Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O)[CH3:36].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:1][CH2:2][CH:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4])[CH3:36]
Reactant: CCc1ccccc1O
Reactant: CC(CO)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccccc1OCC(C)N1C(=O)c2ccccc2C1=O
Reaction time: 40 h
Yield: 39.7 %

Procedure:
A solution of 5.0 g (24.4 mmol) of 2-(2-hydroxy-1-methylethyl)-1H-isoindole-1,3(2H)-dione (Y. Becker, A. Eisenstadt, J. K. Stille, J. Org. Chem., 1980, 45, 2145) and triphenylphosphine (7.00 g, 27.0 mmol) in 40 mL of dry tetrahydrofuran was stirred at 20° C. for 1 h. To the solution was added 2-ethylphenol (3.90 g, 32.0 mmol) and diethyl azodicarboxylate (5.0 mL, 32.0 mmol) and the solution was stirred an additional 40 h. The reaction mixture was concentrated in vacuo and the residue was diluted in diethyl ether and washed with water and brine. The organic layer was concentrated in vacuo and the crude product was purified by flash silica chromatography using 5% ethyl acetate/hexanes solution as eluent to give 3.0 g (40%) of 2-[2-(2-ethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione as a colorless oil: 1H NMR (CDCl3) δ0.96 (t, 3H), 1.60 (d, 3H), 2.40 (m, 2H), 4.18 (dd, 1H), 4.48 (t, 1H), 4.84 (m, 1H), 6.80 (m, 1H), 6.90 (m, 1H), 7.10 (m, 2H), 7.70 (m, 2H), 7.84 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=1)=[O:11].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(C(=O)CC(c2ccccc2Cl)C2CCCC2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccccc1Cl)C1CCCC1)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(2-chloro-phenyl)-3-cyclopentyl-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a light yellow oil, MS (ESI+): m/z=330.2 [M+H]+.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:5][O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>O1CCOCC1>[ClH:1].[CH:2]1([CH2:5][O:6][CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CC(COCC2CC2)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 125 %

Procedure:
A solution of 4N HCl in dioxane (5 mL, 20.0 mmol) was added to a solution of tert-butyl 4-[(cyclopropylmethoxy)methyl]piperidine-1-carboxylate (Intermediate 199, 0.75 g, 2.77 mmol) in dioxane (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h before being evaporated to dryness to provide the title compound as a pale pink sticky solid (0.7 g, 125%). Method B HPLC-MS: MH+ (free-based) requires m/z=170 Found: m/z=170, Rt=0.87 min.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][CH:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1([F:15])[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/C1CCC(F)(F)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Ethyl(E)-3-(4,4-difluorocyclohexyl)acrylate (520 mg, 2.39 mmol) obtained in step 1 was dissolved in ethanol (8.0 mL), and 10% palladium/carbon (containing water) (200 mg) was added. After displacing inside of the reaction vessel with hydrogen gas, the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite (registered trademark), and the solvent was evaporated under reduced pressure to give ethyl 3-(4,4-difluorocyclohexyl)propionate (522 mg, yield 99%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:35]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
To a stirred solution of tert-butyl 4-(2-hydroxyphenyl)-piperazine 20 (1 g, 0.0035 mol.) and cesium carbonate (2.34 g, 0.0071 mol.) in 5 mL of DMF anhydrous was added a solution of ethyl 4-bromobutanoate (6a) at rt. The resulting mixture was heated at 70° C. overnight (12 h). The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was complete, the reaction mixture was diluted with 25 mL of ethyl acetate and filtered to remove cesium carbonate. The filtrate was washed with saturated aqueous NaHCO3 solution, dried over Na2SO4 and evaporated to give tert-butyl 4-(2-(4-ethoxy-4-oxobutoxy)phenyl)-piperazine-1carboxylate 21a which was purified by silica gel chromatography using a gradient elution of ethyl acetate and hexane. Colorless oil (1.1 g, 78%). 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=6.4 Hz, 3H); 1.45 (s, 9H); 2.14 (q, J=7.2 Hz, 2H); 2.53 (t, J=7.2Hz, 2H); 3.00 (br s, 4H); 3.58 (br s, 4H); 4.04 (t, J=6.4 Hz, 2H); 4.12 (q, J=6.4 Hz, 2H); 6.84-6.97 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:16])[CH2:15][O:14]2)=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:16])[CH:15]=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccsc1-c1ccc(C2(C)CO2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccsc1-c1ccc(C(C)C=O)cc1
Yield: 98 %

Procedure:
In 25 ml of acetonitrile was dissolved 5.0 g (0.0232 mole) of 4-(3-methyl-2-thienyl)acetophenone, followed by the addition of 8.7 g (0.046 mole) of trimethylsulfonium methyl sulfate. To the mixture was added with stirring at room temperature 2.5 g (0.0464 mole) of sodium methylate. After having been stirred for one hour, the mixture was freed from the solvent by distillation under reduced pressure. To the residue was added 20 ml of toluene, and the solution was washed several times with water, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure to obtain 5.2 g (97.4% yield) of almost pure oily 2-[4-(3-methyl-2-thienyl)phenyl]-2-methyloxirane. This oxirane compound was dissolved in 25 ml of toluene, admixed with 0.5 g of powdered Molecular Sieves 4A, and refluxed for one hour. The Molecular Sieves was removed by filtration and the filtrate was freed from the solvent by distillation under reduced pressure to obtain 5.1 g (98% yield) of oily 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25]Br)[C:15]=3[C:16]=2[CH3:17])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1>CN1CCCC1=O.C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][NH:34][CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[C:15]=3[C:16]=2[CH3:17])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)NCCC2CCCCC2)oc2cccc(OCCCBr)c12
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)NCCC2CCCCC2)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 100 °C

Procedure:
4-(3-Bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid (2-cyclohexyl-ethyl)-amide (100 mg) and 3-picolyl amine (250 μl) were dissolved in 1-methylpyrrolidone (2 ml) and heated at 100° C. for two hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 3-methyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid (2-cyclohexyl-ethyl)-amide. ESI-MS: m/z 450 (MH+); 1H-NMR (CDCl3): δ 0.85-1.85 (13H, m), 2.05 (2H, quintet, J=6.5 Hz), 2.72 (3H, s), 2.90 (2H, t, J=6.5 Hz), 3.46 (2H, m), 3.85 (2H, s), 4.15 (2H, t, J=6.5 Hz), 6.53 (1H, t, J=6 Hz), 6.62 (1H, d, 8 Hz), 7.01 (1H, d, J=8 Hz), 7.26 (2H, m), 7.68 (1H, dd, J=1.5 Hz, 8 Hz), 8.49 (1H, br d, J=3.5 Hz), 8.56 (1H, br s).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[C:20]([F:27])[C:19]=3[C:28]([F:31])([F:30])[F:29])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>[C].[Pd]>[F:31][C:28]([F:29])([F:30])[C:19]1[C:20]([F:27])=[C:21]([O:24][CH2:25][CH3:26])[CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][CH:10]([CH:7]2[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]2)[CH2:11][CH2:12]1
Reactant: CCCC1CCC(C2CCC(C=Cc3ccc(OCC)c(F)c3C(F)(F)F)CC2)CC1
Agent: [Pd]
Product: CCCC1CCC(C2CCC(CCc3ccc(OCC)c(F)c3C(F)(F)F)CC2)CC1
Reaction time: 2 h

Procedure:
7.89 g of β-(4-(4-propylcyclohexyl)cyclohexyl)-2-trifluoromethyl-3-fluoro-4-ethoxy styrene obtained in Example 7 was dissolved in 200 ml of a mixed toluene-solmix solvent. A palladium carbon catalyst was added to the solution in a nitrogen atmosphere and a hydrogenation reaction was conducted at ambient temperature and pressure for 2 hours. After the completion of the reaction, the catalyst was removed by filtration. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (eluent: heptane:toluene=4:1) to obtained 1-(2-trifluoromethyl-3-fluoro-4-ethoxyphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethane. This was further recrystallized twice from a heptane/ethanol mixed solvent to obtain 5.35 g of pure 1-(2-trifluoromethyl-3-fluoro-4-ethoxyphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethane. The compound showed a liquid crystal phase and the transition point was as described below.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:11][C:5]1[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:2][NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(Cl)c1Cl
Product: CCOC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(Cl)c1Cl

Procedure:
From 192 mg (629 μmol) of the compound from Example 40A and 72 μl (755 μmol) of ethyl chloroformate, in the same way as for Example 123A, 184 mg (78% of theory) of the title compound were prepared.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:19]=[O:20].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:19]=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CN2CCc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCN2Cc1ccccc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Into a 1,000 mλ reaction flask equipped with a thermometer, a stirrer, a condenser and a dropping funnel, 209 g (1.0 mol) of 1-benzylindoline and 365.5 g (5.0 mols) of N,N-dimethylformamide (DMF) were charged, and the temperature was raised to a liquid temperature of from 30 to 40° C. Then, while stirring at the same temperature, 161.0 g (1.05 mols) of phosphorus oxychloride was dropwise added thereto over a period of about two hours from the dropping funnel. After completion of the dropwise addition, stirring was continued for three hours at from 80 to 100° C. After completion of the reaction, the reaction solution was cooled to room temperature and put into 1 kg of ice water. At a temperature of from 30 to 40° C., a 24% sodium hydroxide aqueous solution was dropwise added thereto to bring the liquid alkaline, whereby the precipitated solid was collected by filtration, washed with water and dried to obtain 230.2 g (yield: 97%) of 1-benzyl-5-formylindoline as a slightly yellow powder.
Reaction SMILES: C(O[C:4]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH3:22])([CH3:21])[CH:9]=1)=[N:5][C:6]#[N:7])C.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.ClCCl.CCOC(C)=O>CCCCCC>[C:6]([NH:5][C:4]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH3:21])([CH3:22])[CH:9]=1)=[N:26][CH:23]1[CH2:25][CH2:24]1)#[N:7]
Reactant: CCOC(=NC#N)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Reactant: NC1CC1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)C=C(C(=NC2CC2)NC#N)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.5 %

Procedure:
A mixture of 98 mg of N-cyano -6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboximidic acid ethyl ester, 30 mg of cyclopropylamine, and 1 ml of dichloromethane was stirred at room temperature for 1.5 hours. The reaction mixture was subjected to silica gel column chromatography (AcOEt:n-hexane=l:l) and then recrystallization from a mixture of acetone and n-hexane to obtain 30 mg of N-cyano-N'-cyclopropyl-6-nitro-2,2-dimethyl-2H-1-benzopyran -4-carboxamidine represented by formula shown below.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=[C:2]1[NH2:9].[CH3:10][C:11]1([CH3:19])[C:13]([CH3:15])([CH3:14])[CH:12]1[C:16](O)=[O:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=[C:2]1[NH:9][C:16]([CH:12]1[C:13]([CH3:15])([CH3:14])[C:11]1([CH3:19])[CH3:10])=[O:17]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Nc1nc2c(s1)CCC2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)C(C(=O)Nc2nc3c(s2)CCC3)C1(C)C

Procedure:
A mixture of 5,6-dihydro-4H-cyclopentathiazole-2-ylamine (177 mg, 1.26 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (244 mg, 1.52 mmol), 4-dimethylaminopyridine (50.0 mg, 0.41 mmol) and triethylamine (351 μL, 2.52 mmol) in 20 mL of THF was processed according to the method of Example 118A to provide the title compound: MS (DCI/NH3) m/z 265 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([C:28](=[O:30])[CH3:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:32][O:33][C:34](=[O:67])[NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47]1[NH:48][CH:49]=[C:50]([C:52]2[CH:57]=[CH:56][C:55](B3OC(C)(C)C(C)(C)O3)=[CH:54][CH:53]=2)[N:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3](=[O:31])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:55]4[CH:56]=[CH:57][C:52]([C:50]5[NH:51][C:47]([CH:43]6[CH2:44][CH2:45][CH2:46][N:42]6[C:40](=[O:41])[CH:36]([NH:35][C:34]([O:33][CH3:32])=[O:67])[CH:37]([CH3:39])[CH3:38])=[N:48][CH:49]=5)=[CH:53][CH:54]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([C:28](=[O:30])[CH3:29])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
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: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(C)=O)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 29.4 %

Procedure:
{1-[1′-Acetyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (150 mg, 0.304 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (151 mg, 0.304 mmol) under an argon atmosphere. Potassium carbonate (83.9 mg, 0.608 mmol) and Pd(PPh3)4 (34 mg, 0.030 mmol) were added, followed by DME (8 mL) and water (2 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[1′-Acetyl-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (69.8 mg): LCMS-ESI+: calc'd for C41H51N9O7: 781.9 (M+). Found: 782.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.91-7.82 (m, 10H), 5.68 (m, 1H), 5.59-5.37 (m, 2H), 5.25 (m, 1H), 4.34 (m, 1H), 4.24 (d, J=7.5 Hz, 1H), 4.11-4.02 (m, 2H), 3.88 (m, 1H), 3.66 (s, 6H), 3.47 (d, J=7.2 Hz, 1H), 2.60 (m, 1H), 2.29-2.10 (m, 8H), 1.05-0.89 (m, 12H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[O:7][N:6]=[CH:5][C:4]=1[C:8](Cl)=[O:9].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[F:1][C:2]([F:12])([F:11])[C:3]1[O:7][N:6]=[CH:5][C:4]=1[C:8]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9]
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1cnoc1C(F)(F)F
Product: O=C(c1cnoc1C(F)(F)F)N1CCCCC1

Procedure:
of boiling point (4 mbar) 62° to 68° C., prepared from 5-trifluoromethyl-4-isoxazolecarboxylic acid chloride and piperidine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.F[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C(#N)C>[OH:34][C:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:23]2[CH:35]=[CH:36][C:37]([N+:38]([O-:40])=[O:39])=[C:21]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]3)[CH:22]=2)[CH2:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@H](C(=O)O)CC3)c2)CC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a suspension of trans-4-aminocyclohexanecarboxylic acid (0.199 g, 1.392 mmol) and DIPEA (0.553 mL, 3.16 mmol) in ACN (5 mL) was added 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol (0.375 g, 1.265 mmol). The reaction was stirred at 75° C. After 48 hours, the reaction mixture was concentrated, diluted with water (10 mL) and extracted with DCM and EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide trans-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid (0.524 g, 1.249 mmol, 99% yield) as an orange powder.
Reaction SMILES: C(N(CC)C[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH2:17][C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:28][CH3:29])[C:21]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])C.FC1C=CC=CC=1S(CC1C(C(OC)=O)=C(OC)C(C2C=COC=2)=CC=1)(=O)=O.[CH2:65]([N:67](CC)[CH2:68][CH2:69]N)[CH3:66]>>[CH2:65]([N:67]([CH2:68][CH3:69])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH2:17][C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:28][CH3:29])[C:21]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:66]
Reactant: CCN(CC)CCCNc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Reactant: CCN(CC)CCN
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(-c2ccoc2)c1OC
Product: CCN(CC)CCNc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 192, starting from methyl 6-(2-fluorobenzenesulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 96) and N,N,-diethylethylenediamine, as brown solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4=[C:24]5[S:30][CH:29]=[CH:28][C:25]5=[N:26][CH:27]=[C:22]4[N:21]=[C:20]3[C@H:31]([OH:33])[CH3:32])[CH2:15][O:14]2)(=O)=O)=CC=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C.CO>[N:34]([CH2:12][C@@H:13]1[O:14][CH2:15][C@@H:16]([N:19]2[C:23]3=[C:24]4[S:30][CH:29]=[CH:28][C:25]4=[N:26][CH:27]=[C:22]3[N:21]=[C:20]2[C@H:31]([OH:33])[CH3:32])[CH2:17][CH2:18]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c([C@@H](C)O)nc4cnc5ccsc5c43)CO2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN=[N+]=[N-])OC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (25 mg, 0.052 mmol) and sodium azide (5.0 mg, 0.077 mmol) in DMF (0.5 mL) was stirred at 60° C. overnight. After cooling to room temperature, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give desired product (12 mg, 65%). LCMS calculated for C16H19N6O2S (M+H)+: m/z=359.1. Found: 359.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][C:13]#[N:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:16][NH:17][NH2:18]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([NH2:14])[N:17]([CH3:16])[N:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)CC#N)c1
Reactant: CNN
Solvent: CO
Product: COc1cc(OC)cc(-c2cc(N)n(C)n2)c1
Yield: 81.7 %

Procedure:
A solution of 3-(3,5-dimethoxyphenyl)-3-oxopropanenitrile (1.4 g, 6.82 mmol) and methyl hydrazine (0.54 ml, 10.23 mmol) in methanol (5 ml) was irradiated using a microwave at 160° C. for 0.25 h. The solution was evaporated under reduced pressure and the resulting crude product was purified by column chromatography (eluent 10% MeOH in CH2Cl2) to yield 1.3 g (82%) of the title compound. [1H-NMR (DMSO-d6, 360 MHz) δ 6.82 (d, 2H), 6.38 (t, 1H), 5.69 (2, 1H), 5.25 (s, 2H), 3.77 (s, 6H), 3.58 (s, 3H); UPLC-MS RtJ=0.69 min; [M+H]+=234.1]
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][N:7]=1)=[O:4].[CH:14]([N:17](C(C)C)CC)(C)[CH3:15].Cl.C(N)C>C(#N)C>[Br:13][C:9]1[N:10]=[C:11]2[N:17]([CH2:14][CH3:15])[CH2:2][C:3](=[O:4])[NH:5][C:6]2=[N:7][CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(CBr)Nc1ncc(Br)nc1Br
Agent: CCN
Agent: Cl
Solvent: CC#N
Product: CCN1CC(=O)Nc2ncc(Br)nc21
Temperature: 70 °C
Yield: 36 %

Procedure:
To a solution of 2-bromo-N-(3,5-dibromopyrazin-2-yl)acetamide (See Example 4.A) (1 equiv) and diisopropylethylamine (3 equiv) in acetonitrile was added ethanamine hydrochloride (1.05 equiv). The solution was allowed to heat to 70° C. for 30 min. The solution was condensed under reduced pressure and purified using column chromatography (0-75% ethyl acetate in hexanes) to afford the title compound in 36% yield. MS (ESI) m/z 257.5 [M]+, 259.4 [M+2]+.