Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:11]1[C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N=C(c1cccc(-c3cccnc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {4-methyl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M22) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (162 mg).
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:4]=12>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:4]=12
Reactant: CCn1ncc2c(Cl)c(CO)cnc21
Agent: O=[Mn]=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1ncc2c(Cl)c(C=O)cnc21
Reaction time: 6 h
Yield: 67.5 %

Procedure:
Wet MnO2 (110 g) was refluxed for 90 minutes in 1 L of toluene with a Dean-stark trap for the separation of water. This suspension was then cooled and the 4-chloro-1-ethyl-1H-pyrazolo-[3,4-b]pyridine-5-methanol (17.5 g, 82.7 mmole) was added in 50 ml of toluene. The reaction mixture was then stirred for 6 hours and filtered with the aid of a filter pad. The toluene was evaporated and the residue added again to 100 g of wet MnO2 freshly prepared in the above manner. After additional 4 hours the reaction was briefly warmed at 55° and then filtered again through a filter pad. The residue which remained after evaporation of the toluene was purified by preparative high performance liquid chromatography (10% ethyl acetate/hexane, 250 ml/min) to yield 11.70 g of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde, mp 89°-90° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.ClCCl>[Cl:15][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: ClCc1ccc2ccccc2c1

Procedure:
To 1.26 mol of naphth-2-yl-methanol in 1.5 liters of toluene there are slowly added 3.8 mol of thionyl chloride. The mixture is then heated at reflux for two hours. After cooling, the solvent is evaporated off. The crude product is taken up in toluene twice and evaporated. The oil obtained is taken up in dichloromethane, washed and dried. After filtering and evaporating, the oil obtained is distilled to yield the expected product.
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[Cr](O)(O)(=O)=[O:15].C(O)(C)C>CC(C)=O>[CH:1](/[CH:6]1[CH2:7][CH2:8][CH:9]([C:12]([OH:15])=[O:13])[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/C1CCC(C=O)CC1
Reactant: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCC/C=C/C1CCC(C(=O)O)CC1
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A solution of 1.6 g of 4-(1E-pentenyl)cyclohexanecarboxaldehyde in 120 ml of acetone was cooled to -10° C., treated dropwise with 8N chromic acid (about 10 ml) until the colour of the reaction mixture remained brown-orange and the mixture was stirred for a further 1 hour. Excess chromic acid was reduced by adding isopropanol. The green solution was subsequently partitioned three times in water/methylene chloride. The organic extracts were washed twice with water and the wash-water was back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and evaporated. The pale brown crystalline residue (2.01 g) was dissolved partially in 20 ml of petroleum ether. Undissolved residue was filtered off and the filtrate was evaporated. Recrystallization of the residue obtained from 60 ml of petroleum ether at -78° C. gave 866 mg (49.5%) of 4-(1E-pentenyl)cyclohexanecarboxylic acid as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12][Br:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncnn2c(CCO)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnn2c(CCBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.8 %

Procedure:
To a suspension of 1-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (1.28 g, 2.60 mmol) in anhyrous THF (32 ml) at 0° C. was added CBr4 (1.03 g, 3.1 mmol)) followed by Ph3P (0.75 g, 2.9 mmol) and the reaction was stirred at rt for 24 h. The reaction mixture was poured into H2O (100 ml) and extracted with 150 ml EtOAc. The organic layer was washed with satd. aq NaHCO3, brine and dried over Na2SO4 and was concentrated to give a yellow oil (1.6 g), which was used without further purification. MS [M+H]+=557.2; LCMS RT=3.27 min.
Reaction SMILES: [F:1][C:2]1([F:17])[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]([F:13])([F:12])[C:4]([F:15])([F:14])[C:3]1=[O:16].[Cl:18][C:19]([Cl:24])([Cl:23])C(O)=O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1([F:17])[C:7]([F:9])([F:8])[C:6]([F:10])([F:11])[C:5]([F:12])([F:13])[C:4]([F:14])([F:15])[C:3]1([C:19]([Cl:24])([Cl:23])[Cl:18])[OH:16]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: O=C1C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OC1(C(Cl)(Cl)Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Temperature: -10 °C
Reaction time: 17 h

Procedure:
A solution of 30 g of perfluorocyclohexanone and 31.7 g of trichloroacetic acid was stirred in a pre-dried reaction vessel containing 113 mL of hexamethylphosphoramide. This mixture was cooled to −10° C. in a dry ice/acetone bath. Slight gas evolution was noted before and during the ketone addition. The stirred milky white reaction mixture was maintained at about 0° C. for an hour and then allowed to warm to 23° C. and stirring was continued 17 hours. The clear yellow solution was quenched with 150 mL of 10% HCl and then transferred to a separatory funnel with 400 mL of ethyl ether. This organic phase was washed with 4×500 mL of dilute HCl and then 300 mL of saturated NaCl solution. The solvent was removed by evaporation. The residue (33.7 g) contained 40.8% product by GC, confirmed by fluorine NMR. This carbinol can be converted to the corresponding acrylate by methods previously described (cf. Example 24).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH2:16][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45].Cl>CCOC(C)=O>[CH3:43][S:44]([O:15][CH2:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=[C:10]([CH2:16][N:17]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:11]=1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(CO)cc(-c3ccc(F)cc3)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(COS(C)(=O)=O)cc(-c3ccc(F)cc3)c2)cc1
Reaction time: 1 h

Procedure:
To a solution of N-((4′-fluoro-5-(hydroxymethyl)biphenyl-3-yl)methyl)-N-(4-fluorobenzyl)-4-methylbenzenesulfonamide (100 mg, 0.203 mmol) and Et3N (0.15 mL) in EtOAc (5 mL) at −30° C. was added methanesulfonyl chloride (25 mg, 0.218 mmol) in EtOAc (10 mL) slowly with stirring. After 1 h, a small amount of 1N aq HCl and EtOAc were added to the reaction mixture. The EtOAc layer was separated, dried over MgSO4 and concentrated in vacuo to obtain the product as a viscous material. It was enough pure to use for next step without any further purification. MS (ESI): (M+H)+=572.18.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:31][C:30]1[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=1)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 75 %

Procedure:
A solution of ethyl 5-(benzyloxy)-3-bromo-1H-indole-2-carboxylate, Ref. WO96/18393 (6.77 g, 20.3 mmol, Ref. 96/18393) in N,N-dimethylformamide (10+5 mL rinse) was added slowly (10 min) to a cooled (0° C.) and stirred suspension of sodium hydride (0.72 g, 30 mmol) in N,N-dimethylformamide (30 mL). The reaction was stirred for 1 h and then 4-fluorobenzylbromide (3.7 mL, 5.7 g, 30 mmol) was added. The cold bath was removed and the mixture was stirred for 18 h. The reaction was quenched by pouring over ice water (400 mL) and then the product was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Flash chromatography of the residue over silica gel using 50% dichloromethane/hexane gave 6.80 g (75%) of the desired product containing trace impurities. The product had: 1H NMR (300 MHz, CDCl3) δ 6.84-7.53 (m, 12 H), 5.72 (s, 2 H), 5.13 (s, 2 H), 4.38 (q, 2 H), 1.40 (t, 3 H).
Reaction SMILES: [CH2:1]([N:4]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1Br)[S:5]([CH3:8])(=[O:7])=[O:6])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][S:5]([N:4]1[C:9]2[C:10](=[CH:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)[C:2]([CH3:3])=[CH:1]1)(=[O:7])=[O:6]
Reactant: C=CCN(c1cc([N+](=O)[O-])ccc1Br)S(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(S(C)(=O)=O)c2cc([N+](=O)[O-])ccc12
Yield: 62.9 %

Procedure:
According to the method of Martin, Helv. Chem. Acta. (1989) 72:1554, a mixture of N-allyl-N-(2-bromo-5-nitrophenyl)methanesulfonamide (2.45 g, 7.31 mmol), palladium acetate (83 mg, 0.37 mmol), tri-o-tolyl phoshpine (222 mg, 0.73 mmol) and diisopropylethylamine (1.42 g, 11.0 mmol) in 10 ml of toluene was heated to reflux for 18 hr. The reaction was cooled and filtered through a fine Whatman glass fiber filter to remove the palladium. The mixture was diluted with 100 ml of ethyl acetate, then washed successively with 1M HCl (50 ml) and brine. The extracts were dried (anhydrous MgSO4) and concentrated. The crude product was dissolved in acetone. Silica gel (10 g) was added then the solvent was removed at reduced pressure. The resultant powder was applied to silica gel column (110 g) and eluted with 25% ethyl acetate/hexane to give 1.17 g of 1-methanesulfonyl-3-methyl-6-nitro-1H-indole (63% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
4-(3-Hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 61.6 mmol), 3-trifluoromethylphenol (19.4 g, 64.7 mmol), triphenylphosphine (1.40 g, 73.9 mmol) and tetrahydrofuran (200 ml) were mixed. While stirring the mixture at room temperature, DEAD (21.1 ml, 80.0 mmol) was added thereto dropwise and heated at reflux for 2 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=87:13) to afford the title compound as a pale yellow oil (20.5 g, yield 86%).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[CH3:6][C:7]1[C:8](N2C=NC=N2)=[N:9][C:10](=[O:13])[NH:11][CH:12]=1.C(O)(=O)C>CN(C)C=O>[CH2:3]([S:5][C:8]1[C:7]([CH3:6])=[CH:12][NH:11][C:10](=[O:13])[N:9]=1)[CH3:4]
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCSc1nc(=O)[nH]cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
786 mg (18 mmol) of a 55% strength sodium hydride emulsion are added to 0.7 ml (9 mmol) of ethylmercaptan in 25 ml of dry dimethylformamide at 0° C. and the mixture is stirred for 30 minutes at 0° C. 1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are then added and the mixture is stirred for 3 hours at room temperature. The reaction mixture is neutralized by addition of acetic acid, concentrated and chromatographed on silica gel using dichloromethane/methanol 20/1. 0.64 g (62.7% of theory) of 4-ethylthio-5-methylpyrimidin-2(1H)-one is obtained with melting point 181°-184° C. 1H NMR (60 MHz, d6 -DMSO), δ[ppm]: 11.45 (s, 1H), 7.55 (s, 1H), 3.10 (q, 2H), 1.90 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:25])[C:18]=2[N+:22]([O-])=O)[C:13]1=[O:26])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:22][C:18]1[C:17]([CH3:25])=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[CH:21][N:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:8])[CH3:7])[C:13]2=[O:26]
Reactant: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1N
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with tert-butyl methyl(2-(6-methyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)ethyl)carbamate (110 mg, 0.00031 mol) and ethanol (5 mL, 0.08 mol), and the solution was heated at 85° C. Ammonium chloride (300 mg, 0.006 mol) in water (2 mL, 0.09 mol) was added followed by iron (200 mg, 0.003 mol) in two portions. The reaction was stirred for 1 hour and poured onto dichloromethane (200 mL) and extracted. The solvent was removed under reduced pressure and the residue was purified by flash chromatography. to afford the desired product as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4](=[S:6])=[S:5]>>[CH3:1][N:2]([CH3:4])[C:3](=[S:6])[S:5][S:5][C:4](=[S:6])[N:2]([CH3:3])[CH3:1]
Reactant: S=C=S
Reactant: CNC
Product: CN(C)C(=S)SSC(=S)N(C)C
Reaction time: 0.82 h

Procedure:
The work was carried out as in Example 3, but now the rate of addition of carbon disulfide corresponded to the rate at which dimethylamine was released during the reaction. No further carbon disulfide was added after 46 minutes and the reaction had ended after 49 minutes. This method yielded a total of 35.85 g of tetramethyl thiuram disulfide, corresponding to 99.6% of theoretical.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[O:32][CH3:33]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[O:32][CH3:33]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: COc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 82.2 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (923 mg, 4.0 mmol) was coupled to 2-(4-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.30 g, 5.2 mmol) as described in Example 3 part g), affording 5-(4-fluoro-3-methoxyphenyl)-2-trifluoromethyl[1,8]naphthyridine (1.06 g, 83%). δH (360 MHz, CDCl3) 3.95 (3H, s), 6.99-7.04 (1H, m), 7.06 (1H, dd, J 7.7 and 2.1), 7.30 (1H, dd, J 2.5 and 8.4), 7.56 (1H, d, J 4.2), 7.82 (1H, d, J 8.4), 8.52 (1H, d, J 8.4), 9.27 (1H, d, J 4.2). m/z (ES+) 323 [MH]+.
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:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:24][N:12]1[C:13]2[C:14]([C:20]([F:21])([F:23])[F:22])=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:17][C:18]=2[C@@H:10]2[CH2:9][NH:8][CH2:26][CH2:25][C@H:11]12
Reactant: CN1c2c(cc(O)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: BrCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1c2c(cc(OCc3cccnc3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method as a white solid (48 mg, 49%) 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), 3-bromomethyl-pyridine (141 mg, 0.56 mmol) and K2CO3 (156 mg, 1.12 mmol). MS (ESI): 364 (base, M+H).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10](OC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Si:1]([O:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C=O)O[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Methyl {[tert-butyl(dimethyl)silyl]oxy}(4-methoxyphenyl)acetate (0.5 g, 1.61 mmol) was dissolved in toluene (10 mL) and cooled to −78° C. under a nitrogen atmosphere. DIBAL (1.0M in toluene, 1.9 mL, 1.93 mmol) was added slowly and the mixture was stirred at −78° C. for 1 h. The reaction mixture was poured onto a mixture of ice (20 g) and CHCl3 (20 mL). The mixture was stirred at r.t. for 30 minutes. The layers were separated and the water phase extracted with CHCl3. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated, obtaining 99% (0.45 g) of the title compound. The product was used directly in the next step without further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.[C:41]1([CH2:47][SH:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>ClCCl>[CH2:47]([S:48][CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:8]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: SCc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CSCc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.6 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (300 mg, 0.53 mmol) (preparation 25) was dissolved in stirred dichloromethane (4 ml) and phenylmethanethiol (0.13 ml, 1.05 mmol) and triethylamine (0.15 ml, 1.05 mmol) added. The reaction mixture was stirred for 48 hr at room temperature and then the solvent removed under reduced pressure. The residue was partitioned between methanol (100 ml) and hexane (100 ml) and the methanol layer washed with a further amount of hexane (100 ml). The solvent was then removed under reduced pressure from the methanol layer. The residue was purified by column chromatography on silica gel eluting with a solvent system of ethyl acetate:hexane (3:2) increasing in polarity to ethyl acetate:methanol (98:2). This gave title compound (100 mg) as a foam. MS: 599 (MH+).
Reaction SMILES: BrC1N=C(C[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])C=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([CH2:25]O)[C:21]([F:24])=[N:22][CH:23]=1>>[CH2:11]([O:10][P:9]([CH2:25][C:20]1[C:21]([F:24])=[N:22][CH:23]=[C:18]([Br:17])[CH:19]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: OCc1cc(Br)cnc1F
Reactant: CCOP(=O)(Cc1cccc(Br)n1)OCC
Product: CCOP(=O)(Cc1cc(Br)cnc1F)OCC

Procedure:
Prepared according to the same procedure as diethyl (6-bromopyridin-2-yl)methylphosphonate, starting with (5-Bromo-2-fluoropyridin-3-yl)methanol. 1H-NMR (CDCl3, 500 MHz) δ: 8.18 (d, J=1.2 Hz, 1H), 7.94 (dt, J=8.4, 2.5 Hz, 1H), 4.10-4.16 (m, 4H), 3.10-3.20 (m, 2H), 1.31 (t, J=7.2 Hz, 6H). 13C-NMR (CDCl3, 126 MHz) δ: 147.1, 144.5, 117.0, 116.5, 62.7, 26.9, 25.7, 16.5. Mass spec.: 328.0 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:16]([OH:18])=O)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.CC[N:21]([CH:25]([CH3:27])[CH3:26])C(C)C.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CCOC(C)=O.CN(C=O)C>[CH:25]1([NH:21][C:16]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)=[O:18])[CH2:27][CH2:26]1
Reactant: COCCNc1cc(C(=O)O)c2ccccc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCNc1cc(C(=O)NC2CC2)c2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a DMF (0.1 M) solution of 3-{[2-(methyloxy)ethyl]amino}-1-naphthalenecarboxylic acid (1 eq.) from the previous step, Hunig's base (3 eq.) and cyclopropylamine (1.5 eq.) was added portionwise O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting reaction solution was stirred at RT for 48 h. The now reddish solution was diluted with EtOAc and washed sequentially with 1 N aq. NaOH, water and brine. The organic extract was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a white solid.