Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[CH3:13][C:14]1(C)OC(=O)CC(=O)[O:15]1.ClC(OC(C)C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:5][C:3]1[CH2:2][N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:14](=[O:15])[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CC(C)OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(O)=CC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To Boc-Gly-OH (1 g, 5.71 mmol) in DCM (12 mL) under N2 atmosphere at 0° C. was added DMAP (1.743 g, 14.27 mmol) and Meldrum's acid (0.987 g, 6.85 mmol). A solution of isopropyl chloroformate (8.56 mL, 8.56 mmol) in toluene was added dropwise. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with 15% KHSO4 twice, dried over sodium sulfate, filtered and evaporated. The crude product was taken in 50 mL of EtOAc and refluxed for 1 h. After volatile materials were evaporated, the crude product was triturated with EtOAC and the resulting solid was filtered and dried to provide a yellow solid (75%). LCMS (m/z): 200.1 (MH+), 0.504 min.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[N:6]=[CH:5][C:4]([C:3]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 79 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using morpholine instead of 4-aminotetrahydropyran, to the title compound (90 mg, 79%) which was obtained as a white solid. MS: m/e=381.3 [M+H]+.
Reaction SMILES: [N:1]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([CH:18]([CH:24]([CH2:30][CH2:31][CH3:32])[C:25]([O:27]CC)=[O:26])[C:19](OCC)=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[Na+]>CO>[O:20]=[C:19]1[NH:8][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:9][C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:18]1[CH:24]([CH2:30][CH2:31][CH3:32])[C:25]([OH:27])=[O:26]
Reactant: CCCC(C(=O)OCC)C(C(=O)OCC)C(=O)c1ccccc1
Reactant: N=C(N)N1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)O)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O

Procedure:
To a solution of piperidine-1-carboximidamide (dimer complexated with H2SO4) (0.6 g; 4.71 mmol) and diethyl 2-benzoyl-3-propylsuccinate (1.51 g; 4.71 mmol) in methanol (5 mL) was slowly added a solution of sodium methoxide in methanol (25% w:w) (2.16 mL; 9.43 mmol) and the reaction was heated to reflux for 21 h. The volatiles were removed under reduced pressure and the crude residue was used as such in the next reaction.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](B(O)O)[CH:5]=[CH:4][CH:3]=1.Cl[C:12]1[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=2)[N:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:1][C:2]1[N:7]=[C:6]([C:12]2[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=3)[N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1cccc(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cccc(F)n3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 6-fluoropyridin-2-ylboronic acid (289.0 mg, 2.05 mmol) in dioxane (1 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (300.0 mg, 1.02 mmol), K3PO4 (434.0 mg, 2.05 mmol), and Pd(PPh3)4 (27.6 mg, 0.02 mmol) under nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.05%-0.2% ethyl acetate in petroleum ether to afford methyl 2-(6-fluoropyridin-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (260.0 mg, 72%).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH3:14])=[O:12])[CH:4](O)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[S:1][CH2:2][CH:3]=[CH:4]2)=[O:12]
Reactant: COC(=O)c1cccc2c1SCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1SCC=C2
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Methyl thiochroman-4-ol-8-carboxylate (0.337 g, 1.50 mmol) was dissolved in toluene (25 ml) and was treated with p-toluenesulphonic acid (0.028 g, 0.15 mmol). The mixture was then heated to reflux with stirring. After 2 h, the reaction mixture was allowed to cool and was washed with sodium hydrogen carbonate solution. The aqueous layer was then extracted with EtOAc (1x), and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow oil which was purified by silica-gel chromatography (pentane: Et2O 2:1 as eluant) to give the title compound as a pale yellow oil (0.270 g, 87%)
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](O)=[O:26]>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[O:26])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: O=C(O)c1ccccn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1ccccn1
Yield: 54.7 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.38 mmol) and pyridine-2-carboxylic acid (41 mg, 0.33 mmol) as starting materials. The title compound (66 mg, 46.8%) was isolated as off white solid; MS (ESI): 366 [M+H]+.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>>[CH3:6][N:7]([CH:9]=[C:19]1[C:14](=[O:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18]1)[CH3:8]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 110 °C

Procedure:
To tert-butoxy bis(dimethylamino)methane (20.8 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g) and the resulting mixture was heated at 110° C. for 16 h. After cooling to rt, the mixture was purified by flash chromatography on silica gel using a gradient elution of 5% methanol in methylene chloride to 10% methanol in methylene chloride. Concentration of the combined fractions containing the major product afforded the desired product a (11.8 g) as a dark orange oil which was used in the next step without any further purification.
Reaction SMILES: O.[C:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]N)=[CH:6][CH:5]=1)#[N:3].C1N2CN3CN(C2)CN1C3.C(O)(=[O:24])C.S(=O)(=O)(O)O>O>[C:2]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:24])=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
500 g of p-cyanobenzylamine crude product (p-cyanobenzylamine 92% by weight, p-xylylenediamine 8% by weight) obtained by hydrogen reduction of terephthalonitrile in the presence of sponge metal nickel catalyst was mixed with 2.5 kg of water while stirring at 40° C. or less and the mixture was stirred for 3 hours. The crystals which precipitated were separated by centrifugation while washing with water to obtain 500 g of p-cyanobenzylamine hydrate (water content: 21% by weight). 500 g of the p-cyanobenzylamine hydrate, 420 g of hexamethylenetetramine, and 2.0 kg of acetic acid were mixed and the internal temperature was elevated to 80° C. while stirring. An aqueous sulfuric acid solution of 300 g of 98% by weight sulfuric acid and 165 g of water was added dropwise thereto over 20 minutes. Further, the reaction mixture was stirred at 100° C. for 1 hour. After the internal temperature was decreased to 50° C., 300 g of 98% by weight sulfuric acid was added. The reaction mixture was concentrated to dryness under reduced pressure. To the concentrated residue was added 900 g of 1% by weight sulfuric acid and stirred vigorously at 100° C. for 3 hours. Thereafter, the reaction mixture was cooled to room temperature for 2 hours. The crystals which precipitated were filtered, washed with water, and dried to obtain 295 g (yield: 75%) of p-cyanobenzaldehyde. The purity was 99.5% or more. Under nitrogen atmosphere, 295 g of the p-cyanobenzaldehyde and 4.5 g of 2,2-azobisisobutyronitrile were mixed. The temperature was elevated to 105° C. and 190 g of chlorine was bubbled over 3 hours with vigorous stirring. After dry nitrogen gas was introduced into the reaction mixture for 1 hour, the solvent was distilled under reduced pressure to obtain 302 g (yield: 81%) of p-cyanobenzoyl chloride. The purity was 98.5%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[NH2:19]>>[CH3:26][O:25][C:21]1[CH:20]=[C:18]([NH:19][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:17]=[C:16]([O:15][CH3:14])[C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C(=O)O)cc1C#N
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1ccc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1C#N

Procedure:
Compound 68 is synthesized following a similar method as in Example 1 and using 3-cyano-4-methoxybenzoic acid and 3,4,5-trimethoxyaniline as materials. Total yield of the two steps: 60%.
Reaction SMILES: CC1C=CC(S([CH:11]2[CH:15]([C:16]3[CH:21]=[C:20]([C:22]([NH2:24])=[O:23])[CH:19]=[CH:18][N:17]=3)O[CH:13]=[N:12]2)(=O)=O)=CC=1.[NH3:25]>CO>[NH:12]1[CH:11]=[C:15]([C:16]2[CH:21]=[C:20]([C:22]([NH2:24])=[O:23])[CH:19]=[CH:18][N:17]=2)[N:25]=[CH:13]1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)C2N=COC2c2cc(C(N)=O)ccn2)cc1
Solvent: CO
Product: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
2-[4-(4-methylphenyl)sulfonyl-4,5-dihydro-1,3-oxazol-5-yl]pyridine-4-carboxamide (23 g, 63.98 mmol) was added to a solution of NH3 in MeOH (5 g/120 mL) and stirred overnight at 125° C., concentrated and purified by flash column chromatography to give the title compound (5 g, 36.8%). [M+H] Calc'd for C9H8N4O, 189. Found, 189.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH:2]1[C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([O:14][CH3:15])=[C:10]([CH:13]=1)[CH:11]=O.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C[O-].[Li+]>CN(C)C=O.CO.O>[O:1]1[CH2:5][CH:4]=[CH:3][CH:2]1[C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([O:14][CH3:15])=[C:10](/[CH:11]=[CH:19]/[C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[O:20])[CH:13]=1
Reactant: COc1cc(OC)c(C2C=CCO2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C2C=CCO2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
5-(2,5-Dihydro-furan-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-121A, 0.10 g, 0.43 mmol) and 4-acetylbenzenesulfonamide (Ex-26A, 0.085 g, 0.43 mmol) were dissolved in a dimethylformamide-methanol solution (2.9 mL, 7:3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.13 g (70%) of the title compound as a yellow solid, mp 194–195° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.23 (d, 2H, J=8.2 Hz), 8.03 (d, 1H, J=15.3 Hz), 7.97 (d, 2H, J=8.2 Hz), 7.69 (s, 1H), 7.65 (d, 1H, J=15.3 Hz), 7.55 (brs, 2H), 6.73 (s, 1H), 6.06–6.09 (m, 1H), 5.90–5.98 (m, 2H), 4.86–4.92 (m, 1H), 4.63–4.68 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z=416 ([M+H]+, 100%). Anal. Calcd. C21H21NO6S: C, 60.71; H, 5.09; N, 3.37; S, 7.72. Found: C, 60.95; H, 5.24; N, 3.46; S, 7.72.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:23]=[C:22]([F:24])[CH:21]=[C:20]([O:25][C:26]([F:29])([F:28])[F:27])[N:19]=1>ClCCCl>[F:24][C:22]1[CH:21]=[C:20]([O:25][C:26]([F:29])([F:27])[F:28])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Nc1nc(F)cc(OC(F)(F)F)n1
Solvent: ClCCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(F)cc(OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.6 g (0.015 mol) of 2-methoxycarbonylbenzenesulfonyl isocyanate in 15 ml of 1,2-dichloroethane were added over the course of 15 minutes to a stirred mixture of 2.95 g (0.015 mol) of 2-amino-4-fluoro-6-trifluoromethoxypyrimidine and 100 ml of 1,2-dichloroethane at 25° C., and the mixture was stirred at 25° C. for 12 hours. The solution was concentrated under reduced pressure, and the residue was stirred with 1:1 ether/petroleum ether. Filtration with suction and drying yielded 4.8 g (73.3% of theory) of the title compound of melting point 157-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=O.Cl.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][NH2:22].C([O-])(=O)C.[Na+]>CO>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][N:22]=[CH:4][C:3]1[C:2]([Br:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=1[Br:11]
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Reactant: NNc1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(C=NNc2ccc(F)cc2F)c(Br)c1
Yield: 74.9 %

Procedure:
2,6-Dibromo-4-methylbenzaldehyde (89.5 g, 0.322 mol), (2,4-difluorophenyl)hydrazine hydrochloride (58.25 g, 0.322 mol) and sodium acetate (26.9 g, 0.328 mol) were heated in methanol (1.25 L) at reflux for 3.5 hours. The mixture was cooled and the precipitate was collected by filtration and partitioned between ethyl acetate (750 mL) and water (250 mL). The ethyl acetate layer was combined with a second ethyl acetate extract, washed successively with water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford the title compound as an off-white solid (97.5 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:22]=[C:23]([C:27]3([C:33]([OH:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)[CH:14]=1.[CH2:36](O)[CH3:37]>>[CH2:36]([O:34][C:33]([C:27]1([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:15]3[CH:14]=[C:13]([NH:12][CH2:11][CH2:10][C:4]4[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=4[Cl:2])[N:18]=[C:17]([O:19][CH3:20])[N:16]=3)[CH:22]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)=[O:35])[CH3:37]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1(c2cccc(-c3cc(NCCc4ccc(Cl)cc4Cl)nc(OC)n3)c2)CCOCC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 20 μL, 0.08 mmol) is added to a solution of 4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid [20 mg, 0.04 mmol, Example 80(a)] in ethyl alcohol (4 mL) and the reaction mixture is stirred overnight at 75° C. The reaction is cooled to room temperature, quenched with water, extracted twice with ethyl acetate. The combined extracts are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluting with ethyl acetate/heptane to afford 4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid ethyl ester [16 mg, Example 80(c)]. LCMS: RT=2.74 minutes; MS: 530, 532 (M+H); 1H NMR (300 MHz, CDCl3): □8.05 (1H, s), 7.9 (1H, d, J=3.5 Hz), 7.4-7.55 (3H, m), 7.2 (2H, s), 6.4 (1H, s), 5 (1H, b), 4.18 (2H, q, J=2 Hz), 4.05 (3H, s), 3.98 (2H, m), 3.75 (2H, b), 3.65 (2H, t, J=3.5 Hz), 3.1 (2H, t, J=2 Hz), 2.6 (2H, d, J=4 Hz), 2.1 (2H, m), 1.2 (3H, t, J=2 Hz). IC50=223 nM
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=S.Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH:17]2[NH2:19])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>[Hg](Cl)Cl.C(#N)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:18][CH:17]2[NH:19][C:2]2[S:1][CH2:7][C:5](=[O:6])[N:4]=2)=[CH:14][CH:15]=1
Reactant: NC1CC1c1ccc(F)cc1
Reactant: O=C1CSC(=S)N1
Agent: Cl
Agent: Cl[Hg]Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NC2CC2c2ccc(F)cc2)=N1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.4 %

Procedure:
In a three-neck flask equipped with argon inlet was charged with rhodanine (200 mg, 1.5 mmol, 1.4 eq), anhydrous Acetonitrile (5 mL), 2-(4-fluoro-phenyl)-cyclopropylamine HCl salt (200 mg, 1.1 mmol, 1 eq) and diisopropylehtylamine (0.58 mL, 3 eq). The mixture was cooled to 0° C. and mercury (II) chloride (376 mg, 1.3 eq) was added. The reaction mixture was stirred at 0° C. for 30 minutes and room temperature for another 1.5 hours. The reaction mixture was filtered through a celite cake and washed with dichloromethane (3×20 mL), methanol (3×20 mL) and diethyl ether (3×20 mL). The filtrate and washing solutions were combined and concentrated by rotavaping to afford crude product. The crude was purified by flash chromatography (40 gram prepacked column by Isco, Inc., 230400 mesh, eluant: 0-10% methanol in dichloromethane) to obtain 136 mg of pure product. The structure was confirmed with
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[C:11]#N.[OH-:13].[Na+].[OH2:15]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[C:11]([OH:15])=[O:13]
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1cc2ccsc2nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1nc2sccc2cc1C(=O)O
Reaction time: 3 h
Yield: 56 %

Procedure:
6-Amino-thieno[2,3-b]pyridine-5-carbonitrile described in Preparation Example T-5 (104 mg, 0.594 mmol) was dissolved in a mixture solution of water (1.5 mL) and sulfuric acid (1.5 mL), and the solution was stirred for 3 hours under reflux. An aqueous solution of 5N sodium hydroxide was added to the reaction solution at 0° C., to neutralize the solution. The precipitated solid was filtered, and title compound (65 mg, 0.33 mmol, 56%) was obtained as a pale yellow solid.
Reaction SMILES: B.C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.Br.[Br:29][CH2:30][C:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:32]>C1COCC1>[Br:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[OH:32]
Reactant: O=C(CBr)c1cccnc1
Agent: B
Agent: Br
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
A solution of borane-THF (1 M solution, 15 mL) was added dropwise to a 0° C., stirred solution of (S)-2-methyl-CBS-oxazaborolidine monohydrate (0.738 g, 2.5 mmol) in THF (10 mL) over a period of 10 min. After stirred at 0° C. for 10 minutes the mixture was then added dropwise into a cold (0° C.) stirred suspension of 3-(2-bromoacetyl)pyridine hydrobromide (7.0 g, 24.9 mmol) in THF (50 mL) over a period of 10 minutes. After addition was completed the mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was cooled to 0° C. and quenched with dry HCl (0.5 M in methanol, 9 mL) The mixture was further diluted with water and extracted with ethyl acetate. The extract was washed with water and dried with MgSO4. Evaporation and purification by flash column chromatography (methylene chloride/methanol 95/5) gave (1 R)-2-bromo-1-(3-pyridinyl)-1-ethanol as a brown oil (1.72 g, 34%). This solid (1.71 g, 8.5 mmol) was dissolved in THF (15 mL) and 5 N aqueous sodium hydroxide (30 mL) was added. After the solution was stirred at room temperature for 10 minutes, the mixture was diluted with water and extracted with methylene chloride. The extract was washed with water, dried with MgSO4, and concentrated to give a white solid (0.72 g, 72%): MS m/z 122 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:31]([C@H:34]4[CH2:39][CH2:38][C@H:37]([C:40]([O:42]CC)=[O:41])[CH2:36][CH2:35]4)=[C:30]4[C:25]=3[C:26](=[O:46])[C:27]([CH3:45])=[CH:28][NH:29]4)[C:20]([C:47]([F:50])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:51][CH3:52])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:31]([C@H:34]4[CH2:35][CH2:36][C@H:37]([C:40]([OH:42])=[O:41])[CH2:38][CH2:39]4)=[C:30]4[C:25]=3[C:26](=[O:46])[C:27]([CH3:45])=[CH:28][NH:29]4)[C:20]([C:47]([F:48])([F:50])[F:49])=[CH:19][N:18]=2)=[C:12]([O:51][CH3:52])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c(=O)c(C)c[nH]c32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](C(=O)O)CC4)c4[nH]cc(C)c(=O)c34)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of Ethyl trans-4-(5-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohexanecarboxylate (Example 304, 72.0 mg, 0.097 mmol) in THF (0.125 mL) and MeOH (0.129 mL) was charged with a solution of lithium hydroxide, monohydrate (20.2 mg, 0.48 mmol) in H2O (0.129 mL) and allowed to stir at rt for 30 hrs. The reaction was concentrated under reduced pressure. The material was purified on an Isco combi-flash unit using DCM/MeOH (100:0→95:5) as eluent to afford 45 mg (60%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 1.24-1.33 (m, 6 H) 1.66-1.86 (m, 4 H) 1.96-2.04 (m, 2 H) 2.12-2.14 (m, 3 H) 2.15-2.22 (m, 2 H) 3.39-3.43 (m, 1 H) 3.46-3.50 (m, 1 H) 3.91-3.94 (m, 3 H) 4.05-4.11 (m, 4 H) 6.88-6.94 (m, 1 H) 7.03-7.07 (m, 1 H) 7.47-7.52 (m, 1 H) 7.83-7.86 (m, 1 H) 8.01-8.06 (m, 1 H) 8.33-8.35 (m, 1 H) 8.50-8.59 (m, 1 H). MS (ES+): m/z 718.22/719.26 (100/98) [MH+]. HPLC: tR=1.43 min (Micromass TOF: polar—3 min).