Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]#[N:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:13][S:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:28][NH:29][CH3:30].C([O-])(O)=O.[Na+]>CN(C=O)C.C1COCC1>[C:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:16][C:12]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=2)=[CH:15][S:14][N:13]=1)#[N:27]
Reactant: CC(C)C[C@H](Nc1nscc1-c1ccc(C(=O)CBr)cc1)C(=O)NCC#N
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](Nc1nscc1-c1ccc(C(=O)CN(C)C)cc1)C(=O)NCC#N

Procedure:
N2-{4-[4-(bromoacetyl)phenyl]isothiazol-3-yl}-N1-(cyanomethyl)leucinamide (29 mg, 0.064 mmol) was dissolved in DMF (0.6 mL) and dimethylamine (0.13 mL of a 2 M solution in THF, 0.26 mmol) was added. The reaction mixture was stirred until disappearance of the starting material was observed by TLC (˜1 h). Aqueous sat. NaHCO3 was added, the product was extracted with EtOAc (3×), dried over MgSO4, concentrated in vacuo and purified by flash chromatography with dichloromethane, methanol and ammonium hydroxide to yield N1-(cyanomethyl)-N2-{4-[4-(N,N-dimethylglycyl)phenyl]isothiazol-3-yl} leucinamide.
Reaction SMILES: [CH:1](=[N:5][CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:9])[CH:2]([CH3:4])[CH3:3]>CO.O=[Pt]=O>[CH2:1]([NH:5][CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=NCCC(C)c1ccccc1-c1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)CNCCC(C)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.79 g of 1-isobutylideneamino-3-p-biphenylyl-butane (obtainable by boiling 3-p-biphenylylbutylamine with isobutyraldehyde in benzene for 5 hours) in 75 ml of methanol is hydrogenated, after adding 0.3 g of PtO2, at 20° and normal pressure until hydrogen absorption ceases. The mixture is filtered and worked up in the customary manner to give 1-isobutylamino-3-p-biphenylyl-butane.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:35])[C@H:8]([CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].Cl[C:37]1[N:42]=[CH:41][C:40]([C:43]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]2)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.C(O)CC>[NH2:48][C:46]([C:43]1([C:40]2[CH:39]=[CH:38][C:37]([C:18]3[CH:17]=[CH:16][C:15]([C@H:10]([NH:9][C@H:8]([C:7]([NH:6][C:3]4([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:35])[CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[C:11]([F:13])([F:12])[F:14])=[CH:20][CH:19]=3)=[N:42][CH:41]=2)[CH2:45][CH2:44]1)=[O:47]
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: NC(=O)C1(c2ccc(Cl)nc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCCO
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)cn2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A stream of nitrogen was passed through a solution of DMF/1-propanol (1 mL, 4 mL respectively), N1-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-L-leucinamide from Example 1, Step 15, (150 mg), 1-(6-chloropyridin-3-yl)cyclopropanecarboxamide from Step 5 (74 mg) and 2 M Na2CO3 (400 μL) for 15 minutes followed by the addition of palladium acetate (II), complex (4:1) with triphenylphosphine (16 mg). The mixture was warmed to 80° C. for 8 hours under nitrogen. The mixture was cooled to room temperature, poured into ice (20 g) and saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×60 mL). The combined extracts were washed with brine and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2 (Combiflash) using ethyl acetate and hexanes (60% for 10 minutes, then 60 to 100% for 30 minutes) as eluants, followed by a swish using diethyl ether and hexanes to yield the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([CH2:17][CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2]>[Ni].CO>[NH2:2][CH2:1][CH2:3][C:4]1([CH2:17][CH3:18])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]1
Reactant: CCC1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CO
Product: CCC1(CCN)CCN(C(=O)OC(C)(C)C)CC1
Yield: 72.3 %

Procedure:
The process is performed according to the procedure described in Example 12 (step 12.2.). Starting with 0.96 g (3.83 mmol) of tert-butyl 4-cyanomethyl-4-ethylpiperidine-1-carboxylate and 1.12 g (19.15 mmol) of Raney nickel in 50 mL of methanol under a hydrogen atmosphere (70 psi) at 50° C., and after chromatography on a column of silica gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.71 g of expected product is obtained in the form of a wax.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[CH:50]=[C:51]([CH2:54][NH2:55])[S:52][CH:53]=1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:51]4[S:52][CH:53]=[C:49]([CH3:48])[CH:50]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1csc(CN)c1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1csc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)c1
Yield: 80 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (4-methylthiophen-2-yl)methanamine, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.24 (m, 2H), 7.08-6.98 (m, 2H), 6.82 (s, 1H), 6.78 (s, 1H), 6.09 (s, 1H), 5.96 (t, J=5.2 Hz, 1H), 4.66 (d, J=5.2 Hz, 2H), 4.42 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.49 (s, 3H), 2.22 (s, 3H); MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH2:31][CH3:32].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: CCCBr
Agent: N
Product: CCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382as a yellow oil (23 mg, 69%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 1-bromopropane (20 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ0.98 (t, J=7.3 Hz, 3H), 1.78-1.92 (br, 2H), 2.11-2.25 (m, 5H), 2.28-2.42 (m, 1H), 2.53-2.80 (m, 5H), 3.05-3.25 (br, 2H), 3.31 (dt, J=10.2, 3.6 Hz, 1H), 3.37-3.45 (br, 1H), 3.60-3.72 (br, 1H), 3.89 (s, 3H), 6.85 (s, 1H), 6.87 (s, 1H), 7.05 (dd, J=8.7, 2.6 Hz, 1H), 7.21-7.27 (m, 2H) ppm. MS (CI, NH3): 431.2 (base, M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1NCCCN1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.3 %

Procedure:
10% of palladium-carbon (0.237 g) was added to a solution containing N-(3-morpholinopropyl)-2-nitroaniline (1.040 g) in ethanol (12 ml) and the mixture was stirred for 7 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated, thereby yielding the entitled compound (0.667 g) as blackish brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.C([Li])CCC.[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[C:20]([Cl:32])[CH:19]=1>C1COCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:15][O:16][C:17](=[O:33])[C:18]1[CH:23]=[CH:22][C:21]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:20]([Cl:32])[CH:19]=1
Reactant: COc1ccc(Br)cn1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)nc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.8 %

Procedure:
To a cooled solution (−78° C.) of 2-methoxy-5-bromopyridine (1.13 g, 6 mmol, reference example 41a) in THF (12 mL) is added over 10 min (2.5M)n-butyllithium (2.4 mL, 6 mmol) and the resulting solution stirred for 15 min. To this solution is added dropwise (0.5M)zinc chloride (12 mL, 6 mmol) and the temperature of this arylzinc bromide allowed to warm to 0° C. with stirring. To a cooled solution (0° C.), in a separate flask, of palladium bis(dibenzylideneacetone) (288 mg, 0.5 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (276 mg, 0.5 mmol) in THF (2 mL) is added a solution of 3-chloro-4-trifluoromethanesulfonyloxy-benzoic acid methyl ester (1.59 g, 5 mmol) (reference example 39) in THF (2 mL) followed by the arylzinc bromide solution. The resulting solution is heated to 65° C. and stirred for 2.5 hours then cooled to 20° C., diluted with ether, washed with sat NH4Cl soln and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 25% ether in hexanes) to give 428 mg of title compound as a yellow crystalline solid. 1H NMR(CDCl3) δ 3.95 (s, 3H), 4.00 (s, 3H), 6.84 (d, J=9 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.72 (dd, J=9, 2 Hz, 1H), 7.98 (dd, J=8, 2 Hz, 1H), 8.15 (s, 1H), 8.25 (d, J=2 Hz, 1H). MS (EI) m/z 277 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[H-].[Na+].I[CH:14]([CH2:16][CH3:17])[CH3:15].C(N1C=CC(C2SC=CC=2)=N1)(CC)C>CN(C)C=O.CC(OC)(C)C.O>[CH:14]([N:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:9]=[N:8]1)([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)I
Reactant: c1csc(-c2cc[nH]n2)c1
Agent: CCC(C)n1ccc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCC(C)n1nccc1-c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13 %

Procedure:
3-(2-thienyl)-1H-pyrazole (23.2 mmol) was dissolved in 100 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (28.0 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, 2-iodobutane (35.0 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. 650 mg of a mixture of 1-sec-butyl-3-(2-thienyl)-1H-pyrazole and 1-sec-butyl-5-(2-thienyl)-1H-pyrazole (82:18; 13% yield) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13](O)[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1.C(N(S(F)(F)[F:27])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([N:8]2[C:17](=[O:18])[CH:11]3[CH2:12][CH:13]([F:27])[CH2:14][CH2:15][N:10]3[C:9]2=[O:19])=[N:6][CH:7]=1
Reactant: O=C1C2CC(O)CCN2C(=O)N1c1ncc(Cl)cc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C1C2CC(F)CCN2C(=O)N1c1ncc(Cl)cc1F
Reaction time: 1 h

Procedure:
2.6 g of 2-(5-chloro-3-fluoro-pyridin-2-yl)-7-hydroxitetrahydroimidazo-[1,5-a]-pyridin-1,3-dione (isomer B, Example H10) in 80 ml dichloromethane is treated at −55° C. to −65° C. with 1.9 ml of diethylaminosulfur trifluoride (DAST) and stirred at the same temperature for 1 hour. The reaction mixture is then allowed to stir at 20° C. over night. The resulting brownish solution is treated with ice and water and extracted with ethyl acetate. The combined extracts are washed with water, dried, filtered through a small silicagel column and evaporated to give the desired product with m.p. 154-157° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[C:23]3[C:22]4[CH2:21][CH2:20][CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:28](C)=O.[Na+]>CO>[F:1][CH2:2][CH2:3][N:4]([CH3:28])[CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[C:23]3[C:22]4[CH2:21][CH2:20][CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1
Reactant: FCCNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(CCF)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
A solution of 1-N-(2-fluoroethyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (100 mg, 0.30 mmol, 1.00 equiv) in methanol (10 mL) was added HCHO (37%, 1 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The NaBH(OAc)3 (250 mg, 1.18 mmol, 4.00 equiv) was added and the resulting solution was stirred for additional 1 h at ambient temperature. After completion of the reaction, the reaction was then quenched with saturated aqueous sodium bicarbonate, extracted with 3×50 ml of dichloromethane. The combined organic layers were dried in an oven under reduced pressure and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/MeOH (10:1) to afford the corresponding 1-N-(2-fluoroethyl)-1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (47.8 mg, 46%) as a white solid. MS: (ES, m/z): 349 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 1.23-1.32 (m, 2H), 1.50-1.60 (m, 2H), 1.76-1.95 (m, 2H), 2.27-2.35 (m, 2H), 2.40 (s, 3H), 2.50-2.60 (m, 3H), 2.84 (d, 2H), 2.99-3.05 (m, 4H), 4.05-4.15 (m, 1H), 4.57 (d, 2H), 4.86 (d, 1H), 8.39 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][CH2:12]C[C:10]1=[O:16])=[O:8])([O-:3])=[O:2].C1(=O)NCCCC1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[C:7]([N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:10]1=[O:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C1CCCCCN1C(=O)c1cccc([N+](=O)[O-])c1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Synthesized as for N-(3-nitrobenzoyl)caprolactam (Example XXV) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13]([C:15]1[C:16]([C:21](O)=[O:22])=[N:17][CH:18]=[N:19][CH:20]=1)[CH3:14].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:13]([C:15]1[C:16]([C:21]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=2[OH:12])=[O:22])=[N:17][CH:18]=[N:19][CH:20]=1)[CH3:14]
Reactant: CCc1cncnc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCc1cncnc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
A mixture of 2-amino-4-trifluoromethyl-phenol (0.27 g), 5-ethyl-pyrimidine-4-carboxylic acid (0.27 g), WSC (0.25 g), and pyridine (5 ml) was stirred at 80° C. for 1 hour, at 100 for 1.5 hours, and at 115° C. for 0.5 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.34 g of 5-ethyl-N-(2-hydroxy-5-trifluoromethyl-phenyl)-pyrimidine-4-carboxamide.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[CH:9]=[O:10].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(O)(=O)CCCCCCCCCCCCC.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:5]2[CH:6]=[CH:7][C:2]([I:1])=[C:3]([CH:9]=[O:10])[C:4]2=[O:8])=[CH:14][CH:13]=1
Reactant: O=Cc1c(I)cc[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: O=Cc1c(I)ccn(-c2ccc(F)cc2)c1=O
Reaction time: 24 h
Yield: 41.9 %

Procedure:
4-Iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (16.0 g, 64.3 mmol), 4-fluorophenylboronic acid (26.8 g, 193 mmol, Aldrich), copper(II) acetate (23.4 g, 129 mmol, Aldrich), and myristic acid (58.7 g, 257 mmol, Aldrich) were stirred together in 800 mL of toluene. To this solution was added 2,6-lutidine (60 mL, 514 mmol, Aldrich) and the reaction was stirred vigorously for 1 day. An additional 5 g of 4-fluorophenylboronic acid was added and the reaction was stirred vigorously for an additional 3 days. The reaction mixture was concentrated in vacuo and the resulting material was suspended in 10% methanol/ethyl acetate. Celite® was added and the mixture was stirred for 5 minutes. Next the mixture was filtered through a plug of Celite®, concentrated in vacuo, and the resulting material was suspended in ethyl acetate and water. The mixture was filtered through Celite® again to remove additional copper that had precipitated out, washing well with ethyl acetate. The filtrate was washed with 1N aqueous HCl, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting solid was triturated with ethyl acetate to yield 9.25 g (42%) of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde as a yellow solid. The filtrate was concentrated in vacuo and the remaining solid was triturated again with ethyl acetate to yield an additional 5.75 g (68% total yield) of the desired product as a yellow solid. 1H NMR (DMSO-d6) δ 9.57 (s, 1H), 7.68 (d, 1H, J=7.2 Hz), 7.58-7.54 (m, 2H), 7.40 (t, 2H, J=8.8 Hz), 7.02 (d, 1H, J=7.2 Hz); MS (ESI+) m/z 344.13 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH:27]=[O:28])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH2:27][OH:28])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC=O)cnc3[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CCO)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
To a stirred solution of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetaldehyde (65 mg, 0.158 mmol) in dry methanol at 0° C. (5 mL) was added sodium borohydride (60 mg, 1.58 mmol). The resulting mixture was stirred at room temperature for 2 h, quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-ethanol (20 mg, 30.7%) as a white solid: LC/MS m/e calcd for C23H28N2O3S [M+H]+ 413.56, observed 413.2; 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (s, 1H), 7.87-7.92 (m, J=8.3 Hz, 2H), 7.79 (s, 1H), 7.58-7.63 (m, J=8.3 Hz, 2H), 6.36 (s, 1H), 4.31 (t, J=7.8 Hz, 1H), 3.78 (t, J=6.8 Hz, 2H), 3.10 (s, 3H), 2.90 (t, J=6.8 Hz, 2H), 2.25-2.33 (m, 1H), 2.07-2.15 (m, 1H), 1.62-1.87 (m, 5H), 1.46-1.56 (m, 2H), 1.19-1.31 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH2:12]([N:16]=[C:17]=[S:18])[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:12]([NH:16][C:17](=[S:18])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=S
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CCO
Product: CCCCNC(=S)Nc1ccc(NNC=O)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (7.5 g, 0.05 mole) and butyl isothiocyanate (5.7 g, 0.05 mole) were mixed in ethanol (120 ml) and the mixture was refluxed for 30 minutes. The resulting solution was chilled in ice and upon scratching the product crystallized out as a white solid. The mixture was filtered and the solid was washed with ether. The product was dried to give a pale tan crystalline powder. Yield 9.8 g (74%), m.p. 129°-131° C.
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]>C(O)C.O1CCCC1>[CH2:22]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: OCCc1ccc(O)cc1
Reactant: C=CCCCCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCCCCCCOc1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Sodium ethoxide (4.98 g) was added to a solution (240 ml) of 2-(4-hydroxyphenyl)ethyl alcohol (8.68 g) in absolute ethanol and the mixture was stirred at 50° C. for 30 minutes. A solution of 7-octenyl bromide (10 g) in anhydrous tetrahydrofuran was dropwise added thereto and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was concentrated, poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel chromatography (eluent; ethyl acetate:hexane=1:5) to give the subject compound (10.76 g) as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].Cl[C:14]1C=C(C=CC=1CC(C1C=CC(O)=CC=1O)=O)C(OC)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:14])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)c(Cl)c1
Product: COC(=O)c1ccc(C)c(OC)c1

Procedure:
starting with 3-methoxy-4-methylbenzoic acid (see step 1 of Intermediate F). MS (ESI): m/z 181.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH2:4][O:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:16]([O-])=O)=[CH:11][CH:12]=2)[C:7]1=[O:19])=[O:3]>[Pd].CO>[NH2:16][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH2:15][N:6]([O:5][CH2:4][C:2]([CH3:1])=[O:3])[C:7]2=[O:19])=[CH:12][CH:11]=1
Reactant: CC(=O)CON1CCc2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)CON1CCc2ccc(N)cc2C1=O
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A solution consisting of 2-methylcarbonylmethoxy-7-nitro-1,2,3,4-tetrahydroisoquinolin-1-one (500 mg, 1.9 mmol), 10% palladium on carbon (80 mg) and methanol (70 mL) was hydrogenated at 40 psi for 1 hour. The solution was filtered through Celite® and concentrated to give the title compound (400 mg, 90% yield).