Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:24]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]=1)[C:14]([O:16][C@H:17]([CH3:20])[CH2:18][OH:19])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:24]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:23]=1)[C:14]([O:16][C@H:17]([CH3:20])[CH2:18][O:19][C:1](=[O:3])[CH3:2])=[O:15])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: C[C@H](CO)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Acetyl chloride (2.3 mL, 33.1 mmol) and (1R)-2-hydroxy-1-methylethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (17) (11.8 g, 22.1 mmol) were dissolved in 400 mL of anhydrous dichloromethane. A solution of pyridine (2.7 mL, 33.1 mmol) in dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The product was extracted with dichloromethane, washed with 5% NaHCO3, 10% citric acid, and dried over Na2SO4. After concentration the resulting residue was further dried under vacuum. The crude product (18) (12.9 g, 100% yield) was isolated as a foamy solid. 1H NMR (400 MHz, CDCl3): δ 1.15 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.03 (s, 3H), 2.95 (dd, J=14.0, 6.8 Hz, 1H), 3.01 (dd, J=14.0, 6.8 Hz, 1H), 3.99 (dd, J=12.0, 6.4 Hz, 1H), 4.12 (dd, J=12.0, 3.2 Hz, 1H), 4.50 (dd, J=14.0, 6.8 Hz, 1H), 4.93 (d, 1H, NH), 5.07 (m, 1H), 5.10 (s, 4H), 6.65 (dd, J=8.0, 2 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.28-7.46 (m, 10H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O>C1COCC1>[Br:14][C:6]1[S:7][CH:8]=[CH:9][C:5]=1[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CC)Cc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1ccsc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To 150 mL of THF solution of (9-4) (5.3 g, 26.9 mmol), N-bromosuccinimide (4.8 g, 26.9 mmol) was added portionwise at 0° C. and the mixture was stirred at 0° C. overnight. The organic fraction was extracted with water and CHCl3, washed with NaHCO3 aq., and dried over anhydrous Mg2SO4. The crude product was further purified by column chromatography using hexane as the eluent give (9-5) as a colourless liquid (6.9 g, 93%). 1H NMR (CDCl3, 300 MHz, ppm): 7.18 (d, 1H, J=5.7 Hz), 6.76 (d, 1H, J=5.7 Hz), 2.50 (d, 2H, J=7.2 Hz), 1.55-1.62 (m, 1H), 1.25-1.34 (m, 8H), 0.85-0.90 (m, 6H).
Reaction SMILES: C(O[N:9]([C:12]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][O:19]2)[CH:15]=[CH:14][CH:13]=1)[CH:10]=[O:11])C1C=CC=CC=1.[CH2:21]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]#[CH:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]#[CH:39])[CH2:20][C@@H:18]([C:16]1[CH:15]=[CH:14][C:13]([O:19][CH2:18][C:16]2[CH:17]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:12]([NH:9][CH:10]=[O:11])[CH:17]=1)[OH:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#CCCOCCCCCCNCc1ccccc1
Reactant: O=CN(OCc1ccccc1)c1cccc([C@@H]2CO2)c1
Product: C#CCCOCCCCCCN(Cc1ccccc1)C[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Yield: 159.6 %

Procedure:
A stirred mixture of 2-(benzyloxy-5-[(2R)-oxiran-2-yl]phenylformamide (R Hett et al, Organic Process Research & Development, 1998, 2, 96-99) (8.6 g) and N-benzyl-6-(but-3-ynyloxy)hexan-1-amine (9.1 g) was heated at 120° for 2 h. The mixture was purified by chromatography (Merck 9385) eluting with cyclohexane/ethyl acetate (2:1) to give the title compound (13.47 g). LCMS RT=2.68 min.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C(#N)C>[C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)ONCCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)ONCCC1CCN(c2ncccn2)CC1

Procedure:
N-t-butoxycarbonyloxy 2-(piperidin-4-yl)-ethylamine (prepared per Method K′ above), DIEA (0.75 mL) and 2-bromopyrimidine (204 mg) (Aldrich) in acetonitrile (5 mL) were heated under reflux overnight. The solvent was removed under reduced pressure and the black liquid was subjected to a column chromatography, eluted with 1:1 EtOAc/hexanes, to give pure N-t-butoxycarbonyloxy 2-[1-(pyrimidin-2-yl)piperidin-4-yl]-ethylamine as a pale yellow oil. 1H NMR (CDCl3) δ=8.21 (d, J=5.1 Hz, 2H), 6.36 (t, J=5.1 Hz, 1H), 4.64 (d, J=13.8 Hz, 2H), 3.14–3.07 (m, 2H), 2.76 (dt, J=2.7, 13.2 Hz, 1H), 1.69 (d, J=13.8 Hz, 1H), 1.57–1.30 (m, 11H), 1.20–1.03 (m, 3H);
Reaction SMILES: [CH2:1]([C:4]1([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:27]([SnH:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>>[CH2:36]([Sn:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:3]/[CH:2]=[CH:1]/[C:4]1([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH2:37][CH2:38][CH3:39]
Reactant: C#CCC1(O[Si](C)(C)C)CCCCC1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](C/C=C/C1(O[Si](C)(C)C)CCCCC1)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To a stirred mixture of 31.5 g of 1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. The stirred mixture is heated to about 80° C. The initial exothermic reaction is moderated, and the temperature is subsequently maintained at 130°-135° C. for one hour.
Reaction SMILES: [CH:1]([CH:4]1[C:8](=O)[O:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].[CH3:20][CH2:21][O:22][C:23]([C:25]([CH3:45])=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24]>C1(C)C=CC=CC=1>[CH2:21]([O:22][C:23](=[O:24])[CH:25]([C:8]1[O:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2])[CH3:45])[CH3:20]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C1N=C(c2ccc(C(F)(F)F)cc2)OC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C

Procedure:
4-Isopropyl-2-(4-trifluoromethyl-phenyl)-4H-oxazol-5-one (1.0 g, 3.69 mmol) and (carbethoxyethylidine)triphenyl-phosphorane (2.67 g, 7.37 mmol) are stirred in toluene (20 mL) at reflux 3 hr. The mixture is concentrated in vacuo and the residue is purified over silica eluting with 9:1 hexanes:ethyl acetate affording 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propionic acid ethyl ester as a pale orange oil, 1.11 g, 85%. MS (M++1) 356.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH3:29]>C(#N)C>[CH2:28]([O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH3:29]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(OC)ccc(-c2ccc3c(c2)COC3=O)c1OC
Temperature: 80 °C
Yield: 57 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and ethyl iodide (130 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (50 mg, 57%).
Reaction SMILES: C([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=13)[CH:13]=[N:12][CH:11]=[CH:10]2)(OCC)=O.[OH-].[K+]>C(O)C.O>[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=13)[CH:13]=[N:12][CH:11]=[CH:10]2
Reactant: CCOC(=O)Nc1cc2ccncc2c2sc3ccccc3c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc2ccncc2c2sc3ccccc3c12
Yield: 103 %

Procedure:
Two hundred mg (0.62 mM) of 6-carbethoxyaminobenzothieno[3,2-h]isoquinoline (9), prepared in the preceding Example, was added to a solution of 2 g KOH in 5 ml ethanol and 2 ml water. Two layers formed. The mixture was stirred and heated at reflux for approximately 2-3 hr. A yellow solid separated after about an hour, and was collected via filtration and air dried to give 160 mg product, m.p. 220° C.-225° C. This initial product was recrystallized twice from a mixture of DMF and water to provide 120 mg final product, m.p. 223.5° C.-224.5° C., which was then characterized via I.R. and mass spectrometry as compound 10.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@H:5]([C:6]2([CH3:10])[CH3:9])[C:4](=[O:11])[O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:9][C:6]1([CH3:10])[C:7](=[C:2]([CH3:1])[CH3:12])[CH2:8][C@H:5]1[C:4]([OH:11])=[O:3]
Reactant: CC1(C)OC(=O)[C@@H]2C[C@H]1C2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)=C1C[C@@H](C(=O)O)C1(C)C
Yield: 78.1 %

Procedure:
A solution of 3.68 g (21.9 mmol) of 4a in 60 mL of benzene with 416 mg (2.19 mmol) of p-toluenesulfonic acid monohydrate was heated in an oil bath at 100-110° C. for 24 h. A mini Dean-Stark trap was used for azeotropic distillation. Benzene was evaporated on a rotary evaporator, and the residue was treated with 2N aqueous Na2CO3 solution. The basic aqueous solution was washed with ether, then acidified to pH 2 with hydrochloric acid, and again extracted with ether. The combined ether extracts were washed with water, brine, dried, and concentrated to give 2.87 g (17.1 mmol, 78% yield) of 5a as clear oil after chromatography (silica gel, eluted with 20% to 25% of ethyl acetate in hexanes). Optical purity: 79% ee (after methylation); [α]24D−22.0 (c 0.1, MeOH); 1H NMR (CDCl3): δ 1.19 (3H, s), 1.37 (3H, s), 1.48 (3H, s), 1.58 (3H, s), 2.55 (1H, m), 2.81 (2H, m); 13C NMR (C6D6): δ 183.49, 135.57, 123.27, 47.47, 45.09, 28.15, 25.94, 22.09, 19.51, 18.52; EI-MS m/z (%): 168 [M]+ (38), 153 (38), 135 (8), 125 (21), 123 (27), 107 (59), 93 (29), 81 (100), 67 (30), 53 (16), 41 (25); HREIMS: obsd. 168.1152, calcd. for C10H16O2 (M+): 168.1150.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:13]1[C:5]2[CH:4]=[CH:3][NH:9][C:7](=[O:8])[C:6]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COC(Cc1ncccc1C(N)=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc2ncccc12
Yield: 66.7 %

Procedure:
A mixture of 2-(2,2-dimethoxyethyl)nicotinamide (8.33 g, 39.7 mmol) and TsOH.H2O (940 mg) in toluene (100 mL) was refluxed for 14 h. Toluene was removed under reduced pressure, then the residue was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 1:1 and with EtOAc) to yield 1,6-naphthyridin-5(6H)-one as a light yellow solid (3.87 g, yield 66%). ESI MS: m/z 147 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:28])([CH3:27])[CH2:9][C:10]([NH2:26])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.C=O.[C:33](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:27])([CH3:28])[CH2:9][C:10]([NH:26][CH3:33])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:11]([F:12])([F:14])[F:13])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1ccnc2ccccc12)C(F)(F)F
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CNC(Cc1ccnc2ccccc12)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A solution of 3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine (42.0 mg, 0.1 mmol) and formaldehyde (8 μL, 0.1 mmol) in dichloroethane (2 mL) was stirred for 30 min at room temperature in the presence of 4A molecular sieves (200 mg). The reaction mixture was acidified with acetic acid (57 μL, 1.0 mmol), stirred for 16 h and treated with sodium triacetoxy borohydride (42.4 mg, 0.2 mmol). The resulting mixture was stirred at room temperature for 3 h and quenched with NaHCO3 (sat. 6 mL). Phases were separated and the aqueous layer was extracted with CHCl3 (2×4 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (20%–40%, EtOAc:Hexanes) to give 24.0 mg (55%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(C=O)cc2)nc1
Reactant: O=C1CSC(=O)N1
Agent: N
Solvent: CCO
Product: CCc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)nc1

Procedure:
A mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (27 g), ethanol (300 ml), 2,4-thiazolidinedione (33 g) and concentrated aqueous ammonia (14 ml) was heated under reflux for 5 hours. The precipitated crystals were separated. Recrystallization from 1,2-dichloroethane gave 21.6 g (57.6% of crystals of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[C:13](O)(=[O:15])[CH3:14]>[OH-].[Na+]>[C:13]([NH:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: COc1cc(CN)nc(SC)n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CNC(C)=O)nc(SC)n1

Procedure:
A mixture of 3.05 g (16.5 mmole) of 6-aminomethyl-4-methoxy-2-methylthiopyrimidine (from Example 4) and 50 ml of glacial acetic acid was heated at reflux for 16 hours, and was then evaporated. The residue obtained was dissolved in 20 ml of five percent aqueous sodium hydroxide solution and extracted with four 30 ml portions of chloroform. The combined extracts were washed twice with 30 ml portions of water and then with 30 ml of saturated aqueous sodium chloride solution. The combined extracts were then dried over magnesium sulfate and evaporated to provide 6-acetylaminomethyl-4-methoxy-2-methylthiopyrimidine as an off-white solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([NH:15][CH3:14])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c[nH]c(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added HATU (0.168 g, 0.442 mmol), DIPEA (0.097 ml, 0.553 mmol) and methyl amine (2M in THF) (0.276 ml, 0.553 mmol). The reaction mixture was stirred at RT overnight. Purification was accomplished by HPLC, the desired fractions collected and lypholized to afford methyl 3-chloro-4-[(methylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.046 g, 57.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.39 (br. s., 1H) 7.73-7.83 (m, 1H) 7.46 (d, 1H) 3.80 (s, 3H) 2.70 (d, 3H). MS: m/z 217.0 (M+1).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1([CH3:31])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]#[C:22][C:23]3[CH:30]=[CH:29]C(CO)=[CH:25][CH:24]=3)[CH:12]=[CH:11][C:10]1=2>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[CH:29]=[CH:30][C:23]([C:22]#[C:21][C:13]2[CH:12]=[CH:11][C:10]3[C:9]([CH3:31])([CH3:8])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]=3[CH:14]=2)=[CH:24][CH:25]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CO)cc3)ccc21
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
1.7 ml of acetic anhydride were added to a mixture of 1.5 g (4.7 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzyl alcohol (Example 20) and 8.7 ml of pyridine. The mixture was stirred for 16 hours at room temperature, after which it was poured onto ice/water and acidified. The precipitated solid was filtered off under suction, washed with water and dried. 1.3 g (77%) of the title compound of melting point 136°-139° C. were obtained in this manner.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:11][C:12]1[C@@H:17]([C@H:18]([CH2:20][OH:21])[OH:19])[O:16][C:14](=[O:15])[C:13]=1[OH:22])[CH:7]([CH2:9][OH:10])[OH:8].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:6]([O:11][C:12]1[C@@H:17]([C@H:18]([CH2:20][OH:21])[OH:19])[O:16][C:14](=[O:15])[C:13]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]([CH2:9][OH:10])[OH:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 127.9 %

Procedure:
Under an argon atmosphere, water and sodium hydrogen carbonate (1.42 g) were added to 3-O-glyceryl ascorbic acid (1.42 g) obtained in Example 1, and the mixture was stirred at room temperature for 30 minutes. To the mixture, benzyl bromide (2.61 g) was added, and the resultant mixture was heated up to 50° C. and stirred for 2 hours. Thereafter, the mixture was concentrated under reduced pressure, then, dissolved in methanol. Then, the resultant solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 6.13 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:10/3/0.4), and concentration was performed under reduced pressure to obtain to obtain 3-O-glyceryl-2-O-benzyl ascorbic acid (2.47 g).
Reaction SMILES: [NH2:1][C:2]([CH2:8][O:9][CH3:10])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH3-]C#N.[Na+].Cl>O.CO>[CH2:11]([NH:1][C:2]([CH2:8][O:9][CH3:10])([CH2:5][O:6][CH3:7])[CH2:3][OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: COCC(N)(CO)COC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC(CO)(COC)NCc1ccccc1
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
A mixture of crude 4-aza-3,3-bis-(methoxymethyl)-1-oxaspiro[4.5]decane (66A, 40.0 g, 0.174 mol) and 6N HCl (100 mL) was refluxed for 1 h. The mixture was cooled and washed with Et2O (3×100 mL). The volume of the aqueous layer was reduced to 25 mL by rotary evaporation, basified with excess 50% NaOH solution and extracted with a mixture of Et2O/CH2Cl2 (3:1, 2×200 mL). The organic layers were combined, the solvent removed and the resulting crude oil distilled to give 16.4 g (63.2%) of 2-amino-2,2-bis-(methoxymethyl)ethanol, (bp 109°-110°/15 mm). This material also contains some of the --NCH3 compound. This material was further purified by conversion to the --NCH2Ph derivative. Thus, a mixture of crude 2-amino-2,2-bis-(methoxymethyl)ethanol (15.0 g, ~0.10 mol), benzaldehyde (Aldrich, 7.42 g, 0.07 mol), NaBH3CN (Aldrich, 4.4 g, 0.07 mol) and CH3OH (100 mL) was stirred at 5° for 15 min then at RT for 2 h. H2O (50 mL) then excess 12N HCl was then added to the flask. The volume of the mixture was reduced to 50 mL by rotary evaporation. The mixture was washed with Et2O (100 mL), basified with 50% NaOH solution and extracted with Et2O (200 mL). After removal of the solvent the crude oil (15.54 g) was distilled to give 11.64 g of 2-benzylamino-2,2-bis-(methoxymethyl)ethanol, bp 118°-119°/0.10 mm, shown to 99.7% pure by GLC (10% OV-17 on Chromasorb W at 250°), (C,H,N). A mixture of 2-benzylamino-2,2-bis-(methoxymethyl)ethanol (8.25 g, 0.0345 mol), 5% Pd/C (Aldrich, 1.0 g), abs. EtOH (250 mL) and glacial HOAc (25 mL) was hydrogenated in a Parr apparatus at 40 psi for 15 min. The catalyst was removed by filtration through a pad of Celite® and the solvent removed to give the crude product which after crystallization from abs. EtOH gave a 48.6% yield of 2-amino-2,2-bis-(methoxymethyl)ethanol acetate, mp 119.5°-120.5°, (C,H,N).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH:8]1([Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Br[Mg]C1CCCCC1
Reactant: BrCCCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: BrCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 1,5-dibromopentane (16 gm, 69.97 mmol) in THF (20 ml) was added a solution of (Li2CuCl4 in ether, 14 ml) under nitrogen at 5-10° C. and stirred for 25 minutes. Cyclohexyl magnesium bromide (10 gm, 69.97 mmol) was added dropwise with stirring for about 30 minutes. The reaction mixture was stirred at 0° C. for another 1 h and stirred at room temperature for 12 hr. The reaction mixture was cooled to 0° C. in ice, saturated NH4Cl solution (20 ml) was added and the resulting mixture was extracted with EtOAc (4×25 ml). The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane as an eluent. The pure product was an oily liquid (12.84 gm).
Reaction SMILES: [SH-:1].[Na+].Cl[C:4]1[N:9]([CH2:10][CH2:11][CH2:12]Cl)[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:19]1([C:5]2[C:6](=[O:18])[N:7]([CH2:15][CH2:16][CH3:17])[C:8](=[O:14])[N:9]3[CH2:10][CH2:11][CH2:12][S:1][C:4]=23)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCn1c(=O)c(-c2ccccc2)c(Cl)n(CCCCl)c1=O
Reactant: [SH-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Sodium hydrosulfide (3.3 g) was added to a solution of 6-chloro-1-(3-chloropropyl)-5-phenyl-3-propyluracil (7 g) in DMF (60 ml) little by little under ice cooling and the mixture was stirred for 1 hour. The reaction solution was concentrated to dryness. The residue was dissolved in methylene chloride-H2O, and the organic layer was washed with water and dried. The solvent was evaporated and the resulting crude crystals were recrystallized from methanol to give colorless crystals (3.85 g, 62%).