Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)CCl.[CH:36]1([C:42](O)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:36]1([C:42]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][NH:11][C:12]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:18])[C:19]([NH:21][C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[N:27][CH:26]=[CH:25]4)=[O:20])=[CH:7][CH:8]=2)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(COC(=O)C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139) in pyridine was added EDC, DMAP, and cyclohexanecarboxylic acid, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl cyclohexanecarboxylate (E142).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]2[C@H:27]([CH3:28])[CH2:26][O:25][C@H:24]([CH2:29][OH:30])[CH2:23]2)[CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][S:9]([O:30][CH2:29][C@H:24]1[O:25][CH2:26][C@@H:27]([CH3:28])[N:22]([C:16]2[CH:15]=[C:14]([Cl:13])[N:19]=[C:18]([NH:20][CH3:21])[N:17]=2)[CH2:23]1)(=[O:11])=[O:10]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1nc(Cl)cc(N2C[C@@H](COS(C)(=O)=O)OC[C@H]2C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 96.2 %

Procedure:
Triethylamine (1.95 mL, 14.07 mmol) and methanesulfonyl chloride (0.52 mL, 6.67 mmol) were added dropwise to a solution of {(2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methanol (1.52 g, 5.57 mmol) in CH2Cl2 (50 mL) at 0° C., and the mixture was stirred at 0° C. under nitrogen for 45 minutes. It was then poured into saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3×100 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (1.88 g) as a foam that was crushed into an off-white solid. LC-MS (ES) m/z=351, 353 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH:6]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>CO>[CH:6]1([CH:12]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[NH:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClCC1CO1
Reactant: NCC1CCCCC1
Solvent: CO
Product: OC(CCl)CNC(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.7 Grams of epichlorohydrin and 10.2 g of cyclohexylmethylamine are dissolved in 50 ml of methanol. The mixture is stirred for 8 hours at room temperature. Methanol is removed by evaporation under reduced pressure. The resulting crude oily substance is purified by a silica gel column chromatography (chloroform:methanol=8:1) to obtain 8.2 g of N-(dicyclohexylmethyl)-N-(3-chloro-2-hydroxypropyl)amine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][OH:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[CH3:15][S:16]([O:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:18])=[O:17]
Reactant: OCCOc1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc2ccccc2c1

Procedure:
As described in Example 2, 13.5 g of 2-(2-naphthyloxy)ethanol in 400 ml of dichloromethane is reacted with 9.5 g of methanesulfonyl chloride in the presence of 11.4 g of triethylamine to give the product as tan crystals.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1([CH2:19][NH:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:14]1([CH2:19][N:20]([CH2:21][CH3:22])[C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCNCC1CCCC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (3.00 g, 15.6 mmol) in toluene (60 mL) was added N-(cyclopentylmethyl)-N-ethylamine (2.70 g, 21.2 mmol) synthesized by the method described in International Patent Publication WO2006/073973 and potassium carbonate (6.50 g, 47.0 mmol), and the mixture was refluxed by heating for 68 hours. The reaction mixture was cooled to room temperature, then added with water, and extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)benzaldehyde (3.34 g, 71%) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]#N)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=CC=CC=1.C(OC([C:31]1C2C(=CC=CC=2)C=C[N:32]=1)(C)C)(=O)C1C=CC=CC=1>>[CH2:1]([C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:31]#[N:32])[C:11]=2[CH:10]=[CH:9][N:8]=1)[CH3:6]
Reactant: N#Cc1cccc2c(-c3ccccc3)nccc12
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Product: CCc1nccc2c(CC#N)cccc12

Procedure:
1-Ethylisoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-ethyl-5-dichloroacetylaminomethylisoquinoline. The product was reacted successively in the same way as in steps (c), (d), (e) and (f) of Example 18 to afford 1-ethylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-ethylisoquinoline-5-acetic acid having a melting point of 166.2° to 180.8° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[OH:44])/[C:8]([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[OH:44])/[C:8]([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([S:18][CH2:19][C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)cs1
Reaction time: 0.42 h
Yield: 39 %

Procedure:
Under nitrogen atmosphere, diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (33.5 g) was suspended in dichloromethane (100 ml) and anisole (35 ml). Trifluoroacetic acid (80 ml) added dropwise below 5° C. for 40 minutes. After stirring below 5° C. for 25 minutes, the reaction mixture was poured into IPE (1.8 l). Resulting precipitate was collected by filtration and dried under reduced pressure. The powder was poured into pH 6.86 buffer (550 ml). The suspension was adjusted to pH 6.9 with 2N-potassium hydroxide, then was stirred at 15° C. until insoluble material disappeared. The solution was subjected to column chromatography on HP-20 (700 ml). The column was washed with water (1.4 l) and the object compound was eluted with 25% aqueous 2-propanol. The active fractions were collected, and adjusted to pH 3.5 with 3N-hydrochloric acid. After stirring at 30° C. for 2 hours, resulting precipitate was filtered and washed with water (50 ml) two times. The precipitate was suspended in water (150 ml), and adjusted to pH 2.0 with 1N-hydrochloric acid. After stirring at room temperature for one hour, the precipitate was collected and washed with water (20 ml). The precipitate was suspended in water (150 ml) again, and then adjusted to pH 2.0 with 1N hydrochloric acid. After stirring at room temperature for one hour, it was adjusted to pH 2.8 with 2N potassium hydroxide. After stirring at the same temperature for 30 minutes, the precipitate was collected, washed with water (20 ml), and dried under reduced pressure to afford 3.75 hydrates of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid as crystal (9.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:14]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH3:15]>CCOC(C)=O>[CH2:14]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:17](=[O:16])[C@H:18]([CH3:20])[NH:19][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:15]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=197-199° C.). The reaction was monitored by tlc (Rf=0.6 in EtOAc) and the product was purified from bi-products by silica gel chromatography using EtOAc as the eluent, followed by recrystallization from EtOAc.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC#N>C1COCC1>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cnc(N)cn1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)Oc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Amino-5-methyl-pyrazine (2.00 g, 21.25 mmol) was dissolved in THF (80 mL), cooled to 0° C., and treated with pyridine (1.77 g, 22.3 mmol) followed by the dropwise addition of phenylchloroformate (3.49 g, 22.3 mmol) in THF (30 mL). After stirring for 3 h, 100 mL of MeCN was added and the reaction mixture was reduced to a volume of 100 mL in vacuo. The title compound as white crystals was collected by filtration (2.5 g, 55%) and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH2:12][C:13](=[O:15])[CH3:14])[N:7]=[N:8][C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[N:7][N:8]([CH2:12][C:13](=[O:15])[CH3:14])[C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Clc1ccc2[nH]nnc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cn1nnc2cc(Cl)ccc21
Product: CC(=O)Cn1nnc2ccc(Cl)cc21

Procedure:
A mixture of 5 g of 5-chlorobenzotriazole, 1.4 g of chloroacetone, 5.1 g of potassium carbonate and 0.5 g of potassium iodide is stirred into 50 ml of acetone at room temperature for 48 h. The mixture is subsequently filtered, the filtrate concentrated by evaporation in a vacuum, and the residue purified by flash chromatography. In this way, two isomeric products, 1-(5-chlorobenzotriazol-1-yl)-propan-2-one and 1-(6-chlorobenzotriazol-1-yl)-propan-2-one, are isolated in approximately the same quantities, the first of which is then used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[C:11]([O:16][CH2:17][CH3:18])=[N:12][C:13](Cl)=[N:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[C:11]([O:16][CH2:17][CH3:18])=[N:12][C:13]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1nc(Cl)nc2c1[nH]c1c(Br)cccc12
Reactant: C1CNCCN1
Solvent: Cc1cc(C)cc(C)c1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1c(Br)cccc12
Yield: 88.6 %

Procedure:
0.8 g (2.4 mmol) 6-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole and 0.8 g (9.3 mmol) piperazine were refluxed in 10 ml mesitylene for 2.5 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 0.8 g (85%) 6-bromo-4-ethoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 376, 378 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH3:17].[CH2:18]([O:25][C:26]([NH:28][C@@H:29]([C:32](O)=[O:33])[CH2:30][OH:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][C:30](=[O:31])[C@@H:29]([CH2:32][OH:33])[NH:28][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCC(=O)[C@@H](CO)NC(=O)OCc2ccccc2)c1
Yield: 85.8 %

Procedure:
According to the procedure of Preparation 4(c), except using tert-butyl 4-fluoro-3-(methylaminomethyl)benzoate (4.00 g, 16.7 mmole), N-(benzyloxycarbonyl)-D-serine (4.00 g, 16.7 mmole), HOBt.H2O (2.3 g, 17 mmole), DCC (2.4 g, 11.6 mmole), and 1:1 DMF/CH2Cl2 (100 mL), the title compound (6.60 g, 79%) was prepared as a sticky foam following flash chromatography on silica gel (50% EtOAc/hexanes): MS (ES) m/e 461.1 (M+H)+.
Reaction SMILES: COC1C=CC(OC)=CC=1C[NH:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH3:28])[C:17]3[CH:21]([CH2:22][C:23]([OH:25])=[O:24])[O:20][B:19]([OH:26])[C:18]=3[CH:27]=2)[CH:10]=[CH:9][N:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:23]([OH:25])=[O:24].[NH2:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH3:28])[C:17]3[CH:21]([CH2:22][C:23]([OH:25])=[O:24])[O:20][B:19]([OH:26])[C:18]=3[CH:27]=2)[CH:10]=[CH:9][N:8]=1
Reactant: COc1ccc(OC)c(CNc2nccc(Oc3cc(C)c4c(c3)B(O)OC4CC(=O)O)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Oc2ccnc(N)n2)cc2c1C(CC(=O)O)OB2O
Product: O=CO
Yield: 80.3 %

Procedure:
A suspension of {6-[2-(2,5-dimethoxy-benzylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.32 g, 0.69 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) and refluxed for 18 hours. A second portion of trifluoroacetic acid was added (1 mL, 12.98 mmol) and the solution was refluxed for another 18 hours. The mixture was concentrated and purified by preparative HPLC (CH3CN/0.1% formic acid in water) to give [6-(2-amino-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid formic acid salt as a white solid (0.10 g, 46%) after lyophilization. 1H NMR (400 MHz, DMSO-d δ9.26 (br s, 1H), 8.14 (d, J=6.24 Hz, 1H), 8.11 (s, 1H), 7.24 (d, J=2.34 Hz, 1H), 7.17 (br s, 2H), 7.08 (d, J=2.34 Hz, 1H), 6.26 (d, J=5.86 Hz, 1H), 5.51 (dd, J=9.76, 2.73 Hz, 1H), 3.08 (dd, J=15.61, 2.73 Hz, 1H), 2.29 (d, 3H), 2.10 (dd, J=15.76, 9.76 Hz, 1H). MS (ESI) m/z: 316 [M+1].
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:8]([C:12]1[N:16]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:15]2[CH:24]=[CH:25][C:26]([S:28]([N:31]3[CH:35]=[CH:34][C:33]([NH:36][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[N:32]3)(=[O:30])=[O:29])=[CH:27][C:14]=2[N:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(N)n3)ccc2n1CC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(NC(=O)C4CCC4)n3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Cyclobutanecarbonyl chloride (30 mg, 30 uL, 0.26 mmol) was added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazol-3-amine (37 mg, 0.087 mmol) (see Example 21 for preparation) and DIPEA (34 mg, 46 uL, 0.26 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 14.3 mg (33%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.56 (m, 4 H), 1.59 (s, 9 H), 1.76-1.88 (m, 1 H), 1.91-2.01 (m, 1 H), 2.06-2.18 (m, 2 H), 2.17-2.27 (m, 2 H), 2.26-2.37 (m, 1 H), 3.10-3.24 (m, 1 H), 3.25-3.35 (m, 2 H), 3.84-3.95 (m, 2 H), 4.41 (d, J=7.62 Hz, 2 H), 6.87 (d, J=2.93 Hz, 1 H), 7.88 (d, J=8.9 Hz, 1 H), 7.92 (dd, J=8.8, 1.5 Hz, 1 H), 8.18 (d, J=2.93 Hz, 1 H), 8.25 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=499.8; Anal. Calcd for C25H33N5O4S+0.80 TFA+0.20 EtOAc+0.10H2O (612.68): C, 54.11; H, 5.86; N, 11.43. Found: C, 54.12; H, 5.92; N, 11.34.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]([OH:13])=[O:12])[CH2:5]2.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:18][C:19]([CH3:24])=[CH:20][C:21](Cl)=[O:22].Cl>[N+](C1C=CC=CC=1)([O-])=O.C(Cl)Cl.C(=S)=S>[CH3:18][C:19]1([CH3:24])[CH2:20][C:21](=[O:22])[C:10]2[CH:9]=[C:8]3[CH2:7][CH:6]([C:11]([OH:13])=[O:12])[CH2:5][C:4]3=[CH:3][C:2]=2[O:1]1
Reactant: CC(C)=CC(=O)Cl
Reactant: O=C(O)C1Cc2ccc(O)cc2C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc3c(cc2O1)CC(C(=O)O)C3
Temperature: 90 °C

Procedure:
9.8 g (5.5 mmol) of 5-hydroxy-indan-2-carboxylic acid are dissolved in 20 ml of nitrobenzene and 20 ml of carbon disulphide and 16.12 g (121 mmol) of aluminum trichloride are added in portions. 7.8 g (66 mmol) of dimethylacryloyl chloride in 20 ml of nitrobenzene are then added dropwise and the mixture is heated to 90° C. for 3 h. After cooling, 40 ml of concentrated hydrochloric acid and 40 g of ice are added and the mixture is shaken twice with 100 ml of CH2Cl2 each time. The combined CH2Cl2 phases are evaporated, the nitrobenzene is distilled off in a water jet vacuum and the residue is taken up in 100 ml of 10% strength NaOH solution. The NaOH phase is shaken twice with 100 ml of CH2Cl2 each time, then acidified using concentrated HCl solution with ice cooling and extracted 3 times using 100 ml of CH2Cl2 each time. After drying over Na2SO4, the solution is evaporated and the residue is flash chromatographed on silica gel (eluent: CH2Cl2 /acetone 10:1)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:18][CH3:19])[C:9]1=O)=[O:5])[CH3:2].[C:21](P(=O)(OCC)OCC)#[N:22].[C-]#N.[Li+].O>C1COCC1.CN(C=O)C>[C:21]([C:9]1[C:10]2[C:15](=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][C:8]=1[CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])#[N:22]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCOC(=O)CCC1CCc2c(OC)cccc2C1=O
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1=C(C#N)c2cccc(OC)c2CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
2-(2-Ethoxycarbonylethyl)-3,4-dihydro-5-methoxy-1(2H)-naphthalenone (1.1 g, 4 mmol), from Step 1, was dissolved in 15 mL of dry THF and cooled to 0° C. Diethyl cyanophosphonate (1.18 mL, 8 mmol), commercially available from Aldrich Chemical Company, was added, followed by 8 mL of a 0.5M solution of lithium cyanide (4 mmol) in DMF. The reaction mixture was stirred at ambient temperature overnight and then poured into water. The aqueous mixture was extracted with three portions of diethyl ether/ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 100 mL of toluene and 1.1 g of p-toluenesulfonic acid was added. The reaction mixture was heated at reflux for 2 h and allowed to cool to ambient temperature. The toluene solution was poured into 5% aqueous sodium bicarbonate and the aqueous mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 10% ethyl acetate in hexane to give 0.8 g (70% yield) of the title compound; MS DCl--NH3 M/Z: 286 (M+H)+, 303 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.O=S(Cl)Cl.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)#[N:11].C(Cl)Cl>O1CCCC1>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1ccc(C(=O)CCc2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=CCc2ccc(F)cc2)n2ccnc2)cc1
Reaction time: 0.17 h

Procedure:
Imidazole (0.55 g, 8 mmol) is dissolved in dry tetrahydrofuran. The solution is cooled on icebath and SOCl2 (0.16 ml, 2 mmol) is added dropwise to the cooled solution. The mixture is stirred for 10 min. 1-(4-cyanophenyl)-3-(4-fluorophenyl)-1-propanone (0.34 g, 1.3 mmol) is added and the mixture is stirred in room temperature for 4 days. Methylene chloride is added and tie mixture is washed with water. The organic layer is dried and the solvent is evaporated. The residue contains 35% of the product (1H NMR) as a 9:1 mixture of the isomers. The product is purified by flash chromatography (eluent CH2Cl2 -MeOH 99:1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[CH3:14][NH2+]C.C=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10](=[CH2:14])[CH:11]=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCO)CC1
Reactant: C[NH2+]C
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)C1CCN(C(C)=O)CC1

Procedure:
3.95 g (23.3 mmol) of 2-(1-acetylpiperidin-4-yl)ethanol, 2.12 g (26.3 mmol) of dimethylammonium chloride and 3 ml (40 mmol) of 37% formaldehyde solution are heated at 110° C. for 2 hours with stirring. The mixture is allowed to cool and is extracted several times with diethyl ether. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness by evaporation. 2-(1-acetylpiperidin-4-yl)propenal is obtained in the form of a yellowish oil which can be further reacted without further purification.