Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-]>ClCCl>[CH3:23][NH:22][CH2:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9](=[CH:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH2:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cccc(C2=CCC(=CC3SC(=O)NC3=O)C=C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
2 g (4.7 mmol) of tert-butyl [4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]methyl-carbamate and 20 ml of dichloromethane are introduced into a round-bottomed flask. 2.2 ml (28.2 mmol) of trifluoroacetic acid are added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into aqueous bicarbonate solution and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. 1.3 g (85%) of the expected product are obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[BrH:13].N([O-])=O.[Na+].[OH-].[Na+]>>[Br:13][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Br
Reactant: Nc1cc2cccnc2c(Br)n1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: Brc1cc2cccnc2c(Br)n1
Reaction time: 8 h
Yield: 34 %

Procedure:
To 6-amino-8-bromo-1,7-naphthyridine (6.554 g) synthesized according to Tetrahedron Letters, 12, 1233, 1966 was added 48% hydrobromic acid (55 ml). Sodium nitrite (4.141 g) was added thereto in small portions under ice-cooling, and the mixture was stirred overnight. The reaction mixture was basified by adding 5N sodium hydroxide thereto, and it was extracted with ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellowish orange solid (2.856 g, yield; 34%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1>C(O)C.O.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c(C(=O)O)c1

Procedure:
20.1 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 87 ml morpholine. The temperature of the thick mixture rose to 75° C. After being stirred at reflux temperature for five hours, the mixture was poured into ice water, made acidic with concentrated HCl, filtered, dried and recrystallized from ethanol to give 20.3 grams 2-morpholino-5-nitrobenzoic acid. m.p. = 168°-170° C. The nitro compound was reduced catalytically in ethanol-water (3:1) with 5% palladium on carbon catalyst to give 5-amino-2-morpholinobenzoic acid. m.p. = 307°-308° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:6].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[CH:5]([OH:6])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(OC)c(C(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(OC)c(C(O)c2cccc(N)c2)c1
Yield: 63.1 %

Procedure:
100 g of 2,5-Dimethoxy-3'-nitrobenzophenone was dissolved in 1.3 liters of ethanol. With the addition of a 10% palladium on carbon catalyst, the solution was charged in an autoclave, and hydrogenated for 8 hours at 130° C with an initial hydrogen pressure of 100 kg/cm2. The filtrate obtained on removal of the catalyst was concentrated to obtain white crystals. Filtration and air drying provided 57 g of the subject compound, which had a melting point of 132° to 134° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.C(O[C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=2)[CH:27]=1)=O)(C)(C)C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=4)[CH:27]=3)[CH2:23][C:22](=[O:39])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: Cc1cc(-c2cccc(C3=Nc4ccc(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (121 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (37 mg).
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:8]([Cl:26])=[CH:9][C:10]([OH:25])=[C:11]([CH:24]=1)[C:12]([N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:15])=[O:13].Br[CH2:28][CH2:29][CH2:30][C:31]#[N:32].C([O-])([O-])=O.[K+].[K+]>ClCCl>[Br:6][C:7]1[C:8]([Cl:26])=[CH:9][C:10]([O:25][CH2:28][CH2:29][CH2:30][C:31]#[N:32])=[C:11]([CH:24]=1)[C:12]([N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:15])=[O:13]
Reactant: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1OCCCC#N
Temperature: 50 °C
Yield: 68 %

Procedure:
To a stirring DMF solution (6 mL) containing 5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (300 mg, 0.81 mmol) was added 4-bromo-butyronitrile (0.096 mL, 0.97 mmol) and K2CO3 (223 mg, 1.62 mmol). The mixture was heated at 50° C. for 8 hrs. Additional 0.5 eq. of 4-bromobutyronitrile and 0.5 eq of K2CO3 were added and the mixture was heated for another 8 hrs. The mixture was diluted with dichloromethane, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography to afford 5-bromo-4-chloro-2-(3-cyano-propoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide (241 mg). MS [M+H]+: 439.1; tR=2.62 min (method 1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:23]2[CH2:24][CH2:25][N:20]([CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][CH2:22]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(CCl)ccc1Cl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1cc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)ccc1Cl

Procedure:
A mixture of 10.3 parts of 1-chloro-4-(chloromethyl)-2-nitrobenzene, 25.2 parts of 1-(diphenylmethyl)piperazine and 120 parts of ethanol is stirred and refluxed for 4 hours. The reaction mixture is cooled and evaporated. The residue is taken up in about 100 parts of water and the products is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and hexane (1:2 by volume). The product is filtered off, washed with hexane and dried, yielding 19.6 parts of 1-(4-chloro-3-nitrophenylmethyl)-4-(diphenylmethyl)piperazine; mp. 101.6° C.
Reaction SMILES: [O:1]=[C:2]1[C:13]2[C:14]3[C:6](=[C:7]([C:27]4[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=4)[CH2:30][O:31]C(=O)C)[NH:8][C:9]=3[CH:10]=[C:11]([NH:15][C:16]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])[CH:12]=2)[CH:5]=[N:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].O1CCCC1>CO>[OH:31][CH2:30][C:29]1[CH:28]=[C:27]([C:7]2[NH:8][C:9]3[CH:10]=[C:11]([NH:15][C:16]([C@@H:18]4[CH2:20][C@H:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:17])[CH:12]=[C:13]4[C:2](=[O:1])[NH:3][N:4]=[CH:5][C:6]=2[C:14]=34)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)OCc1cccc(-c2[nH]c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc4c3c2C=NNC4=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NN=Cc2c(-c3cccc(CO)c3)[nH]c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc1c23
Yield: 99.5 %

Procedure:
The title compound of Example 85 (0.288 g, 0.58 mmol) and K2CO3 (0.161 g, 1.17 mmol) were stirred in methanol (0.2 M, 1.7 mL) and tetrahydrofuran (0.2 M, 1.7 mL) for 1.5 hours at 22° C. After the solution was filtered and acidified with two drops of glacial acetic acid, the volatiles were removed in vacuo. Silica gel chromatography (40:60 to 0:100 hexane/ethyl acetate) afforded the title compound (0.26 g) as a yellow powder in 95% yield.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:32]2[CH2:31][C:30]2[CH:33]=[CH:34][C:27]([CH3:26])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Reactant: Cc1ccc(CN)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (855.1.1 mg, 8.45 mmol, 1.178 mL) and para-methylbenzylamine (465.3 mg, 3.84 mmol, 0.489 mL) resulting in the formation of a bright yellow precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Recrystallisation of the cream/yellow residue from a minimum amount of boiling ethyl acetate and excess petrol yielded the title product as a fine pale yellow crystalline solid (1.090 g, 3.10 mmol, 81%). 1H NMR: (300 MHz, DMSO) δ ppm 2.21 (s, 3H, HO, 4.20 (d, 1H, J=15.62 Hz, H9), 4.40 (d, 1H, J=15.36 Hz, H9′), 6.95 (d, 2H J=7.97 Hz, H11, H13), 7.04 (d, 2H J=8.00 Hz, H10-H14) 7.27 (m, 5H, H1-H5), 7.55 (m, 2H, H6-H7) 7.74 (d, 1H, H8). 13C NMR: (75 Hz, DMSO) δ 20.90 (CH3), 42.53 (N—CH2), 90.57 (O—C—N), 122.89, 123.15, 128.36, 128.38, 128.61, 129.66, 130.85, 132.91, 133.03, 135.37, 135.84, 139.51 (Ar), 167.10 (C═O). IR: 1398, 1468, 1660, 2921, 3138 cm−1.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[N:4][C:3]=1[CH3:18].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:18][C:3]1[N:4]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]=1[C:20]1[S:19][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1nc(N2CCN(C)CC2)c2nnnn2c1Br
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N2CCN(C)CC2)c2nnnn2c1-c1cccs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A 50 mL round bottom flask was charged with 5-bromo-6-methyl-8-(4-methylpiperazin-1-yl)tetrazolo[1,5-a]pyrazine (0.72 g, 2.3 mmol), thiophene-2-boronic acid (0.46 g, 3.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol), Cs2CO3 (1.2 g, 3.7 mmol), 1,4-dioxane (12 mL) and water (6 mL). After the air was purged by bubbling N2 into the solution, the resulting mixture was stirred at 100° C. under N2 atmosphere overnight. Work-up: the reaction mixture was poured into 0.1 M HCl (40 mL) and washed with EtOAc (50 mL×2). The aqueous layer was then basified with solid NaHCO3 and extracted with CH2Cl2 (50 mL×3). The combined CH2Cl2 layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5% MeOH in CH2Cl2, to afford 165 mg (23%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ: 7.59 (dd, J=5.1, 1.2 Hz, 1H), 7.38 (dd, J=3.6, 1.2 Hz, 1H), 7.21 (dd, J=5.1, 3.6 Hz, 1H), 4.40 (br, 4H), 2.60 (t, J=5.1 Hz, 4H), 2.47 (s, 3H), 2.38 (s, 3H). MS m/z: 316 (M+H+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[CH3:6])[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(CCc2ccccc2OCCC2CCCCN2C(=O)OC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccccc2OCCC2CCCCN2C)c1
Yield: 53.4 %

Procedure:
Following a procedure similar to that described in Example 38, 1.70 g of 1-t-butoxycarbonyl-2-(2-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}ethyl)piperidine [prepared as described in Example 47(a)] were reacted with a dispersion of 0.294 g of lithium aluminum hydride in 30 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.730 g (yield 53%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].[O:16]([CH2:23][C:24]([NH:26][CH:27]1[C:55](=[O:56])[N:29]2[C:30]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:31](OS(F)(=O)=O)[CH2:32][S:33][C@H:28]12)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:16]([CH2:23][C:24]([NH:26][CH:27]1[C:55](=[O:56])[N:29]2[C:30]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:31]([CH:1]=[CH2:2])[CH2:32][S:33][C@H:28]12)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)F)CS[C@H]12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.05 h
Yield: 88.8 %

Procedure:
A solution of palladium (II) acetate (3.6 mg, 0.016 mmol, 0.1 eq.) in 1-methyl-2-pyrrolidinone (2 mL) was treated with vinyl tri-n-butylstannane (58.4 mL, 0.2 mmol, 1.2 eq.) under an inert atmosphere and allowed to stir for 3 minutes. The resulting dark suspension was then treated with diphenylmethyl 7-phenoxyacetamido-3-[(fluorosulfonyl) oxy]-3-cephem-4-carboxylate (100.0 mg, 0.16 mmol, 1.0 eq.) in one portion and the reaction mixture was allowed to stir for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with 3×20 mL of water. The organic fraction was dried over magnesium sulfate then concentrated. The crude brown residue was purified by flash filtration through a pad of silica gel (W. R. Grace, 951W) first with dichloromethane (50 mL) to remove the residual stannane and then with 10% ethyl acetate in dichloromethane (75 mL), which upon concentration furnished 74.8 mg (85%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:40][C:39]([CH3:41])=[N:38][C:37]=2[C:42](O)=[O:43])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[S:40][C:39]([CH3:41])=[N:38][C:37]=2[C:42]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[O:43])=[CH:34][CH:35]=1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.3 %

Procedure:
To a solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (100 mg, 387 μmol) in DMF was added DIPEA (202 μL, 1.16 mmol) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (137 mg, 580 μmol) and HATU (176 mg, 465 μmol). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1 M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give 2-(((2S,3R)-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione as a light yellow oil (130 mg, 71%). MS (ESI) 478 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(O)=O.[Na+].[CH3:18][N:19](C=O)C>CC#N>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]#[N:19])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 6-nitroindole (4.86 g 30 mmol) in DMF (24.3 mL) and CH3CN (243 mL) was added dropwise a solution of C1SO2NCO (5 mL, 57 mmol) in CH3CN (39 mL) at 0° C. After addition, the reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was poured into ice-water, basified with sat. NaHCO3 solution to pH 7-8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).
Reaction SMILES: [C:1]([N:6]([C:22]1[C:27]([N+:28]([O-])=O)=[C:26]([CH3:31])[CH:25]=[CH:24][N:23]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]2[C:20]#[N:21])=[CH:10][CH:9]=1)(=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C>[Fe].C(O)C>[Cl:19][C:17]1[CH:16]=[C:15]([C:20]#[N:21])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:6]3[C:22]4=[N:23][CH:24]=[CH:25][C:26]([CH3:31])=[C:27]4[N:28]=[C:1]3[CH2:2][CH2:3][CH3:4])=[CH:9][CH:10]=2)[CH:18]=1
Reactant: CCCC(=O)N(Cc1ccc(-n2cc(Cl)cc2C#N)cc1)c1nccc(C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2C#N)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 2-[N-butyryl-N-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]amino]-4-methyl-3-nitropyridine (700 mg), iron powder (894 mg), acetic acid (1.8 ml) and ethanol (15 ml) was stirred under reflux for 15 hours. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned into ethyl acetate (100 ml) and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography (n-hexane-ethyl acetate =1:1) to give 3-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (565 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1([C:22]2[CH:23]=[CH:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:26][CH:27]=2)[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][C:14]1([C:22]2[CH:27]=[N:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=2)[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CC(C)(O)c1ccc(C2(CN)CCC(F)(F)CC2)cn1
Product: CC(C)(O)c1ccc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol. LCMS (MH+): m/z=457.1, tR (minutes, Method F)=1.97
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@@H:19]([O:21][CH2:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])[CH3:20])(C(C)(C)C)(C)C>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[OH:26][C:24]([CH3:25])([CH3:27])[CH2:23][CH2:22][O:21][C@H:19]([C@@H:13]1[C@:14]2([CH3:18])[C@H:10]([C@@H:9]([OH:8])[CH2:17][CH2:16][CH2:15]2)[CH2:11][CH2:12]1)[CH3:20]
Reactant: C[C@H](OCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](OCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 80 °C
Yield: 84.9 %

Procedure:
The compound of Example 8E (230 mg, 0.58 mmol) is dissolved in 8 mL of 1 N tetra-n-butylammonium fluoride in tetrahydrofuran and warmed overnight at 80° C. The reaction mixture is partitioned between ether and water; the organic phase was washed with brine and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 0% to 50% ethyl acetate in hexanes to isolate the titled compound (140 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[CH:13](OC)(OC)[O:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[N:4]=[CH:13][O:14][CH3:15]
Reactant: COC(OC)OC
Reactant: Cc1cc([N+](=O)[O-])cc(N)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC=Nc1cc([N+](=O)[O-])cc(C)c1C

Procedure:
66.4 g of 2,3-dimethyl-5-nitroaniline, 0.4 l of trimethyl orthoformate and 1.6 g of para-toluenesulphonic acid are mixed and heated to reflux for 3 hours.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[CH:17]=[C:9]2[N:10]=[C:11]([O:15][CH3:16])[C:12]([Br:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Br:14][C:12]1[C:11]([O:15][CH3:16])=[N:10][C:9]2=[CH:17][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[CH:13]=1
Reactant: COc1nc2cn(CC(C)(N)C#N)nc2cc1Br
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1nc2cn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc2cc1Br

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-bromo-5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (100 mg described in Example 193) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (67.5 mg, 41%). MS (ES): M/Z [M+H]=514. 1H NMR: (400 MHz, CHLOROFORM-d): 1.93 (s, 3H), 4.05 (s, 3H), 4.76 (d, J=14.4 Hz, 1H), 4.90 (d, J=14.4 Hz, 1H), 7.78 (d, J=8.6 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H), 8.12 (s, 1H) and 8.20 (s, 2H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).