Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]1[O:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:36][N:37]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:32][C:33]3[O:34][C:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[N:36][N:37]=3)=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: ClCc1nnc(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(OCc3nnc(-c4ccccc4)o3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 80 °C
Yield: 38 %

Procedure:
To a solution of N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide (0.20 g, 0.58 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added cesium carbonate (0.32 g, 0.99 mmol) and catalytic amount of n-tetrabutylammonium iodide, followed by the addition of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole (0.15 g, 0.76 mmol). The reaction mixture was heated at 80° C. for 20 hours and concentrated in vacuo, followed by the addition of dichloromethane (100 mL). The mixture was washed with water (70 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo. The residue was recrystallized in ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexanes to afford the title compound as a colorless solid in 38% yield (0.11 g): 1H NMR (300 MHz, DMSO-d6) δ 8.84 (t, J=5.9 Hz, 1H), 8.69 (d, J=8.0 Hz, 1H), 8.04-8.01 (m, 2H), 7.69-7.57 (m, 3H), 7.37-7.29 (m, 4H), 7.27-7.21 (m, 1H), 6.50-6.43 (m, 2H), 5.64 (s, 2H), 4.42 (d, J=5.9 Hz, 2H), 2.58 (s, 3H); MS (ES+) m/z 500.2 (M+1), 522.2 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[CH2:16]([O:15][C:13](=[O:14])[C:12](=[CH:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)OCC
Temperature: 145 °C

Procedure:
A mixture of aniline (25.6 g, 0.275 mol) and diethyl 2-(ethoxymethylene)malonate (62.4 g, 0.288 mol) was heated at 140-150° C. for 2 h. The mixture was cooled to room temperature and dried under reduced pressure to afford 2-phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 11.00 (d, 1H), 8.54 (d, J=13.6 Hz, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9](Cl)[CH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+]>>[OH:11][CH2:10][CH2:9][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCCl
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OCCNc1cccc(Cl)c1

Procedure:
A mixture consisting of 50.8 gm of 3-chloro-aniline, 36 gm of ethylenechlorohydrin and 50 gm of anhydrous sodium carbonate was refluxed for four hours, while stirring. Thereafter, the reaction mixture was suction-filtered while still hot, and the filter cake was washed with ethyl acetate. The filtrate was then distilled in vacuo; the desired product passed over at 182° C./14 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13]1(C)C=CC=C[CH:14]=1>S(Cl)(Cl)=O>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([Cl:11])=[N:10][C:2]=1[Cl:1])[CH3:14]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A suspension of 2,6-dichloro-5-fluoronicotinic acid (43 g, 205 mmol) in thionyl chloride (200 mL) and toluene (200 mL) was refluxed for 3 h to yield a clear solution. The solution was cooled and the solvent was evaporated under vacuum. The residue was cooled in an ice bath and cold anhydrous ethanol was added slowly. After stirring 15 min at 0° C., the solution was refluxed for 30 min under argon. The solution was cooled and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 48.5 g (99%) of 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester (65) as colorless viscous oil. 1H-NMR (DMSO-d6): δ 1.32 (t, J=7.2 Hz, 3H), 4.37 (q, J=7.2 Hz, 2H), 8.46 (d, J=8.0 Hz, 1H); EIMS m/z 238 (M).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)[CH:35]=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([N:34]([CH3:35])[CH3:33])=[O:30])[CH2:24][CH2:23]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(CC(=O)O)CC3)nc1OCC2
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(CC(=O)N(C)C)CC3)nc1OCC2
Temperature: 25 °C

Procedure:
2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid from Example 334 (0.050 g, 0.00011 mol) dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) Dimethylamine hydrochloride (0.0373 g, 0.000457 mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.137 mmol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrated to give 335, analyzed by rHPLC. MS: (ESI+)=466.3
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]([CH2:12][CH3:13])=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:14](Cl)[CH:15]=[C:16]([CH3:18])[CH3:17]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[CH3:17][C:16](=[CH:15][CH2:14][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10](=[O:11])[CH2:12][CH3:13])[CH3:18]
Reactant: CCC(=O)Cc1ccccc1
Reactant: CC(C)=CCCl
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Product: CCC(=O)C(CC=C(C)C)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
192 g (2.4 mol) of 50% sodium hydroxide and 6 g of hexadecyl-trimethylammonium bromide are placed in a 2-liter flask provided with a thermometer, stirrer and reflux condenser and there is then added dropwise while stirring within 0.5 hour a mixture of 296 g (2 mol) of ethyl benzyl ketone and 251 g (2.4 mol) of prenyl chloride. The mixture is warmed to 60° C. and stirred for 3 hours. The mixture is left to cool and 500 ml of ice/water are added thereto. The mixture is extracted four times with ether and washed neutral with water. The phase separation can be facilitated by the addition of a small amount of alcohol. After drying over sodium sulphate, the ether is evaporated and a fractional distillation is then carried out. There are thus obtained 224 g of 2-methyl-5-phenyl-oct-2-en-6-one of boiling point 106° C./3 mmHg; nD20 =1.5092-88; yield 75%.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]=[C:13]([NH:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:12]=2)C=CC=CC=1>[Pd].C1COCC1>[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]=[C:13]([NH:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:12]=1
Reactant: CCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCC)cc(NC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)Nc1cc(N)cc(NC(=O)CCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of 2.77 g (4.9 mmol) of [3,5-bis[(1-oxodecyl)amino]phenyl]carbamic acid phenylmethyl ester and 0.6 g of 10% palladium on carbon in 60 ml of THF was shaken under a hydrogen atmosphere at room temperature and pressure for 8 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure. The resultant solid was triturated with ether and filtered to give 1.94 g (92% yield, mp 152°-154°) of N,N'-(5-amino-1,3-phenylene)bisdecanamide.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[N:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[CH2:19].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:19][CH2:18][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: C=Cc1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CCc2cccnc2)CCN2CCCC12
Temperature: 100 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
A mixture of 9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (100 mg, 0.44 mmol), 3-vinyl-pyridine (185 mg, 1.762 mmol), tetrabutylammonium bromide (425 mg, 1.32 mmol) and 50% NaOH solution (6 mL) was stirred at 100° C. for 18 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 9-methyl-6-(2-pyridin-3-yl-ethyl)-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (58 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.41 (d, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.58 (s, 1H), 7.2 (d, 1H), 7.1 (dd, 1H), 4.4 (m, 2H), 3.99 (bs, 1H), 3.2 (dd, 1H), 3.17 (t, 2H), 2.84-2.7 (m, 3H), 2.5 (m, 1H), 2.41 (s, 3H), 2.2 (dd, 1H), 1.9 (m, 4H). Separation by chiral HPLC provided enantiomers 134a and 134b.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26](=[O:29])[O:27][CH2:28][C:23]=2[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:29])[O:27][CH2:28][C:23]=2[CH:22]=1
Reactant: O=C1Nc2ccc(Cl)cc2CO1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)CN3C(=O)OCc4cc(Cl)ccc43)CC2)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (303 mg, 1 mmol, 1 equiv), 6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one (72) (183 mg, 1 equiv), and Cs2CO3 (56 μL, 4 equiv) in 2 ml of DMF was stirred at 60° C. overnight. The reaction solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resultant crude residue was purified by flash chromatography to give 6-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one (73): MS (ES) [M+H]+ expected 450.1, found 450.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18](O)=[O:19])=[CH:14][CH:13]=1)=[O:11].S(Cl)([Cl:25])=O.Cl.S(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([Cl:25])=[O:19])=[CH:14][CH:13]=1)=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Agent: Cl
Agent: O=S(O)O
Solvent: C1COCCO1
Product: O=C(Cl)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3.54 g of 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetic acid, 3.57 g of thionyl chloride and 30 ml of dioxane was stirred at a temperature of 80° C. for 4 hours. An excess amount of thionyl chloride and dissolved hydrochloric acid gas, sulfurous acid gas and dioxane were distilled off by a rotary evaporator to obtain 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetyl chloride as the residue after distillation.
Reaction SMILES: [Ru:1].[Ru].[Cl-:3].[NH4+].[C:5]1([C@H:11]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:13][CH2:14][CH2:15][CH2:16][CH2:17]C2C=CC=C(C)C=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=O)C.C1([C@@H](O)C)C=CC=CC=1>C(N(CC)CC)C.C(O)=O>[Ru:1].[Cl-:3].[NH4+:13].[C:5]1([C@H:11]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:42]2[CH:43]=[CH:44][C:39]([CH3:36])=[CH:40][CH:41]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(CCCCN[C@@H](c2ccccc2)[C@@H](NS(C)(=O)=O)c2ccccc2)c1
Reactant: CC(=O)c1ccccc1
Agent: [Ru]
Agent: C[C@H](O)c1ccccc1
Agent: [Cl-]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: Cc1ccc(CCCCN[C@@H](c2ccccc2)[C@@H](NS(C)(=O)=O)c2ccccc2)cc1
Reaction time: 5 h

Procedure:
In a 25-ml Schlenk tube, 4.4 mg (0.00341 mmol, S/C=1000) of the ruthenium dimer complex produced in Example 9, acetophenone (0.82 g, 6.86 mmol), and 3.4 ml of a formic acid-triethylamine (5:2) azeotrope were mixed with each other, and the reaction was allowed to proceed at 60° C. for 5 hours. GC analysis of the reaction liquid showed that (S)-1-phenylethanol was formed with a conversion of 99.2% and 95.0% ee.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH:16]=[C:4]1[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])[CH3:15]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1C(=O)CCC(C)(C)C1=O
Yield: 95.5 %

Procedure:
According to Scheme 2 Step 1: A solution of 4,4-dimethylcyclohexane-1,3-dione (157 mmol, 22 g) and of 1,1-dimethoxy-N,N-dimethylmethanamine (235 mmol, 31.3 mL) was stirred at room temperature for 1 hour. After evaporation and trituration in petroleum ether, 29.2 g (150 mmol, 95%) of 2-((dimethylamino)methylene)-4,4-dimethylcyclohexane-1,3-dione were obtained as a pale orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]2[CH2:18][CH2:19][C:20](O)=[O:21].N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([N:8]1[C:9]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]3[C:20](=[O:21])[CH2:19][CH2:18][CH:6]([C:5]=23)[CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C(CCC(=O)O)C(c1ccccc1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c3c1C(=O)CCC3C(c1ccccc1)N2C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5-methoxy-2-phenyl-2,3-dihydroindole-3-propionic acid (10.2 g) synthesized as in Example 1, steps 1 and 2, was dissolved in anhydrous methylene chloride (80 ml). Pyridine (2.77 ml), then acetic anhydride (3.24 ml) were added to the solution under cooling with ice, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice water. The organic layer of the mixture was separated, washed with 1N hydrochloric acid, water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 11.5 g (99%) of the titled compound as a crude rubber-like product.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.CN(C)C=O.[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(N(CC)CC)C>[F:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:34])[NH:2][C:3]2[CH:19]=[CH:18][C:17]3[C:8]4[NH:9][C:10](=[O:16])[C:11]5[N:12]([CH:13]=[CH:14][N:15]=5)[C:7]=4[CH2:6][C:5]=3[CH:4]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Yield: 21.5 %

Procedure:
The preparation is carried out as in Example 36 but from 1.5 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 30 ml of dimethylformamide, 0.97 g of triethylamine and 2.64 g of 3-fluorophenyl isocyanate. There is obtained 0.44 g of 8-[3-(3-fluoro-phenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-4-one in the form of a light brown solid melting above 260° C. (Analysis, % calculated C: 64.00, H: 3.76, F: 5.06, N: 18.66, O: 8.52, % found C: 64.1, H: 3.4, N: 18.6).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14](C)[C:13](O)=[C:12](CC)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:34]=[CH:33][C:25]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])=[O:27])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O:32][CH2:31][CH2:30][CH2:29][NH:28][C:26](=[O:27])[C:25]1[CH:33]=[CH:34][C:22]([C:21]([F:35])([F:36])[F:20])=[CH:23][CH:24]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(C)c1O
Reactant: O=C(NCCCO)c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCCOc1ccccc1OC(=O)c1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of 0.5 g of crude 3-ethyl-4-hydroxy-5-methylphenyl benzoate, 0.48 g of 3-(4-(trifluoromethyl)benzamido)propan-1-ol, 0.54 g of triphenylphosphine and 10 ml of tetrahydrofuran was added dropwise a solution of 0.41 g of diisopropylazodicarboxylate dissolved in 2 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.87 g of 3-ethyl-5-methyl-4-(3-(4-(trifluromethyl)benzamido)propyloxyphenyl benzoate (90% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2([C:10]([OH:12])=[O:11])[C:7]([CH2:9][CH:3]1[CH2:4][CH2:5]2)=[O:8].[C:14]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH3:14][O:11][C:10]([C@@:6]12[C:2]([CH3:13])([CH3:1])[C@@H:3]([CH2:4][CH2:5]1)[CH2:9][C:7]2=[O:8])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)C2CCC1(C(=O)O)C(=O)C2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)[C@@]12CC[C@@H](CC1=O)C2(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a mixture of ketopinic acid 6a 0.182 g (1 mmol) and K2CO3 1.1 g (8 mmol) stirred in DMF 10 ml was added MeI 0.125 ml (0.284 g, 2 mmol). The reaction mixture was allowed to stir for 18 hrs at ambient temperature. The reaction mixture was dissolved in water 80 ml and extracted with 3×30 ml portions of diethyl ether. The organic phase was washed with NaHCO3 saturated solution, dried over MgSO4 and concentrated in vacuo to give yellow oil 0.184 g (94%). 1H NMR (300 MHz, CDCl3) δ ppm 3.75 (s, 3H), 2.53 (ddd, J=18.29, 3.7 Hz, 1H), 2.36 (ddd, J=14.99, 11.82, 3.99 Hz, 1H), 2.10 (t, J=4.4 Hz, 1H), 2.02 (m, 1H), 1.92-1.98 (d, J=18.40 Hz, 1H), 1.79 (ddd, J=14.16, 9.35, 4.95 Hz, 1H), 1.41 (ddd, J=12.65, 9.49, 4.26 Hz, 1H), 1.15 (s, 3H), 1.07 (s, 3H). Exact mass calculated for C11H16O3 m/e 196.11. found 196.22.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CCOCC>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(N)cc1C
Solvent: CCOCC
Product: COC(=O)CNc1ccc(C)c(C)c1
Yield: 81.7 %

Procedure:
3,4-Dimethylaniline (70.0 g) and methyl bromoacetate (44.2 g) were stirred at 100° under nitrogen for 2 h. The cooled reaction mixture was poured into ether (700 ml) and filtered. The collected solid was washed with ether (2×100 ml) and the combined filtrates were concentrated to give a solid (45.6 g) which was purified by FCC on triethylamine deactivated silica eluting with dichloromethane:petroleum ether (1:3) to give a solid (21.8 g), a portion of which (2.5 g) was purified further by FCC as above to give the title compound (2.06 g), m.p. 53°-55°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CNc2nc(Nc3cccc(OC)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 34.7 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.20 g, 0.70 mmol) (prepared according to Example 1, step A), 1,4-dioxane (20 mL), 3-methoxy-benzenamine (0.13 g, 1.0 mmol), and p-toluenesulfonic acid monohydrate (49 mg, 0.26 mmol). The mixture was heated at 105° C. for 2 days. To the mixture was added an aqueous solution of NaHCO3 (saturated, 0.5 mL) and the organic solvent was removed under vacuum. The aqueous layer was extracted with DCM twice. The combined organic layers were dried, filtered and concentrated. The crude product was purified by silica gel column chromatography to provide the desired product (90 mg, 30%). LCMS for C19H20ClN4O2 (M+H)+: m/z=371.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:21][OH:22])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[H-].[Na+].CCOC(C)=O>O1CCCC1.[Cl-].[Na+].O>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:21][OH:22])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CCO)c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1C(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 18.2 %

Procedure:
To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (38.0 mg, 0.0810 mmol) in tetrahydrofuran (1.00 mL) was added NaH 60% in mineral oil (60:40, Sodium hydride:mineral Oil, 3.56 mg, 0.0890 mmol). The mixture was heated to 60° C. for 3 hrs. The reaction was cooled to rt and distributed between brine and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried, and concentrated to provide a yellow solid. Purification on HPLC (reverse phase, AA) provided 4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a white solid (6.5 mg, 18.2% yield). LCMS: (AA) ES+ 441, 443, 445; 1H NMR (400 MHz, MeOD) δ 7.50-7.45 (s, 1H), 7.45-7.37 (d, J=8.4 Hz, 1H), 7.30-7.22 (m, 1H), 5.79-5.63 (m, 1H), 3.83-3.71 (t, J=4.8 Hz, 4H), 3.60-3.50 (q, J=6.9, 6.0 Hz, 2H), 3.50-3.41 (d, J=3.2 Hz, 4H), 2.52-2.37 (m, 2H).