic acid was added. After 4 hours, another 0.5 ml of perphthalic acid was added and after 3 hours of stirring, the mixture was cooled to 5° C. The crystals were separated and washed with water and with an aqueous solution of sodium bicarbonate and dried to obtain 0.586 g of the expected product.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[C:7](C)=[C:8]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:9][N:10](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:11][CH:12](OC)OC.Cl[CH2:33]Cl>>[F:30][C:29]1[C:28]([CH3:33])=[C:27]2[C:8](=[CH:7][C:6]=1[F:5])[CH:9]=[N:10][CH:11]=[CH:12]2
Reactant: ClCCl
Reactant: COC(CN(Cc1ccc(F)c(F)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(F)c(F)cc2cnccc12
Temperature: 50 °C

Procedure:
Aluminium trichloride (111.7 g, 838 mmol) was suspended in dichloromethane (250 mL) at 0° C. A solution of N-(3,4-difluoro-2-methylbenzyl)-N-(2,2-dimethoxyethyl)-4-methylphenyl-sulphonylamine (24, 68.3 g) in dichloromethane (250 mL) was added. The reaction mixture was heated at 50° C. for 2 hours, before being cooled to 0° C. and poured on ice. The organic layer was separated, and the aqueous layer extracted twice more with dichloromethane/isopropanol (3:1). The combined organic phase was extracted twice with saturated sodium bicarbonate solution and dried over magnesium sulphate, before filtration and evaporation gave 63.5 g of crude dark brown semi-solid product. This was purified by chromatography on silica gel. Elution with ethyl acetate/heptane (5%:95% to 35%:65%) gave 11.3 g of the title compound 25 as a tan-coloured solid. Rt=0.86 min (Method G). Detected mass: 180.1 (M+H+).