Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CCOCC.[BrH:34].BrBr>C(O)(=O)C.C(Cl)Cl>[Br:34][C@@H:19]1[CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17][C:18]1=[O:28]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Br
Agent: BrBr
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)[C@H](Br)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
50 g. of 5α-cholestan-3-one is dissolved in 750 ml. of acetic acid and 5000 ml. of ether, combined with 1 ml. of hydrobromic acid in acetic acid (37% strength), and gradually added dropwise to a solution of 22 g. of bromine in 50 ml. of acetic acid. The mixture is agitated for another 30 minutes, diluted with methylene chloride, and washed in succession with water, sodium bicarbonate solution, and water. After drying and evaporation, 61.5 g. of crude 2α-bromo-5α-cholestan-3-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[N:17]1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:30]#[C:29][CH:31]3[CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[N:17]1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1)C(F)(F)F
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1)C(F)(F)F
Yield: 7.6 %

Procedure:
The title compound was prepared according to the procedure described in Example 111 using N-(4-chloro-3-(3-(4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide (Intermediate-146, 0.300 g, 0.568 mmol), ethynylcyclopropane (0.056 g, 0.852 mmol), TBAF (0.444 g, 1.72 mmol), bis(triphenylphosphine)palladium(II) chloride (0.016 g, 0.022 mmol) and DMSO (3.0 mL) to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.75 (m, 2H), 0.90 (m, 2H), 1.55 (m, 1H), 4.43 (d, J=6.0 Hz, 2H), 7.38 (d, J=6.6 Hz, 1H), 7.46-7.51 (m, 3H), 7.64 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 10.06 (in, 1H), 12-13 (br s, 1H). MS (m/z): 461.12 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:6][C:7]1([CH3:29])[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:11]=2[C:10](=[O:22])[C:9]2[CH:23]=[CH:24]C(C=C)=C[C:8]1=2.C[N+]1([O-])CC[O:34]CC1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[Na].[Na]>[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[OH:34][CH:1]([C:2]1[CH:24]=[CH:23][C:9]2[C:10](=[O:22])[C:11]3[C:12]4[C:17](=[CH:16][C:15]([C:20]#[N:21])=[CH:14][CH:13]=4)[NH:18][C:19]=3[C:7]([CH3:6])([CH3:29])[C:8]=2[CH:3]=1)[CH2:5][OH:4]
Reactant: C=Cc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na]
Solvent: CC(C)(C)O
Product: CC1(C)c2cc(C(O)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To the THF (1 ml) solution of 6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-24, 20 mg, 0.064 mmol), t-butanol solution of osmium tetraoxide (19 μl, 0.3 eq.) and 50% aqueous solution of N-methylmorpholine-N-oxide (30 μl, 2.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. To the reaction solution, 10% aqueous solution of disodium ethylenediamine tetraacetic acid was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (21 mg, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6](OCC)[CH:5]=1)([O-])=O.[C:20](OCC)(=[O:22])[CH3:21]>[Pd]>[CH2:20]([O:22][CH:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:21]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1OCC
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(N)cc1)OCC
Yield: 60 %

Procedure:
Ethyl 4-nitro-2-ethoxycinnamate obtained in step (i) was hydrogenated using Pd (10%)/C—H2 (60 psi) (11 g) in ethyl acetate (150 ml) at RT and chromatographed using ethyl acetate/hexane to yield the title compound as viscous oil (9.41 g, yield 60%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)(=O)C>CN(C)C=O.O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: Nc1c2c(nc3cccc(O)c13)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2nc3c(c(N)c12)CCCC3
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
8-Hydroxy-1,2,3,4-tetrahydro-9-acridinamine hydrochloride (18.07 g) was suspended in 500 ml of dry dimethylformamide. Potassium carbonate (22.6 g) was added, and the reaction mixture was stirred vigorously for 30 mins. Ethyl bromoacetate (18.0 g) was added dropwise, and the reaction was stirred vigorously overnight. The reaction mixture was distributed between ethyl acetate and water, and the organic layer was separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phase was washed with water, dried, filtered, and the filtrate evaporate. The residue was purified by flash chromatography (ethyl acetate, then 5% triethylamine/ethyl acetate) to give 15.75 g (72.91%) of product, mp 141°-142° C.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:43]=[CH:42][C:41]([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[CH:40][C:8]=1[C:9]([NH:11][C:12]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31](C(OC(C)(C)C)=O)[CH3:32])[CH:22]=[CH:21][C:13]=1[C:14]([O:16]C(C)(C)C)=[O:15])=[O:10])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)(Cl)[Cl:64]>CO.O1CCOCC1>[ClH:64].[ClH:64].[OH:6][C:7]1[CH:43]=[CH:42][C:41]([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[CH:40][C:8]=1[C:9]([NH:11][C:12]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][CH3:32])[CH:22]=[CH:21][C:13]=1[C:14]([OH:16])=[O:15])=[O:10]
Reactant: CC(=O)Oc1ccc(-c2cccnc2)cc1C(=O)Nc1cc(-c2ccccc2N(C)C(=O)OC(C)(C)C)ccc1C(=O)OC(C)(C)C
Reactant: ClC(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CNc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cc(-c3cccnc3)ccc2O)c1
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (2.3 mL) was added to a solution mixture of tert-butyl 2-(2-acetoxy-5-(pyridin-3-yl)benzamido)-4-(2-((tert-butoxycarbonyl)(methyl)amino)phenyl)benzoate (0.28 g) in methanol (2 mL) and dioxane (4 mL), followed by stirring at room temperature for 6 hours. The reaction mixture was adjusted to a pH of 5.5 with a 10% aqueous solution of citric acid, and chloroform was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Trifluoroacetic acid (4 mL) was added to the obtained residue, followed by stirring at room temperature for 20 minutes. The solvent was evaporated under reduced pressure, and toluene was added to the residue. The solvent was evaporated under reduced pressure, and a 4 mol/L hydrogen chloride-dioxane solution (5 mL) was added to the residue, followed by stirring at room temperature for 5 minutes. The solvent was evaporated under reduced pressure, and diethyl ether was added to the residue. The solid substance was collected by filtration to obtain 0.18 g of 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-(2-(methylamino)phenyl)benzoic acid dihydrochloride as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([S:19][CH2:20][CH3:21])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([S:19]([CH2:20][CH3:21])=[O:27])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCS(=O)c1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Reaction time: 1 h

Procedure:
A solution of (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone, 571 mg, 1.885 mmol, Example 324) in chloroform (16 mL) was cooled to −15° C. and treated with 3-chloroperoxybenzoic acid (503.7 mg, ˜2.25 mmol, ˜70% purity from Aldrich) and the reaction was stirred at the same temperature for 1 hour. The reaction mixture was diluted with methylene chloride (20 mL) and washed with 10% aqueous sodium thiosulfate (2×5 mL), 10% aqueous sodium carbonate (2×5 mL), brine, dried and concentrated to give (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone as a white solid. MS (M+H)+: 320.
Reaction SMILES: [OH-].[K+].[CH2:3](Cl)/[CH:4]=[CH:5]/[CH2:6]Cl.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl-]>O>[CH:4]([CH:5]1[CH2:6][C:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[CH2:3]
Reactant: ClC/C=C/CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.1 %

Procedure:
Diethyl 2-vinylcyclopropane-1,1-dicarboxylate was prepared as follows: Fifty percent aqueous potassium hydroxide solutin (168 g) was added dropwise to a vigorously stirred solution of 125 g (1.0 mol) trans 1,4-dichlorobutene-2, 80 g (0.50 mol) diethyl malonate and 3.2 g tricaprylymethylammonium chloride while the temperature was maintained at 25°-30° C. When the addition was complete, the reaction mixture was stirred at ambient temperature for an additional five hours. Water was then added to the reaction mixture to completely dissolve the suspended salts in the aqueous phase. The phase layers were separated and the aqueous portion extracted three times with ethyl ether. Distillation of the combined organic solutions gave 21.3 g of the desired diethyl 2-vinylcyclopropane-1,1-dicarboxylate. Bp 64°-66° C. (0.15 mm); nD27° 1.4512; [lit.bp 69°-72° C. (0.5 mm); nD19° 1.4528]. Infrared and proton nmr spectra were consistent with the desired compound. Upon acidification and extraction of the aqueous phase, 19.6 g 2-vinylcyclopropane-1,1-dicarboxylic acid was recovered so that the overall yield of cyclized product was 45.3%.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl.Cl>[Br:18][CH2:19][C:20]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: CC(C)Nc1ccccc1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 54.8 %

Procedure:
To a solution of N-isopropylaniline (21.58 g, 180 mmol) in CH2Cl2 (350 mL) was added triethylamine (26.7 mL, 190 mmol). The solution was cooled to 0° C. and bromoacetyl bromide (14.0 mL, 160 mmol) was added slowly over 1 hour. The reaction was warmed to room temperature and was stirred for 24 hours. The reaction was diluted with 5% aqueous HCl. The organic solution was washed with 5% aqueous HCl (2×), aqueous NaHCO3 (1×), and brine (1×). The organic solution was filtered through a silica gel pad, eluting with CH2Cl2. Recrystallization from hexanes (60 mL) provided 22.47 g of 2-bromo-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 7.45 (m, 3H), 7.21 (m, 2H), 4.89 (m, 1H), 3.52 (s, 2H), 1.05 (d, 6H); MS 256.2 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC>CN(C=O)C.C1COCC1.O.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>[CH3:8][C:5]1[CH:4]=[N:3][C:2]([CH:9]=[CH2:10])=[CH:7][N:6]=1
Reactant: Cc1cnc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cnc(C)cn1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-methyl pyrazine (2.0 g, 11 mmol) was dissolved in DMF:THF (3:1, 24 mL). Tributylvinyltin (3.0 g, 12.6 mmol) and Pd(PPh3)4 (0.172 g, 0.143 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 3 h. The reaction mixture was cooled to RT and diluted with water (240 mL) and extracted with ethyl acetate (3×150 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-methyl-5-vinylpyrazine as a light yellow oil (1.0 g, 71% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.I[CH2:43][CH:44]([CH3:46])[CH3:45]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: CC(C)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 66.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 1-iodo-2-methylpropane (0.115 mL; 1 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.140 g (66%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:14]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O>[C:9]([O:8][C:7](=[O:13])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]1[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)[N:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
tert-Butyl N-(4-aminobutyl)carbamate (22.01 g, 116.9 mmol) was added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (36.80 g, 116.9 mmol), prepared in Parts A-D of Example 1, in distilled water. The reaction was heated at 80° C. for 1.5 hours and then stirred at room temperature for four hours. The reaction was not complete, and triethylamine (16 mL, 115 mmol) was added. The reaction was stirred overnight at room temperature. A precipitate formed, which was isolated by filtration and washed with hexanes to provide 39.92 g of tert-butyl[4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate as a yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:23][CH2:24][C@@H:25]([C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1)[OH:26]>>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])[C:11]1[CH:21]=[CH:22][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:23][CH2:24][C@H:25]([OH:26])[C:27]3[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1)[CH3:20]
Reactant: CCOC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)CNC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl {[4-(4-oxo-1-piperidineyl)benzoyl]amino}acetate (which was obtained in Example 161) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp >140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.1 Hz, 3H), 1.20-1.35 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.90 (m, 5 H), 2.90 (s, 3H), 3.70-3.85 (m, 2H), 3.93 (d, J=5.8 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 4.47 (dd, J=7.9, 4.4 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.90-7.00 (m, 3H), 7.16 (d, J=2.0 Hz, 1H), 7.72 (d, J=8.9 Hz, 2H), 8.58 (t, J=5.8 Hz, 1H); MS (ES) m/z: 535.2 (MH+); HRMS Calcd. for C26H37N4O7S(MH+): 535.2221. Found: 535.2216.
Reaction SMILES: Br.[NH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:4]#[N:5].[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31](O)=[O:32])=[O:23]>>[C:4]([CH:3]([NH:2][C:31]([C@@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@@H:25]1[NH:24][C:22]([C:14]1[N:13]([CH3:12])[C:21]2[C:16]([CH:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])=[O:32])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:5]
Reactant: Cn1c(C(=O)NC2CCCCC2C(=O)O)cc2ccccc21
Reactant: N#CC(N)c1ccccn1
Agent: Br
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)c2ccccn2)cc2ccccc21

Procedure:
Amino-pyridin-2-yl-acetonitrile hydrobromide and 2-[(1-Methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarboxylic acid were coupled as described in Example 1 to provide methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(cyano-pyridin-2-yl-methyl)-carbamoyl]-cyclohexyl}-amide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13](C=O)[CH2:12][CH2:11]2)[N:7]=[C:6]([N:18]2[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]2)[C:5]=1[N+:25]([O-:27])=[O:26])[CH3:2].[OH-].[Na+].O>CO>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[N:7]=[C:6]([N:18]2[CH2:19][CH2:20][S:21](=[O:24])[CH2:22][CH2:23]2)[C:5]=1[N+:25]([O-:27])=[O:26])[CH3:2]
Reactant: CCOc1nc(N2CCN(C=O)CC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
1.2 gm (3 millimols) of 6-ethoxy-2-(N-formyl-piperazino)-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine (m.p. 209°-211°C) were refluxed together with 1.2 gm (30 millimols) of sodium hydroxide in 80 ml of methanol for 3 hours. The reaction mixture was then poured into water, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried with sodium sulfate, and the chloroform was removed in vacuo. Yield: 1 gm (89.6% of theory), m.p. 222°-223°C (ethanol).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1.[Br:28]C(F)(F)C(Br)(F)F>C1COCC1>[Br:28][C:15]1[CH:16]=[C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)[CH:18]=[N:19][C:14]=1[F:13]
Reactant: Fc1ccc(C23CCCN2CCC3)cn1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1ncc(C23CCCN2CCC3)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.4 %

Procedure:
n-BuLi (2.5M in hexanes, 0.252 mL, 0.63 mmol) was added to di-isopropylamine (0.082 mL, 0.63 mmol) in THF and stirred at room temperature for 10 minutes, then cooled to -78° C. 7a-(6-Fluoro-3-pyridinyl)-hexahydro-1H-pyrrolizine (123 mg, 0.60 mmol, from Example 12d) and 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.215 mL, 1.80 mmol) were added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2N HCl, and the mixture was washed with Et2O. The aqueous layer was basified with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried, (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (64 mg, 37%). 1H NMR (CDCl3, 300 MHz) δ1.59-1.71 (m, 2H), 1.79-2.06 (m, 6H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 8.14 (dd, J=8.8, 2.2 Hz, 1H), 8.19 (dd, J=2.2, 1.2 Hz, 1H); MS (CI/NH3) m/z: 285/287 (M+H)+.
Reaction SMILES: C(O[C:9]1[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[CH:10]=1)C1C=CC=CC=1.[H][H].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[Pd].C1(C)C=CC=CC=1.ClCCl.O>[CH3:14][CH:12]1[C:11](=[O:15])[CH:10]=[C:9]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([C:19]([F:18])([F:27])[F:28])[CH:21]=2)[CH2:13]1
Reactant: [H][H]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC1CC(OCc2ccccc2)=CC1=O
Agent: [Pd]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC1CC(Nc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 25 °C

Procedure:
A mixture of 3-(benzyloxy)-5-methylcyclopent-2-enone (intermediate 22, 210 mg, 1.04 mmol) and Palladium on carbon (10%, 127 mg) in toluene (3.0 mL) is treated with hydrogen (3.4 bar) for 9 h. The mixture is filtered, and the filtrate is treated with 3-(tri-fluormethyl)aniline (130 μL, 1.04 mmol) and Ytterbium(III) trifluormethanesulfonate (3 mg, 5 μmol) and stirred at room temperature over night. Another portion of 3-(trifluor-methyl)aniline (65 μL, 0.52 mmol) is added, and the mixture is stirred over night. Water and dichloromethane is added, and the phases are separated. The organic phase is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 136 mg; ESI mass spectrum [M+H]+=256; Retention time HPLC: 0.55 min (X012_S01).