Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[C:22]([CH3:28])[CH:23]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Reactant: CSc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1C
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-3-methyl-phenol (85 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a chemelute™ cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-3-methyl-phenoxy)-nicotinamide (118 mg) as an off-white foam.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:29].O1CCOCC1>O1CCOCC1>[ClH:29].[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8]
Reactant: COC(=O)CCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCCCCNC(=O)[C@@H](N)Cc1ccccc1

Procedure:
To a solution of the title compound of Example 2 (43.1 g, 0.11 mole) in 100 ml of dioxane was added 100 ml of 6 M hydrogen chloride/dioxane. After about 30 min. the solution was concentrated in vacuo to dryness and the residue triturated thoroughly with diethyl ether. The solid was collected and washed well with diethyl ether, giving 34.7 g of the title compound, which was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[CH:9]=2)=[CH:6][N:7]=1.[C@@H:21]1([NH2:30])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:30][C@@H:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CCNC(=O)c1nc(-c2cccc(CBr)c2)cnc1N
Reactant: N[C@H]1CCc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1nc(-c2cccc(CN[C@H]3CCc4ccccc43)c2)cnc1N
Reaction time: 7 h
Yield: 38.8 %

Procedure:
The 3-amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (112 mg, 1.0 eq) was dissolved in acetonitrile (5 mL) and treated with (1S)-2,3-dihydro-1H-inden-1-amine (133.8 mg, 3.0 eq), diisopropylethylamine (69.3 mg, 1.6 eq) at ambient temperature. After being stirred for 7 h, the white suspension was filtered on Celite and concentrated in vacuo. The resulting residue was purified by flash column chromatography to give the 3-amino-6-(3-{[(1S)-2,3-dihydro-1H-inden-1-ylamino]methyl}phenyl)-N-ethylpyrazine-2-carboxamide (50.2 mg, 39% yield): 1H NMR (400 MHz, CD3OD): δ 8.72 (s, 1H), 8.21 (s, 1H), 8.11 (d, 1H), 7.61 (d, 1H), 7.58 (t, 1H), 7.49 (d, 1H), 7.39 (d, 2H), 7.39 (d, 2H), 7.37 (m, 1H), 4.38 (s, 2H), 3.47 (m 1H), 3.23 (m, 1H), 3.01 (m, 1H), 2.64 (m, 1H), 2.39 (m, 1H); MS (EI) for C23H25N5O: 388.22 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:18]>CN(C=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[CH2:16][NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[C:4]([O:13][CH3:14])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=C(CCl)Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: COc1cc(NCC(=O)Nc2ccc(F)cc2)ccc1-c1cnco1

Procedure:
A solution of 1D, (101 mg, 0.53 mmol) and 2-chloro-4′-fluoroacetanilide (50 mg, 0.27 mmol) in DMF (0.15 mL) was heated at 100° C. for 15 h. After the reaction had cooled, the solvent was removed under reduced pressure, and the residue was subjected to preparative HPLC to give 1 as a tan solid. LC/MS: ret. timeA32 3.527 min., MS (M+H)+=342.
Reaction SMILES: C([O:3][C:4](=[O:36])[C@@H:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:26]([O:25][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:33][CH2:34][CH3:35])[C:4]([OH:36])=[O:3])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OCc3ccccc3)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)OCc3ccccc3)cc2)cc1)C(=O)O
Yield: 94.4 %

Procedure:
3-[4-{2-(4-[Benzyloxycarbonylamino]phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid ethyl ester (described in Example 52) (0.16 g; 0.32 mmole) was dissolved in tetrahydrofuran and lithium hydroxide (9 mg; 0.38 mmole) dissolved in water (1 ml) was added. The resulting mixture was stirred over night. Hydrochloric acid (1M; 1 ml) was added. Tetrahydrofuran was evaporated and the remaining water residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated to give 0.14 g (92.8% yield) of 3-[4-{2-(4-[benzyloxycarbonylamino]-phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C)C=O.C(OCC)(=O)C>[C:14]1([CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:24]3[C:23](=[O:25])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:30])=[CH:4][CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccc(OCCCCc2ccccc2)cc1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCCCCc2ccccc2)cc1
Yield: 109.9 %

Procedure:
A solution of 1.20 g of p-chloromethyl-(4-phenylbutoxy)benzene and 1.15 g of potassium phthalimide in 20 ml of N,N-dimethylformamide was stirred at 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, and the dilution was washed with three portions of water and then with saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residual solid was recrystallized from ethyl acetate to give 1.85 g of N-[p-(4-phenylbutoxy)benzyl]phthalimide. Melting point 106°-107.5° C. ##STR32##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:19](B1OC(C)(C)C(C)(C)O1)([CH3:21])=[CH2:20].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([C:19]([CH3:21])=[CH2:20])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:13][CH:14]=1
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(Cl)cn2)c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)OC)cc(-c2ccc(Cl)cn2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of methyl 3-bromo-5-(5-chloropyridin-2-yl)benzoate (78.0 mg, 0.24 mmol)) in DMF (1.2 mL) and water (0.4 mL) was 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (53.9 μL, 0.29 mmol), palladium(II) acetate (2.68 mg, 0.012 mmol), 3,3′3″-phosphinidynetris(benzenesulfonic acid)trisodium salt (20.4 mg, 0.036 mmol) and diisopropylamine (85.0 μL, 0.60 mmol) and the mixture was heated to 80° C. After 1 h, the reaction was filtered and the filtrate was purified by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (59 mg). MS 388.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[CH:19]=[CH:18][O:17][C:16]=24)[NH:13][C:12]([CH3:21])([CH3:20])[C:11](=[O:22])[C:10]3([CH3:24])[CH3:23])=[C:5]([CH3:25])[O:4][N:3]=1.[BrH:26].[NH+]1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[Br:26][C:18]1[O:17][C:16]2=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:25])[CH:8]=[C:9]3[C:14]([NH:13][C:12]([CH3:20])([CH3:21])[C:11](=[O:22])[C:10]3([CH3:24])[CH3:23])=[C:15]2[CH:19]=1
Reactant: Br
Reactant: Cc1noc(C)c1-c1cc2c(c3ccoc13)NC(C)(C)C(=O)C2(C)C
Agent: [Na+]
Agent: [OH-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc2c(c3cc(Br)oc13)NC(C)(C)C(=O)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-1,2,3,4-tetrahydro-furo[2,3-h]quinolin-3-one (31 mg) obtained in Example 93, 3) in THF (1.0 ml) was added pyridinium hydrobromide perbromide (29 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane→hexane-ethyl acetate=3:2) to give the title compound (17 mg, 44%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C:7]([CH3:28])([CH3:27])[C:8]([NH:10][C:11]1[O:15][N:14]=[C:13]([C:16]([CH3:26])([CH3:25])[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:12]=1)=[O:9].C(OCC)C>CN(C=O)C>[CH3:26][C:16]([C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:7]([S:3][C:1](=[O:4])[CH3:2])([CH3:28])[CH3:27])=[O:9])[O:15][N:14]=1)([CH3:25])[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CC([O-])=S
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
Potassium thioacetate (6.6 g, 58.0 mmol) is added at 0° C. to a solution of 2-bromo-N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-propionamide (15.0 g, 38.6 mmol) in DMF (150 mL). After stirring the reaction mixture at room temperature for 12 h, ice water and diethyl ether are added. The two phases are separated, the organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product that is purified by silica gel chromatography to afford 8.7 g of thioacetic acid S-(1-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylcarbamoyl}-1-methyl-ethyl)ester as a pale yellow solid. Yield: 58%; m/z 383 [M−H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.35 (6H, d, J=8.07 Hz), 1.45-1.88 (12H, m), 2.37 (3H, s), 3.30-3.58 (2H, m), 3.69-3.87 (2H, m), 4.58 (1H, t), 6.35 (1H, s), 9.44 (1H, br. s.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]1.[H-].[Na+]>CN(C=O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCN(CCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (1 g, 5.8 mmol) in 20 mL of anhydrous DMF was added 3-(4-methyl-1-piperazinyl)-1-propanol (1.2 g, 7.59 mmol). Sodium hydride (60%) (467 mg, 11.68 mmol) was added portionwise and the reaction was stirred at rt for 90 min at which time it was quenched with a solution of saturated NH4Cl (5 mL) and most of the DMF was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with a minimum amount of water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure to give 1-methyl-4-(3-{[3-(methyloxy)-4-nitrophenyl]oxy}propyl)piperazine as a yellow solid (1.8 g total isolated, some residual DMF in product) (ESIMS (M+H)+=311)
Reaction SMILES: [C:1]([C:3]1[C:14]2=[C:15]3[N:10]([CH:11]([CH3:16])[CH2:12][CH2:13]2)[CH:9]=[C:8]([C:17]([OH:19])=[O:18])[C:7](=[O:20])[C:6]3=[CH:5][CH:4]=1)#[N:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].CN(C)C=O>C(O)(=O)C.O>[CH3:16][CH:11]1[N:10]2[C:15]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]4[NH:23][N:22]=[N:21][N:2]=4)[C:14]=3[CH2:13][CH2:12]1)[C:7](=[O:20])[C:8]([C:17]([OH:19])=[O:18])=[CH:9]2
Reactant: [N-]=[N+]=[N-]
Reactant: CC1CCc2c(C#N)ccc3c(=O)c(C(=O)O)cn1c23
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC1CCc2c(-c3nnn[nH]3)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 120 °C

Procedure:
A mixture of 1.4 g (5 mmole) of 8-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 0.75 g (11 mmole) of sodium azide, 0.6 g (11 mmole) of ammonium chloride and 50 ml of N,N-dimethylformamide was heated at 120° C. for three days in a sealed vessel followed by decantation into 100 ml of water. To this mixture was added 2 ml of glacial acetic acid, and the mixture was cooled. The solid was separated by filtration and recrystallized from aqueous N,N-dimethylformamide to provide white needles of 6,7-dihydro-5-methyl-1-oxo-8-(5-tetrazolyl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 270° C. (dec.). Analysis: Calculated for C15H13N5O3 : %C, 57.9; %H, 4.2; %N, 22.5; Found: %C 57.8; %H, 4.0; %N, 22.7. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>C(Cl)Cl>[P:1]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:21]([CH:22]=[O:23])[CH:20]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCSP(=O)(Cl)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OCC)Oc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of O-ethyl S-propyl chlorothiophosphate prepared by the method detailed in Example 1 was charged into a glass reaction vessel equipped with a stirrer and thermometer. The solution was cooled to a temperature of about -10° C. and triethylamine (2.23 ml) was added followed by the dropwise addition with stirring of 3-hydroxybenzaldehyde (1.95 grams; 0.016 mole) dissolved in methylene chloride (10 ml). Stirring was continued for a period of about 2 hours while maintaining the temperature of the reaction mixture at about 0° C. After this time the reaction mixture was transferred into a separatory funnel and was washed twice with water (100 ml), twice with dilute aqueous sodium hydroxide (50 ml; 0.1 N) and again twice with water (100 ml). The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent leaving an orange oil. This oil was subjected to high vacuum for a period of one hour to yield the desired product O-ethyl S-propyl O-(3-formylphenyl) thiophosphate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:21][C:22]([OH:24])=[O:23])[C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)CBr
Reactant: Cc1ccc([C@@H]2CCC(C)(C)C(=O)N2)cc1F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc([C@@H]2CCC(C)(C)C(=O)N2CC(=O)O)cc1F
Reaction time: 0.25 h

Procedure:
To a stirred solution of (S)-6-(3-fluoro-4-methylphenyl)-3,3-dimethylpiperidin-2-one from Step A (80 mg, 0.340 mmol) in DMF (3 mL) at ambient temperature was added NaH (19 mg of a 60% dispersion in oil, 0.476 mmol). After 15 min, methyl bromoacetate (0.051 mL, 0.544 mmol) was added and the mixture was stirred for 16 h. Sodium hydroxide (0.061 mL of a 10 M solution, 0.612 mmol) was added and the mixture stirred for 2 h. The crude product was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The compound was further purified by SFC, utilizing a ChiralPak AD column and eluting with CO2:MeOH—91:9, to give the title compound. MS: m/z=294 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(#N)C>[CH3:18][S:19]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CCCC[C@H]1CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Yield: 50.8 %

Procedure:
The thus obtained compound (2) (5.1 g; 35.4 mmol) is dissolved in triethylamine (10.37 g; 103 mmol) and acetonitrile (127 ml), and methanesulfonyl chloride (8.13 g; 71 mmol) is dropwise added thereto under ice-cooling. The resultant mixture is ice-cooled for 1 hour and allowed to react at room temperature for 3 hours. The reaction mixture is washed with water, dried and concentrated, followed by addition of diethyl ether. Precipitated crystals are collected by filtration to give trans-1,2-bis(methanesulfonyloxymethyl)cyclohexane (3) (5.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:27]([O-])=O)=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:14]=[CH:13]2>[Pd]>[NH2:27][C:11]1[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:4][C:3]=2[O:2][CH3:1])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(cnn3COCC[Si](C)(C)C)c2[N+](=O)[O-])c(OC)c1
Agent: [Pd]
Product: COC(=O)Cc1ccc(Oc2ccc3c(cnn3COCC[Si](C)(C)C)c2N)c(OC)c1
Reaction time: 0.75 h

Procedure:
To a solution of methyl 2-(3-methoxy-4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yloxy)phenyl)acetate (46 mg, 0.09 mmol) was added a catalytic amount of 10% palladium on carbon. The resulting mixed was stirred under an atmosphere of hydrogen for 45 min. After that time the reaction mixture was filtered through celite and concentrated under reduced pressure to give the product as a pale solid. 1H NMR (400 MHz) (CDCl3) δ 7.97 (s, 1H); 7.08 (d, J=8.8, 1H); 6.93 (d, J=1.8, 1H); 6.91 (d, J=8.8, 1H); 6.76 (dd, J=1.8, 8.2, 1H); 6.65 (d, J=8.2, 1H); 5.70 (s, 2H); 4.28 (bs, 2H); 3.95 (s, 3H); 3.71 (s, 3H); 4.58 (m, 4H); 0.92 (t, J=8.2, 2H), 0.0 (s, 9H).
Reaction SMILES: [N:1]([C:4]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=2)[N:7]=[C:6]([CH3:26])[N:5]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C:4]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=2)[N:7]=[C:6]([CH3:26])[N:5]=1
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)nc(C)nc1N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CCCc1c(N)nc(C)nc1Cn1ccnc1-c1cccc(F)n1
Reaction time: 4 h

Procedure:
Pd/C (10%, 10 mg) is added to a solution of 4-azido-6-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-2-methyl-5-propyl-pyrimidine (2 mmol) (125) in MeOH (20 ml) and the mixture is stirred under H2 at 30 psi for 4 hours. The catalyst is filtered out and the filtrate is evaporated in vacuo. The resulting light yellow solid (126) is used in the next step without further purification.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[N+:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2)([O-:27])=[O:26]>CN(C)C=O.C(OCC)(=O)C>[N+:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[N:32]=[CH:31]2)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc([N+](=O)[O-])ccc32)CC1
Yield: 22.2 %

Procedure:
tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (30.6 mmol, 8.56 g), potassium carbonate (61.3 mmol, 8.47 g) and 5-nitro-1H-indazole (30.6 mmol, 5 g) were combined and heated to 100° C. in N,N-dimethylformamide (30 mL) for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and concentrated at reduced pressure. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 30% ethyl acetate/heptane to 50% ethyl acetate/heptane) to afford the title compound (2.35 g). MS (ESI) m/z 291.0 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([NH2:24])[CH:3]=1.[OH-].[Na+].Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:3]=1
Reactant: BrCCOCCBr
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc(N)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc(N3CCOCC3)cc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
Into a 100 ml round bottomed flask charged with 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-amine (3.1 g, 7.40 mmol) and tetrabutylammonium iodide (0.137 g, 0.370 mmol) was added 6N sodium hydroxide (18.51 ml, 111 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.87 ml, 14.81 mmol). The reaction was heated to 110° C. and was monitored by LCMS. The reaction was complete after 2 h. The reaction was cooled to RT and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phase was washed with brine (30 mL), the organic extracts were combined, concentrated in vacuo, and the residue was purified by flash chromatography on silica gel eluted with a solution of (2N ammonia in methanol)/chloroform (0% to 10%). The fractions containing product were combined, then concentrated in vacuo to provide the desired product (1.62 g, 3.31 mmol, 44.8% yield) as a brown solid. NMR & LCMS were consistent with the structure. MS (ES+) m/e: 487.1, 488.1 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.42 (s, 3H) 3.03-3.21 (m, 4H) 3.78-3.89 (m, 4H) 5.43 (s, 2H) 6.28 (d, J=7.58 Hz, 1H) 6.38 (d, J=2.02 Hz, 1H) 6.99 (t, J=7.96 Hz, 1H) 7.29 (d, J=2.27 Hz, 1H) 7.34 (d, J=7.83 Hz, 1H)