Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:12]3[C:17]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])=[C:16]([CH3:26])[N:15]=[C:14]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:13]=3)[CH:10]=[CH:11][C:2]1=2.[OH-].[Na+]>CO>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:12]3[C:17]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20])=[C:16]([CH3:26])[N:15]=[C:14]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:13]=3)[CH:10]=[CH:11][C:2]1=2
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)OCCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)OCCCO2
Yield: 70.7 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.092 g; 0.213 mmol), sodium hydroxide 10N (0.213 mL; 2.13 mmol) in methanol (2.1 mL). Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane furnished 0.063 g (70%) of the title compound as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:31]([O:34][CH2:35]Cl)[CH2:32][CH3:33].O>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:35][O:34][CH2:31][CH2:32][CH3:33])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Reactant: CCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 1 h

Procedure:
0.45 g (3.26 mmol) of potassium carbonate was added at 60° C. to a suspension of 0.65 g (2.04 mmol) of 7-benzyl-3-phenylxanthine from stage a) in 20 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 0.29 ml (2.65 mmol) of propoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 1.5 hours. 20 ml of water were then added, the mixture was extracted three times using 24 ml of methyl tert-butyl ether each time, and the combined organic phases were washed twice with 12 ml of water each time, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column heptane/ethyl acetate (5/7).
Reaction SMILES: Cl.C([N:9]([C@@H:13]1[C@@:20]2([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:17]([CH2:18][CH2:19]2)[CH2:16][N:15]2[C:25](=[O:41])[C:26]([OH:40])=[C:27]([C:29](=[O:39])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:28]=[C:14]12)[C:10](=O)[OH:11])C1C=CC=CC=1.[CH:42](N(C(C)C)CC)(C)C.C(Cl)(=O)C.N(C)C.CO>C(Cl)Cl>[C:10]([NH:9][C@@H:13]1[C@@:20]2([CH3:24])[C:21]([CH3:22])([CH3:23])[C@H:17]([CH2:18][CH2:19]2)[CH2:16][N:15]2[C:25](=[O:41])[C:26]([OH:40])=[C:27]([C:29]([NH:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[O:39])[N:28]=[C:14]12)(=[O:11])[CH3:42]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](N(Cc1ccccc1)C(=O)O)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)N[C@H]1c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C[C@H]2CC[C@]1(C)C2(C)C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To a stirred solution of benzyl((7S,10R,11R)-2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocin-11-yl)carbamate hydrochloride salt (0.025 g, 0.055 mmol) and diisopropyl-ethylamine (0.175 mL, 1 mmol) in CH2Cl2 (3 mL) was added acetyl chloride (0.036 mL, 0.5 mmol). After 4 h, 2M Me2NH/methanol (1 mL) was added and stirring continued at room temperature. After 16 h, the reaction mixture was concentrated and purified by preparative-HPLC using methanol/water (0.1% trifluoroacetic acid) to afford the title compound (0.0188 g, 0.038 mmol, 69% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 11.99 (1H, s), 7.56 (1 H, t, J=5.8 Hz), 7.33 (2 H, dd, J=8.5, 5.2 Hz), 7.04-7.09 (2 H, m), 6.42 (1 H, d, J=9.2 Hz), 5.52 (1 H, d, J=9.2 Hz), 5.17 (1 H, dd, J=15.4, 8.7 Hz), 4.54-4.66 (2 H, m, J=14.8, 14.6, 14.6, 6.0 Hz), 3.70 (1 H, d, J=15.3 Hz), 3.48 (3H, s, from CH3OH), 2.09 (1 H, t, J=8.1 Hz), 1.94 (3 H, s), 1.78-1.87 (1 H, m), 1.41-1.49 (1 H, m), 1.38 (3 H, s), 1.30-1.37 (1 H, m), 0.99 (3 H, s), 0.95-0.98 (1 H, m), 0.94 (3 H, s). LCMS (M+H) calcd for C24H30FN4O4: 457.23; found: 457.27. Purity: >98%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=[O:3])[CH3:2].N[C:32]1[C:37](C)=[CH:36]C(C)=[CH:34][C:33]=1C(C1CCCCC1)=O>>[Cl:30][C:25]1[C:26]([CH3:29])=[N:27][O:28][C:24]=1[NH:23][S:20]([C:19]1[CH:18]=[CH:17][S:16][C:15]=1[C:13]([NH:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:1]([CH:2]1[CH2:36][CH2:37][CH2:32][CH2:33][CH2:34]1)=[O:3])=[O:14])(=[O:21])=[O:22]
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Reactant: Cc1cc(C)c(N)c(C(=O)C2CCCCC2)c1
Product: Cc1cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C(=O)C2CCCCC2)c1

Procedure:
3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that cyclohexyl 2-amino-3,5-dimethylphenyl ketone was used instead of 2′-amino-3′,5′-dimethylacetophenone.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][CH2:4][NH:5][C:6]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][C:7]=1[NH2:8].Cl.[C:25](=N)(OC)[CH3:26].C(=O)([O-])O.[Na+]>CO>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([CH2:4][CH2:3][C:2]([F:1])([F:22])[F:23])[C:25]([CH3:26])=[N:8][C:7]=2[CH:9]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCCC(F)(F)F
Reactant: COC(C)=N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCC(F)(F)F
Yield: 77.8 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(3,3,3-trifluoropropyl)aminoanilin-5-yl)benzoxazole (see Working Example 85-1) (300 mg, 0.93 mmol) was added methyl acetimidate hydrochloride (120 mg, 1.11 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, after which it was filtered and concentrated to yield the title compound (250 mg, 93% yield) as white crystals.
Reaction SMILES: I[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[O:32]1[C:43]2[C:44]3[C:39]([C:40](B(O)O)=[CH:41][CH:42]=2)=[N:38][CH:37]=[CH:36][C:35]=3[CH2:34][CH2:33]1.C(OCC)(=O)C>COCCOC.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>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:40]2[C:39]3[C:44]4=[C:35]([CH2:34][CH2:33][O:32][C:43]4=[CH:42][CH:41]=2)[CH:36]=[CH:37][N:38]=3)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
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: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc2c4c(ccnc14)CCO2)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of methyl 2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.065 g; 0.136 mmol) in a mixture of DME-water (3:1) (0.480 mL) were added potassium carbonate (0.057 g; 0.409 mmol), tetrakis(triphenylphosphine)palladium(0) (0.016 g; 0.014 mmol) and 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid (0.044 g; 0.205 mmol). The solution was stirred for 30 min at 140° C. under a microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-80%) in heptane furnished 0.048 g (68%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:33])[NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:17]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:33])[NH:23][S:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(=O)(=O)c3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)NS(=O)(=O)c2ccccc2)c1
Yield: 48.9 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(phenylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (250 mg, 0.44 mmol, 1.0 eq.) in methanol (8 mL) and 1N sodium hydroxide aqueous solution (6.6 mL, 6.6 mmol, 15.0 eq.) was heated to reflux for 1 h, Thin layer chromatography (petroleum ether:ethyl acetate=1:1) and LC-MS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure and the residual was acidified with 1 M hydrochloric acid solution to pH=3. The white solid precipitated was collected by filtration and washed with acetone to give 100 mg of 3,3-dimethyl-2-(3-(phenylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a off-white solid, yield: 50.4%. LC-MS(M+1)=465.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][C:8]=2[C:9]([O:13][CH2:14][CH3:15])=[N:10][C:11]=1[CH3:12])=[O:5])C.[OH-].[Na+]>>[CH2:14]([O:13][C:9]1[C:8]2[N:16]=[N:17][N:18]([CH2:19][CH3:20])[C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH3:12])[N:10]=1)[CH3:15]
Reactant: CCOC(=O)c1c(C)nc(OCC)c2nnn(CC)c12
Agent: [Na+]
Agent: [OH-]
Product: CCOc1nc(C)c(C(=O)O)c2c1nnn2CC

Procedure:
20 g. of 4-ethoxy-1-ethyl-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester are hydrolyzed with aqueous sodium hydroxide to obtain 4-ethoxy-1-ethyl-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:13]1[C:5]2[CH:4]=[CH:3][NH:9][C:7](=[O:8])[C:6]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COC(Cc1ncccc1C(N)=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]ccc2ncccc12
Yield: 66.7 %

Procedure:
A mixture of 2-(2,2-dimethoxyethyl)nicotinamide (8.33 g, 39.7 mmol) and TsOH.H2O (940 mg) in toluene (100 mL) was refluxed for 14 h. Toluene was removed under reduced pressure, then the residue was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 1:1 and with EtOAc) to yield 1,6-naphthyridin-5(6H)-one as a light yellow solid (3.87 g, yield 66%). ESI MS: m/z 147 [M+H]+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH3:20]>C(CC(C)(C)C)(C)C>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CCC(=O)O
Reactant: C=CCC
Agent: O=S(=O)(O)O
Solvent: O=CO
Solvent: CC(C)CC(C)(C)C
Product: CCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 1 cc of iso-octane and 1 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 100° C. for 2 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH2:17])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH:17][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccnc(CN)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1ccnc(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 4-(t-butyloxycarbonylaminomethyl)-2-aminomethyl-pyridine(600 mg, 2.63 mmol), NMM (341 ml, 3.03 mmol), 4-DMAP (920 mg, 0.16 mmol) and benzyl chloroformate (433 ml, 3.30 mmol) in methylene chloride (15 ml) was stirred at room temperature overnight. The mixture was diluted with methylene chloride (50 ml) and then washed with water and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give an oil. The crude product was purified by MPLC using 70% ethyl acetate in hexane as eluting solvent to give the title compound 844 mg (100%).
Reaction SMILES: C([Mg]Cl)CCCCCCC.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].[O:17]=[C:18]1[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:21]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:19]1>O1CCCC1>[C:26]([O:25][C:23]([NH:22][C@@H:21]([CH2:20][CH2:19][C:18](=[O:17])[C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:30]([O:32][CH3:33])=[O:31])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: CCCCCCCC[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)C#C[Si](C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 2-L, 3-neck jacketed round bottomed flask equipped with an overhead mechanical stirrer, N2-inlet and temperature probe was charged with octylmagnesium chloride (2.1 M, 248.3 g, 0.560 mol) and tetrahydrofuran (1 vol, 102 g) and the solution was chilled to 0° C. (internal temperature). Trimethylsilyl acetylene (57.5 g, 0.585 mol) was added subsurface by syringe over about 25 min (Tmax=13° C.). The solution was stirred at 0° C. for 1 hour and was then cooled to −10° C. (internal temperature). A solution of (S)-1-tert-butyl 2-methyl 5-oxopyrrolidine-1,2-dicarboxylate (125 g, 0.509 mmol) in tetrahydrofuran (250 g) was added subsurface by rotary pump over a 2-hour period. The flask and pump were rinsed with about 25 g of tetrahydrofuran, which was added to the reaction flask. The reaction was monitored by HPLC until completion. A 2-L flask was charged with water (870 g) and NH4Cl (174 g) and the contents were mixed until all of the solid dissolved. About ½ of the 20% NH4Cl solution (504 g) was removed Isopropyl acetate (380 g) was added to the flask and the mixture was cooled to <5° C. The reaction solution was added to the isopropyl acetate/NH4Cl solution over about 20 minutes (Tmax=5° C.). The bath was removed and the mixture was allowed to warm to above 10° C. The mixture was transferred to a separatory funnel and the layers were separated. The gray semi-solid that was present was kept with the organic layer. The aqueous layer was extracted with isopropyl acetate (328 g) and the organic layers were combined. The organic layer was washed with the remainder of the 20% NH4Cl solution and with 20% NaCl solution (435 mL). The organic layer was concentrated and diluted with isopropyl acetate a total of two times. The mixture was filtered to remove precipitated salts. The isopropyl acetate solution of the title compound was used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH2:35]([NH2:37])[CH3:36]>>[CH2:35]([NH:37][C:30](=[O:32])[C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:34])[CH3:36]
Reactant: CCN
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: CCNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 62 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with ethylamine to give the title compound as a beige solid (160 mg, 62%), except that the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum 1.04 (t, 3H), 1.65 (d, 3H), 3.17 (m, 2H), 5.15 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.01 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.44 (br t, 1H), 8.53 (m, 3H), 10.70 (br s, 1H); Mass spectrum MH+ 468.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:15][CH3:16])[C:10]=2[Br:14])[CH:5]=1)(=[O:3])[CH3:2].C[O-].[Na+].Cl.[C:21](OCC)(=[O:23])[CH3:22]>>[Br:14][C:10]1[C:9]([O:15][CH3:16])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][C:4]([C:1]([OH:3])=[CH:2][C:21](=[O:23])[CH3:22])=[CH:5]2
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
139.4 Grams (0.499 moles) of 2-acetyl-5-bromo-6-methoxynaphthalene and 1450 ml of ethyl acetate are placed in a flask equipped with refrigerator and stirrer and, under stirring and at the temperature of 45° C., 30 g (0.556 moles) of sodium methoxide are added. The temperature of the reaction mixture goes up to 55° C. and is kept at 65° C. for one hour, then other 10 g (0.185 moles) of sodium methoxide are added and, after half an hour, still other 10 g (0.185 moles) of sodium methoxide, always under stirring and keeping the temperature at 65° C. for another hour and half. The reaction mixture is then cooled to room temperature and brought to pH 4 by adding a concentrated aqueous solution of hydrochloric acid. The reaction mixture is then heated to reflux for 15 minutes, cooled to 5° C. in one hour and kept at this temperature for 2 hours. The precipitated solid is filtered, abundantly washed with water on the filter, then washed with ethyl acetate and dried in oven under vacuum obtaining 145.7 g of product with a yield equal to 90.8%.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][OH:17])[C:12](=[O:14])[N:13]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16][O:17][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[C:12](=[O:14])[N:13]=1
Reactant: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCO
Reactant: C1=COCCC1
Solvent: ClCCl
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-(2-hydroxyethyl)thiazol-4(5H)-one (3.2 g, 12.6 mmol) and p-toulenesulfonic acid (500 mg) in 3,4-dihydro-2H-pyran (10 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with CH2Cl2 (100 mL), then washed with sat'd NaH2PO4, and dried over MgSO4. After being filtered and concentrated in vacuo, the crude residue was purified by flash chromatography (3:2; Hexane:EtOAc) to give the title compound as an oil. MS (ES+): 339 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.[CH2:16]([NH:18][C:19](=[O:29])[CH:20]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:21])[CH3:17].O>O1CCOCC1.CO>[CH2:16]([NH:18][C:19](=[O:29])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:10]2[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=2)=[CH:24][CH:23]=1)[CH3:21])[CH3:17]
Reactant: CCNC(=O)C(C)c1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CCNC(=O)C(C)c1ccc(-c2ccncc2)cc1
Reaction time: 48 h

Procedure:
Under inert gas atmosphere 36 mg (0.049 mmol) PdCl2(dppf)xCH2Cl2, 28 mL (56 mmol) 2N sodium carbonate solution and 3.35 g (27.2 mmol) pyridine-4-boronic acid are added to 7.50 g (24.7 mmol) N-ethyl-2-(4-iodo-phenyl)-propionamide (V1.1) in 45 mL 1,4-dioxane and 15 mL methanol. The mixture is stirred for 2 d at reflux. After that time, water is added and the mixture is extracted with EtOAc (2×). The combined organic layers are washed with water and 150 mL 1N HCl are added. The aq. layer is separated, filtered and alkalized with 1N NaOH. The precipitate is filtered off and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:36]=[CH:35][C:30]([CH2:31][NH:32][CH2:33][CH3:34])=[CH:29][CH:28]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH2:33]([N:32]([CH2:31][C:30]1[CH:35]=[CH:36][C:27]([C:26]([F:25])([F:37])[F:38])=[CH:28][CH:29]=1)[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1)[CH3:34]
Reactant: CCNCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
[4-(2-{[2-(methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.200 g, 0.577 mmol) was dissolved in DMF (10 ml), N-[4-(trifluoromethyl)benzyl]ethanamine (0.129 g, 0.635 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.204 g, 0.635 mmol) and N-ethyl-N,N-diisopropylamine (0.157 g, 1.212 mmol) was added. The solution was stirred overnight at room temperature. Water (100 ml) was added and the water phase was extracted with diethyl ether (3×20 ml). The organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 30/70 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the solvent was removed by evaporation to give 0.085 g of methyl 2-({2-[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethyl}thio)benzoate (yield 27.7%).