Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:17]([N:18]([CH3:20])[CH3:19])=[CH:16][C:8]([CH:9](O)CS(C)(=O)=O)=[CH:7][C:6]=1[N:21]([CH3:23])[CH3:22])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[NH:27]([CH2:34][CH2:35][C:36]#[N:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O>[NH:27]([CH:34]=[C:35]([CH2:9][C:8]1[CH:7]=[C:6]([N:21]([CH3:23])[CH3:22])[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:17]([N:18]([CH3:19])[CH3:20])[CH:16]=1)[C:36]#[N:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#CCCNc1ccccc1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1C(C)(C)C

Procedure:
A mixture of 4.66 g. of 4-tert. butyl-3,5-bis(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 1.28 g. of sodium methylate and 3.3 g. of β-anilinopropionitrile in 35 ml. of dimethylsulfoxide was stirred at room temperature under nitrogen for 60 minutes. The mixture was poured into 200 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and then evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethanol, there was obtained α-(anilinomethylene)-4 -tert. butyl-3,5-bis(dimethylamino)hydrocinnamonitrile having a melting point of 150° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: [O-][n+]1cccc(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COc1ccc[n+]([O-])c1
Yield: 78 %

Procedure:
A solution of 3-chloropyridine-N-oxide (5.3g, 40 mmol) and 25% NaOMe in MeOH (25 ml) was refluxed for 24 hours under an argon atmosphere. The solvent was removed under reduced pressure and the residue was treated with CH2Cl2 and water. The organic phase was separated and dried (Na2SO4) and the solvent removed to give a residue which was triturated with hexane to yield 4 g (78%) of product as a crystalline solid, m.p. 99°-101° C. The structural assignment is supported by the proton NMR spectrum.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Br:23])[C:15]=1OC.Cl>CN(C=O)C.O>[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Br:23])[C:15]=1[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:11]#[N:12]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: COc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(c1ccc(Cl)cc1)c1c(Br)cc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
NaH (0.0772 mol) was added portionwise at 0° C. under N2 flow to a mixture of 4-chloro-benzeneacetonitrile (0.0643 mol) in DMF (50 ml). The mixture was stirred at 0° C. under N2 flow for 1 hour. A mixture of 1,3-dibromo-2-methoxy-5-nitro-benzene (0.0643 mol) in DMF (50 ml) was added at 0° C. under N2 flow. The mixture was stirred at RT for 3 hours, hydrolized with H2O and HCl 3N and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 60/40). The pure fractions were collected and the solvent was evaporated, yielding 12.8 g (46%) of (±)-2,6-dibromo-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (interm. 76).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].[NH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1>CC(C)=O>[F:5][C:4]([F:7])([F:6])[C:3]1[N:9]=[C:10]2[N:14]([CH:2]=1)[CH:13]=[CH:12][S:11]2
Reactant: O=C(CBr)C(F)(F)F
Reactant: Nc1nccs1
Solvent: CC(C)=O
Product: FC(F)(F)c1cn2ccsc2n1
Temperature: 25 °C

Procedure:
3-Bromo-1,1,1-trifluoroacetone (11.0 mmol) is added to a solution of 2-aminothiazole (10.0 mmol) in acetone (20 mL) and the mixture is stirred at reflux for 20 h. The obtained precipitate is filtered off, treated with hydrobromic acid (2.0 M, 40 mL), stirred at reflux for 1 h and cooled to RT. The mixture is made basic by addition of ammonium hydroxide solution (15%) and the resulting free base is crystallized from EtOH to give the desired product. LC-MS: tR=0.78 min; [M+H]+=192.95.
Reaction SMILES: [Mg].[CH2:2]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=2)([OH:32])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCCCCCOc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a suspension of magnesium turnings (0.48 g) in tetrahydrofuran (10 ml) was added dropwise a solution of 4-hexyloxybromobenzene (5 g) in tetrahydrofuran (70 ml) and stirred for 1 hour at ambient temperature. Then to the reaction mixture was added 1-benzyloxycarbonyl-4-piperidone (4.12 g) and stirred for 2 hours under ice-cooling. The reaction was quenched with saturated NH4Cl aq. and extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with (hexane/ethyl acetate)=(3/1). The fractions containing the object compound were collected and evaporated under reduced pressure to give 1-benzyloxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (3.44 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([NH2:9])=[N:6][C:7]=1Cl.C(N(CC)CC)C.[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[NH2:9][C:5]1[N:6]=[C:7]([NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:2]([Br:1])=[C:3]([Cl:10])[N:4]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Nc1nc(Cl)c(Br)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1nc(N)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
A stirred solution of 5-bromo-4,6-dichloropyrimidin-2-amine (Reference Example 1, 14.00 g, 0.0576 mole), and triethylamine (41.8 mL, 0.2997 mole) in DMF (55 mL) was treated with tert-butyl 2-aminoethylcarbamate (9.24 g, 0.0576 mole). The reaction mixture was stirred at ambient temperature for 18 hours, then volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid that was triturated with ether to remove color. The ether-insoluble material was collected by filtration and dried under vacuum to provide tert-butyl 2-(2-amino-5-bromo-6-chloropyrimidin-4-ylamino)ethylcarbamate (18.02 g, 85.2% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.42 (s, 9H), 3.25 (t, J=6 Hz, 2H), 3.47 (t, J=6 Hz, 2H). MS (DCl—NH3) m/z=366 (M+H)+.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=1>CCCCCC.C(OCC)(=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1ccc(COc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 4-chlorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC). HPLC/MS: m/e=477 (M+1); Rt=4.91 min; 1H-NMR 500 MHz (CDCl3): δ 5.50 (s, 2H), 7.02 (d, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 1H), 7.22-7.30 (m, 4H), 7.40 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 8.62 (s, 1H). 2-(4-Chlorobenzyloxy)-4-(2-chloro-4-thiomethyl phenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf by-product of the thiomethyl anion displacement of the 4-chloro substituent on the 4-(2,4-dichlorophenyl) ring. HPLC/MS: m/e=489 (M+1); Rt=4.81 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.50 (s, 2H), 7.03 (m, 2H), 7.10-7.20 (m, 2H), 7.24-7.30 (m, 3H), 7.38 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 8.60 (s,1H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[CH:9]=[O:10])=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:22].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl.[S-2].[Na+].[Na+]>CC(O)(C)C.O.C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:8]=2[C:9]([OH:22])=[O:10])=[CH:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzaldehyde (1.16 g, 4.08 mmol) in tBuOH (11.60 mL), water (7.30 mL), acetonitrile (7.30 mL) was added sodium dihydrogen phosphate (1.47 g, 12.25 mmol), 2-methyl-2-butene (2.16 mL, 20.42 mmol) and sodium chlorite (1.11 g, 12.25 mmol) and the reaction mixture was stirred at 25° C. for 2 hours. The reaction was acidified with 1N HCl and diluted with ethyl acetate. Sodium sulfide was added to remove the slightly yellow color. The 2 layers were separated and the aqueous layer extracted 2 additional times with ethyl acetate. The organics were combined, dried with MgSO4, filtered and evaporated to give 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzoic acid (1.0 g, 82%) as a yellow solid that was used in the next step without further purification. 1H NMR (400 MHz, DMSO) δ 8.01 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.33-7.18 (m, 3H), 7.14-7.01 (m, 2H) ppm.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=O)C.Cl[C:34]([O:36][CH3:37])=[O:35].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:37][O:36][C:34]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[C:6]=2[CH2:5]1)=[O:35]
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
According to Scheme 11: To a solution of 3-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11t) (0.05 g, 0.123 mmol) in dry CH2Cl2 (2 ml) at 0° C. methyl chloroformate (12 mg, 0.13 mmol) and NEt3 (19 mg, 0.191 mmol) was added, the mixture was stirred at 0-5° C. for 60 min, then at 25° C. for 18 h. After addition of aqueous saturated NaHCO3 (2 ml), the mixture was extracted with CH2Cl2 (10 ml), the organic layer was dried over Na2SO4, solvents were evaporated in vacuo and the crude product was purified by purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 31 mg of 3-(3-cyano-phenyl)-1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester (17a).
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][N:7]=[C:8]([CH2:28][C:29]([CH3:31])=[CH2:30])[C:9](=[C:11]([O:26][NH2:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[N:23][O:24][CH3:25])[C:19]([NH:21][CH3:22])=[O:20])[CH3:10])[CH3:5]>CN(C=O)C>[CH2:4]([O:6][N:7]=[C:8]([CH:28]=[C:29]([CH3:30])[CH3:31])[C:9](=[C:11]([O:26][NH2:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[N:23][O:24][CH3:25])[C:19]([NH:21][CH3:22])=[O:20])[CH3:10])[CH3:5]
Reactant: C=C(C)CC(=NOCC)C(C)=C(ON)c1ccccc1C(=NOC)C(=O)NC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCON=C(C=C(C)C)C(C)=C(ON)c1ccccc1C(=NOC)C(=O)NC
Temperature: 23 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
48.4 g of solid sodium methoxide in 400 ml of DMF were stirred at 23° C. for 3 hours, and 174 g of the amide from Example 8 in 250 ml of DMF were then added dropwise. The mixture was subsequently stirred at 23° C. for 18 hours and then worked-up similarly to Example 6. This gave 154 g of the title compound as a colorless solid which, according to NMR, GC and HPLC analysis, contained approximately 12% of the starting material (Example 8).
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][O:17][CH3:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([NH2:38])=[CH:37][C:30]=2[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([NH:38][C:2]3[N:19]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[CH2:16][O:17][CH3:18])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:37][C:30]=2[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COCc1ccccc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: COCc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
7-[8-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-Methoxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.40 g, 1.46 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.46 g, 1.75 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.5 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (d, J=6 Hz, 1H), 7.61 (d, J=6 Hz, 1H), 7.51-7.42 (m, 4H), 7.00-6.89 (m, 3H), 6.79 (s, 1H), 3.62-3.45 (m, 4H), 3.29 (s, 3H), 2.84-2.74 (m, 4H), 1.52 (s, 9H). MS=500 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15]C)=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO.O>[CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([OH:15])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Temperature: 22.5 °C
Reaction time: 18 h

Procedure:
A mixture of Bicyclo[2.2.2]octane-1,4-dicarboxylic acid dimethyl ester (III, Example 80, 20.4 g, 89.5 mmol), barium hydroxide octahydrate (14 g, 44.7 mmol) in methanol (160 ml) and water (40 ml) is stirred at 20-25° C. for 18 hour. The mixture is diluted with water (600 ml) and extracted with hexane (150 ml×2). The aqueous mixture is acidified (6 N hydrochloric acid) to pH=1-2 and extracted with chloroform (150 ml×2). The combined chloroform extracts are concentrated. The residue is dissolved in toluene, filtered and concentrated to give the title compound, mp=169-173° C.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:9][O:10][C:11](=[O:39])[C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:38])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34](=[O:37])[CH:35]=[CH2:36])=[CH:14][CH:13]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.COC1C=CC(O)=CC=1>C(O)C>[OH:7][CH:8]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:9][O:10][C:11](=[O:39])[C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:38])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34](=[O:37])[CH:35]=[CH2:36])=[CH:16][CH:17]=1
Reactant: C=CC(=O)OCCCCCCOc1ccccc1C(=O)Oc1ccc(C(=O)OCC(OC2CCCCO2)c2ccccc2)cc1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=CC(=O)OCCCCCCOc1ccccc1C(=O)Oc1ccc(C(=O)OCC(O)c2ccccc2)cc1
Temperature: 55 °C

Procedure:
The crude (R)-4-(4-(6-acryloyloxyhexyloxybenzoyloxy)benzoic acid 2-(tetrahydropyran-2-yloxy)-2-phenyl-ethyl ester (11) was dissolved in 35 ml of ethanol and 0.25 g (1 mmole) of pyridinium 4-toluensulfonate and 40 mg of 4-methoxyphenol were added. The mixture was heated at 55° C. for 15 h. After cooling to 0° C. the product precipitated. 3.2 g of a white solid was obtained (60%).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:29]=[CH:28][C:10]([NH:11][C:12]2[C:17]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:22]([NH:21][C:19]([NH:18][C:17]1[C:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]3[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=3)=[CH:29][CH:28]=2)=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCNC(=O)Nc1cccnc1Nc1ccc(CCN)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1
Yield: 32.8 %

Procedure:
N-{2-[4-(2-Aminoethyl)anilino]-3-pyridinyl}-N′-hexylurea formate (0.24 g, 0.60 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.242 g, 0.60 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.15 g, 0.197 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH2:17][CH2:18]I)[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:16][CH2:17][CH2:18][CH:14]3[O:13][C:12](=[O:15])[CH:11]=[C:10]23)=[CH:4][CH:3]=1
Reactant: O=C1C=C(N(CCCI)Cc2ccc(Cl)nc2)CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C2C(CCCN2Cc2ccc(Cl)nc2)O1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
31.55 g (80.36 mmol) of 4-[[(6-chloropyridin-3-yl]methyl](3-iodopropyl)amino]furan-2(5H)-one (II-3) are dissolved in 900 ml of tetrahydrofuran and cooled to −78° C., and 42.19 ml (84.38 mmol) of a 2.0M solution of lithium diisopropylamide in tetrahydrofuran are added. After 10 minutes of stirring at −78° C., the mixture is warmed to room temperature and stirred at room temperature for a further 30 minutes. After addition of 20 ml of methanol, the mixture is concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 18.05 g (85% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridine-2(4H)-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[NH2:23][CH:24]([CH3:26])[CH3:25]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:19][NH:23][CH:24]([CH3:26])[CH3:25])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: CC(C)N
Product: CC(C)NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (75 mg) was reacted with 2-aminopropane similarly to as described in the synthesis of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(4-methylpiperazin-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide to afford 10-bromo-9-fluoro-3-((isopropylamino)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 34 mg (40%) of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-[(isopropylamino)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=411.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:16])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>O>[CH2:6]([O:5][CH2:4][CH:3]1[CH2:2][O:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCOCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCOCC1CO1
Temperature: 40 °C
Yield: 67 %

Procedure:
To the crude 1-chloro-3-decyloxy-2-propanol prepared as described above and cooled to 40° C. was added NaOH (50% aqueous, 76 g, 2.2 mole) and water (44 g). The temperature rose to 50° C., then the mixture was heated to 85°-90° C. for three hours. Analysis by GC showed the crude product contained 11% unreacted alcohol and 75% of the expected epoxide. Water (200 ml) was added to dissolve precipitated salt. The aqueous phase was separated (pH 4) and the organic phase washed with 5% NaCl solution to pH 7-8 (2×400 ml). The crude product (435 g, 102%) was fractionally distilled at 12 mmHg to yield 286 g of (decyloxy)methyloxirane (67% overall based on epichlorohydrin). GC showed the product was 97% pure.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35](Cl)=[CH:34][C:33]=4Cl)[C@@H:16]([O:17]CC4C=CC(Cl)=CC=4Cl)[C@@:13]3([CH3:40])[O:14][CH3:15])[C:6]=2[N:7]=1>CO.CCN(CC)CC.[Pd]>[NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:28][C@H:27]([CH2:29][O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@@H:16]([OH:17])[C@@:13]3([CH3:40])[O:14][CH3:15])[C:6]=2[N:7]=1
Reactant: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(C)c2c(=O)[nH]c(N)nc21
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CO[C@]1(C)[C@H](O)[C@@H](COCc2ccccc2)O[C@H]1n1cc(C)c2c(=O)[nH]c(N)nc21
Reaction time: 36 h

Procedure:
A mixture of the product from Step C (64 mg, 0.1 mmol) in MeOH (5 mL) and Et3N (0.2 mL) and 10% Pd/C (24 mg) was hydrogenated on a Parr hydrogenator at 50 psi at r.t. for 1.5 days, then filtered through a Celite pad which was thoroughly washed with MeOH. The combined filtrate was evaporated and the residue purified on a silica gel column (3×4 cm) with CH2Cl2/MeOH (30/1, 20/1) as eluent to yield 2-amino-5-methyl-7-(5-O-benzyl-2-C,2-O-dimethyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one. The compound (37 mg) was further hydrogenated in EtOH (2 mL) with 10% Pd/C and under atmospheric pressure of hydrogen. After stirring 2 days at r.t., the reaction mixture was filtered through Celite, the filtrate evaporated and the crude product purified on a silica gel column (1×7 cm) with CH2Cl2/MeOH (30/1, 20/1 and 10/1) as eluent to yield the title compound (12 mg) after freeze-drying.