Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=CC=1.[C:21](O)(C(F)(F)F)=[O:22]>ClCCCl>[CH3:21][O:22][C:15]1[CH:16]=[N:17][C:18]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[N:10][C:9]=2[NH2:8]
Reactant: COc1ccc(CNc2nccc3cccnc23)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cnc2c(N)nccc2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of N-(4-methoxybenzyl)-1,7-naphthyridin-8-amine (340 mg, 1.15 mmol) in 1,2-dichloroethane (5.80 mL) was added TFA (2.67 mL, 34.5 mmol). The reaction was stirred at 75° C. for 8 hours and then concentrated. The residue was partitioned between DCM and aqueous sodium bicarbonate. The organic layer was concentrated and purified by silica-gel chromatography, eluting with 50-100% EtOAc in DCM, to provide the title compound (171.7 mg, 0.98 mmol) as an off-white solid. LC/MS (ESI+) m/z=176 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[CH3:20][O-:21].[Na+].O>CO>[CH3:20][O:21][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc2nc(Cl)cc(CCNC(C)=O)c2c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(OC)cc(CCNC(C)=O)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A mixture of N-[2-(2-chloro-6-methoxyquinolin-4-yl)ethyl]acetamide (0.9 g, 3.2 mmol) and sodium methoxide (30 g, 28% methanol solution) in methanol (20 ml) was stirred at 60° C. overnight. The reaction mixture was poured into water, and the organic layer was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate) and recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the title compound (0.46 g, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH3:2]>C(Cl)Cl.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCOc1ccc(-c2ccc(C=CC(=O)OCC)cc2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a stirred solution of 3-(4′-heptyloxybiphenyl-4-yl)acrylic acid ethyl ester (2.65 g, 7.23 mmol) in CH2Cl2 (60 ml) was added palladium on activated carbon (Pd ca.10 wt %, 1.07 g), and then the mixture was set under H2 atmosphere. After being stirred for 2 h, the mixture was filtered through a pad of Celite and washed with CH2Cl2. Filtrate and washings were combined and concentrated in vacuo to give 3-(4′-heptyloxybiphenyl-4-yl)propionic acid ethyl ester (crude, 2.74 g) which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:24][C:15]1[C:14]([CH2:25][NH:26][CH3:27])=[CH:13][N:12]([S:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])(=[O:11])=[O:10])[C:16]=1[C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of tert-butyl {[1-[(3-cyanophenyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (435 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 245 mg, 65%).
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][S:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9].O.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[C:3]([CH2:4][S:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])([OH:12])=[O:2]
Reactant: COC(=O)CCSCC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCSCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of methyl 3-((2-methoxy-2-oxoethyl)thio)propanoate (5.0 g, 26 mmol) in THF/MeOH/water (60 mL, 4:1:1) was added lithium hydroxide monohydrate (4.375 g, 101 mmol). The resulting mixture was stirred at room temperature overnight before it was concentrated under reduced pressure. The residue obtained was diluted with water (˜100 mL) and the resulting solution was acidified with 6N HCl. The mixture was partitioned between water and ethyl acetate. The organic extract was washed with more water, separated, dried over sodium sulfate, filtered and evaporated to afford 3-((carboxymethyl)thio)propanoic acid (3.64 g, 85%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.55-2.57 (t, 2H) 2.75-2.79 (t, 2H) 3.27 (s, 2H) 12.41 (s, 2H)
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
Analogously to Example 1j), 1.4 g (2.69 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-benzyloxyphenylmethyl)-hexanoic acid in 2.9 ml of DMF are silylated with 1.87 g (12.4 mmol) of tert-butyldimethylchlorosilane and 1.5 g (22 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.2 g of potassium carbonate in 63 ml of methanol/THF/water 3:1:1 and column chromatography (SiO2, hexane/ethyl acetate 2:1) of the crude product yields the title compound: TLC Rf (D)=0.17; tRet (II)=33.7 min; FAB-MS (M+H)+ =634.
Reaction SMILES: FC1C=CC([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:20])[N:9]=2)=CC=1C.C(C1C=CC=CC=1)(=O)C.COCCOC1C=CC=CC=1C(OC)=O.[F:46][C:47]1[CH:55]=[CH:54][C:50](C(O)=O)=[CH:49][C:48]=1[CH3:56]>>[F:46][C:47]1[CH:55]=[CH:54][C:50]([N:11]2[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][CH:8]=[N:9][C:10]2=[O:20])=[CH:49][C:48]=1[CH3:56]
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: Cc1cc(-c2cc(-c3ccccc3)[nH]c(=O)n2)ccc1F
Agent: COCCOc1ccccc1C(=O)OC
Solvent: CC(=O)c1ccccc1
Product: Cc1cc(-n2c(-c3ccccc3)ccnc2=O)ccc1F

Procedure:
Using the same or analogous synthetic techniques described in Example 1, 4-(4-fluoro-3-methylphenyl)-6-phenylpyrimidin-2(1H)-one was prepared by replacing 1-[(4-hydroxy-3-methyl)phenyl]ethanone with commercially available acetophenone and methyl 2-{[2-(methyloxy)ethyl]oxy}benzoate with commercially available 4-fluoro-3-methylbenzoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][SH:7].[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:12][CH2:11][C:10]([O:9][CH3:8])=[O:13]
Reactant: SCc1cccs1
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCNCC1
Product: COC(=O)CCSCc1cccs1

Procedure:
A solution of 2-thiophenemethanethiol (12 grams), methylacrylate (7.94 grams), piperidine (3 mL) and N-benzyltrimethylammonium hydroxide (3 mL) was stirred for 16 hours at room temperature. The reaction mixture was distilled in vacuo to yield the desired title compound. Yield: 16.5 grams (83%). Bp: 140° C. at 1 mmHg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.[CH3:18][NH:19][CH3:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:18][N:19]([CH3:20])[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)CCCN1CCSc2cc([N+](=O)[O-])ccc21
Yield: 41.5 %

Procedure:
A solution of 4-(3-chloropropyl)-7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (0.7 g, 2.57 mmol), dimethylamine (2M solution in THF) (2.57 mL, 5.13 mmol), potassium iodide (0.426 g, 2.57 mmol), and potassium carbonate (1.773 g, 12.83 mmol) in dry acetonitrile (20 mL) was stirred at 80° C. for 6 hours in a sealed tube. The reaction was then brought to room temperature and diluted with water (60 mL), and the product was extracted into ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (1:9 (2 M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title product (0.3 g, 42%) as a thick syrup. 1H NMR (DMSO-d6) δ 7.85-7.80 (m, 2H), 6.85 (d, 1H, J=8.7 Hz), 3.77 (t, 2H, J=5.1 Hz), 3.47 (t, 2H, J=7.2 Hz), 3.06 (t, 2H, J=5.1 Hz), 2.24 (t, 2H, J=6.6 Hz), 2.14 (s, 6H), 1.75-1.65 (m, 2H); ESI-MS (m/z, %): 282 (MH+, 100).
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:7]2)[C:5](=[O:22])[NH:4][C:3]1=[O:23]>C(O)C.[Pd]>[CH3:1][N:2]1[C:6]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[C:5](=[O:22])[NH:4][C:3]1=[O:23]
Reactant: CN1C(=O)NC(=O)C12CCN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)NC(=O)C12CCNCC2
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Palladium (10% on carbon; 1.0 g) was added to a solution of benzyl 1-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (7.82 g, 24.6 mmol) in ethanol (100 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 2 h, methanol (50 mL) was added to the reaction mixture and the mixture was continued to be stirred under hydrogen (1 atm). After 4 days, the mixture was filtered through celite, washed with acetone and concentrated. The mixture was diluted in acetic acid (50 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 2 h, the mixture was filtered through celite, and concentrated to give the acetate salt of the title compound (2.98 g). MS 184.1 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C1COCC1.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 24 h

Procedure:
Amine preparation: To a solution of 1-BOC-piperazine (867 mg) in dry THF (8 mL) was added triethylamine (0.97 mL) followed by dimethylcarbamoyl chloride (0.51 mL). After stirring for 24 h the reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent was removed in vacuo to yield 4-dimethylcarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (940 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 166-168° C.; 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 1 H), 7.09 (s, 1 H), 6.99 (s, 1 H), 4.34-4.24 (m, 2 H), 4.08-3.99 (m, 1 H), 3.11 (t, J=8.1 Hz, 2H), 2.12-2.05 (m, 1 H), 1.92-1.76 (m, 1 H), 1.05-1.00 (m, 1 H), 0.94-0.86 (m, 3 H), 0.80-0.71 (m, 1 H), 0.53-0.46 (m, 2 H), 0.33-0.21 (m, 1 H); HRMS (ESI) calcd for C18H19N3OCl3 (M+H)+: 398.0594; found m/z 398.0575.
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)Cl.C1(C)C=CC=CC=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:3]1[O:5][CH2:4]1
Reactant: ClC[C@@H]1CO1
Reactant: Oc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(OC[C@H]2CO2)cc1
Reaction time: 39 h
Yield: 81.7 %

Procedure:
To a reaction vessel were added (S)-epichlorohydrin (99% ee, 30.0 g, 0.32 mol), benzyltrimethylammonium chloride (0.80 g), toluene (70 ml) and water (70 ml), and the mixture was cooled with ice. After addition of phenol (20.3 g, 0.22 mol), thereto 24% aqueous NaOH solution (54.0 g, 0.33 mol) was dropped in a period of one hour under stirring. The mixture was stirred for 30 minutes under ice-cooling and then for 39 hours at room temperature. After the reaction the aqueous layer was removed and the organic layer was neutralized with 5% aqueous HCl solution (70 ml) and washed with water (40 ml). After removal of toluene, the residue was distilled to give objective (R)-glycidylphenyl ether (27.0 g, yield 83%, optical purity 98% ee) as a colorless liquid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:17](C)[C:18](=O)C(F)(F)F)[C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+]>CO.C(Cl)Cl.[Cl-].[Na+].O>[CH3:18][NH:17][C:9]1[C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: COC(=O)c1ncc(-c2ccccc2)nc1N(C)C(=O)C(F)(F)F
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CNc1nc(-c2ccccc2)cnc1C(=O)OC
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
Methyl 3-(methylamino)-5-phenylpyrazine-2-carboxylate. A solution of methyl 3-amino-5-phenylpyrazine-2-carboxylate (360 mg, 1570 μmol) in DCM (10 mL) was treated with DIPEA (547 μl, 3141 μmol) and trifluoroacetic anhydride (275 μl, 1963 μmol). The reaction stirred under nitrogen at 23° C. After 14 hours, the reaction was diluted with DCM (50 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo affording methyl 5-phenyl-3-(2,2,2-trifluoroacetamido)pyrazine-2-carboxylate as an orange solid, which was carried forward to the next reaction. A suspension of methyl 5-phenyl-3-(2,2,2-trifluoroacetamido)pyrazine-2-carboxylate (511 mg, 1571 μmol) and potassium carbonate (651 mg, 4713 μmol) in DMF (10 mL) was treated with iodomethane (196 μl, 3142 μmol). The reaction flask was capped with a septum and heated to 65° C. After 4 hours, the reaction was cooled to 23° C., diluted with EtOAc (75 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 5-25% EtOAc/hexane), affording 221 mg (41%, 2 steps) of methyl 5-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)pyrazine-2-carboxylate as an yellow solid. A solution of methyl 5-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)pyrazine-2-carboxylate (253 mg, 746 μmol) in MeOH (2 mL) and DCM (2 mL) was treated with sodium methoxide (0.5M solution in MeOH (2983 μl, 1491 μmol)). The reaction was stirred under nitrogen at 23° C. After 90 minutes, the reaction was diluted with brine (25 mL) and extracted with DCM (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated, affording 179 mg (99%) of methyl 3-(methylamino)-5-phenylpyrazine-2-carboxylate as a yellow solid. Mass: Calculated: 243.261. Observed: 244.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (1H, s), 8.07-8.17 (2H, m), 7.95 (1H, br. s.), 7.46-7.55 (3H, m), 4.00 (3H, s), 3.18 (3H, d, J=4.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18][C:19]1[CH:24]=[C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)[CH:22]=[C:21]([CH3:29])[N:20]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][C:25]([C:23]3[CH:24]=[C:19]([CH3:18])[N:20]=[C:21]([CH3:29])[CH:22]=3)([OH:26])[CH3:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: Cc1cc(C2(C)CO2)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc(C)n1
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF and sodium hydride (120 mg, 3 mmol) was added. The reaction mixture was stirred for 10 min and 2,6-dimethyl-4-(2-methyloxiran-2-yl)pyridine (210.6 mg, 1.3 mmol) was added dropwise to the reaction mixture with constant stirring. The reaction mixture was stirred at RT overnight. The reaction mixture was poured on crushed ice and the precipitate obtained was filtered under vacuum; washed with water and hexane to obtain 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(2,6-dimethylpyridin-4-yl)propan-2-ol (323 mg) which was dissolved in DCM (3 mL) and cooled to 0° C. Thionylchloride (3 mL) was added dropwise and the reaction mixture was allowed to cool to RT. The reaction mixture was then stirred at RT for 2 h. Thionylchloride was evaporated under vacuum by azeotropic distillation with DCM. 1N NaOH solution was added to basify (pH-12-13) the reaction mixture and the compound extracted with EtOAc (2×30 mL). The organic layer was concentrated under vacuum to get the crude desired product. The crude compound was further purified through reverse phase HPLC. Yield: 17 mg. 1H NMR (CD3OD, D1-HCl salt) δ (ppm): 7.95 (s, 2H), 7.66 (s, 1H), 7.58 (s, 1H), 7.25 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.22 (m, 2H), 3.10 (s, 6H), 2.10 (s, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][O:22][CH3:23])[CH:17]=[CH:16][C:15]=1[CH:24]([CH2:39][CH:40]=[CH2:41])[C:25]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][O:37][CH3:38])=[CH:31][CH:30]=1)([CH3:28])[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[CH3:23][O:22][CH2:21][O:20][C:18]1[CH:19]=[C:14]2[C:15]([CH:24]([CH2:39][CH:40]=[CH2:41])[C:25]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][O:37][CH3:38])=[CH:33][CH:34]=3)([CH3:26])[CH2:28][O:13]2)=[CH:16][CH:17]=1
Reactant: C=CCC(c1ccc(OCOC)cc1O)C(C)(CO)c1ccc(OCOC)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=CCC1c2ccc(OCOC)cc2OCC1(C)c1ccc(OCOC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
Diethyl azodicarboxylate (5.94 ml) was added dropwise to an ice-cold solution of (2RS,3RS)-3-(2-hydroxy-4-methoxymethoxyphenyl)-2-(4-methoxymethoxyphenyl)-2-methyl-5-hexen-1-ol (6.9 g) and triphenylphosphine (11.24 g) in anhydrous 1,4-dioxane (120 ml) over 25 minutes under nitrogen atmosphere. The reaction mixture was stirred for 20 minutes at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give a crude product, which was then purified by flash column chromatography (silica gel: Merck Kieselgel 60, eluent: hexane/ethyl acetate=100/1→20/1→9/1) to give (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-(2-propenyl)chroman (6.5 g, Yield 98.6%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][N:14](C)C=O>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][O:9][CH3:10])=[CH:7][C:2]=1[C:13]#[N:14]
Reactant: COCc1ccc(OC)c(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: COCc1ccc(OC)c(C#N)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
To a solution of 2-bromo-1-methoxy-4-methoxymethyl-benzene (460 mg, 1.991 mmol) in dimethylformamide (5 mL) at room temperature was added zinc cyanide (140.3 mg, 1.195 mmol). The reaction mixture was degassed by passing argon through for 30 min before tetrakis(triphenylphosphine)palladium (138 mg, 0.119 mmol) was added. The reaction mixture was heated at 80° C. for 12 h and stirred at room temperature for 2 d. It was diluted with diethyl ether (50 mL) and washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 30% ethyl acetate in hexanes yielded 2-methoxy-5-methoxymethyl-benzonitrile (268 mg, 76%) as a clear oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][N:16]=2)[C:11]([OH:19])=[C:10]([C:20](OCC)=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C2C(=CC=CN=2)C(O)=C(C(OCC)=O)C1=O)C1C=CC=CC=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[S:57]([NH2:60])(=[O:59])=[O:58].NC1C=CC(Br)=CC=1S(N)(=O)=O>>[NH2:60][S:57]([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[NH:50][C:20]([C:10]1[C:9](=[O:25])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[C:12]([C:11]=1[OH:19])=[CH:13][C:14]([Cl:18])=[CH:15][N:16]=2)=[O:21])(=[O:58])=[O:59]
Reactant: CCOC(=O)c1c(O)c2cc(Cl)cnc2n(Cc2ccccc2)c1=O
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Agent: Nc1ccc(Br)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1ccccc1NC(=O)c1c(O)c2cc(Cl)cnc2n(Cc2ccccc2)c1=O

Procedure:
The title compound was prepared according to the procedure of Example 84C substituting ethyl 1-benzyl-6-chloro-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate for the product of Example 84B and substituting 2-amino-benzenesulfonamide for the product of Example 84A. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.64 (s, 2 H) 7.25 (m, 5 H) 7.44 (t, J=7.72 Hz, 1 H) 7.52 (s, 2 H) 7.67 (m, 1 H) 7.93 (m, 2 H) 8.56 (d, J=2.57 Hz, 1 H) 8.87 (d, J=2.57 Hz, 1 H) 12.34 (s, 1 H) 16.76 (s, 1 H).