Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:42]=[CH:41][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:27]([C:25]1[S:26][C:19]2[C:20](=[N:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[F:1])=[O:11])=[CH:42][CH:41]=2)[CH:24]=1)=[O:28]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCNC(=O)OC(C)(C)C)sc34)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate (380 mg, 0.64 mmol) in 10 ml of methylene chloride was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 270 mg, 85%.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:51])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]C)=[O:48]>>[C:47]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:51])=[O:17])([OH:49])=[O:48]
Reactant: COC(=O)CCCCCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 184, the title compound was prepared in 47% overall yield by alkylation of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one with 2-[(9-methoxy-9-oxononyl)oxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example followed by saponification. The diacid product was a colorless solid, mp 63°-65° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=O.[C:19]([NH2:22])(=[S:21])[CH3:20]>C(O)C>[CH3:20][C:19]1[S:21][C:2]2[CH2:17][CH2:16][C:5]3=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]3[C:3]=2[N:22]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Solvent: CCO
Product: CCOC(=O)c1sc(SC)c2c1CCc1sc(C)nc1-2
Yield: 44.2 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.09 g), thioacetamide (0.90 g) and ethanol (100 ml) was refluxed under heating for 7 hours, after which it was concentrated under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:19 to 1:9, v/v) to yield ethyl 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-e]benzothiazole-6-carboxylate (0.86 g, 44%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 143-144° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9][CH:10]1[N:13]([CH2:14][C:15]([OH:17])=O)[C:12](=[O:18])[CH2:11]1.ClC(OCC)=O.[CH2:25]([O:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([O:32][NH:33][C:15](=[O:17])[CH2:14][N:13]1[CH:10]([S:9][CH3:8])[CH2:11][C:12]1=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NOCc1ccccc1
Reactant: CSC1CC(=O)N1CC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSC1CC(=O)N1CC(=O)NOCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
Triethylamine (2 ml) was added to a solution of (4-methylthio-2-oxo-azetidin-1-yl)acetic acid (1.67 g) in dry chloroform (15 ml) cooled to -10° C. After 5 mins ethyl chloroformate (1.6 ml) was added, then after a further 5 mins a solution of O-benzylhydroxylamine free base (1.67 g) in chloroform was added. The solution was allowed to warm to room temperature and stirred for 16 hours then washed with brine, dried (MgSO4) and evaporated. Chromatography of the residue on silica gel (petroleun ether/ethyl acetate) gave N-benzyloxy-(4-methylthio-2-oxo-azetidin-1-yl)acetamide as a clear gum (22% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[CH2:22]Br>CN(C)C=O>[C:1]([O:5][C:6](=[O:9])[N:7]([CH2:22][C:14]1[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]=1[Br:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc(Br)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1c(Br)cccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of methyl-carbamic acid tert-butyl ester from Preparation 1 (5.347 g, 40.76 mmol) in 200 ml anhydrous dimethylformamide was added sodium hydride (2 g of a 60% suspension in mineral oil, 50 mmol) portion-wise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 30 minutes, at which time the initial off-gassing had completed. 1-bromo-2-bromomethyl-3-nitro-benzene (12 g, 40.7 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extract with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give (2-bromo-6-nitro-benzyl)-methyl-carbamic acid tert-butyl ester as a yellow oil (11.761 g, 84%). MS: (M+H)+ 345.1.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[CH2:10][CH:5]2[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:3]1.[H-].[Na+].[CH3:34]I>O1CCCC1>[CH3:34][N:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2](=[O:1])[O:3][C:4]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:5]2[CH2:10]1)=[O:12]
Reactant: O=C(Nc1ccccc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of tetrahydro-3-oxo-N,1,1-triphenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide (60 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added 60% sodium hydride (10 mg, 0.25 mmol), and the mixture was stirred at room temperature for 1 hour. Next, methyl iodide (0.15 g, 1.1 mmol) was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (30 mg, yield 48%).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2SC=CN=2)=[CH:4][CH2:3]1.FC(F)(F)S([O:36][C:37]1C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC=2C(C)(C)[CH2:45][CH:46]=1)(=O)=O>>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([C:25]2[O:36][CH:37]=[CH:46][CH:45]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67), 250.0 mg (0.52 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiofuran (prepared by the addition of 53.4 mg (0.52 ml, 0.78 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (-78° C.) of 53.4 mg (0.784 mmol) of furan in 1.0 mL of THF).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][S:26](O)(=[O:28])=[O:27]>C(Cl)(Cl)Cl>[CH2:7]([C:1]1[CH:6]=[CH:5][C:4]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 68 %

Procedure:
To a solution of 1-phenyloctadecane (0.69 g, 2.5 mmol) in CHCl3 (5 mL) was added chlorosulfonic acid (0.5 mL, 7.5 mmol) and the mixture was stirred at rt for 22 h. The mixture was poured on ice and extracted with CH2Cl2. The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel (70-230 mesh) with hexane/ethyl acetate (49:1) to give the product as a white solid (0.63 g, 1.7 mmol, 68%), mp 32-33° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.25 (m, 22H), 1.65 (m, 2H), 2.72 (t, 2H, J=7.8 Hz), 7.42 (d, 2H, J=8.4 Hz), 7.93 (d, 2H, J=8.4 Hz); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.1, 29.3, 29.5, 29.6, 29.7, 30.9, 31.9, 36.0, 126.9, 129.5, 141.7, 151.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2].[C:19](#[N:22])[CH:20]=[CH2:21].CO[Na]>CO>[C:19]([CH2:20][CH2:21][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])#[N:22]
Reactant: C=CC#N
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Agent: CO[Na]
Solvent: CO
Product: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Yield: 26.2 %

Procedure:
To a solution of compound 75 (10.5 g, 41 mmol) and acrylonitrile (17.4 g, 328 mmol) in absolute CH3OH (100 mL) was added a catalytic amount of CH3ONa (216 mg, 4 mmol) at room temperature with stirring under N2. The mixture was stirred at room temperature for 10 h under N2. The mixture was diluted with aqNaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified with silica gel column chromatography (PE:EtOAc=5:1) to give compound 76 (3.3 g, 20%) as a light yellow oil.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:19]I>CN(C)C=O>[CH3:18][C:12]([C:9]1[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A suspension of 924 (23 mmol) of sodium hydride (60% in oil) in 21 mL of dry N,N-dimethylformamide was stirred under nitrogen in an ice bath as a solution of 4.68 g (21 mmol) of ethyl (+/-)-2-(4-nitrophenyl)propionate in 20.5 mL of dry N,N-dimethylformamide was added gradually over about 10 minutes. An intense violet color developed during the addition. The mixture was then allowed to warm to room temperature. After about 1 hour, the mixture was again cooled in an ice bath as a solution of 1.44 mL (3.28 g; 23 mmol) of methyl iodide in 5 mL of dry N,N-dimethylformamide was added dropwise by syringe over about 10 minutes, while maintaining the internal temperature at 10-15° C. The mixture was allowed to warm to room temperature, and the color changed to brown. After 1 hour, an additional 187 mL (426 mg, 3 mmol) of iodomethane was added. By the next day, the mixture consisted of a suspension of some grayish solid in a golden liquid. It was stirred vigorously and quenched by gradual addition of 10 mL of 5% aqueous potassium bisulfate solution. The mixture was partitioned between 400 mL of diethyl ether and 400 mL of water. The organic layer was washed with an additional 3×400 mL of water and then with 50 mL of saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 19:1 hexane-ethyl acetete) yielded 4.31 g (87%) of an oil; homogeneous by TLC in 9:1 hexane-ethyl acetete. 400 MHz 1H NMR (CDCl3) was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>>[CH2:1]([C:3]1([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: c1ccc2[nH]ccc2c1
Product: CCC1(c2c[nH]c3ccccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and indole, the title compound is prepared as in example 1.89 mg (54%). LC-MS m/z 280.0 (M++1).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25](Cl)[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H][H]>O1CCOCC1.[Pd]>[CH2:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][N:26]=2)=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Yield: 111.5 %

Procedure:
Six (6) g of hydrogenation catalyst in which 5 % of Pd was carried on activated carbon and a small amount of sodium acetate were placed in an eggplant-shaped flask. After replacing the atmosphere inside the flask with nitrogen, 6 g of the above Compound D dissolved in 90 ml of dioxane was slowly dropped into the flask through a dropping funnel. After replacing the inside atmosphere with hydrogen with stirring, hydrogen was supplied from a gas reservoir. The reaction was continued until hydrogen absorption ceased. Thereafter the atmosphere was replaced with nitrogen, and the catalyst was removed by filtration. The solvent was recovered from the filtrate. Thus obtained crude product was purified by column chromatography and recrystallization to provide 6.1 g of purified 2-(4-octyloxyphenyl)-5- ethoxycarbonylpyrimidine (Compound E).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:42])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:22])[F:21])[C:12]([N:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[C:38]([CH3:40])[N:37]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M306) (0.46 g, 0.77 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (344 mg, 93%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:2]1[C:3]2[N:4]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH3:20]
Reactant: CCNCC
Reactant: CCc1nnc2c(Cl)nc3ccc(OC)cc3n12
Solvent: CN(C)C=O
Product: CCc1nnc2c(N(CC)CC)nc3ccc(OC)cc3n12
Yield: 23 %

Procedure:
4-Chloro-1-ethyl-8-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline (520 mg., 0.002 mole) and 673 mg. (0.008 mole) of diethylamine in 10 ml. of N,N-dimethylformamide were stirred at room temperature overnight. The reaction mixture was poured over ice and the precipitate was separated by filtration, washed with water and air dried. Recrystallization from diethyl ether and petroleum ether than afforded 140 mg. (23% yield) of pure 4-diethylamino-1-ethyl-8-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 135°-138° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:42])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:42])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCOCC4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(N4CCOCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M289) (383 mg, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (230 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([Mg]Br)[CH3:12].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH2:11][CH3:12])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CCC(O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 15 g (73.9 mmol) 5-bromo-2-fluorobenzaldehyde in diethyl ether (100 ml) at 0° C. were slowly added 27.1 ml (81.3 mmol) of ethyl magnesium bromide solution (3 M in diethyl ether). After stirring at 0° C. for 3 h, water (20 ml) was carefully added upon which a white precipitate formed. The solid was filtered off and washed with tert-butyl methyl ether. The combined filtrates were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude title compound thus obtained (16.1 g, 93% of th.) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)/C=C/C1(c2ccc(F)c(F)c2)CCCCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC1(c2ccc(F)c(F)c2)CCCCC1
Reaction time: 6 h

Procedure:
To a solution of (E)-ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)acrylate (550 mg, 1.869 mmol) in MeOH (20 mL) was added ˜150 mg of 10% Pd/C (wet, 50%), and the mixture was stirred under hydrogen (50 psi) for 6 hrs. The catalyst was removed by filtering through Celite and the solvent was evaporated off to give ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)propanoate as an oil. LC/MS: m/e 297.16 (M+H)+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:39]3[N:40]=[CH:41][C:42]4[CH:48]=[C:47](Br)[C:46](=[O:50])[N:45]([CH:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:43]=4[N:44]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.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>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:39]3[N:40]=[CH:41][C:42]4[CH:48]=[C:47]([C:6](=[O:8])[CH3:7])[C:46](=[O:50])[N:45]([CH:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:43]=4[N:44]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C

Procedure:
Tributyl(1-ethoxyvinyl)tin (0.39 mL, 1.15 mmol) was added to a mixture of 4-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (440 mg, 0.77 mmol), prepared as in Example 2, and tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.077 mmol) in toluene (5 mL). The reaction mixture was heated at 110° C. for 1 hour then cooled to room temperature. The solid so formed was collected by filtration and washed with toluene, then dried to give 4-[6-(6-acetyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester. M++1: Calc'd. 534.6. Found 534.2.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[C:8](=O)[C:9](=[O:13])[NH:10][C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1.[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[O:13]=[C:9]1[C:8](=[N:22][NH:21][C:20]2[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=2)[C:7]2[CH:6]=[C:5]3[O:1][CH2:2][O:3][C:4]3=[CH:12][C:11]=2[NH:10]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2cc3c(cc2C1=O)OCO3
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc4c(cc32)OCO4)cc1
Yield: 55 %

Procedure:
The title compound was prepared from 5H-[1,3]dioxolo[4,5-f]indole-6,7-dione (Lackey and Sternbach, Synthesis 1993, 993–7) and 4-sulfonamidophenylhydrazine hydrochloride in 55% yield as an orange crystalline solid following Procedure G: mp>220° C.; 1H NMR (DMSO-d6): δ 12.63 (s, 1H), 10.89 (s, 1H), 7.73 (d, J=7 Hz, 2H), 7.50 (d, J=7 Hz, 2H), 7.22 (s, 2H), 7.13 (s, 1H), 6.56 (s, 1H), 6.00 (s, 2H). Anal. Calcd for C15H12N4OsS: C, 50.00; H, 3.36; N, 15.55. Found: C, 50.08; H, 3.35; N, 15.49.