Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][C:13]2[O:14][C:15]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][CH2:25][CH3:26])[C:16]=3[C:17]=2[CH3:18])=[CH:10][CH:9]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[O:14][C:15]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][CH2:25][CH3:26])[C:16]=3[C:17]=2[CH3:18])=[CH:27][CH:28]=1
Reactant: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CCCc1c(O)ccc2oc(Cc3ccc(O)cc3)c(C)c12
Reaction time: 0.25 h

Procedure:
Under nitrogen, ethanethiol (3.1 gm; 50 mmoles) was added dropwise over 5 minutes to a mixture of 99% sodium hydride (1.2 gm; 50mmoles) in dimethylformamide (100 mL). After stirring for 15 minutes, a solution of 2-(4-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran (2.1 gm; 6.7mmoles) in dimethylformamide (DMF) (25 mL) was added in one portion. The mixture was refluxed for 1.5 hours, cooled, acidified with 20% citric acid and extracted with ether. The ether solution was washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting oil crystallised on standing at room temperature overnight. The crystals were slurried with hexane, filtered, washed with hexane, and air dried to yield 2-(4-hydroxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran, mp. 138°-142° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH:37]1[CH2:42][CH2:43][OH:44]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH:37]([CH2:42][CH2:43][OH:44])[CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN1CCNCC1CCO
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1CCO

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[3-(2-hydroxy-ethyl)-4-methyl-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(1-Methyl-piperazin-2-yl)-ethanol following General Procedure B.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[Cl:10].[Na+].[I-].[C:13]([S-:15])#[N:14].[K+]>CN(C=O)C.O>[Cl:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH2:2][N:14]=[C:13]=[S:15]
Reactant: N#C[S-]
Reactant: Fc1ccc(Cl)c(CBr)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cl)c(CN=C=S)c1
Temperature: 90 °C

Procedure:
To a solution of 2-(bromomethyl)-1-chloro-4-fluorobenzene (25, 22.3 g, 100 mmol) in dry DMF (150 mL) were added NaI (16.0 g, 107 mmol) and KSCN (19.5 g, 200 mmol) The mixture was heated under N2 at 90° C. for 18 h. After cooling to RT, the mixture was diluted with water (200 mL), and extracted with EtOAc (200 mL×2). The combined extracts were washed with brine, dried over MgSO4, and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with petroleum ether to provide 1-chloro-4-fluoro-2-(isothiocyanatomethyl)benzene (26).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)([CH3:13])[CH2:11][O:10][S:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[OH2:25]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:25])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)n1
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)n2)COS1(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2-oxo-2lambda*4*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (8.83 g, 23.4 mmol) in acetonitrile (60 ml) and H2O (30.0 ml) was added RuCl3 hydrate (0.971 g, 4.68 mmol) and NaIO4 (10.01 g, 46.8 mmol). The reaction mixture was stirred at 0° C. for 2 h. H2O and DCM were added, the phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in DCM and filtered through silica gel, the filtrate was evaporated and the residue was triturated with TBME (10 ml) and n-hexane (100 ml). The resulting precipitate was filtered and washed with n-hexane to yield the title compound as a colourless crystalline solid. HPLC RtH4=1.16 min; ESIMS: 393, 395 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 7.63-7.59 (m, 1H), 7.47-7.42 (m, 2H), 4.73 (d, 1H), 4.47 (d, 1H), 2.00 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.[CH3:29]OS(OC)(=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O.CCOCC>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:29])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(OCc2ccccc2)c(Cl)cc1F
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c1=O
Yield: 62.2 %

Procedure:
A mixture of 1.85 g (4.46 retool) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy) phenyl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione, 492 μL (5.20 mmol) of dimethylsulfate, and 749 mg (8.92 mmol) of sodium bicarbonate in 20 mL of acetone was warmed under reflux for 3 h. Evaporation removed the solvent to give a viscous residue. It was dissolved in 50 mL of ether and washed twice with 30 mL of water, dried (MgSO4) and concentrated in vacuo to give white solid which was flash chromatographed over silica gel, eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 1.19 g of the title compound as a white solid, m.p.: 145°-147° C.; 1 -NMR (CDCl3, 200 MHz) ppm 7.4 (m, 6H), 6.85 (d, 1H), 6.4 (s, 1H), 5.1 (s, 2H), 3.55 (s, 3H) .
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.C1C=CN=CC=1.[FH:23]>O1CCOCC1>[F:23][C@@H:5]1[C@H:6]([OH:11])[C@@H:7]([CH2:9][OH:10])[O:8][C@H:4]1[N:3]1[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]1=[O:12]
Reactant: F
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Yield: 75 %

Procedure:
2,2′-Cyclouridine is treated with a solution of 70% hydrogen fluoride/pyridine in dioxane at 120° C. for ten hours to provide after solvent removal a 75% yield of 2′-deoxy-2′-fluorouridine. The 5′-DMT and 3′-cyanoethoxydiisopropyl-phosphoramidite derivitized nucleoside is obtained by standard literature procedures [Gait, Ed., Oligonucleotide Synthesis. A Practical Approach, IRL Press, Washington, D.C. (1984)], or according to the procedure of Example 4-a.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[H-].[Na+].[CH3:7][NH:8][C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[N:12]1)=[O:10].O>CN(C=O)C>[CH3:7][N:8]([CH2:3][O:2][CH3:1])[C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:27])([F:28])[F:26])=[CH:20][N:19]=2)=[N:12]1)=[O:10]
Reactant: CNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(C)C(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
Chloromethyl methyl ether (0.16 g, 2.0 mmol) was added to a solution of sodium hydride (60% in oil, 0.09 g, 2.2 mmol) and N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.67 g, 2.0 mmol) in DMF (10 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, the mixture was stirred overnight. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a colorless viscous substance of N-methyl-N-methoxymethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.18 g, yield: 23.8%). 1H-NMR (CDCl3, TMS, ppm): δ 1.87 (s, 3H), 3.52 (s, 3H), 3.53 (s, 3H), 5.18 (s, 2H), 5.46 (s, 1H), 7.80-7.95 (m, 1H), 8.50-8.65 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C1COCC1>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCNc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in THF (30 mL) was added N1,N1-dimethylethane-1,2-diamine (310 mg, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, the residue was dissolved in dichloromethane and washed with 1 N HCl aq and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete as indicated by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (280 mg, 50%) as a purple solid: ESI MS m/z 181 [C9H16N4+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:33]=[C:31]([NH:30][C:26]4[CH:25]=[C:24]([OH:23])[CH:29]=[CH:28][CH:27]=4)[N:32]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: N=C(N)Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3cccc(O)c3)ncc1CC2
Yield: 0.8 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (210 mg, 7.94 mmol), N-(3-hydroxy-phenyl)-guanidine nitrate (170 mg, 7.94 mmol), NaOH (32 mg, 7.94 mmol), and 2-methoxyethanol (2 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (10% MeOH:EtOAc) gave the pure title product as a yellow solid (20 mg, 8%): mp 310° C. (dec). Anal. RP-HPLC: tR 10.3 min (0-60% MeCN, purity 92%). 1H-NMR (DMSO-d6): δ 9.50 (s, 1H, OH/NH), 9.28 (s, 1H, OH/NH), 8.38 (s, 1H, Py-H), 7.37 (t, 1H, J 2.3, Ph-H), 7.27 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 7.08 (t, 1H, J 8.3, Ph-H), 6.40 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 3.05 (m, 4H, CH2—CH2), 2.78 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 168.71, 159.05, 158.88, 157.42, 155.97, 155.20, 141.75, 128.81, 127.83, 115.89, 109.69, 108.35, 105.87, 24.72, 23.09, 19.38. MS (ESI+): m/z 311.06 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:5]1[S:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:6]=1[CH2:18][OH:19])([F:4])[CH3:3].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH3:20][S:21]([O:19][CH2:18][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[N:8][S:9][C:5]=1[C:2]([F:4])([F:1])[CH3:3])(=[O:23])=[O:22]
Reactant: CCc1ccc(-c2nsc(C(C)(F)F)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2nsc(C(C)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 28 °C
Reaction time: 0.5 h

Procedure:
Into a 25-mL round-bottom flask, was placed [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methanol (32 mg, 0.11 mmol, 1.00 equiv), dichloromethane (2 mL), MsCl (0.0258 g), triethylamine (34.2 mg, 0.34 mmol, 2.99 equiv). The resulting solution was stirred for 0.5 h at 28° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water, the organic phase was collected. The aqueous phase was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.061 g (crude) of [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C15H17F2NO3S2, 362.4 (M+H). found 362.4.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([CH3:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27])[C:21](O)=[O:22].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([C:21]([NH:14][CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:16])[CH3:15])[CH:8]=2)=[O:22])[CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27]
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(O)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A solution of 3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzenemethanamine (Example 8; 5.80 g, 24.5 mmol) in dry dichloromethane (20 mL) was added to a cooled (0° C.) suspension of 3,5-dichloro-4-hydroxybenzoic acid (4.2 g, 20.4 mmol) and BOP reagent (9.80 g, 22.3 mmol) in dry dichloromethane (50 mL). Diisopropylethylamine (10.6 mL, 60.9 mmol) was added slowly, and the cooling bath was removed. The solution was stirred at room temperature for 5 h, then the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 1 M HCl (2×100 mL), saturated aqueous sodium hydrogen carbonate (100 mL), and brine (100 mL), dried (MgSO4), filtered, evaporated, and chromatographed (30% ethyl acetate/hexanes) to give 2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]phenol (7.50 g, 87%) as a white solid.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][C:6]1[C:16]([O:17][CH3:18])=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[C:7]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH3:4][O:5][C:6]1[C:16]([O:17][CH3:18])=[CH:15][C:9]2[CH2:10][CH2:11][N:12]([CH2:1][CH2:2][OH:3])[CH2:13][CH2:14][C:8]=2[C:7]=1[S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1CO1
Reactant: COc1cc2c(c(Sc3ccccc3)c1OC)CCNCC2
Solvent: CO
Product: COc1cc2c(c(Sc3ccccc3)c1OC)CCN(CCO)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethylene oxide (0.5 ml., 0.44 g., 0.010 mole) is added to a stirred solution of 1.58 g. (0.005 mole) of 7,8-dimethoxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine in 100 ml. of methanol at 0° C. The mixture is stirred at this temperature for 2 hours and then allowed to warm to room temperature. Concentration of the mixture in vacuo gives 7,8-dimethoxy-3-(2-hydroxyethyl)-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([OH:19])=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:24][N:12]1[C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[CH:17][C:18]=2[C@@H:10]2[CH2:9][NH:8][CH2:26][CH2:25][C@H:11]12
Reactant: BrCc1ccncc1
Reactant: CN1c2c(cc(O)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1c2c(cc(OCc3ccncc3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general Method C as a light yellow solid (56 mg, 57%) from (4aS,9bR)-8-hydroxy-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 71, 100 mg, 0.27 mmol), 4-bromomethyl-pyridine (141 mg, 0.56 mmol) and K2CO3 (156 mg, 1.12 mmol). MS (ESI): 364 (base, M+H).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([C@@H:13]([CH3:17])[C:14]([OH:16])=O)[CH:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4]1=[O:19].[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26]1[N:31]=[CH:30][C:29]([C:32]2[N:37]=[C:36]([NH2:38])[CH:35]=[N:34][CH:33]=2)=[CH:28][N:27]=1.C1C=NC2N(O)N=NC=2C=1.N1C=CC=CC=1.CC(C)N=C=NC(C)C>C(Cl)Cl>[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([C@@H:13]([CH3:17])[C:14]([NH:38][C:36]3[CH:35]=[N:34][CH:33]=[C:32]([C:29]4[CH:28]=[N:27][C:26]([N:22]5[CH2:23][CH2:24][CH2:25][C@@H:21]5[CH3:20])=[N:31][CH:30]=4)[N:37]=3)=[O:16])[CH:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4]1=[O:19]
Reactant: C[C@H]1CCCN1c1ncc(-c2cncc(N)n2)cn1
Reactant: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CCCN1c1ncc(-c2cncc(NC(=O)[C@H](C)n3cnc4c3c(=O)n(C)c(=O)n4C)n2)cn1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 47 %

Procedure:
A flask was charged with (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid hydrochloride (Intermediate 8) (8.96 g, 31.0 mmol), (S)-6-(2-(2-methylpyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine (7.23 g, 28.2 mmol), HOAt (3.84 g, 28.2 mmol), nitrogen, DCM (141 ml) and stirred at room temperature. The suspension was cooled to 0° C. followed by addition of pyridine (4.60 ml, 56.4 mmol), then DIC (6.59 ml, 42.3 mmol). The reaction was removed from ice bath immediately after addition of DIC was complete. The reaction was complete after 7.5 hours. The reaction mixture was diluted with 100 mL DCM. The organic layer was washed with 0.5 M HCl aq. (2×20 mL). The resulting organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The resulting DCM filtrate was slowly added dropwise to 300 mL of stirred hexanes at room temperature. The resulting solids were collected via vacuum filtration with aide of hexanes and dried on on frit filter overnight to afford off-white solids (6.5 g, 13.25 mmol, 47.0% yield, 93% ee). ESI-MS (EI+, m/z): 491.33, 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 9.10 (s, 1H), 9.05 (s, 2H), 8.91 (s, 1H), 8.36 (s, 1H), 5.85 (d, J=7.2 Hz, 1H), 4.30 (s, 1H), 3.59 (d, J=27.6 Hz, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d, J=7.3 Hz, 3H), 1.72 (s, 1H), 1.24 (d, J=6.3 Hz, 3H)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].CCCCCC>C(#N)C>[Cl:8][C:7]1[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Product: CC(C)N1CCN(c2nccnc2Cl)CC1
Yield: 79.4 %

Procedure:
A mixture 2,3-dichloro-pyrazine (5.0 g, 34 mmol), 1-isopropylpiperazine (6.5 g, 51 mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was stirred at ambient temperature for 2 h. Addition of hexane, followed by filtration and concentration of the filtrate gave 9.5 g of crude material as an orange liquid. Purification by filtration through silica using heptane/EtOAc (3:1), followed by EtOAc/acetone (1:1), provided 6.5 g (79%) of the title compound as a yellow oil which solidified upon cooling. HPLC purity: 98%. MS m/z 241 (M+H)+. HRMS m/z calcd for C11H17ClN4 (M)+ 240.1142, found 240.1138.
Reaction SMILES: [C:1]1([CH:7]([CH:10]=O)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[CH:10]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:14]1
Reactant: CNN
Reactant: O=CC(C=O)c1ccccc1
Solvent: CCO
Product: Cn1cc(-c2ccccc2)cn1
Yield: 102.1 %

Procedure:
1 g of 2-phenylmalonaldehyde (6.75 mmol) were dissolved in 25 ml of ethanol. 0.36 ml of N-methyl-hydrazine (6.75 mmol) were added, the reaction mixture was stirred under reflux for 4 h, the solvent evaporated under reduced pressure to yield 1.09 g of the product.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2Cl)[CH:8]=[CH:7][N:6]=1)=[O:4].NC1C=CC(O)=C([Cl:28])C=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([Cl:28])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1
Reactant: Nc1ccc(O)c(Cl)c1
Product: CNC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-amino-2-chlorophenoxy)pyridine-2-carboxylic acid methylamide, substituting 4-amino-3-chlorophenol for 4-amino-2-chlorophenol. 1H-NMR (DMSO-d6) δ 8.76 (m, 1H), 8.47 (d, 1H), 7.35 (s, 1H), 7.15 (s, 1H), 7.06 (dd, 1H), 6.85 to 6.95 (m, 2H), 5.43 (s, 2H), 2.78 (d, 3H); MS LC-MS [M+H]+=278.1 [M+H]+, RT=2.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg].[CH:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.O>[CH3:17][CH:16]([OH:18])[C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:7]=1
Reactant: Clc1cc(Br)ccc1-c1ccccc1
Reactant: CC=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(-c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
2-Chloro-4-biphenylmagnesium bromide was prepared by known methods from 53.4 g of 2-chloro-4-bromobiphenyl and 5.0 g of magnesium turnings in tetrahydrofuran. A solution of 9.2 g of acetaldehyde in 100 ml of tetrahydrofuran was added dropwise to the cooled Grignard reagent solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture then was cooled, treated successively with 165 ml of saturated aqueous ammonium chloride and 100 ml of water, and poured onto ice. The reaction mixture was extracted with diethyl ether. The diethyl ether extracts were combined, washed three times with water, and dried over anhydrous sodium sulfate. The diethyl ether was evaporated under reduced pressure and the liquid residue was vacuum distilled to give 28.6 g of α-methyl-3-chloro-4-phenylbenzyl alcohol, bp 145°-157°C/0.09 mm. The following elemental analysis was obtained: