Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)[CH2:4]2
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: COc1cccc(/C=C/C(=O)N[C@H]2CN3CCC2CC3)c1

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-methoxyphenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 287 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccnc(Br)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccnc(Br)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
2-Bromo-pyridin-4-carbaldehyde (20.0 g, 107.5 mmol), malonic acid (25.2 g, 241.9 mmol), and piperidine (8.8 mL, 89.2 mmol) were added to pyridine (65.2 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid dried under reduced pressure to give 18.2 g of the titled compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:27][OH:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:27][OH:28])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(CO)C(=O)Nc1ccccc1
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(CO)C(=O)Nc1ccccc1

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-hydroxy-N-phenyl-propionamide to provide the title compound in good yield. LCMS m/z 386 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:18][N:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[C:22]=2[CH:21]=[N:20]1.N1C2C=CC=C(N)C=2C=N1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:8][NH:9][C:10]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[N:20][N:19]2[CH3:18])=[O:11]
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(N2CCCCC2)c(F)c1
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCCC4)c(F)c3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 9.19 (s, 1H), 8.22 (s, 1H), 7.25 (m, 4H), 7.18 (d, 2H), 4.31 (s, 2H), 4.00 (s, 3H), 3.15 (m, 4H), 1.77 (m, 4H), 1.66 (m, 2H); MS (ESI) (M+H)+382.
Reaction SMILES: [C:1]([C@H:4]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]2)(O)=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:73][N:74]1[CH2:79][CH2:78][N:77]([CH:80]2[CH2:85][CH2:84][NH:83][CH2:82][CH2:81]2)[CH2:76][CH2:75]1>CN(C=O)C>[CH3:15][C:13]1[CH:14]=[C:6]([CH2:5][C@@H:4]([O:23][C:24]([N:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:30][CH2:31]2)=[O:25])[C:1]([N:83]2[CH2:82][CH2:81][CH:80]([N:77]3[CH2:76][CH2:75][N:74]([CH3:73])[CH2:79][CH2:78]3)[CH2:85][CH2:84]2)=[O:2])[CH:7]=[C:8]2[C:12]=1[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[N:10]=[CH:9]2
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2cnn(C(=O)OC(C)(C)C)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2cnn(C(=O)OC(C)(C)C)c12

Procedure:
A solution of 440 mg tert.-butyl 5-{(R)-2-carboxy-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-ethyl}-7-methyl-indazol-1-carboxylate, 256 mg (0.8 mmol) TBTU, 146 μL (1.0 mmol) triethylamine and 147 mg (0.8 mmol) 1-methyl-4-piperidin-4-yl-piperazine in 8 mL DMF was stirred for 2 h at RT. The reaction solution was filtered through an injection filter and purified directly by HPLC without any further working up. The fractions containing the product were combined, evaporated down i.vac., made alkaline with 15% K2CO3 solution, extracted three times with 30 mL DCM, the combined organic phases were dried over Na2SO4 and the solvent was eliminated i. vac.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
2-Acetylamino-4-chloromethylthiazole (480 mg), 3-(4-piperidyl)indole (500 mg) and sodium hydrogen carbonate (310 mg) was refluxed in a mixture of N,N-dimethylformamide (5 ml) and tetrahydrofuran (7 ml) for 1 hour and 40 minutes. After the reaction mixture cooled to ambient temperature, it was concentrated under reduced pressure. After addition of water (50 ml), the residue was extracted with ethyl acetate (50 ml) twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (30:1 V/V). The eluate gave 2-acetylamino-4-[4-(3-indolyl)piperidinomethyl]thiazole (270 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][CH2:12][C:13]1[N:17]([CH3:18])[C:16]([SH:19])=[N:15][N:14]=1.[CH3:20]I>O.ClCCl>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]=1[NH:11][CH2:12][C:13]1[N:17]([CH3:18])[C:16]([S:19][CH3:20])=[N:15][N:14]=1
Reactant: CI
Reactant: Cc1cccc(C)c1NCc1nnc(S)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CSc1nnc(CNc2c(C)cccc2C)n1C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.7 g (0.0419 mol) sodium hydroxide in 125 ml water was added in one portion, 10.4 g (0.0419 mol), 3-(2,6-dimethylphenylaminomethyl)-4-methyl-5-mercapto-1,2,4-triazole. After a homogeneous solution was obtained, 6.2 g (0.044 mol) methyl iodide was added dropwise. The reaction mixture was then diluted with 50 ml dichloromethane and vigorously stirred for 0.5 hour. The reaction mixture was diluted with another 100 ml dichloromethane and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a solid residue. The solid was triturated with ethyl ether to give the product as a colorless solid. The product is tabulated in Table I as Compound No. 14-A.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]3)=[O:23])=[CH:18][CH:19]=1
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2cn1
Temperature: 80 °C

Procedure:
The product from Example 63A (500 mg, 3.1 mmol) in toluene (10 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.5 mL, 3.57 mmol) with stirring and then the mixture was heated at 80° C. overnight. The mixture was allowed to cool to room temperature, filtered, the filter cake was washed with toluene, and allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared using methanolic HCl to afford a tan solid (919 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.54 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.78-7.83 (m, 1H), 7.67-7.71 (m, 1H), 7.52-7.57 (m, 2H), 7.30-7.35 (m, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.78 (s, 3H); MS (ESI+) m/z 370/372 (M+H, 79Br/81Br).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:18]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:64][CH:65]([CH3:68])[CH2:66][NH2:67]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:18]=2)[CH:13]=1)[C:8]([NH:67][CH2:66][CH:65]([CH3:68])[CH3:64])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)NCC(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
A mixture of compound 13b (90 mg, 0.21 mmol), DIPEA (134 mg, 1.04 mmol) and HATU (157 mg, 0.41 mmol) in DMF was stirred at rt for 1 h, then 2-methylpropan-1-amine (18 mg, 0.25 mmol) was added. The mixture was stirred at rt overnight and concentrated. The product was isolated by CC to get compound 13 (45 mg, 45%). 1H-NMR (400 MHz, DMSO-d6) δ: 8.57 (m, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 6.94 (s, 2H), 6.39 (s, 1H), 3.82 (d, J=5.6 Hz, 2H), 3.09 (s, 2H), 2.45 (s, 3H), 1.85-1.84 (m, 1H), 1.46 (s, 3H), 1.33-1.25 (m, 12H), 0.94-0.88 (m, 9H), 0.66-0.63 (m, 2H). MS Found: 488 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:16]([O:17]C)=[CH:15][C:14]2[N:13]([CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:12]3[CH:11]=[CH:10][C:9]4[C:25](=[O:28])[CH2:26][CH2:27][C:8]=4[C:7]=3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:14]2[N:13]([CH2:19][CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])[C:12]3[CH:11]=[CH:10][C:9]4[C:25](=[O:28])[CH2:26][CH2:27][C:8]=4[C:7]=3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1C(C)=O)c1c3c(ccc1n2CCCN(C)C)C(=O)CC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(=O)c1cc2c3c4c(ccc3n(CCCN(C)C)c2cc1O)C(=O)CC4
Temperature: 25 °C

Procedure:
A solution of 9-acetyl-8-methoxy-1,2-dihydro-6-(3-dimethylaminopropyl)-cyclopenta[c]carbazole-3-one (84) (22 g, 58.2 mmol, 1 eq) and pyridine hydrochloride (134.4 g, 1164 mmol, 20 eq) in NMP (150 mL) was refluxed for 10 h. The reaction mixture was cooled to room temperature and poured into the 10% aqueous K2CO3 solution (3 L). The precipitated dark green solid was filtered off, washed with water (5×100 mL) and dried. The crude product was purified by column chromatography (eluent 10%-20% MeOH in EtOAc) to give 7.81 (37%) of pure 9-acetyl-8-hydroxy-1,2-dihydro-6-(3-dimethylaminopropyl)-cyclopenta[c]carbazole-3-one as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[CH:8]=[O:9].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O-:19])=[O:18]>>[CH3:7][C:5]1[S:4][C:3]([CH:8]=[O:9])=[C:2]([S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:19])=[O:18])[CH:6]=1
Reactant: O=S([O-])c1ccccn1
Reactant: Cc1cc(Br)c(C=O)s1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2ccccn2)c(C=O)s1

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-bromo-5-methylthiophene-2-carbaldehyde and pyridine-2-sulfinate sodium salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[CH:7]=1.O.C(=O)(O)[O-].[Na+].[I:19]I>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][CH3:12])=[N:9][C:10]=2[I:19])[CH:7]=1
Reactant: CSc1ncc2ccc(F)cn12
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1nc(I)c2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
In a round-bottomed flask, 6-fluoro-3-methylsulfanyl-imidazo[1,5-a]pyridine (178 mg, 0.88 mmol) was dissolved in ethanol (1.6 ml). Water (0.8 ml), sodium bicarbonate (278 mg, 3.31 mmol) and iodine (312 mg, 1.23 mmol) were added. The dark brown suspension was stirred at room temperature overnight then quenched with 10% aqueous Na2S2O3 and extracted with EtOAc (2×). The combined organic layers were washed with 10% aqueous Na2S2O3, water, and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-10% EtOAc) to afford 110 mg (41%) of 6-fluoro-1-iodo-3-methylsulfanyl-imidazo[1,5-a]pyridine as a brown solid.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH3:8].[Li]CCCC.CN([CH:17]=[O:18])C.C>C(OCC)C.CCCCCC>[CH3:8][C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Cc1csc(C)c1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1csc(C)c1C=O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 3-bromo-2,4-dimethylthiophene, B8, (5.9 g, 0.031 mol) in 200 mL of diethyl ether was cooled to -78° C., and a solution of n-BuLi (25.0 mL, 1.6M) in hexanes was added dropwise. When the addition was complete, the reaction was stirred at -78° C. for 4 h. TLC analysis indicated very little conversion so reaction mixture was warmed slowly to -25° C. Then a solution of DMF (4.5 g, 0.062 mol) in 25 mL of ether was cannulated into the reaction mixture which was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with water and extracted twice with diethyl ether. The organic extracts were combined, washed with twice with water and then brine and dried (MgSO4). The solution was filtered and concentrated to provide an amber oil which was dissolved in hexane. The solution was treated with charcoal, filtered through Dicalite, and concentrated to give 2,4-dimethylthiophene-3-carboxaldehyde, C,8, which was used directly in the next step. ##STR60##
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH:5]=[N:6][CH:7]=1.[OH:19]O>C(Cl)Cl.C[Re](=O)(=O)=O.O=[Mn]=O>[Cl:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH:5]=[N+:6]([O-:19])[CH:7]=1
Reactant: OO
Reactant: Clc1cccc(Cl)c1-n1cc2cncc(Cl)c2n1
Agent: C[Re](=O)(=O)=O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: [O-][n+]1cc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
To a solution of 7-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (2.7 g, 9.0 mmol) and methyltrioxorhenium (31 mg, 0.09 mmol) in DCM (6 mL) was added hydrogen peroxide (30% aq., 1.75 mL, 18.0 mmol) and the resulting mixture stirred at room temperature for 18 hours. A catalytic amount of MnO2 was added to the mixture and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was triturated in toluene to afford the title compound as a beige solid (2.5 g, 89% yield). LCMS (Method D): RT=2.57 min, m/z: 314 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(N(C)S(C)(=O)=O)cc1Br
Product: Cc1ccc(N(C)S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N-(3-bromo-4-methylphenyl)-N-methylmethanesulfonamide (Intermediate 197), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17]O)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:27](=[O:29])[NH:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17][N:33]3[CH2:32][CH2:31][CH:30]([N:26]4[C:25]5[CH:36]=[CH:37][C:22]([Cl:21])=[CH:23][C:24]=5[NH:28][C:27]4=[O:29])[CH2:35][CH2:34]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 7.6 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 5.5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5parts of sodium carbonate and 63 parts of N,N-dimethylformamide is stirred and heated in an oil bath at 50°-60° C for 2 hours. The reaction mixture is poured onto water. The precipitated product is filtered off, dried and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water. It is filtered off again and dissolved in a mixture of 4-methyl-2-pentanone and a small amount of N,N-dimethylformamide. The solution is filtered till clear and the filtrate is concentrated to a volume of about 10 parts. The concentrate is triturated in methanol. The precipitated product is filtered off and dried, yielding 1.27 parts of 5-chloro-1-{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2-H-benzimidazol-2-one; mp. 229°-236° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:40]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)C4CCCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclohexanecarbonyl chloride (0.33 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2C2 solution was washed with 1N HCL (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}cyclohexylcarboxamide (0.53 g, 72%) as a white solid: mp 142–144° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.86–7.77 (m, 2H), 7.64–7.61 (m, 1H), 5.18–5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 2.97–2.83 (m, 1H), 2.63–2.47 (m, 2H), 2.26–2.17 (m, 1H), 2.08–2.0 (m, 1H), 1.79–1.61 (m, 5H), 1.43–1.12 (m, 5H); 13C NMR (DMSO-d6) δ 175.58, 172.75, 169.82, 167.49, 166.96, 139.68, 134.75, 132.76, 131.49, 126.99, 121.73, 48.83, 43.90, 37.43, 30.92, 29.20, 25.43, 25.24, 21.96; Anal. Calcd. For C21H23N3O5: C, 63.47; H, 5.83; N, 10.57. Found: C, 63.12; H, 5.68; N, 10.41.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.5 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole) in anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of monomethylene (1M in tetrahydrofuran) (33 ml) was added. The solution was stoppered and stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake (5.5 g, 96%) was recrystallized from tetrahydrofuran-ethanol to give 3.0 g of a white flocculent solid, mp 258°-259° C. after forming a polymorph from 250°-255° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:13]([CH:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(OCC)(SCC)=[S:38].C(O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:13]([CH:15]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[S:38])[NH2:29])=[CH:26][CH:27]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP([O-])(=S)SCC
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1C(Nc1ccc(C#N)cc1)C(=O)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1C(Nc1ccc(C(N)=S)cc1)C(=O)OCC

Procedure:
1.7 g of ethyl (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy-phenyl)-(4-cyano-phenylamino)-acetate, 1.13 ml of diethyl dithiophosphate and 4 ml of ethanol were heated for 2 hrs. to 60° C. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried and evaporated in a vacuum. Chromatography on silica gel gave 1.6 g of ethyl (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy-phenyl)-(4-thiocarbamoyl-phenylamino)-acetate, m.p. 166° C., MS: 523 (M+H)+.