Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[N:16]=[C:17]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[S:18][CH:19]=1)(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH:22]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:28]2[C:20]([C:17]2[S:18][CH:19]=[C:15]([NH2:14])[N:16]=2)=[CH:21]1
Reactant: CC(C)(C)OC(=O)Nc1csc(-c2c[nH]c3ncccc23)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1csc(-c2c[nH]c3ncccc23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a stirred solution of [2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-4-yl]-carbamic acid tert-butyl ester (0.1 g, 0.316 mmol) in CH2Cl2 (2 mL) and stirred at room temperature for 2 h. The solution was poured into ice/water and basified with saturated NaHCO3 and extracted with EtOAc (3×25 mL). The combined organic extracts were dried and concentrated to afford title compound as a pale green solid (0.058 g, 85%); Mass Spec.; MS 217 (M+1)
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Si:11]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([CH:36]([NH2:38])[CH3:37])=[CH:27][C:28]([Cl:35])=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>C(O)C>[Si:11]([O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[C:26]([CH:36]([NH:38][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:37])=[CH:27][C:28]([Cl:35])=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.262 g, 1.31 mmol), 1-[8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloroquinolin-7-yl]ethanamine (0.276 g, 0.657 mmol), and N,N-diisopropylethylamine (0.23 mL, 1.31 mmol) in ethanol (2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude product was used directly in the next step (0.20 g, 57%). LCMS calculated for C27H37ClN7OSi (M+H)+: m/z=538.2; Found: 538.2.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH2:14][CH3:15])[C:8]=1[CH:16]1[C:26](=[O:27])[CH2:25][C:19]2([CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:18][C:17]1=[O:28])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH2:14][CH3:15])[C:8]=1[C:16]1[C:26](=[O:27])[CH2:25][C:19]2([CH2:18][C:17]=1[O:28][CH2:3][C:2]#[CH:1])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH3:6]
Reactant: C#CCBr
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)CC2(CCOCC2)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOC1=C(c2c(CC)cc(C)cc2CC)C(=O)CC2(CCOCC2)C1

Procedure:
A solution of propargyl bromide (0.043 g, 0.36 mmol) in acetone (2 ml) is added dropwise to a mixture of 9-(2,6-diethyl-4-methylphenyl)-3-oxaspiro[5.5]undecane-8,10-dione (0.10 g, 0.3 mmol) and potassium carbonate (0.05 g, 0.36 mmol) in acetone (3 ml) and the reaction is refluxed overnight. The solvent is evaporated in vacuo, and the residue is taken up in ethyl acetate and washed with 2 N aqueous sodium hydroxide solution. The organic phase is concentrated in vacuo, and the residue is further purified by column chromatography on silica gel to give the desired compound as a colourless gum.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18][CH3:19])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([N:16]([S:29]([CH3:28])(=[O:31])=[O:30])[S:29]([CH3:28])(=[O:31])=[O:30])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18][CH3:19])[CH2:4][CH3:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CCNC(=O)c1cc(N)c(Cl)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc1OC

Procedure:
To a solution of N-(diethylaminoethyl)-5-amino 4-chloro-2-methoxybenzamide (1.1 g) and triethylamine (815 mg) in dry methylene chloride (11 ml) is added dropwise a solution of methanesulfonyl chloride (882 mg) in dry methylene chloride (5ml) under ice-cooling and stirring and the resultant mixture is stirred at room temperature for 30 minutes. The reaction mixture is mixed with aqueous sodium hydrogen-carbonate and the methylene chloride layer is separated. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The intermediary N-(diethylaminoethyl)-5-bis(methanesulfonyl)amino-4-chloro-2-methoxybenzamide obtained as a residue is mixed with 10 % aqueous sodium hydroxide (18ml) and methanol (2 ml) and heated at 50° C. for 30 minutes. The reaction mixture is acidified with conc. hydrochloric acid, neutralized with aqueous sodium hydrogencarbonate, salted out with brine, and shaken with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a column of alumina, which is eluted with methylene chloride. The eluate is concentrated and the residue is washed with ethyl acetate - isoproyl ether to give N-(diethylaminoethyl)-4-chloro-5-methanesulfonamido-2-methoxybenzamide (993 mg) as crystals melting at 123° to 123.5° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][CH:10]=[N:11]O)[CH:4]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N#N.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:11]=[CH:10][N:9]=[C:5]2[CH:4]=1
Reactant: ON=CNc1cc(CCl)ccn1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: ClCc1ccn2ncnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of N-(4-(chloromethyl)pyridin-2-yl)-N′-hydroxyformimidamide (4-2) (820 mg, 4.4 mmol) in anhydrous THF (5 mL) cooled to 0° C. was added TFAA (1.1 g, 5.28 mmol) dropwise under N2. The reaction mixture was stirred at room temperature for 3 h. Then the mixture was treated with aqueous NaHCO3 to pH 8, concentrated and purified by chromatography on silica gel to afford the title compound (400 mg). MS (m/z): 168 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17](B(O)O)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[F:12][C:11]([F:14])([F:13])[C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[C:17]2[CH:16]=[N:15][C:24]3[C:19]([CH:18]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:8][N:9]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: FC(F)(F)c1n[nH]c2nccc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
A [1,1-bis-(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane complex (0.74 g) was added to a solution of compound (1c) (2.0 g), quinoline-3-boronic acid (2.5 g), and an aqueous sodium carbonate solution (1 M, 18 mL) in 1,4-dioxane (45 mL) under a nitrogen atmosphere, followed by stirring at 100° C. for 3 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1d) (0.94 g, 33%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][NH:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].[OH-].[Na+]>C(OCC)(=O)C>[CH3:12][NH:13][C:14]1[C:15]([CH2:16][OH:17])=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: CNc1ncccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1ncccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Under a nitrogen gas stream, 14.4 g (0.38 mol) of lithium aluminum hydride was added to tetrahydrofuran (300 mL) under ice cooling, and a tetrahydrofuran (100 mL) solution of crude 2-(methylamino)nicotinic acid was added dropwise to the above mixture. The resulting mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and 152 mL of a 10% aqueous solution of sodium hydroxide was further added thereto. Insoluble materials were filtered off. The filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate:n-hexane=1:1 to 4:1). Thus, 9.10 g (yield: 35%) of the title compound was obtained as a pale yellow viscous product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Cl)cc(N)c1C
Temperature: 80 °C
Yield: 87.8 %

Procedure:
To stirred solution of methyl 5-chloro-2-methyl-3-nitrobenzoate (16 g, 69 mmol) in ethanol (160 mL), ammonium chloride (16 g, 53.4 mmol) dissolved in water (160 mL) and iron powder (31.2 g, 55.85 mmol) were added under stirring. The resulting reaction mixture was heated at 80° C. for 1 h. On completion, water was added to and the reaction mixture filtered through celite. The filtrate was extracted with ethyl acetate and the combined organic layers washed with water, dried and concentrated under reduced pressure giving desired compound (12.10 g, 86%) without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH:30]=O>>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cn1c(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc2ccccc21

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-methylindole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(1-methylindol-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccncc2)CC1
Reaction time: 2 h
Yield: 76 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with isonicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (30 mg, 73%). LCMS calculated for C21H20ClN4O2 (M+H)+: m/z=395.1; Found: 395.1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][N:13]([CH3:17])[SH:14](=[O:16])=[O:15].O>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2].[CH3:12][N:13]([CH3:17])[SH:14](=[O:16])=[O:15]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: CN(C)[SH](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a gently stirring solution comprised of 1 molar equivalent of fuming nitric acid in excess concentrated sulfuric acid is added 1 molar equivalent of 4-methyl-benzene-N,N-dimethylsulfonamide in increments. The mixture is stirred for one hour and then poured over chilled water. The mixture is extracted with a suitable solvent like diethyl ether or dichloromethane. The organic phase is dried over a suitable drying agent like magnesium sulfate and concentrated in vacuo to afford a crude product which may be purified by normal methods such as chromatography or crystallization from a solvent like chloroform or heptane.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:13][CH2:12]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[Pd]>[NH2:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:12][CH2:13]1
Reactant: CN(CC1CCN(c2c([N+](=O)[O-])cnn2C)CC1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CC1CCN(c2c(N)cnn2C)CC1)C(=O)OC(C)(C)C
Yield: 88.2 %

Procedure:
A solution of Intermediate 1, tert-butyl methyl((1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methyl)carbamate (145 mg, 0.41 mmol) in MeOH (40 mL) was passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a red-brown oil (117 mg). To a solution of this amine (115 mg, 0.36 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (0.46 g, 0.89 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (127 mg, 0.36 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (80 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (75% EtOAc/isohexane) gave tert-butyl (1-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a lilac foam (200 mg). This foam (200 mg, 0.30 mmol) was stirred with HCl in 1,4-dioxane (4 M, 3.8 mL, 15.1 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH to yield 101 as a beige solid (99 mg, 53% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.59-7.49 (m, 3H), 7.44 (s, 1H), 7.32-7.22 (m, 2H), 6.90 (br s, 1H), 3.63 (s, 3H), 3.14-2.96 (m, 4H), 2.66 (d, J=6.8 Hz, 2H), 2.45 (s, 3H), 1.77 (d, J=12.6 Hz, 2H), 1.78-1.55 (m, 1H), 1.36-1.22 (m, 2H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[C:18]=1[S:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:8]2.[OH-].[Na+]>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:18]=1[S:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:8]2
Reactant: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (190 mg, 0.42 mmol) (Intermediate #2) was dissolved in methanol (10 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (1.05 mL, 2.1 mmol). The mixture was stirred at ambient temperature for 18 h. and then heated to 65° C. for a further 2 h. Methanol was removed by evaporation under reduced pressure and the clear solution diluted with water (25 ml). 2M HCl was added to pH4 and the mixture extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the title compound as a white solid. (174 mg, 94%)
Reaction SMILES: OC(CC(O)/C=C/[C:11]1[C:21]([CH3:23])([CH3:22])[CH2:20][C:14]2(SCCCS2)[CH2:13][C:12]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH3:31])[CH:25]=1)CC(O)=O.C(N(CC)CC)C.Cl[C:41]([O:43][CH2:44]C)=[O:42]>C(Cl)Cl.CCOCC>[CH3:23][C:21]1([CH3:22])[CH2:20][CH2:14][CH:13]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH3:31])[CH:25]=2)[CH:11]1[C:41]([O:43][CH3:44])=[O:42]
Reactant: Cc1cc(C2=C(/C=C/C(O)CC(O)CC(=O)O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Reaction time: 0.5 h
Yield: 118 %

Procedure:
To a 0°-5° C. solution of 12 (0.90 gm, 1.87 mmol) and triethylamine (315 μL, 2.25 mmol) in 10 mL CH2Cl2 was added dropwise ethyl chloroformate (185 μL, 1.87 mmol). The mixture was stirred for 30 min, diluted with ether, washed with H2O, saturated NaHCO3 and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by SiO2 using 3:2 hexanes:EtOAc as eluent provided 0.61 g of the product. mp 136°-8° C. Anal. C25H31FO3S2 : Theory C: 64.91; H: 6.75. Found C: 65.3I; H: 6.82.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Methyl 3-amino-2-fluorobenzoate hydrochloride (7.77 g, 0.037 mol) was suspended in methylene chloride (100 ml), and pyridine (6.94 g, 0.085 mol) was added dropwise thereto. Benzoyl chloride (5.78 g, 0.041 mol) was added dropwise to this reaction mixture under cooling, and the mixture was agitated overnight at room temperature. After completion of the reaction, the reaction mixture was washed sequentially with a 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and the reaction mixture was dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and then the filtrate was concentrated under reduced pressure. The concentration residue was recrystallized from ethyl acetate, as a result of which 8.79 g (yield: 85%) of the indicated compound was obtained.
Reaction SMILES: [CH2:1]([Br:4])[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9](CCCO)[CH:10]=[CH:11][CH:12]=1>CC#N>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH2:3][CH2:2][CH2:1][Br:4])[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(CCCO)c1
Reactant: C=CCBr
Solvent: CC#N
Product: COc1cccc(CCCBr)c1
Reaction time: 1.5 h

Procedure:
Allyl bromide (25 mL, 0.28 mmol) was added to a solution of 3-(3-methoxyphenyl)propanol (8.8 g, 0.053 mol), N,N′-carbonyldiimidazole (9.6 g, 0.0605 mol) and CH3CN (45 mL) at room temperature. After 1.5 hr at rt and 1.5 hr at reflux, the reaction mixture was cooled, partitioned between EtOAc (250 mL) and H2O (300 mL), the organic layer washed with H2O (300mL), 5% HCl (200 mL), dilute NaHCO3 solution (200 mL), brine (300 mL), and dried (Na2SO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]34[CH2:37][CH:32]5[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]5)[CH2:29]3)[CH2:35]4)[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC(=O)NC1(CCC2C=CC(S(N3C4C(=CC=C(OC)C=4)C(C(=O)C4C=C(OC)C(OC)=C(OC)C=4)=C3)(=O)=O)=CC=2)COC(C)(C)OC1)(C)(C)C>>[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]23[CH2:37][CH:32]4[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]4)[CH2:29]2)[CH2:35]3)[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)Oc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2
Agent: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(CCC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Product: CC(C)Oc1ccc(CCC(N)(CO)CO)cc1C12CC3CC(CC(C3)C1)C2
Yield: 67 %

Procedure:
When the product of Step C was substituted for tert-butyl-5-(4-(6-methoxy-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-ylsulfonyl)-phenethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 13, Step F, the similar process afforded the title compound in 67% yield, as a creamy paste. 1H-NMR (CDCl3) 1.28 (d, 6H, J=6 Hz); 1.68 (s, 6H); 1.82-1.88 (m, 2H); 1.97 (s, 3H); 2.02 (s, 6H); 2.47-2.54 (m, 2H); 3.61 (d, 2H, J=12.1 Hz); 3.68 (d, 2H, J=12.1 Hz); 4.48-4.57 (m, 1H); 6.68 (d, 1H, J=8.4 Hz); 6.88 (dd, 1H, J=8.29, 2.1 Hz); 6.94 (d, 1H, J=2.14 Hz).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([CH3:23])[CH:14]=3)[CH2:9][CH2:10][C@H:2]12.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=2)[N:30]=1>>[F:36][C:34]([F:35])([F:37])[C:31]1[N:29]2[N:30]=[C:25]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH:8]([CH2:11][NH:12][C:13]5[C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[N:16]=[C:15]([CH3:23])[CH:14]=5)[CH2:9][CH2:10][C@@H:2]4[CH2:1]3)[CH:26]=[CH:27][C:28]2=[N:33][N:32]=1
Reactant: Cc1cc(NCC2CC[C@@H]3CNCCN3C2)c2ccccc2n1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: Cc1cc(NCC2CC[C@@H]3CN(c4ccc5nnc(C(F)(F)F)n5n4)CCN3C2)c2ccccc2n1

Procedure:
A mixture of N-[[(9aR)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,6-a]pyrazin-7-yl]methyl]-2-methylquinolin-4-amine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N-[[(9aR)-2-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,3,4,6,7,8,9,9a-octahydropyrido[1,6-a]pyrazin-7-yl]methyl]-2-methylquinolin-4-amine.