Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]2[NH:27][C:26](=[O:31])[C:25]3[NH:32][CH:33]=[CH:34][C:24]=3[C:23]=2[CH:22]=1)=O.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]>CC(N(C)C)=O>[O:31]=[C:26]1[C:25]2[NH:32][CH:33]=[CH:34][C:24]=2[C:23]2[CH:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:14]=[C:12]([NH:11][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:13]=3)[CH:30]=[CH:29][C:28]=2[NH:27]1.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]
Reactant: CN(C)C=CC(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: N=C(N)Nc1ccccc1
Agent: CCC(=O)[O-]
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c2ccc(-c3ccnc(Nc4ccccc4)n3)cc2c2cc[nH]c12
Temperature: 130 °C
Reaction time: 48 h
Yield: 44.1 %

Procedure:
51 mg (0.38 mmol) of phenylguanidine carbonate is added to a suspension of 88 mg (0.25 mmol) of 8-(3-dimethylamino-acryloyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 2 mL of anhydrous dimethylacetamide. The mixture is stirred at 130° C. for 2 days then the solvent is evaporated. The residue is triturated with acetonitrile to give a solid which is collected by filtration then washed with acetonitrile then diisopropyl ether. After drying, 47 mg (44%) of 4-oxo-8-(2-phenylamino-pyrimidin-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1.Br[C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[CH3:37].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:29]3[CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=[CH:27][C:28]=3[CH3:37])=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(C(F)(F)F)cc1Br
Reactant: Cc1ccc2c(N)nccc2c1Nc1ncccc1-c1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(F)(F)F)cc1Nc1nccc2c(Nc3ncccc3-c3ccncn3)c(C)ccc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To 6-methyl-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-1,5-diamine (0.040 g, 0.12 mmol), charged to a 5 mL microwave reaction vessel, 2-bromo-1-methyl-4-(trifluoromethyl)benzene (0.044 g, 0.18 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.016 g, 0.027 mmol), cesium carbonate (0.056 g, 0.17 mmol), and tris(dibenzylideneacetone)dipalladium (o) (0.011 g, 0.012 mmol) were added. The reagents were then suspended in dioxane (2.0 mL). The reaction mixture was stirred at 140° C. for 1 hrs. The reaction mixture was cooled and diluted with excess EtOAc, and partioned with aqueous sodium carbonate. The aqueous layer was back extracted 2× EtOAc. The combined organics were washed with brine, dried with magnesium sulfate and concentrated under vacuum. The resulting residue was loaded on to silica and purified by column Chromatography. (ISCO 40.0 g, 0.5-5% MeOH in DCM, 30 min.) to give 6-methyl-N1-(2-methyl-5-(trifluoromethyl)phenyl)-N5-(3-(pyrimidin-4-yl)pyridin-2-yl)isoquinoline-1,5-diamine as a solid after treatment with diethyl ether. MS (M+H)+ 487.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[S:11]
Reactant: Fc1ccc(N=C=S)c(F)c1
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: CC(C)(C)CNC(=S)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 2,4-difluoro-phenyl isothiocyanate (1.00 g, 5.84 mmol) in dichloromethane (20 mL) at room temperature was added neopentylamine (0.90 mL, 7.6 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.28 g (85%) of 1-(2,4-difluoro-phenyl)-3-(2,2-dimethylpropyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.C(N(CC)CC)C.[CH3:20][C:21]1([CH3:24])[CH2:23][S:22]1>CO>[SH:22][C:21]([CH3:24])([CH3:23])[CH2:20][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: CC1(C)CS1
Reactant: OCc1cc(CO)cc(CS)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(S)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
(5-(mercaptomethyl)-1,3-phenylene)dimethanol (0.163 g, 0.885 mmol) was dissolved in methanol (3 mL) in a small vial and a stir bar was added. To this solution was added triethylamine (0.016 mL, 0.118 mmol) followed by 2,2-dimethylthiirane (0.058 mL, 0.590 mmol) and the resulting mixture was capped and stirred overnight (16 hrs) at room temperature. The reaction was then concentrated, redissolved in dichloromethane, loaded onto a silica ptlc plate (1000 micron) and the plate was developed using 10% methanol in dichloromethane. The band corresponding to the product was scraped, filtered with neat ethyl acetate, and concentrated to give (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.095 g, 0.349 mmol, 59.1% yield). 1H NMR (400 Hz, CDCl3): δ 7.26 (s, 3H), 4.69 (s, 4H), 3.82 (s, 2H), 2.74 (s, 2H), 2.17 (s, 1H), 2.12 (br s, 2H), 1.43 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 138.9, 126.7, 124.3, 65.0, 49.0, 45.4, 38.4, 31.5; MS (m/z), expected: 272.4. found 295.0 (M+Na). See FIG. 30.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.Cl.[C:11]([NH:15][NH2:16])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1.CCO>[C:11]([NH:15][NH:16][C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)NNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of 2,4-dichloro-5-fluoro-pyrimidine (1.84 g, 11.00 mmol) and tert-butylhydrazine hydrochloride (1.25 g, 10.00 mmol) in THF (50 mL) and EtOH (5 mL) was added triethylamine (4.18 mL, 30.00 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove triethylamine HCl salt and the filtrate concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc/Hexanes) to afford 1.7 g of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=2.8 Hz, 1H), 6.47 (s, 1H), 4.60 (d, J=5.8 Hz, 1H), 1.09 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.19 minutes (M+H) 218.81.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][N:21]=[C:22]([CH3:24])[CH3:23])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][O:20][N:21]=[C:22]([CH3:24])[CH3:23])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)=NOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CC(C)=NOCc1nc2c(N)nc3cc(-c4ccccc4)cnc3c2n1CC(C)C
Temperature: 100 °C
Yield: 43.5 %

Procedure:
A flask containing mixture of acetone O-{[4-amino-7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl}oxime (prepared as described in Example 96, 1.16 g, 2.86 mmol), phenylboronic acid (0.42 g, 3.43 mmol), triphenylphosphine (7 mg, 0.026 mmol), 2 M aqueous sodium carbonate (4.3 mL, 8.58 mmol), and 5:1 propanol/water (18 mL) was evacuated under reduced pressure and back-filled with nitrogen gas. Palladium(II) acetate (2 mg, 0.009 mmol) was added, and the flask was again evacuated and back-filled with nitrogen gas. The reaction mixture was heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and was diluted with dichloromethane (40 mL) and water (30 mL). The aqueous layer was extracted with dichloromethane (2×15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to afford a tan solid. The solid was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 0-30% CMA in chloroform) to afford a thick oil that was crystallized from acetonitrile. The crystals were isolated by filtration and dried at 80° C. in a vacuum oven to yield 0.501 g of acetone O-{[4-amino-1-(2-methylpropyl)-7-phenyl-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl}oxime as a white powder, mp 196-197° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([C:18]2[C:27]3[O:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:24]([CH3:34])[C:23](=[O:35])[C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1>C(O)C>[ClH:1].[OH:17][CH:16]([C:18]1[C:27]2[O:26][C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:24]([CH3:34])[C:23](=[O:35])[C:22]=2[CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH3:2])[CH2:10][CH2:11]1
Reactant: Cc1ccccc1N1CCN(CC(=O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1N1CCN(CC(O)c2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1

Procedure:
This compound was prepared according to Example 17, but starting from the compound prepared in Example 2, rather than that prepared in Example 1. m.p. 257°-258° C. (ethanol).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][CH:14]3[C:9](=[C:10]([OH:22])[C:11](=[O:21])[N:12]([CH3:20])[CH:13]3[C:17](O)=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1.C(Cl)CCl.Cl.[CH3:31][NH:32][CH3:33].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:31][N:32]([CH3:33])[C:17]([CH:13]1[N:12]([CH3:20])[C:11](=[O:21])[C:10]([OH:22])=[C:9]2[CH:14]1[CH2:15][CH2:16][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=1)[C:8]2=[O:23])=[O:18]
Reactant: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1C(=O)O
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1C2CCN(Cc3ccc(F)cc3)C(=O)C2=C(O)C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione-5-carboxylic acid (0.012 g, 0.0.034 mol) in DMF (0.5 mL) was added EDC (0.007 g, 0.038 mmol), dimethylamine hydrochloride (0.003 g, 0.038 mmol) and HOBT (0.006 g, 0.038 mmol). After stirring at room temperature, triethylamine (0.008 g, 0.076 mmol) was added. After 2 hours, the reaction mixture was concentrated under vacuum. The residual material was partitioned between CHCl3 and water. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified using reverse phase HPLC on a C18 stationary phase eluting with 15%-85% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.75 (m, 1H), 4.44 (m, 1H), 3.95 (d, J=12.3 Hz, 1H), 3.29 (m, 4H), 3.18 (s, 3H), 1.81 (m, 1H), 1.65 (s, 6H), 1.49 (m, 1H) ppm. ES MS M+1=376.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:45])=[C:16]([N:18]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[N:21]([CH:35]([CH3:37])[CH3:36])[C:20]=3[CH:19]2[C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[CH:17]=1.[CH3:46]I>C1COCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:45])=[C:16]([N:18]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[N:21]([CH:35]([CH3:37])[CH3:36])[C:20]=3[C:19]2([C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[CH3:46])[CH:17]=1
Reactant: CI
Reactant: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(C)(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
KHMDS (1M/THF) (0.237) was added to a solution of 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Example 9) (0.198 mmol) in THF (2 mL) at −78° C. and the mixture was stirred at −78° C. for 15 min. Methyl iodide (0.594 mmol) was added and the mixture was allowed to warm to rt. After 2.5 h, the reaction mixture was diluted with EtOAc and washed with a 5% aqueous citric acid solution. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 1.49 min (HPLC 3); ESI-MS: tR=1.43 min, [M]+ 519/521/523 (LC-MS 1); TLC: Rf=0.41 (1:1 EtOAc/heptanes).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH:2]=[CH2:3].C(OC(=O)C)(=O)C.N1C=CC=CC=1>COCCOC>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[O:15][C:10](=[O:12])[C:7]2=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cnc(C(=O)O)c(C(=O)O)c1
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: C=CCc1cnc2c(c1)C(=O)OC2=O

Procedure:
A mixture of 7 g of crude 5-allylpyridine-2,3-dicarboxylic acid, 9.8 mL acetic anhydride, and 3.3 mL pyridine in 100 mL dry 1,2-dimethoxyethane is stirred under nitrogen and heated at 65° for 1 hour. After adding an additional 1 mL of acetic anhydride, the reaction is heated for 2 hours at 65°, then at reflux overnight. The reaction mixture is filtered, and the solids are washed with ether and ethyl acetate. The combined filtrates are concentrated in vacuo and reevaporated from xylenes to afford the product as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32]C)=[O:31])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([OH:32])=[O:31])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a mixture of methyl 2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]-phenyl]acetate (1.05 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at 50° C. for 2 hrs. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration and dried with air to give crystals (0.91 g, 88%) of 2-[2-[[6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: COC([O:5][C:6]1[C:7]([CH3:18])=[N:8][CH:9]=[C:10]([CH2:12][O:13][C:14]([O:16][CH3:17])=[O:15])[CH:11]=1)=O.Br.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:17][O:16][C:14]([O:13][CH2:12][C:10]1[CH:11]=[C:6]([OH:5])[C:7]([CH3:18])=[N:8][CH:9]=1)=[O:15]
Reactant: COC(=O)OCc1cnc(C)c(OC(=O)OC)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)OCc1cnc(C)c(O)c1
Temperature: 90 °C

Procedure:
A solution of 1 g. of 3-methoxycarbonyloxy-5-methoxycarbonyloxymethyl-2-methylpyridine in an aqueous ethanol (10 ml. of ethanol and 5 ml. of water) was adjusted to pH 1-1.5 with 10% hydrobromic acid. The mixture was heated at 90°C for 30 minutes, then cooled and neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated into a small volume and the addition of n-hexane gave 0.45 g. of the desired product as colorless crystals melting at 187°-189°C, which showed no depression of melting point on admixture with the authentic sample and the IR spectrum coincided with that of the standard completely.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C1N2CC[N:20](CC2)[CH2:19]1.CS(C)=O.[C-]#N.[K+]>O>[CH:12]1([C:10]2[S:9][C:4]3[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:19]#[N:20])[C:3]=3[CH:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1nc(Cl)c2cc(C3CCCCC3)sc2n1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(C#N)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 860.8 %

Procedure:
To a mixture of 4-chloro-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (27.3 g), DABCO (1.2 g) and DMSO (150 mL) was slowly added an aqueous solution (14 mL) of KCN (8 g), followed by stirring at room temperature for 15 hours. To the reaction mixture was added water (150 mL) under ice-cooling, followed by stirring. The precipitate was collected by filtration and dissolved in chloroform. To the organic layer were added MgSO4, activated carbon (2 g), and basic silica gel (100 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (23.7 g).
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]1)(=O)=O.[CH3:26][S-:27].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:14][C:10]1([CH3:13])[O:9][C@H:8]([C@@H:7]([NH:15][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:6][S:27][CH3:26])[CH2:12][O:11]1
Reactant: CC1(C)OC[C@@H]([C@H](COS(C)(=O)=O)NC(=O)OCc2ccccc2)O1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSC[C@H](NC(=O)OCc1ccccc1)[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of the product from Example 27.2 (2.58 g, 6.91 mmol) in dimethylformamide (10 ml) was added sodium thiomethoxide (0.630 g, 8.98 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water (4×), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel (ethyl acetate-petrol, 1:4) giving a colourless oil (2.007 g, 89%). 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.12 (ABq, 2H), 5.07 (br. s, 1H), 4.47 (bit, J=7.2 Hz, 1H), 4.05 (t, J=7.2 Hz, 1H), 3.83 (brq, J=7.2 Hz, 1H), 3.70 (dd, J=8.3, 6.8 Hz, 1H), 2.69 (d, J=7.6 Hz, 2H), 2.15 (s, 3H), 1.42 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([C:19](OCC)=[O:20])=[C:12]([OH:24])[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH2:19][OH:20])=[C:12]([OH:24])[C:11]=3[CH:10]=[CH:9]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cnc2c(=O)n(Cc3ccc(OC)cc3)ccc2c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2ccc3c(O)c(CO)cnc3c2=O)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
Ethyl 7-(4-methoxybenzyl)-4-hydroxy-8-oxo-7,8-dihydro-1,7-naphthyridine-3-carboxylate (4.00 g, 11 mmol) was suspended in anhydrous THF (60 ml) and the mixture was cooled down to −10° C. Lithium aluminum hydride 2M in THF (11 ml, 23 mmol) was added dropwise to the mixture. The cold bath was then removed and the reaction was stirred for two hours at room temperature. Sodium sulfate decahydrate (10 g) was added portionwise to the reaction. The mixture was stirred for 3 hours and then filtered. The cake collected in the filter funnel was extracted for 12 hours in a soxhlet apparatus in a 2:1 mixture of chloroform and methanol. The filtrate was directly loaded unto silica gel and purified by column chromatography on silica gel using a gradient of 0 to 10% metahnol in DCM to give 7-(4-methoxybenzyl)-4-hydroxy-3-(hydroxymethyl)-1,7-naphthyridin-8(7H)-one (1.3 g, 37% yield) as light yellow solid. MS(M+H)+ 313.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][OH:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][O:25][CH3:28])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCc1nc2c(cc1COC)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-ethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[CH:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]#[CH:15])=[CH:17]1
Reactant: C=Cc1c[nH]c2ccccc12
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (4.79 g) in dimethylformamide (25 ml) was added 3-ethenylindole (2.9 g) and potassium carbonate (2.84 g), the mixture was heated at 90° C. for 3 hours under an atmosphere of nitrogen and then left to stir overnight at room temperature. The reaction was diluted with water (100 ml) and extracted with hexane (2×100ml). The organic fractions were separated, combined, evaporated to dryness and purified by column chromatography on silica gel (300 g) eluted with hexane:ethylacetate (97:3) to give the title compound as a white solid (1.3 g), m.p. 120-122 ° C.