Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[Br:7][C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C1C[O:19][CH2:18][CH2:17]1>>[Br:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:17]/[C:18]([O:4][CH2:2][CH3:5])=[O:19])=[CH:10][CH:9]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Br)nc1
Agent: [K+]
Product: CCOC(=O)/C=C/c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
Triethyl phosphonoacetate (26.6 g, 118.8 mmol) was added slowly dropwise to a mixture of Potassium-tert-butoxide (14.5 g, 129.6 mmol) in dry THF (200 mL) at −5° C., stirred for 20 min and then a solution of 6-bromopyridine-3-carboxaldehyde (20 g, 108 mmol) in dry THF (100 mL) was added slowly dropwise at −5° C. and stirred for 30 min. After completion, the reaction mixture was poured into ice water (350 mL) and extracted with EtOAc (2×300 mL). The combined organic extracts were washed with saturated NaHCO3 solution (250 mL), water (250 mL) and brine (250 mL) and dried over anhydrous Na2SO4, filtered and evaporated to get (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate (20 g, 72.9%) as brown color liquid. This is carried to next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O>CO.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cc(N2CCCCC2)ccc1N
Reaction time: 10 h
Yield: 57.1 %

Procedure:
To 2-Nitro-5-piperidin-1-yl-benzamide (948 mg, 4.07 mmol) in Methanol (100 mL) was added Pd/C (10%) followed by H2 (1 ATM). After 10 h, the solution was filtered and concentrated. Flash chromatography (0-5% methanol in methylene chloride) afforded the title compound as a white solid (510 mg, 51% yield). FIA m/z 220.1 (M+H) 218 (M-H)
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](O)=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.CC1C([N:26]2[C:30](=[O:31])[CH:29]=[CH:28][C:27]2=[O:32])=C(C=CC=1)C(Cl)=O>C(N(CC)CC)C.ClCCCl>[CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:26]3[C:30](=[O:31])[CH:29]=[CH:28][C:27]3=[O:32])=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3]([N:26]2[C:27](=[O:32])[CH:28]=[CH:29][C:30]2=[O:31])[CH:2]=1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: Cc1cccc(C(=O)Cl)c1N1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1C=CC(=O)N1c1ccc(Cc2ccc(N3C(=O)C=CC3=O)cc2)cc1

Procedure:
A 6.0 g quantity of 4,4′-dihydroxydiphenylmethane is dissolved in a solution of 12.6 ml of triethylamine in 50 ml of 1,2-dichloroethane in a 250 ml flask. To the solution is slowly added a solution of 15.5 g of methyl maleimidobenzoyl chloride in 50 ml of 1,2-dichloroethane. The mixture is allowed to react at room temperature for 16 hr. The reaction mixture is precipitated in water, filtered under reduced pressure, washed sequentially with water and ethanol, and dried at 60° C. under vacuum for 48 hr, yielding the bismaleimide compound of Formula 20m.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CBr
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1OC
Temperature: 25 °C

Procedure:
A mixture of 2-methoxyphenol (11.3 g), potassium carbonate (25 g), ethyl bromoacetate (12 ml), and acetone (113 ml) was heated under reflux for 4 hours. After cooling to the room temperature, the mixture was filtered and the solvent was distilled off under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound IIbd-a (17 g, 91%) as a pale-yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N(C)c2ccccc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(N(C)c2ccccc2)nc1CBr
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-2-(methyl-phenyl-amino)-thiazole-5-carboxylic acid ethyl ester (3.32 g, 12.0 mmol), N-bromosuccinimide (2.35 g, 13.2 mol) and benzoyl peroxide (291 mg, 1.2 mmol) in carbon tetrachloride (45 mL) was refluxed for 17 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil: MS: (+) m/z 354.9, 356.9 (M+1, 79Br/81Br).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][C:10](O[Si](C(C)(C)C)(C)C)=[CH:9][C:8]=1[OH:21])=O)[CH3:2].Cl[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:26].C(=O)([O-])[O-:36].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:5]1[C:7]2[C:8]([OH:21])=[CH:9][CH:10]=[CH:11][C:12]=2[O:36][C:24]=1[C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:22])[CH3:2]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cccc(O)c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
To a solution of [4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-phenyl]-oxo-acetic acid ethyl ester from step 2 (2.0 g, 6.16 mmol) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (1.65 g, 7.4 mmol, 1.2 eq) in anhydrous N,N-dimethylformamide (100 mL) was added potassium carbonate (1.7 g, 12.3 mmol, 2 eq). The reaction mixture was stirred at 90° C. for 16 h. The mixture was cooled to room temperature then poured into ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). Combined the organic layer was washed by water (2×100 mL), dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by column chromatography eluted with 20% EtOAc/hexane then 50% EtOAc/hexane solution to afford an yellow solid (843 mg, 36%) as product. 1H-NMR (CD3CN): δ 7.79 (d, J=8.0 Hz, 1H), 7.64 (d, 1.9 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.47 (dd, J=2.3, 8.3 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 7.0 (dd, J=2.3, 8.0 Hz, 1H), 4.11 (q, 2H), 1.21 (t, 3H); LC-MS (MH+=3791381).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)C1(NC(=O)c2ccc(CCl)cc2)CCCCC1
Product: COC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 8 h
Yield: 83 %

Procedure:
30 ml of morpholine was added to 4 g (13 mmol) of 1-[[[4-(chloromethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was heated under reflux for 1 hour. The reaction solution was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration to obtain 3.8 g (83%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[O:11][CH3:12])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COC(CN)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCC(OC)c4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)-2-methoxyethanamine (0.071 g, 0.38 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.060 g, 0.16 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.022 g, 0.16 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.037 g, 0.19 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was loaded onto a Biotage SP1 system, eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 67 mg of the title compound (77% yield).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O.C(O)(=O)C.S(=O)(=O)(O)O>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[N:5]=[N:1][C:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[C:13]2[OH:21]
Reactant: O=N[O-]
Reactant: Cc1cccc(C(=O)Cc2ccccc2)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c(O)c(-c3ccccc3)nnc12
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 22.3 %

Procedure:
A solution of sodium nitrite (0.20 g, 2.8 mmol) in water (0.5 mL) was added dropwise, to a solution of 1-(2-amino-3-methylphenyl)-2-phenylethanone (0.42 g, 1.9 mmol) in acetic acid (9 mL) and sulfuric acid (1.5 mL). After the solution was stirred for 20 min at 80° C., the solution was poured into iced water. After the pH was adjusted to 6 with 2 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organics was dried over MgSO4 and concentrated. The material was purified via column chromatography using 5-50% ethyl actetate in hexane as the eluent to yield 0.10 g of 8-methyl-3-phenylcinnolin-4-ol as a gum. MS (ESI) m/z 237; HRMS (ESI, [M+H]+) 237.102;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.FC(F)(F)[C:13]([O:15][C:16](=O)C(F)(F)F)=[O:14].O>CN(C=O)C>[CH3:16][O:15][C:13]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c2ccc(F)cc12
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 5-fluoroindole (5 g, 37.0 mmol) in DMF (40 mL) was treated at 0° C. with trifluoroacetic anhydride (6.1 mL, 42.6 mmol). After 30 min, the reaction was poured into water and the resulting precipitate collected by filtration, washed with water, then dried in vacuo. The solid was then dissolved in 10% aqueous NaOH (200 mL) and heated at reflux for 1 h. The reaction mixture was then cooled, washed with dichloromethane and acidified with aqueous HCl. The resulting white precipitate was collected by filtration, washed with water, taken up in dichloromethane, washed with water, dried (MgSO4) and evaporated in vacuo. The resulting material (5 g, 75%) was dissolved in methanol (80 mL) and treated with concentrated sulphuric acid (2 mL) then heated at reflux overnight. The reaction was cooled and the resulting precipitate collected, washed with water and evaporated in vacuo to give 5-fluoro-1H-indole-3-carboxylic acid methyl ester as a peach-coloured solid (4.5 g, 83%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: NC1CCCCC1
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCCC1
Yield: 82.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclohexylamine (0.113 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 109.7 mg (0.35 mmol, 82.2% yield) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C@@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[OH-].[Na+]>O>[C:1]([CH2:5][C@@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)C[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C[C@H](O)CC#N
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a 3-necked jacketed 3L flask equipped with a mechanical stirrer and connected to an automatic titrater by a pH electrode and a feeding tube for addition of base, was charged H2O (1200 mL), NaCN (37.25 g) and NaH2PO4 (125 g) to bring the solution to pH 7. The water circulator was set to 40° C. After 10 minutes, halohydrin dehalogenase of SEQ ID NO: 32 as cell lysate (250 mL) was added. The reaction mixture was allowed to stir for 5 minutes. Using an addition funnel, ethyl (S)-4-chloro-3-hydroxybutyrate (45 g) was slowly added over 1 hour. The pH was maintained at 7 by the automatic titrater by the addition of 10 M NaOH (27 mL) over 17 hours. Subsequently, gas chromatography of a reaction sample showed complete conversion to product. Celite™ (16 g) was added to the flask, which was then connected to a diaphragm pump, whose exhaust is bubbled into 5M NaOH (200 mL), to remove HCN. The mixture was heated to 60° C. under 100 mm Hg pressure. After 1 hour, a submerged air bubbler was added to the solution to aid the removal of the HCN. After 3 hours, an HCN detector indicated less than 5 ppm HCN in the off-gas. The mixture was allowed to cool to room temperature, then filtered through a Celite™ pad. The filtrate was extracted with butyl acetate (3×800 mL) and the combined organic layers filtered through a pad of activated charcoal. The solvent was removed under vacuum by rotary evaporation to provide 28.5 g of ethyl (R)-4-cyano-3-hydroxybutyrate. The purity was 98% (w/w) by HPLC and the enantiomeric excess was >99% (by chiral GC, the S enantiomer was undetectable). As used herein, the term “enantiomeric excess” or “e.e.” refers to the absolute difference between the mole or weight fractions of major (F(+)) and minor (F(−)) enantiomers (i.e., |F(+)−F(−)|), where F(+)+F(−)=1. Percent e.e. is 100×|F(+)−F(−)|. Enantiomeric composition can be readily characterized by using the gas chromatography method described in Example 6, above, and using methods that are known in the art.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[CH2:13]([O:29][CH2:30][CH:31]([O:34][CH3:35])[CH2:32]O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:13]([O:29][CH2:30][CH:31]([O:34][CH3:35])[CH2:32][O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: OCc1cccc(CO)c1
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CO)c1)OC
Reaction time: 18 h

Procedure:
To a suspension of 2.8 g of sodium hydride in 25 ml of dimethylformamide was added at 0° C. over 30 minutes a solution of 1,3-benzenedimethanol in 75 ml of dimethylformamide. After 30 minutes a solution of 3-(hexadecyloxy)-2-methoxy-1-propanol, 4-methyl benzene sulfonate in 25 ml of dimethylformamide was added over 30 minutes. After stirring 18 hours the mixture was poured into water and extracted with ethylacetate. The solution was dried and the product was purified by chromatography giving 4.7 g.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[NH:14][C:13](=[O:22])[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]3)[CH:7]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:22]=[C:13]1[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11][C:10]2[C:15](=[CH:16][C:17]([C:18]([F:20])([F:21])[F:19])=[C:8]([N:6]3[CH:7]=[C:3]([CH2:2][O:1][C:35](=[O:36])[NH:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:4]=[CH:5]3)[CH:9]=2)[NH:14]1
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(C(F)(F)F)cc2[nH]c1=O
Reactant: O=C=Nc1ccccc1
Product: CCOC(=O)c1cc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(C(F)(F)F)cc2[nH]c1=O
Yield: 89.1 %

Procedure:
Using the compound of Example 17 (200 mg, 525 μmol) and phenyl isocyanate (93.9 mg, 0.788 mmol), and through the process similar to Example 18, 234 mg of title compound were obtained as colorless powder. Yield 89%.
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].[Br:25][C:26]1[C:27]([C:33]([F:36])([F:35])[F:34])=NC(Cl)=N[CH:31]=1.CCN(C(C)C)[CH:40]([CH3:42])[CH3:41].CN(C=O)C>O.CCOC(C)=O>[Br:25][C:26]1[CH:31]=[CH:42][C:40]([N:9]2[CH2:8][CH2:7][N:6]3[C:10]4[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=4[N:12]=[C:5]3[C@H:4]2[CH:1]([CH3:3])[CH3:2])=[CH:41][C:27]=1[C:33]([F:36])([F:35])[F:34]
Reactant: FC(F)(F)c1nc(Cl)ncc1Br
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ccc(Br)c(C(F)(F)F)c1)[C@@H]3C(C)C
Temperature: 130 °C
Yield: 47 %

Procedure:
A mixture of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (45 mg, 0.128 mmol), 5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine (40 mg, 1.2 eq.), DIPEA (90 μL, 4 eq.) and DMF (1.5 mL) was put in Microwave Oven and heated 90 min. at 130° C. The mixture was participated between EtOAc and water. The aqueous layer was extracted twice by EtOAc. The combined organic layers were washed by brine, dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (12 g column, 10-40% EtOAc in Hexanes) to afford 34.4 mg (47% yield) of (R)-methyl 2-(4-bromo-3-(trifluoromethyl)phenyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate.
Reaction SMILES: C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.[CH2:22]([C:24]1[C:33]([CH3:34])=[C:32]([O:35][C:36]([CH:38]2CC2)=[O:37])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:42])[C:30]=2[F:41])[N:25]=1)[CH3:23].O>O1CCCC1.[H-].[Na+]>[CH2:22]([C:24]1[C:33]([CH3:34])=[C:32]([O:35][C:36](=[O:37])[CH3:38])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:42])[C:30]=2[F:41])[N:25]=1)[CH3:23]
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(F)c(F)c2c(OC(C)=O)c1C
Reaction time: 1 h
Yield: 232.8 %

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (1 g) prepared as described in Example 1 was dissolved in 10 ml of methanol to prepare a solution. A solution of 0.5 g of sodium hydroxide in 10 ml of water was added to this solution, and the mixture was stirred at 50° C. for 3 hr. The reaction solution was allowed to stand for cooling and was then poured into 50 ml of water, and the mixture was neutralized with 1 N hydrochloric acid. The precipitate was then collected by filtration to give 700 mg of 2-ethyl-3-methyl-4-hydroxy-5,6-difluoroquinoline. In 20 ml of tetrahydrofuran was suspended in 96 mg of 60% sodium hydride. The 2-ethyl-3-methyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) (446 mg) was suspended in 10 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The mixture was stirred for one hr, 200 mg of acetyl chloride (starting material 2) was then added thereto, and the mixture was stirred at room temperature for 4.5 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 424 mg of 2-ethyl-3-methyl-4-acetyloxy-5,6-difluoroquinoline (compound 12). 1H-NMR data are shown in Table 3.
Reaction SMILES: C1COCC1.[C:6]1([CH3:14])[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CO[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH2:42][CH2:41][CH2:40][CH2:39]2>C(OCOCC)C>[CH3:14][C:6]1[CH:11]=[CH:10][C:9]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:8][CH:7]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: COc1ccc2c(c1)CCCC2
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1CCOC1
Solvent: CCOCOCC
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 63.6 %

Procedure:
A THF solution of p-tolylmagnesium bromide (20.0 mL, 20.0 mmol) was placed under vacuum to remove the volatiles. The solvent was replaced with diethoxymethane (20.0 mL). In a separate flask, NiCl2(PCy3)2 (where Cy=cyclohexyl) (355 mg, 0.514 mmol), PCy3 (285 mg, 1.018 mmol), and 6-methoxy-1,2,3,4-tetrahydronaphthalene (1.639 g, 10.11 mmol) was combined in diethoxymethane (2.5 mL). The Grignard reagent was added to this mixture under a nitrogen atmosphere. The resulting solution was stirred 2 minutes at room temperature and then warmed to 90° C. for 15 hours. The reaction was quenched with half saturated aqueous ammonium chloride solution (30 mL) and was extracted with MTBE (3×30 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with heptane) to provide 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (1.43 g, 64% yield)