Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[O:4][N:3]=1.O[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C@H:18]([NH:23][C:24]3[S:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:28]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=2)=[C:5]([CH3:9])[O:4][N:3]=1
Reactant: Cc1noc(C)c1CO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1nc(-c2ccccc2)cs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCc2c(C)noc2C)cc1)Nc1nc(-c2ccccc2)cs1
Temperature: 5 °C
Reaction time: 21 h

Procedure:
(3,5-Dimethylisoxazol-4-yl)methanol (0.28 g, 1.5 mmol), methyl (2S)-3-(4-hydroxyphenyl)-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate from Step A (0.35 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) were dissolved in tetrahydrofuran (THF). After cooling the reaction mixture to 5° C., DEAD (0.52 g, 3 mmol) was added. The reaction was then stirred at room temperature for 18-24 h. THF was evaporated to obtain crude methyl (2S)-3-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-2-[(4-phenyl-1,3-thiazol-2-yl)amino]propionate.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].Cl[CH2:14][C:15](=[O:17])[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:14][C:15](=[O:17])[CH3:16])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Cn1c(Cl)nc2ccccc21
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (1.53 g) in DMF (20 ml) was added sodium hydride (60% in oil, 0.480 g) at 0° C. by small portions. After stirring for 10 min, chloroacetone (1.19 mL) was added, and the obtained mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (1.73 g).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][OH:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2[C:46]3C4C=C(C)C=NC=4[NH:49][C:45]=3[C:44]([O:55]C[C@H](OC(=O)[C@H](C)N)C)=NC=2)C=CC=1)(=O)=O)C>>[NH2:49][C@@H:45]([CH3:46])[C:44]([O:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)=[C:13]2[C:17]=1[NH:16][C:15]1[N:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:14]2=1)=[O:55]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(OC[C@@H](C)OC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCOC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 215 by using an analogous procedure to that outlined in the preparation of Compound 64. 1H NMR (400 MHz, DMSO) δ ppm 1.18 (t, J=7.33 Hz, 3H) 1.40 (d, J=7.33 Hz, 3H) 2.27 (s, 3H) 3.42 (q, J=7.33 Hz, 2H) 4.20 (d, J=5.05 Hz, 1H) 4.53 (t, J=4.42 Hz, 2H) 4.58-4.69 (m, 2H) 7.12 (d, J=8.08 Hz, 1H) 7.23 (d, J=8.08 Hz, 1H) 7.55 (s, 1H) 7.87 (t, J=7.83 Hz, 1H) 8.00 (dd, J=12.63, 7.58 Hz, 2H) 8.08 (s, 1H) 8.29 (s, 1H) 8.33 (br. s., 2H) 11.95 (s, 1H) [M+H] calc'd for C25H27N3O5S, 482; found, 482.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>C(O)C>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:28])[C:18](=[CH:24][NH:33][CH:30]3[CH2:32][CH2:31]3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:29])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
A solution of 20.5 g (50 mmol) of 4-[3-(acetylamino)cyclopentyl]-α-(ethoxymethylene)-2,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester, in 100 ml of absolute ethanol was cooled to 10° and 3.4 g (60 mmole) of cyclopropylamine was added dropwise maintaining the temperature below 15° with an ice bath. After the addition was complete, the reaction was stirred at 5°-10° for 1.5 hours and then at room temperature for 1 hour. The resulting suspension was chilled to 5° and the solid removed by filtration and washed with ethanol and then hexane. The combined filtrate and washings were evaporated in vacuo and the residue was recrystallized from pentane to give 16.1 g of the title compound.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:8]([CH:11]=1)[CH:9]=[O:10]>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:8]([CH2:9][OH:10])[CH:11]=1
Reactant: COc1ccc(/C=C/c2ccc(F)cc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(/C=C/c2ccc(F)cc2CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.73 g (45.60 mmol) of sodium borohydride are added in portions to a solution of 7.79 g (30.40 mmol) of E-5-fluoro-2-[2-(4-methoxyphenyl)vinyl]benzaldehyde in 500 ml of methanol at 0° C., and the mixture is stirred at room temperature for 2 hours. After reaction is complete, the mixture is concentrated to dryness and the residue is taken up in water and dichloromethane. The aqueous phase is extracted twice more with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→1:1). 6.8 g (85% of theory) of a colorless solid are obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1/[CH:25]=[CH:26]/[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[O:31].[Cl-].[NH4+]>CCCCCC.O1CCCC1.CCOCC>[OH:31][CH:30]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])[C:29]1[CH:32]=[CH:33][CH:34]=[C:27](/[CH:26]=[CH:25]/[C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH:28]=1
Reactant: O=Cc1cccc(/C=C/c2ccc3ccccc3n2)c1
Reactant: N#Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cccc(C(O)c2cccc(/C=C/c3ccc4ccccc4n3)c2)c1
Temperature: -100 °C
Reaction time: 0.08 h

Procedure:
2.5M n-Butyl lithium solution in hexane (2.6 ml) was added dropwise to a stirred solution of 3-bromobenzonitrile (1.2 g, 6.56 mmol) in tetrahydrofuran (20 ml) and ether (20 ml) at -100° to -110° C. under nitrogen. The yellow solution was stirred at -100° C. for 5 minutes, then a solution of 3-[2(E)-(quinolin-2-yl)ethenyl]benzaldehyde (1.7 g, 6.56 mmol) in tetrahydrofuran (7 ml) was added. The dark brown solution was allowed to warm to room temperature, poured onto saturated ammonium chloride solution and extracted with ethyl acetate. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:2) to give a pale yellow solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[N:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[F:28])=[N+:16]=[N-:17]>CO>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[CH:22]=[CH:23][C:18]=1[N:15]1[C:13]([NH2:14])=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[N:17]=[N:16]1
Reactant: COc1ccc(CC#N)cc1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Yield: 1.7 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (1.659 g, 30.7146 mmol) in methanol (50 ml), 4-methoxyphenylacetonitrile (3.728 g, 24.5717 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (4.200 g, 20.4764 mmol) are added portion wise and the mixture is allowed attain room temperature spontaneously and refluxed overnight. The resulting reaction mixture is concentrated, added water, and extracted with chloroform (3×100 mL). The combined organic layers are dried over MgSO4, filtered and concentrated to afford a brownish gummy material (5.900 g, 82% mass balance). The crude residue is purified by column chromatography over silica gel (230-400 mesh), eluting with 15% ethylacetate in hexane, to obtain the title compound as a grey solid (0.120 g, 1.5% yield). A major impurity isolated and characterized is 5-(4-methoxy-phenyl)-3-(2-methoxy-4-trifluoromethyl-phenyl)-3H-[1,2,3]triazol-4-ylamine (2.400 g, ˜33% yield).
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[S:33])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1Cc2c(C(=O)OC(C)(C)C)ncn2-c2ccccc2C1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1Cc2c(C(=O)OC(C)(C)C)ncn2-c2ccccc2C1=S

Procedure:
1 g of t-butyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 50 ml of toluene is treated with 0.82 g of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide and the mixture obtained is heated to boiling under reflux for 6 hours. The mixture is poured into water and the toluene phase is separated. After drying the organic phase over magnesium sulphate and evaporation, the crude product is chromatographed on silica gel. There is obtained t-butyl 5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate on melting point 207°-208°.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=O)[CH2:2]1.C(OC(=O)C)(=O)C>>[C@H:3]12[C:7](=[O:9])[O:12][C:10](=[O:11])[C@H:1]([CH2:6][CH2:5][CH2:4]1)[CH2:2]2
Reactant: O=C(O)C1CCCC(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)[C@H]2CCC[C@@H]1C2
Temperature: 200 °C
Yield: 93.6 %

Procedure:
1,3-Cyclohexanedicarboxylic acid (mixture of cis and trans; 20 g; 0.116 mol) was slurried in acetic anhydride (80 mL; 0.85 mol; 7.3 equiv). The resulting mixture was heated to reflux (at which point it was homogeneous) for 5 h. A distillation head was added and the volatiles were removed by increasing the pot temperature to 200° C. Once no more distillate was collected the residue was cooled to ambient temperature to afford a solid mass. The crude product was recrystallized from hot toluene (40 mL) by the addition of heptane (40 mL) and cooling to 4° C. The precipitated product was filtered, washed with heptane, and dried in vacuo to afford 16.74 g (93%) of 1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:3]=1.O[C:20]1[C:29]2[C:24](=CC=CC=2)[N:23]=[C:22]([C:30]2C=CC(F)=CC=2)[N:21]=1.S(Cl)(Cl)=O.CN(C)C=O>C(Cl)(Cl)Cl>[N:23]1[CH:24]=[CH:29][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:3]=2)=[CH:30][CH:22]=1
Reactant: Oc1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: Fc1ccc(-c2nc(Cl)c3ccccc3n2)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc(Nc3ccncc3)c3ccccc3n2)cc1

Procedure:
4-Chloro-2-(4-fluorophenyl)quinazoline: 4-hydroxy-2-(4-fluorophenyl)quinazoline, from paragraph B, 1 equivalent, was suspended in chloroform and treated with 12 equivalents of thionyl chloride in the presence of a catalytic amount of dimethyl formamide, under reflux for 4 hours. After removal of the solvents under reduced pressure a solid was obtained that was analyzed by TLC. EIMS confirmed the desired product.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.BrC1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36][CH3:37])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36][CH3:37])=[CH:28][CH:27]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: CSCCCOc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSCCCOc1ccc(-c2cc(CO)c(C)o2)cc1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (3.0 g), 1-bromo-4-[3-(methylsulfanyl)propoxy]benzene (2.8 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, purified by silica gel chromatography (0% ethyl acetate/hexane to 40% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.2 g, 84%) as a white crystal.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH:18]=[N:17][N:16]=[N:15]1)=[O:4].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(Cl)Cl>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:7]([CH:12]=1)[CH2:6][NH:5][C:3](=[O:4])[CH2:2][NH:22][CH:19]1[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=C(CBr)NCc1cc(Cl)ccc1-n1cnnn1
Solvent: ClCCl
Product: O=C(CNC1CC1)NCc1cc(Cl)ccc1-n1cnnn1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]acetamide (206 mg, 0.62 mmol) in CH2Cl2 (2.5 mL) at room temperature was added cyclopropylamine (500 μL, 7.22 mmol). The resulting yellow solution was stirred under N2 atmosphere for 1 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (gradient elution with EtOAc then with 10% MeOH-EtOAc) to afford the title compound as a yellow solid after drying in vacuo. 1H NMR (400 MHz, CDCl3): δ 8.97 (s, 1 H), 7.62–7.58 (m, 2 H), 7.46 (dd, J=1.8, 8.6 Hz, 1 H), 7.29–7.27 (m, 1 H), 4.24 (d, J=6.4 Hz, 2 H), 3.37 (s, 2 H), 2.23–2.18 (m, 1 H), 1.63 (br m, 1 H), 0.49–0.40 (m, 2 H), 0.37–0.36 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C@@H:31]([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: OCc1cc(F)c(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[N:11][C:12]([N:20]2C(C)=CC=C2C)=[N:13][C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.O.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[N:11][C:12]([NH2:20])=[N:13][C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCc1nc(N)nc(C)c1OCc1ccccc1

Procedure:
To stirred solution containing 533 mg (1.46 mmol) of 5-(benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-6-pentylpyrimidine in 10 mL of ethanol-water 9:1 were added 1.0 g (14.60 mmol) of hydroxylamine hydrochloride. The reaction mixture was then stirred at reflux during 5 h. A second portion of 1.0 g (14.60 mmol) of hydroxylamine hydrochloride was added and the reaction mixture was stirred at reflux for 16 h. The reaction mixture was then poured into 70 mL of water and then basified to a pH 9-10 with a 1N NaOH aqueous solution. The mixture was extracted with two 70-mL portions of ethyl acetate. The combined organic layer was washed with a 70-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 2:1 hexanes-ethyl acetate afforded the expected product as a colorless oil: yield 334 mg (80%); silica gel TLC Rf 0.25 (2:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 0.86 (t, 3H, J=6.8 Hz), 1.27 (m, 4H), 1.63 (m, 2H), 2.28 (s, 3H), 2.56 (dd, 2H, J=8.0, 8.0 Hz), 4.71 (s, 2H), 5.15 (br s, 2H) and 7.35-7.37 (m, 5H); 13C NMR (CDCl3) δ 13.94, 18.85, 22.41, 28.04, 31.86, 75.90, 127.90, 128.26, 128.26, 128.58, 128.58, 136.76, 142.80, 156.18, 158.79, 161.13 and 164.89; mass spectrum (APCI), m/z 286.1914 (M+H)+ (C34H52N3O requires 286.1919).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=[O:22])[CH3:21].[OH-].[Na+]>CCCCCCCC>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCOCC1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCCC
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1OC
Temperature: 127 °C
Reaction time: 10 h

Procedure:
4-Chloro-3', 4'-dimethoxybenzophenone (276.7 g; 1 mol), N-acetyl morpholine (387.6 g; 3 mol) and powdered sodium hydroxide (40.0 g; 1 mol) in n-octane (600 ml) were refluxed under stirring for 10 hours at a column internal temperature of 127° C. The refluxing condensate (3 l/h) was passed through a column packed with molecular sieves (4 A, 150 g). Subsequently, n-octane (450 ml) was distilled off and toluene (1 l) was added. The mixture was heated to 80° C. and extracted once with 500 ml water and twice with 250 ml water. The organic layer was separated, and dried by azeotropic distillation of a part of the solvent (125 ml) under reduced pressure. On cooling to room temperature, crystallisation already started. Under continuous stirring, 750 ml petroleum ether (bp. 58°-63° C.) was added over a period of 30 minutes. After standing overnight, the crystals were collected by vacuum filtration washed with toluene/petroleum ether (1:3; 400 ml) and dried. Yield: 268 g (69.1%). Mp.: 140°-152° C. The product was 98.1% pure and contained 0.9% of the original ketone. The mother liquor contained an additional 25.2 g of the title compound and 42.2 g of the original ketone. The water washings contained 207 g =1.6 mol N-acetyl morpholine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[C:16]([Li])=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1COCC1.CCOCC.C(Cl)(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([C:16]2[C:11]([F:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [Li]c1cccnc1F
Reactant: O=Cc1ccc(F)cc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)c1cccnc1F
Reaction time: 16 h

Procedure:
A solution of 4-fluorobenzaldehyde (5.86 g, 45 mmol) in dry THF (10 ml) was dropwise added at −70° C. to a solution of 2-fluoro-3-lithiopyridine (prepared from 2-fluoropyridine (3.91 ml, 45 mmol) and LDA (49.5 mmol)) in THF (120 ml). After complete addition, the cooling bath was removed and the reaction was allowed to reach 10° C. Hydrolysis was performed by addition of water, and the mixture is then diluted with ether. After separation of the layers, the ether solution was washed with brine, dried over Na2SO4 and evaporated in vacuum to yield a viscous oil. The alcohol was dissolved in CHCl3 (150 ml) and MnO2 (58.62 g, 0.675 mol) was added at room temperature. After 16 hours, the mixture was filtered on a pad of Celite and concentrated. The residual oil was chromatographied on silica gel (CH2Cl2) and (4-fluorophenyl)(2-fluoro-3-pyridinyl)methanone 37 was isolated as a white solid (4.83 g, 49%).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[NH:3]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cccc2c1[nH]c(=O)c1ccncc12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c1nc(Cl)c1ccncc12
Yield: 92 %

Procedure:
Methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-7-carboxylate (1.0 eq, 85 mg, 0.334 mmol) was stirred in phosphorus oxychloride (2 ml) at 120° C. for 2 hours. The solvent was removed in vacuo. Ice and water were added. The resulting solid was filtered and dried to afford methyl 5-chlorobenzo[c][2,6]naphthyridine-7-carboxylate as a solid (84 mg, 92% yield). LCMS (ES): >95% pure, m/z 273 [M+1]+.