Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1C=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC)(OC)(OC)CCC.[NH2:18][C:19]1[C:20]2[N:21]([N:36]=[N:37][N:38]=2)[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]=1[NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC=CC=1>[CH3:35][C:22]1[N:21]2[N:36]=[N:37][N:38]=[C:20]2[C:19]2[N:18]=[C:3]([CH2:4][CH2:5][CH3:6])[N:25]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]=2[C:23]=1[CH3:34]
Reactant: CCOC(=O)CCCNc1c(C)c(C)n2nnnc2c1N
Reactant: c1ccncc1
Agent: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCC(=O)OCC
Temperature: 25 °C
Yield: 150.2 %

Procedure:
For Examples 40 and 41, pyridine hydrochloride (1.34 g, 11.6 mmol) and trimethyl orthobutyrate (5.42 mL, 34.1 mmol) were sequentially added with stirring to a solution of ethyl 4-[(8-amino-5,6-dimethyltetraazolo[1,5-a]pyridin-7-yl)amino]butanoate (9.1 g, 31 mmol) in toluene (310 mL) under a nitrogen atmosphere. The reaction was heated at reflux for 1.5 hours, allowed to cool to ambient temperature overnight, and concentrated under reduced pressure. The residue was partitioned between chloroform (300 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with chloroform (2×100 mL), and the combined organic fractions were washed with saturated aqueous sodium bicarbonate (2×75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate and isolated by filtration to provide 6.0 g of ethyl 4-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butanoate as a white solid.
Reaction SMILES: [SH:1][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:29](#[N:32])[CH:30]=[CH2:31]>CCO.CN(C)C(N(C)C)=N>[C:29]([CH2:30][CH2:31][S:1][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:32]
Reactant: C=CC#N
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CN(C)C(=N)N(C)C
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CSCCC#N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 92 %

Procedure:
A solution of 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (5 g), acrylonitrile (0.66 g) and 1,1,3,3-tetramethylguanidine (0.1 g) in EtOH (60 ml) is stirred at room temperature for 18 hours and then evaporated to dryness. After the usual work-up, the residue is recrystallized from Et2O to give 5.2 g of 2-[(2-cyanoethyl)thio]methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine m.p. 102°-104° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:13]#[N:14])[CH3:8].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:13][NH2:14])[CH3:8]
Reactant: CCOc1cc(C#N)ccc1OC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(CN)ccc1OC
Yield: 100.6 %

Procedure:
To a suspension of lithium aluminum hydride (1.17 g) in anhydrous tetrahydrofuran (15 mL) was added a solution of 3-ethoxy-4-methoxybenzonitrile (2.73 g) in tetrahydrofuran (15 mL). The mixture was stirred for an hour under water cooling and then for an hour at ambient temperature. Potassium sodium (+)-tartrate aqueous solution was added to the mixture under ice-water cooling. The mixture was diluted with ethyl acetate and the insolubles were filtered off. After evaporation of the filtrate, ethyl acetate was added. The solution was dried over magnesium sulfate and evaporated in vacuo to give 3-ethoxy-4-methoxybenzylamine as yellow oil (2.81 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:32][Si](C)(C)C>CN(C)C=O.C(Cl)Cl.CO>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH2:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (300 mg, 0.88 mmol) and 1 drop of N,N-dimethylformamide in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with oxalyl chloride (84 μL, 0.97 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The resulting reaction mixture was then treated dropwise with 1,1,1,3,3,3-hexamethyldisilazane (560 μL, 2.64 mmol) and subsequently stirred at 25° C. for 15 h. The resulting reaction mixture was diluted with methylene chloride (20 mL) and methanol (15 mL) and then washed with a 5% aqueous sulfuric acid solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionamide (140 mg, 47%) as a yellow foam: mp 72-76° C. (foam to gel); FAB-HRMS m/e calcd for C15H20N2O5S (M+H)+341.1172, found 341.1181.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:6]([CH3:9])=[CH:7][CH:8]=1)[NH2:5].[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:3]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 3-bromo-6-methylaniline (1.00 g , 5.37 mmol) in pyridine (8 mL) was added acetyl chloride (0.76 mL, 10.7 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was extracted with EtOAc, washed with 5% citric acid, dried over MgSO4, concentrated, and triturated with ether to give 0.750 g (61%) of the desired product as off-white crystal. MS (DCI/NH3) m/z: 227.9 (M+H)+, 229.9 (M+2+H)+; 1H NMR (300 MHz, CDCl3) δ 2.21 (s, 6H), 6.90 (m, 1H), 7.04 (d, J=8.14 Hz, 1H), 7.20 (d, J=7.80 Hz, 1H), 8.06 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:36][O:37][C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[CH:17]=[N:18][C:19]2[N:20]([N:30]=[CH:31][C:32]=2[C:33](O)=[O:34])[C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=[O:15])[CH2:10][CH2:9]3.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:36][O:37][C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[CH:17]=[N:18][C:19]2[N:20]([N:30]=[CH:31][C:32]=2[C:33]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:34])[C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)cc1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(C)cc3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 59.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)-7-(4-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.031 g, 0.062 mmol) obtained in step 4 and ethanesulfonamide (0.034 g, 0.309 mmol), the title compound (0.022 g, 60%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:29][C:30]([C@H:32](OS(C(F)(F)F)(=O)=O)[CH3:33])=[O:31]>>[Cl:1][C:2]1[C:3]([F:26])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([CH2:19][N:20]([CH:21]([CH3:23])[CH3:22])[C@H:32]([C:30]([OH:29])=[O:31])[CH3:33])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)C
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C(C)C)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-[(isopropylamino)methyl]-7-methoxyquinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-isopropyl-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 6H); 1.31 (d, 3H); 3.10 (m, 1H); 3.63 (q, 1H); 3.98 (s, 3H); 4.02 (s, 2H); 7.20 (s, 1H); 7.29 (t, 1H); 7.49 (m, 1H); 7.59 (m, 1H); 8.42 (s, 2H); 9.68 (brs, 1H); Mass Spectrum: (M+H)+ 447.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.C1CCN2C(=NCCC2)CC1.N1([C:28](=[O:33])[CH2:29][CH2:30][O:31][CH3:32])C=CN=C1>C(#N)C>[CH3:32][O:31][CH2:30][CH2:29][C:28]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1)=[O:33]
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: COCCC(=O)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCCC(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (3.0 g, 18 mmol) and DBU (5.3 mL, 36 mmol) in 100 mL acetonitrile is added a solution of 1-imidazol-1-yl-3-methoxy-propan-1-one (6.9 g, 45 mmol) in acetonitrile. The reaction mixture is stirred for 15 min at RT and then concentrated under reduced pressure. The residue is poured in water, acidified to pH 5 with 6 M aqueous HCl and the product is extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. Yield: 3.8 g. The product is used in the next step without purification. A-36 is synthesized according to general procedure A1 starting from 3.8 g (15 mmol) A-36c and 6.8 g (24 mmol) A-36b. Yield: 1.23 g.
Reaction SMILES: [CH3:1][NH:2][S:3]([NH:6][CH2:7][C:8]([O:10]CC)=O)(=[O:5])=[O:4].O(C(C)(C)C)[K]>CN(C=O)C>[CH3:1][N:2]1[C:8](=[O:10])[CH2:7][NH:6][S:3]1(=[O:5])=[O:4]
Reactant: CCOC(=O)CNS(=O)(=O)NC
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: CN1C(=O)CNS1(=O)=O
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of ethyl 2-((N-methylsulfamoyl)amino)acetate from the previous step (3.5 mmol) in DMF (50 mL) is added KO-t-Bu (1.56 g, 13.88 mmol) in portions under N2 at RT. The mixture is stirred overnight then quenched with HCl methanol (2 M). After the solvent is removed in vacuo, the residue is washed with water to afford 2-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-3-one (480 mg, 54%). 1H-NMR(CDCl3): δ 7.36 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.87 (m, 1H), 4.68 (s, 2H), 4.03 (d, J=7.2 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.COC[O:20][C:21]1[C:22](=[O:38])[N:23](COC)[CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:26]=1>>[OH:20][C:21]1[C:22](=[O:38])[NH:23][CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2ccncc2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2ccncc2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 3-(methoxymethoxy)-1-(methoxymethyl)-5-[(pyridin-4-ylmethyl)sulfanyl]pyridin-2(1H)-one (Intermediate 23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:15]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)[CH3:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.C([O-])([O-])=O.[Na+].[Na+].[O:46]1[C:50](B(O)O)=[CH:49][C:48]2[CH:54]=[CH:55][CH:56]=[CH:57][C:47]1=2>COCCOC.O>[C:1]([O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:15]([C:16](=[O:25])[N:17]([C:47]2[O:46][C:50]3=[CH:49][CH:48]=[CH:54][C:55]3=[CH:56][CH:57]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH3:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)Nc1ccc(I)cc1)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 125.2 %

Procedure:
4-{[(4-tert-Butyl-phenyl)-(4-iodo-phenylcarbamoyl)-methyl]-methyl-amino}-benzoic acid tert-butyl ester (120 mg, 0.19 mmol) was taken up in 8 mL of DME, 4 mL of ethanol and 2 mL of water. Na2CO3 (81 mg, 2.4 mmol), PdCl2(O-tolyl)2, (15 mg, 0.0019 mmol) and benzo[B]furan-2-boronic acid (62 mg, 0.38 mmol) were then added, flushed with nitrogen and heated to reflux for 1 h. Cooled to RT, EtOAc (20 mL) was added, and filtered through a plug of celite. The solvents were removed under reduced pressure to give a yellow viscous solid. Water was added to the solid to give a yellow precipitate, which was filtered and triturated with methanol to give 140 mg of a white solid. LCMS (M+1=589.6)
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7](=[O:11])[C:6]([C:12]([OH:14])=[O:13])=[CH:5]1)([CH3:3])[CH3:2].[Br:15]Br.ClCCl>C(O)(=O)C.O>[Br:15][C:8]1[C:7](=[O:11])[C:6]([C:12]([OH:14])=[O:13])=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:9]=1[CH3:10]
Reactant: Cc1cc(=O)c(C(=O)O)cn1C(C)C
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1b, 1.50 g, 6.92 mmol based on 90% purity) in glacial acetic acid (10 ml) is added at room temperature bromine (0.60 mL, 11.7 mmol). After stirring for 3 d at room temperature, additional bromine (1.00 mL, 19.5 mmol) is added to the reaction mixture and stirring is continued for 2 h at room temperature. The reaction mixture is diluted with water. Upon addition of dichloromethane a precipitate forms which is filtered off and dried. Yield: 2.55 g; ESI mass spectrum: [M+H]+=274 (bromine isotope pattern); r.t. HPLC: 0.76 min (Z002_002).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[Br:22][C:23]1[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:29])[N:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: O=C(O)c1csc(Br)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2csc(Br)n2)C1
Reaction time: 60 h

Procedure:
A solution containing 1 eq each of (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate, 2-bromothiazole-4-carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding (S)-tert-butyl 1-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate, LCMS (m/z): 416.1 (MH+); LC Rt=1.95 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:32]2[S:26][C:27](=[S:28])[NH:29][C:30]2=[O:31])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3c2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccc3ccccc3c2)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(naphth-2-yl)methoxy]benzaldehyde (5.24 g, 20 mmol) was dissolved in 100 ml of acetic acid. To this solution was added sodium acetate (5.74 g, 70 mmol) and rhodanine (2.66 g, 20 mmol). The reaction mixture was raised to the reflux temperature and maintained at this temperature. The progress of the reaction was monitored by thin layer chomratography.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>CN(C)C=O>[O:19]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=2)[N:15]1[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (291 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (2.5 ml) was added potassium carbonate (276 mg, 2.0 mmol), and the mixture stirred at room temperature for 5 minutes in a 5 ml Personal Chemistry microwave reaction vial. To the above mixture was added tert-butyl 2-bromoacetate (390 mg, 2.0 mmol), the vial was sealed, and subjected to microwave irradiation at 120° C. for 5 min, and then at 140° C. for 40 min until most of the 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one was converted. The reaction mixture was cooled, poured into water (40 mL), extracted with ethyl acetate (2×40 mL), the combined organic phase was washed with water (40 mL), 2N sodium carbonate (10 mL), brine (40 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was dissolved in a mixture of N,N-dimethylformamide-methanol (1 and 2 mL respectively), subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford tert-butyl 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate (247 mg, 0.61 mmol, 61%). LCMS mz 350.0 (M-56+H), 428.0 (M+Na), anal HPLC >98% in purity, 1H NMR (400 MHz; CDCl3) δ 7.67 (m, 4H); 7.40-7.50 (m, 2H); 6.86 (d, J=8.6 Hz, 1H); 4.63 (s, 2H); 3.04 (t, J=7.4 Hz, 2H); 2.76 (t, J=7.4 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:32])[CH:10]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])P(OOCC)(OOCC)=O.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1)[CH:38]=O.[Cl-].[NH4+]>C(OCC)(=O)C.C(Cl)Cl>[CH3:7][O:8][C:9](=[O:32])/[C:10](/[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[CH:38]/[C:37]1[CH:40]=[CH:41][C:42]([N:43]2[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]2)=[C:35]([O:34][CH3:33])[CH:36]=1
Reactant: CCOOP(=O)(OOCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)NC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a methylene chloride (10 mL) suspension of potassium tert-butoxide (290 mg), a methylene chloride (3 mL) solution of benzyloxycarbonylamino(diethoxyphosphono)acetic acid methyl ester (850 mg) was added dropwise at −70° C. After agitating the reaction solution at −70° C. for 2 hours, a methylene chloride (7 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (500 mg) obtained in Example 1 was added dropwise. The reaction solution was agitated at −70° C. for 1 hour, and then agitated at room temperature for 4 hours. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution after the reaction ended, and the organic layer was separated. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate 4:1->elution solvent: hexane:ethyl acetate), and 433 mg (45%) of (Z)-2-benzyloxycarbonylamino-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid methyl ester was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH:1]1([N:5]2[C:14]3[N:13]=[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:20])[C:7](=[O:21])[C@H:6]2[CH2:22][CH3:23])[CH2:4][CH2:3][CH2:2]1.[CH2:24]1[C:29](=[O:30])[N:28](I)[C:26](=[O:27])[CH2:25]1>C1COCC1>[CH:1]1([N:5]2[C:14]3[N:13]=[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[C:16]4[N:28]4[C:29](=[O:30])[CH2:24][CH2:25][C:26]4=[O:27])[N:11]=[CH:10][C:9]=3[N:8]([CH3:20])[C:7](=[O:21])[C@H:6]2[CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCC(=O)N1I
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3)nc2N1C1CCC1
Solvent: C1CCOC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3N3C(=O)CCC3=O)nc2N1C1CCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 150.5 %

Procedure:
(R)-8-cyclobutyl-7-ethyl-2-(1H-imidazol-1-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 111, 0.14 g, 0.448 mmol) was dissolved in 2 mL of THF and NIS (0.20 g, 0.896 mmol) was added. The solution was stirred at 80° C. for 6 hours after which the solution was concentrated and purified by preparative HPLC to give the title compound (276 mg). LCMS: 410.2 m/z (M+H)+; ret. Time: 3.81 (Analytical Method A).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C([Li])(C)(C)C.CN([CH:22]=[O:23])C>O1CCCC1>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][C:8]=1[CH:22]=[O:23]
Reactant: COc1ccc(OC(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To 4-(trifluoromethoxy)anisole (5.0 g, 26 mmol) in tetrahydrofuran (100 mL) cooled to −78° C. was slowly added a solution of tert-butyllithium in pentanes (23 mL, 1.7M, 39 mmol). The resulting solution was stirred at −78° C. for 30 minutes, before N,N′-dimethylformamide (8 mL, 104 mmol) was added. The solution was allowed to stir to ambient temperature and was then quenched with saturated aqueous ammonium chloride (100 mL). The suspension formed was extracted with ethyl acetate (2×100 mL) and the extracts dried (MgSO4). Concentration gave a yellow oil which was purified by silica chromatography to give the title compound as an oil (4.13 g, 18.8 mmol).