Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[CH:8]=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N+:11]([O-:13])[CH:12]=2)=[N:2]1.C(Cl)(Cl)Cl.[N+:22]([O-])([OH:24])=[O:23]>>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:8]([N+:22]([O-:24])=[O:23])=[C:9]3[CH2:17][O:16][CH2:15][CH2:14][C:10]3=[N+:11]([O-:13])[CH:12]=2)=[N:2]1
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cc(Nc2ccon2)cc2c1CCOC2
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(Nc2ccon2)c[n+]([O-])c2c1COCC2
Temperature: 55 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 653 mg of Compound 5 obtained in the above step (1) as crystals in 3.2 ml of fuming nitric acid is stirred at 55° C. for 3 hours. The reaction mixture is chilled, poured onto ice water and shaken with chloroform. The extract is washed with water, aqueous disodium hydrogen phosphate and saturated saline in this order, dried over anhydrous magnesium sulfate and concentrated to remove the solvent. The resultant residue is washed with methanol to give 551 mg of the titled compound as light yellow crystals. Yield: 70% mp.: 174° to 176° C. (dec.)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[ClH:3].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH:25][C:31]([CH:27]1[CH2:30][CH2:29][CH2:28]1)=[O:32]
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and cyclobutanecarboxylic acid chloride as the starting materials in 40% yield. LCMS for C23H23ClN5O (M+H)+: m/z=420.3.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[C:32]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]O)=[CH:36][CH:35]=1)#[N:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:32]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:36][CH:35]=1)#[N:33]
Reactant: N#Cc1ccc(CO)cc1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(C#N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
Diethyl azodicarboxylate (524 mg, 3.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (900 mg, 3.0 mmol), as prepared in step (c) of the Example 1, 4-cyanobenzyl alcohol (400 mg, 3.0 mmol; Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (790 mg, 3.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a white solid (0.95 g, 76%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a mixture of 7-(1-azido ethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.50 g, 1.6 mmol) and (3-fluorophenyl)boronic acid (0.27 g, 1.9 mmol) in 1,4-dioxane (10 mL) was added 1 N solution of sodium carbonate in water (2.1 mL, 2.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.080 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-40% ethyl acetate/hexanes) to give the desired product (0.32 g, 61%). LCMS calculated for C15H13FN5OS (M+H)+: m/z=330.1. Found: 330.0. The product was subjected to chiral HPLC separation (ChiralPak IA Column: 20×250 mm, 5 μm; Mobile Phase: 10% Ethanol 90% Hexanes; Flow Rate: 18 mL/min) to give two enantiomers. On analytic HPLC (ChiralPak IA Column: 4.6×250 mm, 5 μm; Mobile Phase: 10% Ethanol-90% Hexanex; Flow Rate: 1 mL/min), the first enantiomer has retention time of 6.38 minutes and the second peak has retention time of 6.99 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:19]2N(O)N=[N:22][C:20]=2[CH:21]=1.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C.C(=O)([O-])O.[Na+].C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:22][CH:20]1[CH2:21][CH2:19]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 953 ml of DMF, 9.2 g of HOBT, 11.5 g of EDC, 3.4 g of cyclopropylamine and 13.8 g of DIPEA was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over MgSO4. The solvents were removed under reduced pressure and the crude product was pure enough for the next reaction step.
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCC1.[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26]N=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:9]1([C:14]([NH:16][C:17]([NH:38][C:37]2[CH:39]=[CH:40][C:34]([O:33][C:24]3[C:23]4[C:28](=[CH:29][C:30]([O:31][CH3:32])=[C:21]([O:20][CH3:19])[CH:22]=4)[N:27]=[CH:26][CH:1]=3)=[CH:35][CH:36]=2)=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(N=C=S)C1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
1-Cyclopentanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopentanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopentanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (43 mg, yield 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1.[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:4]=1
Reactant: COc1cc(-c2ccsc2)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COc1cc(N)cc(-c2ccsc2)c1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a mixture of 3-(3-methoxy-5-nitro-phenyl)-thiophene (3.78 g, 16.07 mmol), zinc dust (10.72 g, 160.7 mmol), and ammonium chloride (12.89 g, 241.1 mmol) were added methanol (50 mL) and water (25 mL) at room temperature. After addition of water, the reaction became exothermic. The suspension was stirred for 1 h and the reaction mixture was filtered through the Celite. The filter cake was washed with water and methanol. The filtrate was concentrated to remove methanol and the residue was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was then purified by using an ISCO 120 g column, eluting with 0-20% ethyl acetate in hexanes to afford 3-methoxy-5-thiophen-3-yl-phenylamine (3.08 g, 93%) as a light yellow solid: ES(+)-HRMS m/e calculated for C11H11NOS (M+H)+ 206.0634, found 206.0634.
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH2:7][CH2:8][N:9]=1)[N+]([O-])=O.[C:10]1(C)[C:11](C)=[CH:12]C=[CH:14][CH:15]=1.[CH3:18][C:19]([CH3:21])=[O:20]>>[OH:20][CH:19]([C:21]1[CH:12]=[CH:11][CH:10]=[CH:15][CH:14]=1)[CH2:18][NH:1][C:5]1[NH:6][CH2:7][CH2:8][N:9]=1
Reactant: Cc1ccccc1C
Reactant: CC(C)=O
Reactant: O=[N+]([O-])NC1=NCCN1
Product: OC(CNC1=NCCN1)c1ccccc1
Temperature: 160 °C

Procedure:
A mixture of 15.8 parts β-hydroxy-phenyl-amine, 13 parts 2-nitramino-2-imidazoline and 8 parts xylene is stirred and heated for 30 minutes at 160°C. (oil-bath). After cooling the reaction mixtures to a temperature of about 70°C., there are added 40 parts acetone. The whole is filtered warm and after cooling the filtrate to room temperature, the precipicated product is filtered off and dried, yielding 2-(β-hydroxy-phenethyl-amino)-2-imidazoline; m.p. 147°-149°C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.[CH2:14]1CCN2C(=NCCC2)C[CH2:15]1.C1(Br)CC1>O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][CH2:14][CH3:15])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2cccc(Cl)c12
Reactant: C1CCC2=NCCCN2CC1
Agent: BrC1CC1
Solvent: O
Product: CCOc1cnc(Cl)c2cccc(Cl)c12
Temperature: 120 °C
Yield: 1.8 %

Procedure:
To a solution of 1,5-dichloroisoquinolin-4-ol (0.5 g, 2.33 mmol) in DBU (1.7 ml, 11.68 mmol) was added cyclopropylbromide (0.93 ml, 11.68 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 120° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.01 g, 2.1%) as yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.27-8.24 (m, 2H), 7.76-7.74 (d, J=8 Hz, 1H), 7.54 (t, J=8 Hz, 1H), 3.96-3.94 (m, 1H), 0.95-0.90 (m, 4H).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[N+:11]([O-])([OH:13])=[O:12]>CCOCC>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:10]
Reactant: O=[N+]([O-])O
Reactant: COc1ccccc1O
Solvent: O
Solvent: CCOCC
Product: COc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 50 ml of water, 150 ml of ether and 15.0 g of 2-methoxyphenol was added dropwise 12.7 ml of 61% nitric acid, and the mixture was stirred at room temperature for 15 minutes. The ether layer was separated from the aqueous layer and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica-gel column-chromatography using Wakogel® C-200 [eluent: chloroform-n-hexane (1:1)] to give 4.72 g of 2-methoxy-6-nitrophenol.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.O>[OH:16][CH:13]1[CH2:14][CH2:15][N:11]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH2:12]1
Reactant: COC(=O)c1cnc(Br)s1
Reactant: OC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCC(O)C2)s1
Temperature: 82.5 °C

Procedure:
A mixture of methyl 2-bromo-1,3-thiazole-5-carboxylate (3 g, 13.5 mmol), 3-pyrrolidinol (1.3 g, 14.9 mmol) and DBU (4.1 mL, 27 mmol) in dioxane (50 mL) was heated at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted five times with EtOAc. The combined EtOAc extracts were washed with water, dried (Na2SO4) and concentrated to give the crude title compound as a light brown solid. 1H NMR (400 MHz, acetone-d6): δ 7.83 (s, 1H), 4.65 (m, 1 H), 4.33 (m, 1 H), 3.79 (s, 3 H), 3.67-3.45 (m, 4 H), 2.29-2.19 (m, 1 H), 2.11 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH2:5].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH2:4][N:5]=[C:30]=[O:31]
Reactant: NCc1cc(C(F)(F)F)ccc1F
Reactant: O=C(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=NCc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a methylene chloride solution of commercially available 2-fluoro-5-trifluoromethyl benzyl amine(5.23 mmol) at 0° C. was added solid Proton sponge (5.23 mmol) then a 20% solution of phosgene in toluene (5.23 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated to provide the title compound. 1H-NMR (CDCl3): 7.7 ppm (t, 1H); 7.60 ppm (m, 1H); 7.2 ppm (m, 1H); 4.64 ppm (s, 2H).
Reaction SMILES: C=O.[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:36])[F:37])=[CH:19][N:18]=2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH3:39])[CH2:14][CH2:15]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)c(F)c2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Formaldehyde (37 wt. % in H2O; 0.041 mL, 0.50 mmol) was added to a suspension of 2-(2-(2-(2-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (7) (0.046 g, 0.092 mmol) in anhydrous MeOH (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.19 g, 0.10 mmol) was then added in one portion and the resulting mixture stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO3 (10 mL). Solid NaHCO3 was added until the formation of gas ceased, then the layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure to yield the title compound 8 as a white solid (0.043 g, 92%); 1H NMR (400 MHz, d4-MeOH) δ 8.58 (s, 1H), 7.66 (dd, J=13.2, 2.0 Hz, 1H), 7.37 (dd, J=8.5, 2.0 Hz, 1H), 7.28-7.14 (m, 5H), 3.68 (s, 2H), 3.20-3.12 (m, 2H), 3.13-3.04 (m, 2H), 3.01 (d, J=12.0 Hz, 2H), 2.90-2.76 (m, 1H), 2.34 (s, 3H), 2.24-2.12 (m, 2H), 1.90-1.77 (m, 4H). LCMS-A rt 4.888 min; m/z 516.3 [M+H]+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO>[C:5]1([CH:11]2[CH2:12][CH2:13][N:14]([CH2:3][CH2:2][C:1]#[N:4])[CH2:15][CH2:16]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CC#N
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCO
Product: N#CCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
Acrylonitrile (3.1 mL, 44 mmol, 2.5 equiv) was added to a solution of 4-phenylpiperidine (3.0 g, 18 mmol, 1.0 equiv) in EtOH (40 mL) and the mixture was stirred at room temperature for 1.5 hours. The volatiles were removed to give 3.8 g of pure product (brown oil, 99%), which was characterized spectroscopically.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][CH:7]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CC(C)n1nccc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A dry flask was charged with 2-Isopropyl-2H-pyrazole-3-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (101 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.328 g, 0.84 mmol, 82%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24]([OH:26])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:60][C@H:61]([CH2:64][CH2:65][CH2:66][CH3:67])[CH2:62][OH:63]>CN(C=O)C.O>[OH:63][CH2:62][C@H:61]([NH:60][C:24]([C:23]1[N:5]2[CH:6]=[C:7]([CH3:22])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:16])([F:15])[F:17])[C:18]([F:19])([F:20])[F:21])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:26])[CH2:64][CH2:65][CH2:66][CH3:67]
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Reactant: CCCC[C@@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.39 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]-pyridine-3-carboxylic acid Example 91A and 163 mg (0.43 mmol) of HATU were initially charged in 2.5 ml of DMF. 0.2 ml (1.17 mmol) of N,N-diisopropylethylamine and 50.3 mg (0.43 mmol) of (R)-(−)-2-amino-1-hexanol were then added, and the mixture was stirred at RT overnight. 10 ml of water were added, the reaction solution was extracted twice with 20 ml of ethyl acetate and the combined organic phases were washed with 20 ml of water and with 20 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative RP-HPLC (acetonitrile-water+0.1% formic acid), the product fractions were combined and concentrated to dryness and the residue was dissolved in a mixture of 1.5 ml of tert-butanol and 2 ml of water and lyophilized overnight. This gave 42 mg of the target compound (95% pure, 21% of theory).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)[C:41]1[CH:46]=[CH:45]C=[CH:43][CH:42]=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:6]([OH:8])=[O:7])(=[O:3])[C:2]1[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=1
Reactant: CC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a stirred solution of Example 13 Part A compound (197 mg, 0.4 mmol) under argon at 0-5° C. in THF (1.5 mL) was added triethylamine (0.2 mL, 1.6 mmol), DMAP (2 mg, 0.02 mmol) and benzoyl chloride (70 μL, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and after 15 h, it was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 161 mg (71% yield). LC/MS gave the correct molecular ion [(M+H)+=564] for the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6](OC3C=CC=CC=3)[C:5]=2[N:19]=1.C([O-])(=O)C.[NH4+:36].[OH-].[K+]>>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:36])[C:5]=2[N:19]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOC/C=C/c3ccccc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(N)c2nc(C)n(CCOC/C=C/c3ccccc3)c2c1C
Temperature: 150 °C
Yield: 31.7 %

Procedure:
1-[2,6,7-Trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]eth-2-yl [(2E)-3-phenylprop-2-enyl]ether (2.9 g, 7.013 mmol) from Part A and ammonium acetate (54 g) were combined in a glass pressure vessel. The vessel was sealed with a teflon screw cap, and the reaction mixture was heated to 150° C. for 45 hours. The reaction was complete, and the resulting reaction solution was cooled with an ice bath, basified to a pH of about 13 with 1N potassium hydroxide, and washed with dichloromethane (4×500 mL). The combined organic portions were washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a white solid. The resulting white solid was slowly passed through a column containing 200 g silica that had been heated with 1% diethyl ether in dichloromethane using 98/2 dichloromethane/methanol. Two crops of product were isolated from the eluted solution, and both were recrystallized from isopropyl alcohol. The resulting white powder was dried under vacuum for 18 hours to provide 0.7479 g of 2,6,7-trimethyl-1-(2-{[(2E)-3-phenylprop-2-enyl]oxy}ethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 143.7-144.8° C.