Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:26](Br)[C:27]#[CH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:28]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:27]#[CH:26]
Reactant: C#CCBr
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)OC
Reaction time: 16 h

Procedure:
Methyl 2-hydroxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoate (0.5 gm, 1.42 mmol) from Step 1 of Example 25 was dissolved in DMF (5 mL) and propargyl bromide (186 mg, 1.56 mmol) was added followed by cesium carbonate (925 mg, 2 eq.) and the mixture was stirred 16 hrs. The solids were removed by filtration and the filtrate solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:1 ethyl acetate:hexanes as eluant. Methyl 2-propargyloxy-4-(N-t-butyloxycarbonyl-4-piperidinyloxy)benzoate was obtained as a gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH2:15]([C:17]1[CH:27]=[CH:26][C:20](/[CH:21]=[CH:22]/[C:23]([Cl:25])=O)=[CH:19][CH:18]=1)[CH3:16].N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:25].[CH2:15]([C:17]1[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:23]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:26][CH:27]=1)[CH3:16]
Reactant: CCc1ccc(/C=C/C(=O)Cl)cc1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: CCc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-4-ethylcinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>CN(C)C=O>[Br:32][C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:2](=[O:1])[C:3]=2[C:4]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1c(Br)[nH]c2c1C(=O)CCC2
Temperature: 0 °C
Yield: 29.1 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (886 mg, 5 mmol) and catalytic benzoyl peroxide in N,N-dimethylformamide (5 mL) at 0° C. was added N-bromosuccinimide (1.869 g, 10.5 mmol)in four equal portions over 1 hour. The mixture was stirred an additional hour, then poured into ice water, the precipitate collected and rinsed with water then diethyl ether and dried. Purification on Silica gel (5% methyl alcohol in 1:1:1 dichloromethane/ethyl acetate/hexanes) gave 2-bromo-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (376 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])[CH3:4]>O1CCCC1.CO>[CH2:3]([N:5]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])[CH3:4]
Reactant: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(/C=C/C(=O)O)cc2)c1
Yield: 77 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 5.5 eq) of sodium hydroxide and 775 mg (1.83 mmol, 1 eq) of methyl (E)-3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]acrylate in 15 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from dichloromethane/heptane, 580 mg of (E)-3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder (m.p.=116° C.). Yield=77%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:17]([CH2:22][NH2:23])=[N:18][CH:19]=[CH:20][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:23][CH2:22][C:17]2[C:16]([CH3:15])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cccnc1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, C-(3-methyl-pyridine-2-yl)-methylamine and NaBH(OAc)3 in CH2Cl2 gave 4-[(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.89-1.93 (m, 5H), 2.30 (s, 3H), 2.68-2.71 (m, 1H), 2.73-2.87 (m, 2H), 3.90 (s, 2H), 4.02-4.04 (m, 2H), 7.06-7.10 (m, 1H), 7.41-7.44 (m, 1H), 8.38 (d, 1H, J=3.0 Hz).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:19])[C:11]=3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][C:3]=2[O:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:12]2([OH:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)=[C:11]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:28][CH:27]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 34.7 %

Procedure:
To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (5 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 4-fluorophenyl magnesium bromide (0.62 mmol). After stirring for 45 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (45 mg, 35%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][N:5]1[C:14](=[O:15])[CH2:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][C:6]1=[O:16].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][O:4][N:5]3[C:14](=[O:15])[CH2:13][C:8]4([CH2:12][CH2:11][CH2:10][CH2:9]4)[CH2:7][C:6]3=[O:16])[CH2:30][CH2:31]2)=[N:18]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC2(CCCC2)CC(=O)N1OCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
A mixture of 8-(2-bromoethyloxy)-8-azaspiro[4.5]decan-7,9-dione (3.7 g), 1-(1,2-benzisothiazol-3-yl)piperazine (2.2 g), K2CO3 (2.77 g) and NaI (200 mg) was heated was stirring in 125 mil of anhydrous CH3CN under N2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.CC(O)=O>[Zn].CO>[F:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(F)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc(F)cnc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.8 %

Procedure:
To a stirred mixture of 2-amino-5-fluoro-3-nitropyridine (2.46 g, 15.66 mmol) in a mixture of glacial HOAc (10 mL) and MeOH (20 mL) at 0° C. was added zinc dust (5.09 g, 78.3 mmol) portion-wise, and the mixture was allowed to warm slowly to rt. After stirring at rt for 15 h, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated aq NaHCO3. The organic layer was separated and the aqueous layer was extracted with additional EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 5-fluoropyridine-2,3-diamine (1.13 g) as a solid which was not purified further. LCMS (ESI) m/z 128 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:23]=[O:24])C>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:23]=[O:24])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2cccn2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccnn1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyloxymethyl-1H-pyrazole (4.6 g, 24 mmol) in THF (40 mL) is cooled to −78° C. n-Butyllithium (12 mL, 2.5 M in hexanes, 30 mmol) is added dropwise. After stirring at −78° C. for 30 min, DMF (1.0 mL) is added. The reaction mixture is warmed to RT over 1 h. The mixture is partitioned between aqueous NH4Cl and EtOAc. The organic layer is concentrated to afford the title compound as a yellow oil, which is used directly in the next step: (M+1)+=217.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH2:5].C([O-])(=O)C.[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1ccccc1
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
D-Alanine methyl ester (4 g, 28.66 mmol) is taken up in methanol (100 mL). To this is added sodium acetate (5.88 g, 71.65 mmol) and benzaldehyde (2.9 mL, 28.66 mmol). The mixture is stirred for 15 minutes and then a solution of sodium cyanoborohydride (1.08 g, 17.2 mmol) in methanol (5 mL) is added dropwise to the mixture. After stirring for 2 hours methanol is evaporated under reduced pressure and the product is extracted into ether and washed with water (2×). The crude product is purified by silica gel flash chromatography (8:2 hexane:ethyl acetate) to give 3.3 g of N-benzyl D-alanine methyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15]C)[CH:10]=3.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3
Reactant: COc1cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
9-bromo-2-methoxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (700 mg) obtained in Example 101 was suspended in anhydrous methylene chloride (70 ml), and to the suspension was added dropwise a solution of boron tribromide in methylene chloride (1M; 10 ml) at room temperature. The reaction mixture was stirred at room temperature for 12 hours, and poured into ice water (100 ml). To this mixture was added saturated aqueous solution of sodium carbonate until the termination of foaming. The crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with ethanol and ether in succession to obtain the title compound (450 mg, 67%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[CH2:12][N:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=[O:20])[C:9]1([CH3:22])[CH3:21])(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CO.Cl>[CH:13]1([N:11]2[C:10](=[O:20])[C:9]([CH3:21])([CH3:22])[CH:8]([CH:7]=[O:6])[CH2:12]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CN(C2CCCCCC2)C(=O)C1(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cl
Solvent: CO
Product: CC1(C)C(=O)N(C2CCCCCC2)CC1C=O
Reaction time: 1 h

Procedure:
To a solution of Example 1D (0.168 mg, 0.475 mmoles) in methanol (1.5 mL), two drops of 12M HCl was added and stirred for one hour. The solvent was evaporated in vacuo. The residue was taken in dichloromethane (2.5 mL) and Dess-Martin periodinane (0.25 gm, 0.593 mmoles) was added and stirred at room temperature for two hours. The reaction was quenched with 10% sodium bisulfite and extracted with dichloromethane. The organic phase was washed with water, dried with MgSO4, filtered, and evaporated in vacuo to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([NH:9][C:10]1([C:13](O)=[O:14])[CH2:12][CH2:11]1)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C.N>ClCCl>[C:13]([C:10]1([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][CH:18]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:12][CH2:11]1)(=[O:14])[NH2:26]
Reactant: O=C(NC1(C(=O)O)CC1)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)C1(NC(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 369.6 %

Procedure:
To the suspension of 1-(3-nitrobenzamido)cyclopropanecarboxylic acid (0.38 g, 1.519 mmol) in dichloromethane (5 ml), oxalyl chloride (0.199 ml, 2.278 mmol) was added followed by DMF (0.024 ml, 0.304 mmol). Reaction mixture was stirred at room temperature for 3 hr. After complete dissolution of the compound, cold aqueous ammonia (5 ml) was added under cooling. Allowed and stirred the content at room temperature for 1 hr. concentrated the reaction mixture to remove dichloromethane and the obtained slurry was filtered to obtain titled compound (0.28 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][C:33]4[S:32][CH:36]=[CH:35][CH:34]=4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: O=C(Cl)Cc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (150 mg) and triethylamine (0.11 mL) in tetrahydrofuran (5 mL) at room temperature was added 2-thiopheneacetyl chloride under argon at room temperature. The solution was stirred for 30 minutes and then quenched with methanol. The mixture was loaded onto a SCX-2 column and eluted with methanol then 7M NH3 in methanol. The basic fraction was concentrated and the residue purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a yellow oil (150 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Br[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]>CN(C=O)C>[CH3:17][N:16]([CH3:18])[C:14](=[O:15])[CH2:13][N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: CN(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-4-nitropyrazole (Apollo, Cheshire, UK, 500 mg, 3.93 mmol) in DMF (10 ml) was added 55% NaH in oil (198 mg, 4.54 mmol) and the reaction mixture was stirred for 30 min at rt. Then to the reaction mixture was added a solution of 2-bromo-N,N-dimethylacetamide (stage L.3, 720 mg, 4.34 mmol) in DMF (3 ml). The reaction mixture was stirred for 1 h at it then quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with water (2×), brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by Prep. HPLC (H2O (0.1% TFA)/CH3CN 97:2 to 75:25; reverse phase silica gel). The fractions containing product were collected together, basified with NaHCO3 and concentrated before being extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a white solid (HPLC tR 2.06 min (Method A); M+H=213 MS-ES).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][C:26]1[N:27]([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[C:28]([CH3:31])=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:36][C:35]3[CH:34]=[CH:33][C:32]([N:27]4[C:28]([CH3:31])=[CH:29][CH:30]=[C:26]4[CH3:25])=[CH:39][CH:38]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1ccc(C)n1-c1ccc(C=O)cc1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(-n4c(C)ccc4C)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione to 4-(2,5-Dimethyl-pyrrol-1-yl)-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)ccc1S(=O)(=O)NCCN1CCOCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A mixture of 4-bromo-2-methylbenzene sulfonyl chloride (700 mg, 2.6 mmol), 4-(2-aminoethyl)morpholine (372 mg, 2.86 mmol, 1.1 eq), and N,N-diisopropylethylamine (1.0 mL, 5.71 mmol, 2.2 eq) in anhydrous tetrahydrofuran (13 mL, 0.2 M) was stirred at 40° C. under nitrogen for 18 h. Solvent was removed at reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (eluting with 50% to 75% EtOAc/hexane) to give 939 mg (99%) of the desired product as a white solid. 1H-NMR (DMSO-d6) δ 7.73 (d, J=8.4 Hz, 1H), 7.68 (broad s, 1H), 7.65 (dd, J=2.1, 0.6 Hz, 1H), 7.55 (ddd, J=7.3, 2.1, 0.6 Hz, 1H), 3.41 (t, J=4.5 Hz, 4H), 2.88 (t, J=6.3 Hz, 2H), 2.56 (s, 3H), 2.19 (t,=6.6 Hz, 2H), 2.16 to 2.12 (m, 4H); MS LC-MS [M+H]+=363 & 365, RT=1.90 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=O)[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].O.[NH2:17][NH2:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](=[O:8])[NH:18][N:17]=[CH:14]2
Reactant: COc1cc(C=O)c(C(=O)O)cc1OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cc2cn[nH]c(=O)c2cc1OC

Procedure:
4,5-Dimethoxyphthalaldehydic acid (10 g.) and hydrazine hydrate (2.4 ml.) in ethanol (150 ml.) were heated under reflux for 20 hours during which time a white crystalline solid formed. The mixture was cooled in an ice bath, filtered and the resulting product dried to give crude 6,7-dimethoxyphthalazin-1-one (7 g.). A sample was crystallized from water yielding colorless needles, m.p. 254°-256° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][C:8]([S:10][C:5]=2[CH:4]=1)=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:23])[C:18](=[CH:21][CH:22]=1)[CH:19]=O>C(O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]2[CH:19]3[S:10][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=4[CH:7]3[C:8](=[O:9])[O:23][C:17]=2[CH:16]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COc1ccc2c(c1)SC(=O)C2
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(=O)C1c3ccc(OC)cc3SC21
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a stirred solution of 6-methoxythianaphthen-2-one (see Docket B-9459) (20 g, 111 mmol) in a mixture of ethanol (100 mL) and methylene chloride (50 mL) was added 4-methoxysalicylaldehyde (17.5 g, 115 mmol) followed by triethylamine (567 mg, 784 mL, 5.6 mmol) at room temperature. After 30 min, a solid began to precipitate and stirring was continued overnight. The mixture was then diluted with cold hexane (1 L) and filtered to yield 28.7 g (82%) of the title product as an off-white solid, pure by 1H-NMR analysis. An analytical sample was obtained by recrystallization from toluene as light yellow crystals, mp 157-165d° C.: 1H-NMR (300 MHz, CDCl3) d 7.33 (d, J=8.6 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.70 (m, 2H), 6.60 (d, J=2.5 Hz, 1H), 5.22 (d, J=7.2 Hz, 1H), 4.33 (d, J=7.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H); IR (CHCl3) 1759 cm-1 ; MS (FD) m/e 314 (M+); Anal. calc'd. for C17H14O4S: C, 64.95; H, 4.50. Found: C, 65.01; H, 4.58.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[N:8]O)[CH2:4][CH2:3]1.Cl>CCO.[Ni]>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=NO)CC1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: CC1(C)CCC(N)CC1
Yield: 88.6 %

Procedure:
4,4-Dimethylcyclohexanone oxime (D296) (10 g, 71 mmol, 1 equiv) in EtOH (100 ml) was stirred with Raney Ni (1 g, 10% w/w) under an atmosphere of H2 (50 psi) for 4 days. The catalyst was filtered off through a pad of celite and HCl (1M in Et2O, 100 ml, 100 mmol, 1.4 equiv) were added. The precipitate formed was filtered off and dissolved in water. The aqueous phase was washed with Et2O and made strongly basic with KOH pellets then extracted twice with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give 4,4-dimethylcyclohexanamine (F83) (8 g, 89%) as a clear oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1([CH:16]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH:17]([CH3:19])[CH3:18])[CH:15]=[CH:14][N:13]=[CH:12]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:16]([N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(NC(=O)Nc2ccc(F)cc2)cc1)n1ccnc1
Yield: 32.4 %

Procedure:
4-Fluorophenylisocyanate (0.017 mol) was added to a solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.014 mol) in dry THF (100 ml) and the mixture was stirred and refluxed for 2 hours. The mixture was cooled, the precipitate was filtered off and recrystallized from 2-propanone and CH3OH, yielding 1.6 g (32%) (±)-N-(4-fluorophenyl)-N′-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]urea (compound 740).