Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:12]#[N:13])=[N:4][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6]=1[CH3:7].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:12]#[N:13])=[N:4][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6]=1[CH3:7]
Reactant: CCCCn1nc(C#N)c(Br)c1C
Reactant: Nc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCn1nc(C#N)c(-c2ccccc2N)c1C
Yield: 124.6 %

Procedure:
A modification of the method described in Part G of Examples 1-4 was used to couple 4-bromo-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile (2.42 g, 10.0 mmol) and 2-aminophenylboronic acid hydrochloride (2.43 g, 14.0 mmol). Palladium (II) acetate was added as a 5 mg/mL solution in toluene (1.3 mL). The reaction was heated under nitrogen for 17 hours and combined with the product mixture from another run before being subjected to the work-up procedure. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 3.17 g of 4-(2-aminophenyl)-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile as an orange oil. A small amount (0.21 g) of 2-butyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine was also obtained as a beige powder.
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:3]2[N:8]3[CH:9]=[N:10][CH:11]=[C:7]3[CH:6]=[N:5][N:4]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: CSc1nncc2cncn12
Solvent: Cc1ccccc1
Product: CN1CCN(c2nncc3cncn23)CC1

Procedure:
A mixture of 0.83 gm. of 4-(methylthio)-imidazo[1,5-d]-as-triazine, 5.0 gm. of N-methylpiperazine and 8 ml. of toluene is reacted as described in Example 40 giving the desired product, m.p. 163°-166° C.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:28]\[O:29][CH2:30][CH3:31])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:52])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH2:30]([O:29]/[N:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:52])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2])[CH3:31]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCO/N=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: CCO/N=C1\C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 100 %

Procedure:
The title compound II-av was prepared in 100% yield from 3,3:17,17-bis(ethylendioxy)-6(E)-ethoxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.03 (2H, q), 3.40 (1H, dd), 2.70-1.12 (19H, m), 1.20 (3H, t), 1.01 (3H, s), 0.87 (3H, s).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-])[C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:22]>CN(C=O)C>[C:1]([O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH2:17][OH:22])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(COC(=O)c2ccccc2)c[n+]1[O-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccc(CO)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate in 38 ml of DMF was added 11 ml of trifluoroacetic anhydride, followed by stirring at room temperature overnight. After evaporating trifluoroacetic anhydride under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 3.675 g of [6-(hydroxymethyl)pyridin-3-yl]methyl benzoate.
Reaction SMILES: O[C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH:14]=[CH:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[CH:9]([CH2:10][CH2:11]2)[CH2:8][C:7](=[O:21])[CH2:6][CH2:5]1.O.[C:24]1(C)C(S(O)(=O)=O)=CC=C[CH:29]=1.C(OCC)(OCC)OCC>C(O)C>[CH2:24]([O:21][C:7]1[CH2:6][CH2:5][C@@:4]2([CH3:22])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:3]2[CH2:2][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:20])[CH:8]=1)[CH3:29]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C[C@]12CCC(=O)CC1CC[C@@H]1[C@@H]2[C@H](O)C[C@]2(C)C(=O)C=C[C@@H]12
Solvent: CCO
Solvent: O
Solvent: CCOC(OCC)OCC
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Temperature: 5 °C

Procedure:
11α-Hydroxyandrostendione (429.5 g) and toluene sulfonic acid hydrate (7.1) were charged to a reaction flask under nitrogen. Ethanol (2.58 L) was added to the reactor, and the resulting solution cooled to 5° C. Triethyl orthoformate (334.5 g) was added to the solution over a 15 minute period at 0° to 15° C. After the triethyl orthoformate addition was complete the reaction mixture was warmed to 40° C. and reacted at that temperature for 2 hours, after which the temperature was increased to reflux and reaction continued under reflux for an additional 3 hours. The reaction mixture was cooled under vacuum and the solvent removed under vacuum to yield 3-ethoxyandrosta-3,5-diene-17-one.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:17]2[S:22][C:21]([CH:23]=O)=[CH:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:17]2[S:22][C:21]([CH2:23][N:10]3[CH2:11][CH2:12][N:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[CH:20][C:18]=2[N:19]=1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CCOCC4)CC3)cc2n1

Procedure:
Prepared from 1-(tetrahydro-pyran-4-yl)-piperazine and 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde under reductive amination conditions described in Reference Example 39, to give, after silica chromatography purification, the title compound as a white solid (190 mg, 61%) [M+H]+ 439.4
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.[OH-:13].[Na+].Cl>CS(C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([OH:13])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(O)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95.1 %

Procedure:
Step A To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80° C. for 20 h. The mixture was cooled to room temperature, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=O)[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[K+].Cl.[C:20]([O:24][C:25]([CH:27]([O:29][NH2:30])[CH3:28])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+]>O1CCCC1.N1C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[N:30][O:29][CH:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH3:28])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CC(ON)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(ON=C(C(=O)O)c1nc(NC=O)sc1Cl)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 16.1 %

Procedure:
Ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (10.0 g) was added to the 1 N aqueous solution of potassium hydroxide (76.1 ml) at ambient temperature and stirred for 10 minutes. The reaction mixture was adjusted to pH 2.0 with 10% aqueous hydrochloric acid under ice cooling. A solution of 1-tert-butoxycarbonylethoxyamine (8.4 g) in tetrahydrofuran (35 ml) was added to the stirred suspension of the above mixture in pyridine (13.9 ml) at ambient temperature and stirred for 4 hours at same temperature. The resulting mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate, and washed with ethyl acetate. The separated aqueous layer was adjusted to pH 2.0 with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diisopropyl ether and collected by filtration to give 2-(2-formamido-5-chlorothiazol-4-yl)-2-(1-tert-butoxycarbonylethoxyimino)acetic acid (syn isomer) (2.31 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-chloro-4-fluorophenyl-boronic acid (CAS RN 313545-72-1) and using preparative HPLC for the chromatographic purification. Brown sticky solid (33%). MS (ESI): m/z=476.8 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[N+]=[N-]>CO.[Pd]>[CH:12]1([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][NH2:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [N-]=[N+]=NCC(c1ccccc1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: NCC(c1ccccc1)C1CCCCC1
Yield: 104.5 %

Procedure:
To a stirring solution of (2-azido-1-cyclohexyl-ethyl)-benzene (700 mg, 3.06 mmol) in methanol (20 mL) was added palladium on carbon (70 mg, 10 wt. %). The mixture was stirred at 50 Psi H2 overnight, filtered, and washed with methanol, and the filtrate was concentrated in vacuo to give 650 mg (99% yield) of title compound as an oil. 1 H-NMR (400 MHz, CDCl3) δ 7.34-7.16 (m, 5H), 3.13 (t, 1H, J=4.5 Hz), 2.92 (t, 1H, J=2.3 Hz), 2.40 (m, 1H), 1.73-0.74 (m, 11H).
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17](C3CCCCO3)[N:16]=[C:15]([C:24]([OH:26])=[O:25])[CH:14]=2)=[CH:9][CH:8]=1.[CH3:27][CH2:28]O>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:17][N:16]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=2)=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)[nH]n1
Yield: 93 %

Procedure:
3-4 Drops of conc. H2SO4 were added to a solution of 5-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid 1 in EtOH. The reaction mixture was refluxed for 2 days. The reaction mixture was concentrated and diluted with chloroform (100 ml) and washed with saturated NaHCO3 solution, water and brine, and dried over Na2SO4. Evaporation of the solvent under vacuum gave ethyl 5-(4-fluorophenyl)-1H-pyrazole-3-carboxylate 2 as a brown solid (1.05 g, 93%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][Cl:24])=[O:21]>C(OCC)C>[C:20](=[O:21])([O:22][CH2:23][Cl:24])[O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOCc1ccccc1
Reactant: O=C(Cl)OCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCCl)OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(benzyloxy)propanol (synthesized by a procedure described in Wei et al., J. Org. Chem, 54, 5768-5774 (1989):15.1 g) and pyridine (7.18 g) in diethyl ether (150 ml), a solution of chloromethyl chloroformate (11.7 g) in diethyl ether (50 ml) was added dropwise under ice cooling over the period of 20 minutes. After stirring at room temperature for 15 hours, the resulting solid was removed off by filtration and washed with ethyl acetate (100 ml). The filtrate and the washings were combined, and washed with water (100 ml×2) and a saturated sodium chloride aqueous solution (50 ml). After drying the solution over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by subjecting to silica gel chromatography (silica gel 200 g, eluent: ethyl acetate-hexane=1:4) to obtain [3-(benzyloxy)propyl] chloromethyl carbonate (21.0 g) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2](=[O:17])[CH:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[CH:9]=1)[C:4]#[N:5].[H-].[SH2:19].[Na+].Cl.C(NCC)C.O>O.O1CCOCC1>[NH2:1][C:2](=[O:17])[CH:3]([NH:6][C:7](=[O:16])[C:8]1[CH:9]=[C:10]([CH3:15])[N:11]=[C:12]([CH3:14])[CH:13]=1)[C:4]([NH2:5])=[S:19]
Reactant: S
Reactant: Cc1cc(C(=O)NC(C#N)C(N)=O)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCNCC
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)NC(C(N)=O)C(N)=S)cc(C)n1
Temperature: 60 °C
Reaction time: 14 h
Yield: 58.1 %

Procedure:
A mixture of N-(2-amino-1-cyano-2-oxoethyl)-2,6-dimethylisonicotinamide (1.5 g, 0.00646 mol, 1 eq), sodium hydrogen sulfide hydride (1.05 g, 0.00646 mol, 3 eq) in water/1,4-dioxane, diethyl amine hydrochloride (1.0 g, 0.01939 mol, 3 eq) is stirred for 14 h at 60° C. After the completion of the reaction, the reaction mass is allowed to cool, water is added and extracted with ethyl acetate and dried over sodium sulfate. The solvent is evaporated and the crude is recrystallised in diethyl ether to afford 1.0 g of N-(1,3-diamino-1-oxo-3-thioxopropan-2-yl)-2,6-dimethylisonicotinamide; yield: 64%; MS (ESI+): 267;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:22]1([CH:28]2[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>N1C=CC=CC=1>[N:22]1([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:21][C:18]3[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:20][CH:19]=3)=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Reactant: O=C(Cl)N1CCC(N2CCCCC2)CC1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccc(OC(=O)N3CCC(N4CCCCC4)CC3)cc2)cc1OC
Yield: 80.3 %

Procedure:
(Z)-2-(3,4-dimethoxyphenyl)-3-(4-hydroxyphenyl)acrylonitrile (compound 1) (0.28 g) and 4-piperidinopiperidinocarbonyl chloride (0.23 g) were dissolved in pyridine (5 ml), and the resultant solution was stirred for a whole day and night. After completion of reaction, the resultant reaction mixture was added to water (200 ml), and the thus-precipitated product was purified by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (0.38 g, yield: 79%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:42])[C@H:11]([CH:39]([CH3:41])[CH3:40])[CH2:12][C@H:13]([OH:38])[C@@H:14]([N:35]=[N+]=[N-])[CH2:15][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:42])[C@H:11]([CH:39]([CH3:41])[CH3:40])[CH2:12][C@H:13]([OH:38])[C@@H:14]([NH2:35])[CH2:15][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](N=[N+]=[N-])[C@@H](O)C[C@H](C(=O)NCCN2CCCCC2)C(C)C)C(C)C)ccc1OC
Agent: [Pd]
Solvent: CO
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NCCN2CCCCC2)C(C)C)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
Palladium on carbon (Pd/C) 10% (200 mg) is added to a solution of (2S,4S,5S,7S)-5-azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-piperidin-1-yl-ethyl)-amide (780 mg, 1.32 mmol) in MeOH (40 mL) under Ar. Then the reaction suspension is stirred under a atmosphere of hydrogen (H2) for 8 hours. The catalyst is filtered-off over Celite and washed with MeOH. Evaporation of the solvent gives the crude product which is pure according to analysis and used without further purification. MS (LC-MS): 564.1 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.31 minutes.
Reaction SMILES: C(O[K])(C)(C)C.[CH2:7]([NH:9][C:10]([NH:12][C:13]1[S:14][C:15]2[C:21](/[C:22](/[CH3:26])=[N:23]/[O:24][CH3:25])=[CH:20][C:19]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:38][CH2:37][C:36]([CH3:44])([C:39]([O:41]CC)=[O:40])[CH2:35][CH2:34]4)=[N:31][CH:32]=3)=[CH:18][C:16]=2[N:17]=1)=[O:11])[CH3:8]>CS(C)=O>[CH2:7]([NH:9][C:10]([NH:12][C:13]1[S:14][C:15]2[C:21](/[C:22](/[CH3:26])=[N:23]/[O:24][CH3:25])=[CH:20][C:19]([C:27]3[CH:32]=[N:31][C:30]([N:33]4[CH2:38][CH2:37][C:36]([CH3:44])([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]4)=[N:29][CH:28]=3)=[CH:18][C:16]=2[N:17]=1)=[O:11])[CH3:8]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(/C(C)=N/OC)c2s1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(/C(C)=N/OC)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
tBuOK (124 mg, 1.11 mmol) was added to a solution of ethyl 1-[5-[2-(ethylcarbamoylamino)-7-[(E)-N-methoxy-C-methyl-carbonimidoyl]-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate in DMSO (4 mL). The mixture was stirred at ambient temperature for 2 h after which time LCMS indicated clean conversion to the acid. The mixture was filtered through cotton wool to remove solid particulates and purified by preparative HPLC to give Compound 88 as a white solid, 76 mg, 40% yield over 2 steps. 1H NMR (DMSO-d6): δ 10.89 (1H, s), 8.85 (2H, s), 7.95 (1H, d, J=1.62 Hz), 7.76 (1H, d, J=1.69 Hz), 7.16 (1H, t, J=5.50 Hz), 4.32 (2H, dt, J=13.67, 4.40 Hz), 4.09 (3H, s), 3.38 (2H, ddd, J=13.49, 10.48, 3.40 Hz), 3.23 (2H, p, J=6.71 Hz), 2.42 (3H, s), 2.05 (2H, dt, J=13.34, 3.66 Hz), 1.41 (2H, ddd, J=13.34, 10.04, 3.92 Hz), 1.21 (3H, s), 1.14 (3H, t, J=7.15 Hz). MS: 512 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:27][C:26]=2[F:45])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)C>C(OCC)(=O)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([C:19]([F:20])([F:22])[F:21])=[C:10]([N:8]2[C:7](=[O:23])[N:6]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[S:37](=[O:43])(=[O:44])[NH:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:27][C:26]=3[F:45])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9]2)[CH:15]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 91 %

Procedure:
Hydrogenation of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluoro-biphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 84, Step D) was carried out according to the procedure of Example 75, Step D, except that a 4:1 ratio of ethanol and ethyl acetate was used as solvent. The title compound was obtained in 91% yield oas an off-white foam, suitable for use without further purification; nearly homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 626 (M+Li)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[S:36][C:37]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][C:38]=2[N:39]=1.Cl>C(O)(C)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:41]4[CH:42]=[CH:43][C:37]5[S:36][C:35]([CH3:34])=[N:39][C:38]=5[CH:40]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Cc1nc2cc(N)ccc2s1
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc2cc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)ccc2s1

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (which may be prepared according to a procedure similar to Example 27, Step C) and 2-methyl-1,3-benzothiazol-5-amine are heated in isopropanol with catalytic conc. HCl at approximately 85° C. to afford the product. ES-LCMS m/z 590 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH:28]([CH3:52])[CH:29]([OH:51])[CH2:30][O:31]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH2:11]([O:27][CH:28]([CH3:52])[CH:29]([O:51][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:30][OH:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOC(C)C(CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5.01 g of 50% sodium hydride in 100 ml of dimethylformamide containing 15.79 g of benzyl bromide at 0° C., was added 46 g of 3-(hexadecyloxy)-1-(triphenylmethoxy)-2-butanol in 50 ml of dimethylformamide. This mixture was stirred overnight at room temperature then poured into water and extracted with petroleum ether. The organic extract was dried and the solvent removed. The residue was dissolved in a mixture of 190 ml of methanol and 100 ml of tetrahydrofuran, then 400 mg of p-toluenesulfonic acid was added. This mixture was allowed to stand overnight, then the solvent was removed. The residue was dissolved in petroleum ether, washed wtih saturated aqueous sodium bicarbonate, dried and the solvent removed, giving and oil. This oil was purified by HPLC using the system hexane:ethyl acetate (9:1), giving 21.84 g of the desired compound as an oil.