Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]#[C:3][CH:4]1[CH2:6][CH2:5]1.[F:7][C:8]([F:20])([F:19])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[CH2:12][N:13]=[N+:14]=[N-:15]>>[CH:4]1([C:3]2[N:15]=[N:14][N:13]([CH2:12][C:11]3[CH:16]=[CH:17][CH:18]=[C:9]([C:8]([F:7])([F:20])[F:19])[CH:10]=3)[C:2]=2[I:1])[CH2:6][CH2:5]1
Reactant: IC#CC1CC1
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(Cn2nnc(C3CC3)c2I)c1

Procedure:
Synthesized from (iodoethynyl)cyclopropane and 3-trifluoromethyl-benzylazide using general procedure; 0.589 g, 1.498 mmol, 96%; mp=129-134° C. (dec.); IR (υ[cm−1]) 3087, 3011, 1453, 1325, 1165, 1122, 1074, 777, 701; 1H NMR (600 MHz, CDCl3) δ=7.57-7.56 (m, 2H), 7.45 (t, J=7.7, 1H), 7.39 (d, J=7.7, 1H), 5.57 (s, 2H), 1.78-1.72 (m, 1H), 1.06-1.01 (m, 2H), 0.99-0.93 (m, 2H); 13C NMR (151 MHz, CDCl3) δ=153.8, 135.6, 131.7 (q, J=32.6), 131.4, 129.7, 125.6 (q, J=3.7), 125.0 (q, J=3.9), 124.0 (q, J=272.3), 77.9, 53.7, 7.8, 7.5; HRMS (ESI-TOF) (m/z): [M+Na]+ calcd for C13H11F3IN3Na, 415.9847; found 415.9847.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](O)=[O:32])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[C:24]([CH2:31][OH:32])=[CH:23][N:22]=3)[CH2:19][CH2:20]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(C(=O)O)c(C(F)(F)F)n3)CC2)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(CO)c(C(F)(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Half of the crude 57b was combined with triethylamine (50 μL, 0.36 mmol) in 2 mL of THF and treated at 0° C. with ethyl chloroformate (30 μL, 0.31 mmol). The mix was stirred at room temperature for 4 h then it was added to a stirred suspension of sodium borohydride (32 mg, 0.84 mmol) in water and the stirring was continued for 3 h. The mixture was quenched with aqueous NaHCO3 (5 mL) and water (5 mL) and extracted with EtOAc (3×5 mL). The combined extracts were dried and concentrated and the residue was purified by preparative HPLC to afford 58-1: LC-MS 460.1 (MH+), tR=7.49 (Method 2).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:31][N:32]=[C:33]=[O:34]>C(Cl)Cl>[CH3:31][NH:32][C:33]([N:1]1[CH2:5][CH2:4][CH:3]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH2:2]1)=[O:34]
Reactant: CN=C=O
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)C1
Reaction time: 0.5 h

Procedure:
45-3 (0.27 g, 0.93 mmol) was dissolved in methylene chloride (4 mL) and DIEA (0.60 g, 4.67 mmol) and then a methylene chloride solution (1 mL) of methylisocyanate (0.050 g, 0.93 mmol) was added. The solution was then stirred for 30 minutes, after which it was concentrated and purified on a C18 preparative hplc column to afford 45-4. 1H-NMR (CD3OD): 7.37(m, 5H); 5.17(s, 2H); 3.89(m, 4H); 3.59(m, 4H); 3.36(m, 5H); 2.74(s, 3H); 2.47(m, 1H); 2.24(m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH:13](=O)[CH2:14][CH2:15][CH3:16]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)[CH2:14][CH2:15][CH3:16])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CCCC=O
Product: CCCC(c1c[nH]c2ccc([N+](=O)[O-])cc12)c1c[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
ST 1429 was prepared from 5-nitroindole and butyraldehyde prepared using the method described in example 2/1.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH3:32][NH:33][CH2:34][CH3:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=3[CH2:25][N:33]([CH2:34][CH3:35])[CH3:32])[CH:8]=2)[N:3]=1
Reactant: CCNC
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCN(C)Cc1ccc(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
114 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 48 μl of methylethylamine and 32 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 185 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: C[O:2][C:3]1[N:4]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=2.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:12][C:9]1[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=[C:5]2[C:10]=1[NH:11][C:3](=[O:2])[N:4]2[CH2:19][CH:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CCCCCNc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of 8-methoxy-N2-pentyl-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (140 mg) in dry MeOH (15.7 mL) was added 4N HCl in 1,4-dioxane (2.65 mL). The reaction mixture was stirred at room temperature for 3 h and was then neutralised with 2M sodium hydroxide solution. The mixture was concentrated in vacuo and the residue was taken up into water (20 mL). The mixture was filtered under reduced pressure to give the title compound (95 mg) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C(Cl)Cl>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:9](=[O:10])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:3][CH:4]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: Cc1csc(NC(=O)Oc2ccccc2)n1
Yield: 51.2 %

Procedure:
Step 1 A solution of 2-amino-4-methylthiazole (11.42 g, 0.10 mol) in DCM was cooled to 0° C. and treated with TEA (12.1 g, 0.12 mol), then phenyl chloroformate (15.6 g, 0.10 mol) was added dropwise with stirring. The mixture was stirred for 10 minutes, then was washed with NaHCO3 (aq), water and brine, and dried and concentrated. The residue was purified by column chromatography (eluting with 60:40 hexane-EtOAc) to give phenyl 4-methylthiazol-2-ylcarbamate as a white solid (12 g, 51%). 1H NMR (300 MHz, chloroform-d) δ 12.38 (bs, 1H) 7.47-7.40 (m, 2H) 7.30-7.19 (m, 3H) 6.52 (d, J=1.1 Hz, 1H) 2.41 (d, J=0.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]([C:22](=[O:25])[CH2:23]Cl)[CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:5]2.Cl.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:12][CH2:13][NH:14][CH2:23][C:22]1=[O:25])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1Cc2ccc(Br)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CNCCN1C1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Step B (0.17 g, 0.39 mmol) in 10 mL of DCM was added 5 mL of HCl/Et2O and the mixture was stirred at RT for 2 hours and then concentrated. The residue was dissolved in 20 mL of EtOH and added K2CO3 (163 mg, 1.18 mmol), and then the mixture was refluxed for 4 hours. The reaction mixture was filtered and concentrated and the residue was used directly for next step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4](Cl)[N:3]=1.[OH-].[NH4+:12]>>[Cl:8][C:6]1[N:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH2:12])[C:5]=1[NH2:9]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1nc(N)c(N)c(Cl)n1
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
2-Methyl-4,6-dichloro-5-aminopyrimidine (Aldrich, 1.05 g) and ammonium hydroxide (3.0 mL, J. T. Baker, Phillipsburg, N.J., 28.0%-30.0%) were placed in a microwave vial. The vial was sealed and heated in a CEM microwave reactor (CEM Corporation, Matthews, N.C.) at 120° C. and 40 Watts for 25 minutes. The reaction was cooled to room temperature. This procedure was repeated a total of nine times using the following amounts of 2-methyl-4,6-dichloro-5-aminopyrimidine under the same reaction conditions:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH2:12][S:13][CH3:14])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO>[Fe].C(O)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][S:13][CH3:14])=[CH:10][C:4]=1[NH2:1]
Reactant: CSCOc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CSCOc1ccc(N)c(N)c1

Procedure:
4.5 g. of 2-nitro-4-methylthiomethoxyaniline in 95 ml. of methanol and 5 ml. of acetic acid is treated with 8 g. of iron powder and the mixture is refluxed for 4 hours. The hot solution is filtered and the solvent evaporated. The residue is treated with hot tetrahydrofuran. The mixture is filtered and the solvent evaporated to give 1,2-diamino-4-methylthiomethoxybenzene.
Reaction SMILES: CC(C)([O-])C.[K+].O[CH:8](S([O-])(=O)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:23])[CH:12]=1.[Na+:28].[C:29]([O:33][C:34](=[O:48])[CH2:35][CH:36](P(OCC)(OCC)=O)[C:37]([OH:39])=[O:38])([CH3:32])([CH3:31])[CH3:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(C)(C)C.O>[Na+:28].[C:29]([O:33][C:34](=[O:48])[CH2:35]/[C:36](=[CH:8]\[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:23])[CH:12]=1)/[C:37]([O-:39])=[O:38])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1cc(CCC(O)S(=O)(=O)[O-])ccc1-c1ccccc1
Reactant: CCOP(=O)(OCC)C(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CC/C=C(\CC(=O)OC(C)(C)C)C(=O)[O-])ccc1-c1ccccc1
Reaction time: 4 h
Yield: 42.5 %

Procedure:
A solution of potassium tert-butoxide (7.25 g, 64.6 mmol) in THF (24 ml) was added over 1 hour to a stirred solution of sodium 1-hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-propanesulfonate (5.0 g, 15.2 mmol) and 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester (5.5 g, 17.7 mmol) in THF (6 ml) and tert-butanol (30 ml), between −5 and 0° C., under nitrogen. The mixture was stirred between −5 and 0° C. for 4 hours and then a solution of citric acid (13.2 g) in demineralised water (132 ml) was added in one portion. The pH was adjusted to pH4-5 by the addition of aqueous sodium hydroxide solution (40%) and the organic phase was separated. The organic phase was concentrated in vacuo and then recombined with the aqueous phase. Ethyl acetate (55 ml) was added and the organic phase was separated and then washed with a solution of sodium bicarbonate (3.5 g) in demineralised water (50 ml). The organic phase was separated and washed with citric acid (5.0 g) in demineralised water (50 ml), demineralised water (50 ml) and then concentrated in vacuo to an orange oil. The oil was taken up in acetonitrile (30 ml) and a solution of sodium bicarbonate (0.65 g, 4.1 mmol) in demineralised water (5 ml) was added. The solution was azeotropically dried by distillation at a constant volume of acetonitrile and the mixture was granulated at 20-25° C. overnight. The mixture was filtered and the residue dried in vacuo at 45° C. to give the title compound as a white solid (2.6 g, 43% yield, 95% pure by NMR).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[C:20]1[C:29]([CH3:30])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[CH:26]=2)[C:21]=1[O:33][CH2:34][O:35][CH3:36]>C1(C)C=CC=CC=1.CCOCC.O.C1(P([Pd-4](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)C=CC=CC=1>[CH3:32][O:31][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]([O:33][CH2:34][O:35][CH3:36])=[C:20]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[C:29]([CH3:30])=[CH:28]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COCOc1c(-c2ccco2)c(C)cc2cc(OC)ccc12
Temperature: 105 °C
Yield: 76 %

Procedure:
2-(Tributylstannyl)-furan (0.4 mL, 1.29 mmol)) was added slowly to a solution of 2-bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14 (0.4 g, 1.29 mmol) in toluene (10 mL). Reaction mixture was heated at 105° C. A portion (0.01 g) of tetrakis(triphenylphosphino)palladium (0) (0.061 g, 0.053 mmol) was added every 1 h until reaction was complete. Reaction mixture was cooled to RT then diluted with Et2O and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude oil was purified with a gradient of 20% EtOAc in hexanes to give 0.29 g (76%) of the title compound (213) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.36 (s, 3H), 3.37 (s, 3H), 3.93 (s, 3H), 4.85 (s, 2H), 6.49-6.50 (m, 1H), 6.53-6.55 (m, 1H), 7.05 (m, 1H), 7.11 (dd, J1=2.4 Hz, J2=9.2 Hz, 1H), 7.39 (s, 1H), 7.58-7.58 (m, 1H), 8.08 (d, J=9.2 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:45]=[CH:44][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:28][C:29]4[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:30]=4[F:38])[C:14](=[O:39])[N:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:45]=[CH:44][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:28][C:29]4[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:30]=4[F:38])[C:14](=[O:39])[N:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCn1c(=O)n(Cc2cc([N+](=O)[O-])ccc2F)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCn1c(=O)n(Cc2cc(N)ccc2F)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Yield: 95.9 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-nitro-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (45 mg, 0.07 mmol) in methanol (30 mL) was treated with 10% palladium on carbon (45 mg). The reaction mixture was subjected to 48 psi pressure of hydrogen gas in a Parr apparatus for 2 h. At this time, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated in vacuo to afford 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-1-(5-amino-2-fluoro-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (39.8 mg, 92.9%) as an off-white solid: LR-MS for C31H37FN6O5 (M−H)+ at m/z=591.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].[Br:13][CH2:14][CH:15]=[CH:16][CH2:17]Br>CC(C)=O>[Br:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: BrCC=CCBr
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OC/C=C/CBr
Temperature: 55 °C
Yield: 41.1 %

Procedure:
A mixture of 4-hydroxy-3-methoxyacetophenone (10 g, 59 mmol), K2 CO3 (10 g, 1.2 q) and 1,4-dibromo-2-butene (>95% trans, Aldrich, 18 g, 1.2 eq) in acetone (500 ml) was heated at 55° C. for 3 hours. At the end of the reaction, the solvent was concentrated. The crude product was extracted into dichloromethane (750 ml) and the insolubles were filtered; then the solution was concentrated again to an oil. Purification on a silica gel column (SiO2, 100 g, eluted with dichloromethane) yielded 7.25 g (40%) of white solid. Recrystallization from ether gave analytically pure
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH2:11][CH2:12][OH:13])[CH2:7]1)=[O:5].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45]>C(OCC)(=O)C.CO.ClCCl>[C:44]([CH2:43][CH2:42][CH2:41][O:1][C:2]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][C:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([CH2:11][CH2:12][OH:13])[CH2:7]1)=[O:5])([O:46][CH2:47][CH3:48])=[O:45]
Reactant: CCOC(=O)CCCBr
Reactant: O=C(c1cc(-n2cnnn2)ccc1O)N1CCC(CCO)(c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
Combine 1-(2-hydroxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.19 g, 0.5 mmol) and dimethylformamide (5 mL). Add potassium carbonate (82 mg, 0.6 mmol) and 1-bromo-3-carboethoxypropane (0.21 mL, 0.29 g, 1.5 mmol). Heat at 100° C. After 2.5 hours, cool to ambient temperature. After 18 hours, dilute the reaction mixture with ethyl acetate, extract with water, aqueous 1 M hydrochloric acid solution, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia to give the title compound: Rf=0.28 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].[S:17](=[O:20])(=[O:19])=[O:18].O1CCOCC1>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([S:17]([OH:20])(=[O:19])=[O:18])[C:12]([Cl:14])=[O:13])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: O=S(=O)=O
Reactant: COc1cc(CC(=O)Cl)ccc1OC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(C(=O)Cl)S(=O)(=O)O)ccc1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of 4-acetoxy-3-methoxyphenylacetyl chloride (2.42 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide - dioxane complex (15 mmole) dichloroethane at 0° C. This mixture was stirred at room temperature for eighteen hours and evaporated to afford a yellow gum. νmax. (CHCL3) 1800, 1748 cm-1.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>O1CCCC1>[C:1]1([C:7]2[C:15]([CH2:16][C:17]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:19])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cc1c(-c2ccccc2)nn2cccnc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 4 hours at room temperature while nitrogen was bubbled through the mixture. After additional stirring, a solution of 4.19 g (0.041 mole) of di-n-propylamine in 10 ml of anhydrous tetrahydrofuran was added dropwise and the mixture was stirred for about 17 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue (7.3 g) was recrystallized from ethanol-water to give 3.3 g of product (72%), mp 103°-105° C.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Cl[CH:29]([O:42][CH:43]1[CH:48]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH2:58][O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[O:67][CH3:68])=[CH:51][CH:50]=2)[CH2:47][CH2:46][N:45]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:44]1)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:31]=1.[NH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>C1(C)C=CC=CC=1>[CH3:68][O:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[CH2:60][O:59][CH2:58][CH2:57][CH2:56][O:55][C:52]1[CH:53]=[CH:54][C:49]([CH:48]2[CH2:47][CH2:46][N:45]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:44][CH:43]2[O:42][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)=[C:32]([O:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:31]=2)=[CH:50][CH:51]=1
Reactant: COCCCOc1cccc(C(Cl)OC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1
Reactant: C1COCCN1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1N1CCOCC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
The mixture of 0.0074 g of 2-(di-t-butylphosphino)biphenyl, 0.017 g of dipalladiumtris (dibenzylidenacetone)-chloroform complex and 0.055 g of sodium tert-butoxide is admixed under argon with the solution of 0.280 g of tert-butyl 3-[chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 31a) and 0.043 ml of morpholine in 2.0 ml of toluene. The reaction mixture is stirred at 110° C. over 16 hours, subsequently cooled, poured onto water (20 ml) and extracted with ethyl acetate (2×20 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (2:1 EtOAc-heptane); Rt=5.46.
Reaction SMILES: [CH:1]([Si:3]([Cl:6])([Cl:5])[Cl:4])=[CH2:2].[Cl:7][Si:8]([Cl:15])([Cl:14])[CH2:9][CH2:10][SiH:11]([Cl:13])[Cl:12]>>[Cl:4][Si:3]([Cl:6])([Cl:5])[CH2:1][CH2:2][Si:11]([Cl:13])([Cl:12])[CH2:10][CH2:9][Si:8]([Cl:15])([Cl:14])[Cl:7]
Reactant: Cl[SiH](Cl)CC[Si](Cl)(Cl)Cl
Reactant: C=C[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl
Reaction time: 12 h

Procedure:
Vinyltrichlorosilane (16.8 g, 104 mmol) was heated to 60° C. and 100 μL 10% H2PtCl6/IPA-solution was added. 1,1,1,4,4-pentachloro-1,4-disilabutane (20.4 g, 77.7 mmol) was added slowly during 20 min so that the temperature did not exceed 100° C. The reaction was allowed to proceed for 12 hours at 100° C., after which it was distilled under vacuum at 115-130° C./<1 mbar. The yield was 31.5 g (74.3 mmol, 96%).