Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:9][C:8](=[O:23])[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].[N:33](OCCC(C)C)=O.Cl>C(O)C>[CH2:1]([N:5]1[C:10]2[N:11]=[C:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[NH:33][C:9]=2[C:8](=[O:23])[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)CCON=O
Reactant: CCCCn1c(NCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(Cc2ccccc2F)c1=O
Agent: Cl
Solvent: CCO
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc([N+](=O)[O-])cc3)nc21
Temperature: 23 °C
Reaction time: 0.67 h

Procedure:
1-Butyl-3-(2-fluorobenzyl)-6-[2-(4-nitro-phenyl)-ethylamino]-1H-pyrimidine-2,4-dione (2.3 g, 5.2 mmol) was dissolved in ethanol (20 mL) and treated with isoamyl nitrite (Aldrich) (3.6 mL, 26 mmol). Concentrated aqueous hydrochloric acid (1 mL) was added to the reaction mixture. The reaction was stirred at 23° C. for 40 minutes. The ethanol was removed under reduced pressure and the residue washed with diethyl ether. The solid residue was then dissolved in n-butanol (15 mL), and the mixture refluxed for 30 minutes. After cooling to room temperature 1-butyl-3-(2-fluorobenzyl)-6-[2-(4-nitro-phenyl)-ethylamino]-1H-pyrimidine-2,4-dione separated as pale yellow crystals which were collected by filtration (1.91 g, 81%). LCMS, m/z(M+H)=452.24.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-])=O)=[CH:12][C:11]=1[Cl:21])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>Cl.C(O)C.C(OCC)(=O)C.[Fe]>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([NH2:18])=[CH:12][C:11]=1[Cl:21])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1cc(OC)c([N+](=O)[O-])cc1Cl)OCC
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(Cc1cc(OC)c(N)cc1Cl)OCC
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A suspension of (2-chloro-5-methoxy-4 nitrobenzyl)-phosphonic acid diethylester (Compound 56F, 10.3 g, 30.5 mmol), iron powder (16.8 g, 305 mmol) in 2M aqueous hydrochloric acid (25 mL) and ethanol (150 mL) was heated to reflux for 1 hr. The reaction mixture was cooled to RT and solid Na2CO3 (6 g) was added until the pH was 9. The reaction mixture was filtered through celite, the filter cake was washed with dichloromethane and the filtrate was concentrated to give a residue which was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated to give the required material as gum (8 g, 85%). 1H NMR (400 MHz, CDCl3) δ: 6.88 (s, 1H), 6.71 (s, 1H), 4.3 (brs, 2H), 4.05-4.13 (m, 4H), 3.85 (s, 3H), 3.26 (d, J=20.50 Hz, 2H), 1.28 (t, J=7.05 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22](=O)[CH:23]=O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[N:15]=[CH:23][CH:22]=[N:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CC=O
Reactant: Nc1ccc(C(c2cccc(F)c2)n2ccnc2)cc1N
Solvent: CO
Product: Fc1cccc(C(c2ccc3nccnc3c2)n2ccnc2)c1
Yield: 74.5 %

Procedure:
A mixture of 8.1 parts of 4-[(3-fluorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 5 parts of ethanedial and 80 parts of methanol was stirred at reflux temperature. Upon complete reaction, the mixture was evaporated to dry and the residue was taken up in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) was eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 6.35 parts (74.5%) of 6-[(3-fluorophenyl)(1H-imidazol-1-yl)methyl]quinoxaline; mp. 109.7° C. (comp. 15).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11]/[C:12](=[CH:22]\[F:23])/[CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:8][CH:7]=1)(=[O:5])=[O:4].FC(F)(F)C(O)=O.[ClH:34]>C(Cl)Cl>[ClH:34].[NH2:14][CH2:13]/[C:12](=[CH:22]/[F:23])/[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:1])[CH3:26])(=[O:5])=[O:4])=[CH:25][CH:24]=1
Reactant: CN(C)S(=O)(=O)c1ccc(OC/C(=C\F)CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(OC/C(=C\F)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a stirring solution of (Z)-tert-butyl 2-((4-(N,N-dimethylsulfamoyl)phenoxy)methyl)-3-fluoroallylcarbamate (279.0 mg, 0.72 mmol) in CH2Cl2 (4.0 mL) at room temperature was added trifluoroacetic acid (1.0 mL). The resulting mixture was stirred at room temperature for 30 min. All volatiles were removed in vacuo and the residue was co-evaporated with CH2Cl2 (2×20 mL). The resulting oil was taken up in ethyl acetate/MeOH (5:1; 3.0 mL) and then ethereal HCl (2.0 M in diethyl ether; 0.5 mL, 1.0 mmol) was added. The precipitate formed was isolated and dried under reduced pressure to afford (Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)-N,N-dimethylbenzenesulfonamide hydrochloride (196.0 mg, 84%) as a white solid; m.p. 185-187° C.; 1H-NMR (300 MHz; d6-DMSO) δ ppm: 3.39 (6H, br s), 3.54 (2H, br s), 4.81 (2H, d, J 2.3 Hz), 7.16 (2H, d, J 9.0 Hz), 7.24 (1H, d, J 82.3 Hz), 7.25 (2H, br s), 7.77 (2H, d, J 9.0 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH:11]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:16]CN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C(Cl)Cl>CO>[CH3:16][O:14][C:13](=[O:15])[CH2:12][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CC1Cc2ccccc2NC1=O
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
(2-Oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid (2.73 mmol), EDCl (3.27 mmol) and DIEA (3.27 mmol) are dissolved in 10 mL MeOH. About 2 mL of CH2Cl2 is also added to help dissolving the solid. The reaction mixture is stirred at room temperature for 2 hours before removal of the solvent under reduced pressure. The residue is purified by silica gel chromatography (hexane/EtOAc) to give (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester as a white solid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 7.88 (br, 1H), 7.18 (m, 2H), 7.00 (td, 1H), 6.75 (d, 1H), 3.73 (s, 3H), 3.13-2.98 (m, 3H), 2.89 (m, 1H), 2.51 (dd, 1H). MS: (ES+): 220.2 [M+1].
Reaction SMILES: O[C:2](=[O:23])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.O[N:25]1[C:29]2C=[CH:31][CH:32]=[CH:33][C:28]=2N=N1.Cl.CN(C)CCCN=C=NCC.N1CCCCC1>C(Cl)Cl>[N:25]1([C:2](=[O:23])[CH2:3][CH2:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)[N:8]=[C:7]([C:21]#[N:22])[N:6]=2)[CH2:31][CH2:32][CH2:33][CH2:28][CH2:29]1
Reactant: On1nnc2ccccc21
Reactant: N#Cc1nc(CCC(=O)O)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Product: N#Cc1nc(CCC(=O)N2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(3-hydroxy-3-oxopropyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (64 mg) in DCM (6 mL) was added 1-hydroxybenzotriazole (30 mg) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (38 mg). The solution was stirred at room temperature for 15 min and piperidine (22 mg) added. After standing for 18 h, the reaction mixture was washed with HCl (1M, 2×5 ml), H2O then brine and dried with sodium sulfate. After removal of solvent, crystallisation from a trace of acetone/ether gave 4-(3-piperidin-1-yl-3-oxopropyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a white solid, 35 mg.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:17]=[C:16]([NH2:27])[N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:30][C:31]([OH:48])([CH3:47])[CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>>[NH2:27][C:16]1[N:15]=[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][C:31]([CH3:47])([OH:48])[CH3:30])[CH:37]=5)[CH:29]=[CH:28][C:5]=4[C:6]=3[N:7]=2)[N:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:17]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(-c2ccc(F)cc2F)n1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nc(N)nn4-c4ccc(F)cc4F)nc2-3)cn1

Procedure:
Similarly to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazol-3-ylamine was reacted with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 366. LCMS: 536.1.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1>C1COCC1.C(O)C>[O:9]([CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(COc2ccccc2)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To a solution of sodium hydride (55 mg, 60% dispersion in mineral oil, 1.38 mmol) in THF (1 ml) at 0° C. was added phenol (100 mg, 1.06 mmol). After stirred at 0° C. for 10 minutes, the reaction solution was warmed to room temperature and stirred for 10 minutes. The reaction solution was cooled to 0° C. again, and was added a solution of N-(4-(chloromethyl)thiazol-2-yl)acetamide in ethanol (1 ml). The reaction was stirred at room temperature overnight and then was heated at 70° C. for 5 hours. The reaction solution was concentrated and the residue was purified via preparative HPLC to afford N-(4-phenoxymethyl-thiazol-2-yl)-acetamide as a tan amorphous solid (50 mg, 20%). LC/MS m/z 249.15 (M-1)+; HPLC Rt: 2.875 min.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([NH:14][C:15](=[O:38])[CH2:16][CH:17]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)(=[O:21])=[O:20])[CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1)#[N:2]>CO.[Pd]>[NH2:2][CH2:1][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([NH:14][C:15](=[O:38])[CH2:16][CH:17]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)(=[O:21])=[O:20])[CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of N-(7-cyanomethyl-chroman-4-yl)-3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (790 mg, 1.45 mmol) in MeOH (20 mL) in the Parr-bottle was added Pd/C (80 mg) while flushed under N2. The reaction mixture bottle was placed in Parr-shaker. The H2 was filled up the bottle then released-this was done 3 times. After last release, the fresh H2 (50 psi) was then filled up the bottle. The reaction was under hydrogenation for 18 h. Solvent was separated from the Pd/C by passing through the Celite®. Solvent was evaporated in vacuo to give the final product. MS m/z: 548.12 (M+H). Calc'd. for C27H28F3N3O4S-547.06.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:18])=[C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[C:6]([Cl:9])=[CH:7][CH:8]=1.C(=O)(O)[O-:20].[Na+].CS(C)=O>C(OCC)(=O)C>[C:10]([C:5]1[C:4]([F:18])=[C:3]([CH:8]=[CH:7][C:6]=1[Cl:9])[CH:2]=[O:20])(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1c(Cl)ccc(CBr)c1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Yield: 48.9 %

Procedure:
Step 3 A mixture of (3-bromomethyl-6-chloro-2-fluoro-phenyl)-phenyl-methanone (292 mg, 0.896 mmol), sodium bicarbonate (700 mg, 8.33 mmol) and dimethylsulfoxide (10 ml) was heated to 80 degC for 3 hours. The reaction mixture was then allowed to cool, ethyl acetate was added, and the mixture was washed with water, aqueous lithium chloride and brine before drying (MgSO4) and concentrating in vacuo. The residue was purified by silica chromatography eluting with 0-20% ethyl acetate/petroleum ether to furnish 3-benzoyl-4-chloro-2-fluoro-benzaldehyde (115 mg oil, 90% clean). 1H NMR (400 MHz, CDCl3): 10.34 (1H, s), 7.97 (1H, dd), 7.91-7.86 (2H, m), 7.72-7.67 (1H, m), 7.55 (2H, t), 7.44 (1H, d), 7.28 (1H, s). MS: [M+NH4]+ 280
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:22])C(=O)C1>ClCCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Yield: 47.9 %

Procedure:
A solution of methyl 2-methyl-6-nitrobenzoate (TL (1996) 37 5425, 15.6 g, 80 mmol), NBS (21.4 g, 120 mmol) and benzoyl peroxide (200 mg, 0.82 mmol) in 1,2-dichloroethane (250 mL) was heated at reflux for 8 h. The reaction mixture was concentrated to dryness and the crude mixture purified by chromatography over silica gel eluting with 2% ethyl acetate/hexanes to afford 10.5 g of methyl 2-(bromomethyl)-6-nitrobenzoate (XXXVI, yield: 65%). 1H NMR (CDCl3, 400 MHz): δ 3.98 (s, 3H), 4.57 (s, 2H), 7.59 (dd, 1H, J=7.8, 8.4 Hz), 7.78 (d, 1H, J=7.8 Hz), 8.1 (d, 1H, J=8.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.B(F)(F)F.[CH3:17][CH2:18]OCC.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:17][CH3:18])=[O:9])=[CH:11][CH:12]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1

Procedure:
A solution of 10.0 g. 4-aminohydrocinnamic acid in 100 ml. of absolute ethanol containing 16 ml. of boron trifluoride etherate is heated to reflux for 48 hours. The solution is then cooled, poured into 5% aqueous sodium carbonate, and extracted with methylene chloride. Evaporation of the organic extracts yields ethyl 4-aminohydrocinnamate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:29]=[C:30]([OH:32])[CH:31]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]=1[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:29]=[C:30]([O:32][CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:31]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]=1[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CCOCC1
Reactant: CCOC(=O)c1cc(O)cc(OCc2nc3ccccc3c(OCc3ccccc3)c2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2nc3ccccc3c(OCc3ccccc3)c2C)cc(OCC2CCOCC2)c1
Temperature: 80 °C
Reaction time: 13 h
Yield: 97.5 %

Procedure:
A mixture of ethyl 3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}-5-hydroxybenzoate (2.10 g), 4-(bromomethyl)tetrahydro-2H-pyrane (2.29 g), potassium carbonate (0.98 g), and DMF (40 mL) was stirred at 80° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, and then water was added to the residue, followed by extraction with ethyl acetate (150 mL). The organic layer was washed sequentially with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain ethyl 3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate (2.50 g).
Reaction SMILES: [O:1]([C:8]1[N:9]=[C:10]2[C:16]([C:17](O)=[O:18])=[CH:15][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:11]2=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.[CH:39]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:39]1([NH:45][C:17]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=3)[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:15]=2)=[O:18])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Oc3ccccc3)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCCC2)c2nc(Oc3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.115 g, 0.30 mmol), 4-dimethylaminopyridine (0.048 g, 0.39 mmol) and (3-dimethylamino-propyl)-ethyl-carbodiimide (0.075 g, 0.39 mmol) in CH2Cl2 (2 mL) was added a solution of cyclohexylamine (0.039 g, 0.39 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at room temperature overnight, then quenched with water and extracted with ethyl acetate (3×). The organic layer was washed with water and saturated aqueous NaCl solution and dried over MgSO4, filtered and concentrated to afford 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide which was used without further purification.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9]C)=O)[CH2:2]1.[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[N:27]=[C:28]=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[O:9]=[C:7]1[CH:3]2[CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][N:4]2[C:28](=[O:29])[N:27]1[C@@H:25]1[CH2:26][C@H:24]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)N([C@@H]3C[C@H]3c3ccccc3)C(=O)C2C1
Temperature: 25 °C
Yield: 60 %

Procedure:
To A3 in toluene (0.4M) was added dropwise trans-2-phenylcyclopropyl isocyanate (1.05 eq.). The mixture was stirred O/N at rt. DIPEA (1.5 eq.) was added and the mixture refluxed for 20 h. The organic phase was washed with phosphate buffer (2×200 mL, 0.75 M NaH2PO4, pH˜4.5) and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 20-100% EtOAc/petroleum ether to give the title compound in 60% yield. MS (ES+) C20H25N3O4 requires 371, found: 394 (M+Na)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:10][C:9]([NH2:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:24]=[C:25]1[NH:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=3)=[CH:10][C:9]([NH:23][C:30]([C@@H:27]3[CH2:26][C:25](=[O:24])[NH:29][CH2:28]3)=[O:31])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C[C@@H](C(=O)O)CN1
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C[C@@H](C(=O)Nc2cc(-c3cccc(OC(F)(F)F)c3)n(-c3ccccc3)n2)CN1
Yield: 83.5 %

Procedure:
To a solution of 1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (40 mg) prepared according to the same procedures as Preparation 2 in N,N-dimethylformamide (0.3 ml) were sequentially added (R)-5-oxopyrrolidine-3-carboxylic acid (24 mg) prepared in Preparation 5, HOBt.H2O (29 mg) and WSC.HCl (36 mg), and the mixture was stirred at room temperature overnight. To this reaction solution were added a saturated aqueous solution of sodium hydrogen carbonate and water, and the mixture was stirred. The insoluble substance was collected by filtration, washed with water, and dried under reduced pressure to give the titled compound (45 mg).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1>C1COCC1.C(O)C>[Br:1][CH2:2][C@@H:3]([OH:25])[C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][C:6]1[CH:7]=[C:8]([Cl:13])[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)C(=O)CBr)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)[C@H](O)CBr)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
Step BF (6): A 1M solution of LiAlH(OtBu)3 in THF (22.9 mL, 22.9 mmol) was diluted with THF (30.5 mL) and ethanol (56 mL) and cooled to −78° C. A solution of (S)-benzyl 4-bromo-1-(3,5-dichlorophenyl)-3-oxobutan-2-ylcarbamate (5.093 g, 11.45 mmol) in THF (56 mL) was then added dropwise down the side of the flask. After 15 min, TLC indicated no starting material remained. The reaction was carefully quenched with 1M HCl and let warm to rt. The organic solvents were removed in vacuo. The residue was taken up in EtOAc, and the aluminum salts removed via filtration. The organic layer was dried over MgSO4, and concentrated to afford benzyl (2S,3S)-4-bromo-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-ylcarbamate (4.08 g, 80% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.05-7.50 (m, 9H) 5.55 (d, J=5.80 Hz, 1H) 4.99 (d, J=12.8 Hz, 1H) 4.87 (d, J=12.8 Hz, 1H) 3.66-3.77 (m, 1H) 3.56-3.65 (m, 2H) 3.36-3.45 (m, 1H) 3.01 (dd, J=13.73, 3.05 Hz, 1H) 2.59 (dd, J=13.43, 10.38 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH2:27][CH3:28])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][CH2:31][CH2:32][CH2:33]Cl.O>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][CH2:32][CH2:31][O:30][CH3:29])[C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH2:27][CH3:28])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCCCl
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)n(CCCOC)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.1 g (15.2 mmol) of potassium carbonate were added to a hot solution of 3 g (10.0 mmol) of 7-benzyl-3-butylxanthine from stage a) in 90 ml of dimethylformamide at 60° C. and the mixture was stirred at 60° C. for one hour. 1.3 g (12.0 mol) of 3-methoxypropyl chloride were then added dropwise and the mixture was stirred at 100° C. for 3 hours. It was then allowed to cool to room temperature, and was treated with water and extracted using dichloromethane. The organic phase was washed with water and 1 N sodium hydroxide solution, dried using sodium sulfate and concentrated under reduced pressure. The oily residue was purified by flash chromatography on a silica gel column, toluene/ethanol (39/1)