Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:18]([CH2:21][CH2:22][CH2:23][N:24]=[C:25]=[S:26])[CH2:19][CH3:20])[CH3:17]>C(#N)C>[CH2:19]([N:18]([CH2:16][CH3:17])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[S:26])[N:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH3:20]
Reactant: CCN(CC)CCCN=C=S
Reactant: CC(C)NCCS(=O)(=O)c1ccccc1
Solvent: CC#N
Product: CCN(CC)CCCNC(=S)N(CCS(=O)(=O)c1ccccc1)C(C)C
Yield: 76.9 %

Procedure:
A solution of 5.0 g (0.022 mole) of N-[2-(phenylsulfonyl)ethyl]-2-propanamine and 4.30 g (0.025 mole) of 3-(N,N-diethylamino)propylisothiocyanate in 400 ml of acetonitrile was refluxed for 16 hr. The solvent was removed in vacuo and the residue was dissolved in ether. The solution was extracted with three portions of water and was dried over magnesium sulfate. The volume of the ether solution was reduced to 200 ml, and hexane was added until the solution became slightly cloudy. A white solid precipitated to give 6.76 g (76.9%) of white crystalline solid, m.p. 120°-121° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15].Cl[CH2:18][C:19]([CH3:21])=[CH2:20]>CN(C)C=O.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[N:13]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:14](=[O:16])[CH3:15]
Reactant: C=C(C)CCl
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1Br
Temperature: 60 °C

Procedure:
To a suspension of 1.34 g of sodium hydride in 10 mL of dimethylformamide under argon is added dropwise, at 0° C., a solution of 5.8 g of N-(2-bromo-5-nitrophenyl)acetamide obtained in stage c) below in 90 mL of dimethylformamide and the reaction medium is stirred at this temperature for 1 hour. 3.3 mL of 3-chloro-2-methylprop-1-ene are then added and the mixture is then heated at 60° C. for 2 hours. After cooling to room temperature, the mixture is diluted with one litre of water and extracted with four times 80 mL of ethyl acetate. The combined organic phases are washed with three times 50 mL of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate (80/20 by volume) to give 5.2 g of N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-en-1-yl)acetamide in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C@H:2]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[CH:11]=[CH:12][C:4]=2[CH2:3]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42]([NH:1][C@H:2]3[C:15](=[O:16])[N:14]([CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:13][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[CH:11]=[CH:12][C:4]=4[CH2:3]3)=[O:43])[CH:39]=1)[CH2:34]2
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: N[C@@H]1Cc2ccc3[nH]ncc3c2CN(CCN2CCCC2)C1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(CCN2CCCC2)C1=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(2-pyrrolidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one (72 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (78 mg, 0.28 mmol) [Bell et al. WO 2006/031606], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH:12]3[CH2:13][CH2:14][CH:8]2[CH2:9][O:10][CH2:11]3)[S:5][CH:6]=1.C(O)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]([N:7]3[CH:12]4[CH2:13][CH2:14][CH:8]3[CH2:9][O:10][CH2:11]4)[S:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: Brc1csc(N2C3CCC2COC3)n1
Reactant: OB(O)c1ccc(Cl)cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2csc(N3C4CCC3COC4)n2)cc1
Temperature: 92.5 °C
Yield: 86.9 %

Procedure:
To a solution of 8-(4-bromothiazol-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Step-1 of o compound 56, 0.29 g, 1.05 mmol) in a mixture of toluene:ethanol (1.5 ml:4.5 ml) were added (4-chlorophenyl) boronic acid (0.18 g, 1.16 mmol) and potassium carbonate (0.29 g, 2.11 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.05 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with mixture of 10% methanol in dichloromethane (2×10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.28 g, 88.0%). MS: m/z 307 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[S:13][C:6]=12.[BH4-].[Na+]>C1COCC1.CO.Cl[Ni]Cl>[F:1][C:2]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=3)[S:13][C:6]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 5.6 %

Procedure:
Nitro compound 48 (97 mg, 2 mmol) was dissolved in a mixture of THF (7 mL) and MeOH (15 mL); NiCl2.×6H2O (130 mg, 0.5 mmol) was added and the solution was cooled to 0° C. To the cooled mixture NaBH4 (42 mg, 1.1 mmol) was added portion wise. The reaction was stirred for 20 min and quenched with 2 M HCl. The solvents were removed under reduced pressure and the residue was treated with concentrated ammonium hydroxide solution (pH 10) and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (eluent EtOAc) to afford the title compound 49 (46.7 mg, 51% yield) as a white solid. 1H NMR (DMSO) δ (ppm): 8.52 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.63-7.58 (m, 2H), 7.56-7.52 (m, 2H), 7.13 (t, J=8.6 Hz, 1H), 6.61 (d, J=2.2 Hz, 1H), 6.56 (dd, J=10 Hz, 1H), 6.46 (dd, J=5.7 Hz, 1H), 5.57 (s, 2H), 3.29 (s, 3H), MS (m/z): 414.8 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[CH3:15].[H-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[N:7]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=2)[C:6]=1[CH3:15]
Reactant: COC(=O)Cc1c(C)[nH]c2nccc(Cl)c12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2nccc(Cl)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a cooled (0° C.) stirred solution of (4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.1 g, 0.42 mmol) in dry DMF (2.5 ml) is added sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mmol). After stirring at room temperature for 5 hours, the reaction mixture is re-cooled to 0° C. and treated with 4-methylsulfonylbenzyl bromide (0.105 g, 0.42 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is diluted with water (3 ml) and extracted with ether (3×15 ml). The organic portions are combined, washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting crude residue is loaded on a pre-packed packed Isolute™ silica column and eluted with iso-hexane:ethyl acetate (1:8) to yield the titled compound as a white powder. (MH+ 407).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:34])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:34])[CH:24]=[CH:23][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(m-tolyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]2[N:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[CH:15][N:16]=2)=[N:8][CH:9]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[CH2:17]([N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[CH2:11][S:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:18][CH3:19]
Reactant: CCCn1ccnc1CSc1ccc([N+](=O)[O-])cn1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1ccnc1CSc1ccc(N)cn1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
5-nitro-2-[[(1-propylimidazol-2-yl)methyl]sulfanyl]pyridine (4.8 g) was dissolved in 85% ethanol solution (114 ml), calcium chloride (0.95 g) and reduced iron (4.8 g) were added to the mixture, and the mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 6-[[(1-propylimidazol-2-yl)methyl]sulfanyl]pyridine-3-amine (2.8 g).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Br-].[C:18]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:4]=[C:3]([C:18](=[O:25])[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:16]=[CH:15][CH:14]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: O=C1CCCC(=O)O1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CCCC(=O)O)c1
Reaction time: 2 h

Procedure:
Magnesium (0.226 g, 8.58 mmol) was flame dried in a 50 mL RB flask equipped with addition funnel and magnetic stirrer under N2. When the flask had cooled, anhydrous THF (25 mL), a pinch of iodine, and a THF solution of Rieke magnesium (1 mL) were added, followed by a small portion of 3-bromophenoxy-tert-butyl(dimethyl)silane (2.24 g, 7.80 mmol) in THF (3 mL) with slight warming to initiate the reaction. The remainder of the bromide solution (10 mL) was added dropwise over 15 min. After 0.5 h this Grignard solution was added to a solution of glutaric anhydride (0.89 g, 7.8 mmol) in THF (10 mL) with cooling in an ice-H2O bath. After 2 h, the reaction mixture was diluted with EtOAc and washed with 1N NaOH (5×) to extract the product. The aqueous basic solution was cooled in an ice-H2O bath and acidified with 12N HCl, then extracted with CH2Cl2 (3×50 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the crude product. Purification on an ISCO Combiflash eluting with 3-7% MeOH/CH2Cl2 w/NH4OH gave the title compound. MS(M+1)323.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.[Br:24][CH2:25][CH2:26][CH2:27]O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:27][CH2:26][CH2:25][Br:24])=[O:20])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: OCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)OCCCBr)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (3.4 g, 17.7 mmol) was slowly added to a solution of 4-methoxybenzoic acid (2.0 g, 13.1 mmol), 3-bromopropan-1-ol (1.1 mL, 12.6 mmol), and 4-(dimethylamino)pyridine (100 mg) in 80 mL of anhydrous dichloromethane. The mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice, followed by the addition of saturated NaHCO3 solution and brine. The organic layer was dried through MgSO4 and concentrated under reduced pressure. Chromatography (silica gel, 1:10 ethyl acetate/hexane) of the residue afforded 2.1 g (61%) of 3-Bromopropyl 4-methoxybenzoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(OCC)(=O)C.[C:18]1([CH3:24])[CH:23]=CC=C[CH:19]=1>CCCCCC>[C:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([CH3:24])([CH3:23])[CH3:19]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A stirred suspension of 4-hydroxy-phenyl acetic acid (0.152 g, 1 mmol) in anhydrous toluene (5 mL) was heated at 80° C. and N,N-dimethyl formamide-di-ti-butyl acetal (1 mL, 4.17mmol) was added when the solution became homogenous. After 0.5 h, the reaction mixture was cooled to ambient temperature and the volatiles were distilled off in vacuo. The residue was diluted with water and extracted with diethyl ether (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 16% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.11 g, 56%).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]#[N:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:4][C:2]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]#[N:18])[C:6]([CH3:7])=[CH:5][CH:1]=1
Reactant: CC(=O)CCC(C)=O
Reactant: N#CCc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccccc1CC#N
Temperature: 155 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
p-Toluenesulfonic acid (2 mg, 0.16 mmol) and acetonylacetone (2.14 g, 18.7 mmol) were added sequentially to a solution of 2-aminophenylacetonitrile (2.06 g, 15.6 mmol) in toluene (30 mL). The reaction mixture was heated in an oil bath at 155° C. for 1 hour and then allowed to stand at ambient temperature overnight. Acetonylacetone (0.5 mL) and a small amount of p-toluenesulfonic acid were added and the reaction mixture was heated at reflux for 4 hours. The toluene layer was washed sequentially with saturated sodium bicarbonate and water (×2), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to a dark oil. The oil was purified by prep HPLC (AnaLogix, eluted with a gradient of 10-30% ethyl acetate in hexanes) to provide 3.35 g of 2-(2,5-dimethylpyrrol-1-yl)phenylacetonitrile as a pale brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[I-].[Na+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br.C(OCC)(=O)C>CN(C)C=O>[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28][N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccc(F)cc1F
Yield: 57.7 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 101 mg, 0.33 mmol), sodium iodide (53 mg, 0.35 mmol) and 2,4-difluorobenzyl bromide (0.22 mL, 1.68 mmol) in dimethylformamide (0.8 mL) was heated under microwave irradiation at 150° C. for 1 h. Ethyl acetate was added and the solution was washed with 10% aqueous sodium thiosulfate (three times), dried (sodium sulfate), filtered, evaporated, and purified on an RS-4g silica gel column, eluting with 20-100% ethyl acetate/hexanes to give (4R,7S)-1-(2,4-Difluoro-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (82 mg, 58%) as a light brown foam. ES(+)-MS (M+H) 431.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC)[CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)#[N:2].[OH-].[Na+].C1C[O:31][CH2:30]C1>O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:31][CH3:30])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)#[N:2]
Reactant: CCn1c(-c2ccc(C(=O)OC)cc2)c(C#N)c2cc(OC)ccc21
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1c(-c2ccc(C(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 80 °C
Yield: 92 %

Procedure:
Methyl 4-(3-cyano-1-ethyl-5-methoxy-1H-indol-2-yl)-benzoate (350 mg, 1.05 mmol), prepared as described in Example 1Ga step B, is combined with NaOH (40 mg, 1 mmol), H2O (0.8 mL), and THF (3.4 mL) and is heated at 80° C. for 1 hour. The reaction mixture is diluted in H2O and is then ether-washed. The aqueous layer is acidified with aqueous HCl, and is extracted into EtOAc. The organic layer is dried and concentrated to yield 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (311 mg, 92%) as a pure white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][N:10]=[C:9]2[CH2:13]Cl)=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])[CH:3]=1.[CH3:23][NH:24][CH3:25]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][N:10]=[C:9]2[CH2:13][N:24]([CH3:25])[CH3:23])=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])[CH:3]=1
Reactant: CNC
Reactant: O=C(c1ccccn1)c1cc(Br)ccc1-n1cnnc1CCl
Solvent: CCO
Product: CN(C)Cc1nncn1-c1ccc(Br)cc1C(=O)c1ccccn1

Procedure:
A mixture of 0.25 g of 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-chloromethyl-4H-1,2,4-triazole, 10 ml. of ethanol and 0.5 ml. of dimethylamine is refluxed for 1.5 hours. After evaporation of the solvent, the residue is diluted with water and then extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and then the solvent is evaporated. The residue is subjected to chromatography through a column of silica gel (15 g) using a mixture of chloroform-methanol-ethyl acetate (85 : 10 : 5) as an eluent to give 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-dimethylaminomethyl-4H-1,2,4-triazole as crystals. Recrystallization from a mixture of acetone and n-hexane gives colorless prisms, melting at 145° to 146° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][CH:10]1[C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13][CH2:12][N:11]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:20][CH:19]=[CH:18]3>C1COCC1>[Cl:1][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:10]([CH3:9])[C:16]3=2)[NH:20][CH:19]=1
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CC1c2c(ccc3[nH]cc(Cl)c23)OCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
N-chlorosuccinimide (13 mg, 0.10 mmol) was added to a solution of tert-butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 0.030 g, 0.099 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (17.5 mg) as a white solid. MS m/z 337 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][C:21]1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38](N)[CH2:39][CH2:40][CH2:41][CH2:42]C>>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][CH2:21][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:19])(=[O:16])=[O:15])([CH3:11])[CH3:12]
Reactant: CCCCCCN
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCNC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with N-hexylamine, mp 125°-127° C.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>>[CH3:13][C:12]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1ccccc1N
Product: Cc1ccccc1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using o-toluidine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.08 (s, 3H), 2.27 (s, 3H), 2.34 (s, 3H), 4.66 (d, J=3.2 Hz, 2H), 5.70 (bs, 1H), 6.14 (s, 1H), 7.01 (t, J=6.3 Hz, 1H), 7.13 (t, J=6.3 Hz, 2H), 7.18 (d, J=7.5 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.54 (d, J=4.8 Hz, 1H); MS (ESI) m/z 320.7 (M+1)+.