Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11](O)(=[O:17])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:11]([O:10][C@@H:2]1[CH2:1][O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@H:3]12)(=[O:17])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: C=CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCC(=O)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1,4:3,6-dianhydro-D-mannitol (isommanide) (2.00 g, 13.68 mmol), 5-hexenoic acid (1.60 g, 13.68 mmol) and DMAP (0.17 g, 1.4 mmol) in DCM (50 mL) cooled at 0° C., EDAC (3.1 g, 16.42 mmol) was added. The solution was stirred at room temperature for 6 hrs. The solution was diluted with DCM (30 mL), washed with a solution of NaHPO4 5% (2×40 mL) and brine. The organic layer was dried over sodium sulfate and concentrated under vacuo. The residue was purified by flash chromatography (Biotage SP1, 40+M column, TLC method: n-Hexane/EtOAc −8:2, Rf product: 0.35) yielding the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3)CC2)nn1C(C)(C)C

Procedure:
90 mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-phenylpiperazine (0.034 mL, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=N)[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.C[OH:30].O>Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=[O:30])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C2(C)C)cc1
Reactant: CO
Agent: Cl
Solvent: O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 5b (0.121 g, 0.3 mmol) in HCl aq., 2N (2 ml) and methanol (5 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-[3-(4-methylphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 5c (0.118 g, 0.294 mmol, 98%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:42]3[CH2:41][CH2:40][N:39]([C:45]4[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=4)[CH2:44][CH2:43]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 69 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (424 mg, 1.84 mmol), a white solid required compound (486 mg, 1.27 mmol, 69%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][CH:7]([O:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])#[N:2].N1C=C[CH:30]=[CH:29][CH:28]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:30]([O:9][C:8](=[O:10])[CH:7]([O:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][O:5][C:4]1[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:3]=1[C:1]#[N:2])[CH:29]=[CH2:28]
Reactant: N#Cc1cc(C(F)(F)F)ccc1OCC(Oc1ccccc1Cl)C(=O)O
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)C(COc1ccc(C(F)(F)F)cc1C#N)Oc1ccccc1Cl
Reaction time: 3 h

Procedure:
55 g (0.15 Mol) of the acid obtained in Example 2 are dissolved in 120 ml of toluene. Then 2 ml of pyridine and 40 ml of thionyl chloride are added thereto. This mixture is stirred for 3 hours at 80°. Then the solvents are distilled off under reduced pressure and the remaining oil (56 g) is dissolved in 200 ml of toluene. To this solution is added dropwise, at a temperature of 5°-15°, first 12.5 g of allyl alcohol, then 28 g of triethylamine. This reaction mixture is stirred overnight at room temperature and then added with 50 ml of water. The organic phase is separated, dried over sodium sulfate, filtered and then evaporated to dryness. The residue represents 57.8 g of a dark oil, which is dissolved in toluene and cleaned by chromatography over an alumina oxide column. After evaporation of the toluene and distillation, there remains 54 g of the allyl ester as a clear oil, b.p. 165° /0.01 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cc(Cl)cc(Cl)c1
Product: O=Cc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1

Procedure:
Using 3,5-dichlorophenol and 4-fluorobenzaldehyde, the reaction was carried out in the same manner as in Reference Example 1 to obtain 4-(3,5-dichlorophenoxy)benzaldehyde. Subsequently, the same procedure as in Reference Example 99 was followed using sodium borohydride in place of the lithium aluminum hydride. This gave 4-(3,5-dichlorophenoxy)benzyl alcohol. The resulting alcohol (2.03 g), along with carbon tetrabromide (2.75 g), was dissolved in methylene chloride (30 mL). While this solution was stirred at 0° C., triphenyl phosphine (2.17 g) was added. The mixture was stirred at 0° C. for 1 hour and at room temperature for the subsequent 30 min. The solvent was removed under reduced pressure and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired product as a colorless oil (3.12 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>C(OCC)(=O)C>[Cl:35][CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(CO)cc2OC)c(C)o1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(CCl)cc2OC)c(C)o1
Yield: 89.1 %

Procedure:
To mixture of ethyl (2E)-3-{4[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (5.0 g) and toluene (100 mL) was added thionyl chloride (1.88 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl(2E)-3-{4[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (4.69 g, yield 89%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-108° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[CH2:14]1.Br>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[CH2:14]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Oc1cccc(C2CCCNC2)c1
Agent: Br
Solvent: CC#N
Product: Oc1cccc(C2CCCN(CC3COc4ccccc4O3)C2)c1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (54 mg, 0.24 mmol), 3-(piperidin-3-yl)phenol.HBr (60 mg, 0.23 mmol) and KHCO3 (84 mg, 0.84 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 160° C. for 5.5 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of DCM and MeOH (1% triethylamine) as eluent to give 74 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([O:21]CC)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24]NCCNC.C[Al](C)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[O:21])[CH3:24])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCNC
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 112 °C

Procedure:
General Procedure O. To a solution of ethyl 5,6-diphenylpyridine-2-carboxylate (Compound 21, 246 mg, 0.81 mmol) in toluene (5 ml) was added N,N′-dimethylethylenediamine (DMEDA, 78.7 mg, 0.89 mmol) and trimethylaluminum (1.2 ml, 2.44 mmol, 2 M in toluene) dropwise under argon at room temperature. After the mixture was refluxed at 112° C. for 2.5 hours, it was quenched with water, and the products were extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over Na2SO4. The filtered solvents were concentrated in vacuo, and the residue was purified by silica gel chromatography (15% ethyl acetate in hexane) to give title compound as a yellow solid.
Reaction SMILES: [H][H].[C:3]1([CH:9]=[CH:10][CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: C(C=Cc1ccccc1)=Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(CCCCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In Example 4, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 1,4-diphenyl-1,3-butadiene as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 1,4-diphenyl-1,3-butadiene, and 1,4-diphenylbutane was obtained at about 100% yield (See FIG. 6.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[N:27][N:26]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:23]3=[N:24][CH:25]=2)[CH:15]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][NH:46][CH3:47].C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:10]([C:11](=[O:12])[N:46]([CH3:47])[CH3:45])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[N:27][N:26]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])[C:23]3=[N:24][CH:25]=2)[CH:15]=1)[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)O)N(C)C(=O)OC(C)(C)C)c3)cc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)N(C)C)N(C)C(=O)OC(C)(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of (tert-butoxycarbonyl-methyl-amino)-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid, (100 mg, 0.16 mmol), dimethylamine (2 N in THF, 0.12 mL, 0.24 mmol), and diisopropylethylamine (31 mg, 0.24 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 646 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22]>CC(C)=O>[O:23]=[C:21]([CH3:22])[CH2:20][O:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cc(=O)oc2ccccc12
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a solution of 4-hydroxycoumarin (1.62 g, 10 mmol) in acetone (20 ml) were added potassium carbonate (5.53 g, 40 mmol) and chloroacetone (1.38 g, 15 mmol). The resulting mixture was refluxed for 4 h. (monitored by TLC). Evaporation of the solvent gave a residue which was poured into ice water (50 ml). The resulting solid was collected and crystallized from ethyl acetate to afford 4-(2-Oxopropoxy)-2H-1-benzopyran-2-one (1a) (1.28 g, 55.1%) as a white needle crystal. mp: 163°-165° C.; IR(KBr) νmax : 1716, 1625; UV(CHCl3) λmax (log ε): 305 (3.83), 266 (4.05); 1H-NMR (CDCl3): δ2.36 (s, 3H, CH3), 4.77 (s, 2H, OCH2), 5.57 (s, 1H, 3-H), 7.28-7.36 (m, 2H, 6- and 8-H), 7.54-7.63 (m, 1H, 7-H), 7.88-7.94 (m, 1H, 5-H). Anal. Calcd for C12H10O4 : C, 66.05; H, 4.62. Found: C, 66.01; H, 4.64.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1.[CH3:22][NH:23][C:24](=[O:27])[CH2:25][CH3:26]>>[CH3:22][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1)[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Reactant: CCC(=O)NC
Product: CCC(=O)N(C)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and N-methylpropanamide using a similar procedure to that described for Description 15.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][NH:32][CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:37](OC(OC)=O)(OC)=O.CCN(C(C)C)C(C)C>CN(C)C=O>[CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)OC(=O)OC
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a solution of 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 180 mg, 0.300 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (5 mL) were added dimethyl dicarbonate (176 mg, 1.31 mmol, 5.00 equiv) and DIEA (169 mg, 1.31 mmol, 5.00 equiv). The resulting solution was stirred overnight at 25° C. and then quenched with 20 mL of methanol. The resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC using the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (28% CH3CN up to 43% in 8 min, up to 100% in 3 min, down to 28% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 29.9 mg (19%) of the title compound as a white solid. m/z (ES+) 538 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.70 (m, 2H), 7.50-7.35 (m, 4H), 4.90 (m, 1H), 4.70 (s, 2H), 4.00 (m, 2H), 3.80 (m, 4H), 3.60 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.50 and 2.40 (2 singlets, amide rotamers, ArCH3, 3H), 2.16-2.00 (m, 6H), 1.86-1.64 (m, 4H).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl>CCO.[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)(=[O:7])=[O:6]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)NC1CC1
Reaction time: 48 h
Yield: 98.5 %

Procedure:
A solution of N-cyclopropyl-2-nitro benzenesulfonamide (7.9 g, 33.0 mmol) in EtOH (50 ml) was treated with HCl (3.0 ml, 4.0 N in dioxane), Pd/C (10%, 100 mg) and shaken in a Parr Hydrogenator at 50 psi for 48 h. The catalyst was removed by filtration and the solvent evaporated to give 6.9 g (84%) of 2-Amino-N-cyclopropyl-benzenesulfonamide as a light grey solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].Cl([O-])(=O)(=O)=O.CS[C+:23]1[S:27][CH:26]=[CH:25][S:24]1>>[S:24]1[CH:25]=[CH:26][S:27][C:23]1=[C:11]([C:12](=[O:14])[CH3:13])[C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:15]
Reactant: CC(=O)CC(=O)c1nc2ccccc2[nH]1
Reactant: CS[c+]1sccs1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CC(=O)C(C(=O)c1nc2ccccc2[nH]1)=C1SC=CS1
Yield: 29.1 %

Procedure:
By using 2.0 g of 1-(2-benzimidazolyl)-1,3-butanedione and 2.5 g of 2-methylthio-1,3-dithiolylium perchlorate, the treatment was conducted in the same manner as in Example 1. The product was purified by silicagel chromatography, whereby 0.87 g (yield: 29%) of 2-(1,3-dithiol-2-ylidene)-1-(2-benzimidazolyl)-1,3-butanedione was obtained as crystals having a decomposition point of 254° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[C:13](=[O:16])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:16][CH3:13])=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2OC)cc1
Temperature: 100 °C
Yield: 179.7 %

Procedure:
A mixture of 4-bromo benzoic acid ethyl ester (2.7 mL, 16.5 mmol), 2-methoxy boronic acid (2.5 g, 16.5 mmol) and sodium carbonate (7.7 g, 72.6 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL), was flushed with nitrogen for 1 hour. After addition of the tetrakis (triphenylphosphine)palladium (0) catalyst (0.96 g, 0.83 mmol), the reaction mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then rinsed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% dichloromethane in hexane provided the title compound (3.8 g, 89.9%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:20])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(-c2cccc(C(=O)OC)n2)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc(-c2cccc(C(=O)OC)n2)ccc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a DMF solution of methyl 6-(3-ethyl-4-hydroxyphenyl)pyridine-2-carboxylate were added potassium carbonate and methyl iodide, and the whole was stirred at an oil bath temperature of 70° C. for 2 hours to obtain methyl 6-(3-ethyl-4-methoxyphenyl)pyridine-2-carboxylate, which was then stirred in methanol and a 1M aqueous sodium hydroxide solution at an oil bath temperature of 60° C. for 1 hour to obtain an objective compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].[NH4+].[Cl-]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCCl
Product: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Reaction time: 12 h
Yield: 110.2 %

Procedure:
To a stirred solution of 4-bromophenol (25.1 g, 146 mmol), and imidazole (19.9 g, 292 mmol) in 1,2-dichloroethane (150 mL) at 23° C. was added triisopropylsilylchloride (34.4 mL, 161 mmol). The mixture was stirred for 12 h and poured onto saturated aqueous NH4Cl (400 mL), followed by extraction with CH2Cl2 (3×200 mL). The combined extracts were washed with brine (300 mL), dried (Na2SO4), and concentrated in vacuo to give a pale yellow oil which was crude oil was purified via short-path distillation (0.5 mmHg, 130° C.) to yield (4-Bromo-phenoxy)-triisopropylsilane as a colorless oil (53.0 g, 99% yield). Rf 0.81 (3:1 hexanes/EtOAc) IR (thin film) 2945, 2892, 2867 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.30 (2H, d, J=9 Hz), 6.75 (2H, d, J=9 Hz), 1.29-1.18 (3H, m), 1.08 (18H, d, J=7 Hz). 13C NMR (75 MHz, CDCl3) δ 155.0, 132.0, 121.5, 112.9, 17.6, 12.4. HRMS calcd. for C15H26OSiBr (MH+) 329.0936, found 329.0937.
Reaction SMILES: [C:1]([C:3]1[C:9]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:8]([O:16][CH3:17])[C:7]([O:18][CH3:19])=[CH:6][C:4]=1[NH2:5])#[N:2].[C:20]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:25][CH2:24]1)(=O)[CH3:21]>ClCCl.CO>[CH3:17][O:16][C:8]1[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[C:3]([C:4]([N:5]=[C:20]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH2:25][CH2:24]2)[CH3:21])=[CH:6][C:7]=1[O:18][CH3:19])[C:1]#[N:2]
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Reactant: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1OC
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OCC(F)(F)F)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)aniline and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 10(g) (73%). Rf 0.16 (dichloromethane:methanol 95:5, v/v). MS m/z 514 (MH)+.