Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([O-:22])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])=[O:33])([O-:22])=[O:21]
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)c1cccc(-c2ccncc2[N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2[N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution containing 2-phenylpropan-2-amine (5.5 g, 40.4 mmol), diisopropylethylamine (18.8 mL, 108 mmol), 3-(3-nitropyridin-4-yl)benzoic acid (8.8 g, 27.0 mmol) and DMF (180 mL) was added HATU (15.4 g, 40.4 mmol) in one portion. The solution was maintained at room temperature for 1 h then concentrated. Purification on silica gel (50-100% ethyl acetate/hexanes, 60 min. gradient) afforded 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a dark yellow, fluffy solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.21 (s, 1H), 8.93 (d, J=5.02 Hz, 1H), 8.51 (s, 1H), 7.97 (dt, J=7.03, 1.76 Hz, 1H), 7.92 (s, 1H), 7.73 (d, J=5.02 Hz, 1H), 7.52-7.61 (m, 2H), 7.34-7.41 (m, 2H), 7.27 (t, J=7.65 Hz, 2H), 7.16 (t, J=7.28 Hz, 1H), 1.64-1.72 (m, 6H). LCMS: retention time: 2.060 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 362 (MH+).
Reaction SMILES: [C-:1]#[N:2].[Na+].CC1C=CC(S(O[CH2:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(=O)=O)=CC=1>CS(C)=O.S([O-])([O-])(=O)=O.[Fe+2]>[C:1]([CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])#[N:2]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CC#N
Temperature: 90 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
Sodium cyanide (8.2 g) was added to a solution of tert-butyl (S)-2-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate 140, 29.6 g) in DMSO (300 mL) and the resultant mixture was stirred and heated at 90° C. for 5.5 hours. After cooling, the mixture was treated with saturated aqueous iron (II) sulphate solution and the mixture was stirred for a further 5 hours then extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether (5%) to give tert-butyl (S)-2-cyanomethylpyrrolidine-1-carboxylate (13.0 g) as a light yellow oil which was used without further characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([I:11])[CH:3]=1.[CH3:12]C(C)([O-])C.[Na+].CI>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]#[N:10])=[C:4]([I:11])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: N#CCc1ccc(Cl)cc1I
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-(4-Chloro-2-iodophenyl)acetonitrile (1.070 g, 3.9 mmol) was dissolved in THF (50 mL) and cooled to 0° C. Sodium tert-butoxide (0.74 g, 7.7 mmol) was added, and the solution was stirred for 10 minutes (the reaction color changed from colorless to orange.) MeI (0.24 mL, 3.9 mmol) was then added dropwise as a solution in THF (10 mL). The reaction was complete in ten minutes as determined by TLC. The crude residue was purified by silica flash chromatography using 0-15% EtOAc/hexanes. MS m/e=292 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:26])[N:4]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Cl:8])[N:7]=1.[CH2:27]([Sn](CC)(CC)CC)[CH3:28]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([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)=CC=1>[Cl:8][C:6]1[N:7]=[C:2]([CH2:27][CH3:28])[C:3](=[O:26])[N:4]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cn1c(-c2ccccc2)c(Cl)nc(Cl)c1=O)OCc1ccccc1
Reactant: CC[Sn](CC)(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1nc(Cl)c(-c2ccccc2)n(CC(=O)OCc2ccccc2)c1=O

Procedure:
A solution of benzyl (3,5-dichloro-2-oxo-6-phenylpyrazin-1 (2H)-yl)acetate [Parlow et al. (2003) J. Med. Chem. 46, 4050-4062] (1.05 g, 2.70 mmol), tetraethyltin (0.641 mL, 3.24 mmol), and tetrakis(triphenylphosphine)palladium (31.0 mg, 0.027 mmol) in toluene (15 mL) was heated at reflux for 5.5 h. The solution was concentrated in vacuo and the crude product purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 90:10 to give the title compound. MS: m/z=383 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31](Br)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]1.CO>CN1C(=O)CCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]4)[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(Br)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3cccc(N[C@H]4CC[C@H](O)CC4)n3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 160 °C

Procedure:
A mixture of 46A (25 mg, 0.046 mmol) and (trans)-4-aminocyclohexanol (100 mg, 0.868 mmol) in NMP (0.4 mL) was heated at 160° C. in a microwave for 1.5 h (300 W), and then cooled to room temperature. The mixture was diluted by MeOH, and purified by preparative reversed-phase HPLC to give 6-((trans-4-aminocyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-((6-((trans-4-hydroxycyclohexyl)amino)-2-pyridinyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (12 mg, 28%) as a yellow solid. HPLC Rt=2.517 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=575.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[C:21](Cl)=[O:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN1CCC(OC(=O)N(C)c2ccc(Cl)c(Cl)c2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-methyl-N-(3,4-dichlorophenyl)carbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[N-methyl-N-(3,4-dichlorophenyl)carbamoyloxy]-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH2:31][N+](C)(C)C)[CH:30]=1)[N:27]([CH3:36])[CH:26]=[CH:25]2.[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:31][C:29]2[CH:30]=[C:22]([Br:21])[CH:23]=[C:24]3[C:28]=2[N:27]([CH3:36])[CH:26]=[CH:25]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cn1ccc2cc(Br)cc(C[N+](C)(C)C)c21
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3ccn(C)c23)c2ccccc21
Yield: 55 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added (5-Bromo-1-methyl-1H-indol-7-ylmethyl)-trimethyl-ammonium; iodide (111 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(5-Bromo-1-methyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (50 mg, 55%) as a colorless foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8].[H-].[Na+].[CH3:12]I>CS(C)=O>[CH3:12][O:9][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8]
Reactant: CC(O)c1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(C)c1ccccn1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 223 g. of 1-(2-pyridyl)-ethanol in 1500 ml. of dry dimethylsulfoxide is added 2.3 moles of sodium hydride in portions, under nitrogen, maintaining the temperature of 20° C. After two hours, 331 g. of methyl iodide is added at 20° C. After stirring for another three hours, the mixture is poured onto ice-water and extracted three times with ether. The organic phase is washed with water, dried over magnesium sulfate, concentrated in vacuo, and the residue is distilled to give 2-(1-methoxyethyl)pyridine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:37][CH2:38][Sn](CCCC)(CCCC)CCCC.[OH-].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([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)=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:38][OH:37])[CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(CO)cc12
Yield: 12.5 %

Procedure:
To a solution of 3-{1-(1,3-benzodioxol-5-yl)-2[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-5-bromo-1-methyl-1H-indole (from Example 79, 300 mg, 0.534 mmol) in 1,4-dioxane (1.5 ml) under a nitrogen atmosphere was added hydroxymethyltributylstannane (253 mg, 0.79 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (30 mg). The mixture was heated to reflux for 8 hours, and then cooled. Sodium hydroxide solution (1M) was added and the mixture boiled to dissolve the product. The solution was decanted clear of an insoluble tar residue, and washed with diethyl ether. After acidification with concentrated hydrochloric acid, the aqueous mixture was extracted with ethyl acetate. The organic extract was dried (magnesium sulphate) and the solvents were evaporated in vacuo. The residue was flash chromatographed using 2% methanol in dichloromethane as eluant to give the title compound (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3)[C:27]3[N:28]=[CH:29][S:30][CH:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[N:28]=[CH:29][S:30][CH:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3cscn3)ccc12
Yield: 43 %

Procedure:
To a solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-4-yl)isoquinoline-6-sulfonamide (0.070 g, 0.120 mmol) in DCM (1.195 ml) was added TFA (0.276 ml, 3.59 mmol) at room temperature. The resulting mixture stirred for a total of 3 weeks, monitoring every few days by LCMS. The crude mixture was concentrated by allowing the DCM to evaporate and taken up in DMSO. The DMSO solution was injected directly onto the Gilson HPLC for purification to provide 24 mgs (43% yield) of desired product. m/z (ESI) 465.9 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[N:8]([CH:19]=1)[C@@H:9]1[O:18][C@H:13]([CH2:14][N:15]=[N+]=[N-])[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2].[ClH:22]>CO.[Pd].C(O)C>[ClH:22].[C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[N:8]([CH:19]=1)[C@@H:9]1[O:18][C@H:13]([CH2:14][NH2:15])[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
0.80 g of 5-acetyl-5'-azido-2',5'-dideoxyuridine was dissolved in 100 ml of methanol and 10 ml of 0.27M hydrogen chloride in methanol were added. 0.1 g of 5% palladium-on-charcoal catalyst was added as a slurry in ethanol and the mixture was hydrogenated for 3 hours at room temperature and under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to give 0.91 g of hydroscopic 5-acetyl-5'-amino-2',5'-dideoxyuridine hydrochloride of melting point 73°-85° C. (decomposition).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.C[Si](C)(C)[O:12][C:13]([O:22][CH3:23])=[CH:14][C:15]([O:17][Si](C)(C)C)=[CH2:16].C([O-])(O)=O.[Na+]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:13]([CH:14]1[C:15](=[O:17])[CH2:16][CH:5]2[O:4][CH:3]1[CH2:7][CH2:6]2)([O:22][CH3:23])=[O:12]
Reactant: C=C(C=C(OC)O[Si](C)(C)C)O[Si](C)(C)C
Reactant: COC1CCC(OC)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1C(=O)CC2CCC1O2
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To 2,5-dimethoxytetrahydrofuran (39.6 g, 0.3 mol) in CH2Cl2 (anhydrous, 200 mL) at -78° C. under nitrogen was added TiCl4 (66 mL, 0.6 mol). After stirring for 30 min, 1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene, 2, (78 g, 0.3 mol) in CH2Cl2 (anhydrous, 400 mL) was added at a rate such that the internal temperature was maintained below -55° C. The mixture was stirred for 3 h. Saturated NaHCO3 was added until the mixture was neutral to pH paper. The aqueous layer was extracted with ether (3×1 L). The dried (MgSO4) combined organic layers were concentrated to dryness. The residue was purified by flash chromatography (20% EtOAc/hexanes) to afford 20.5 g (37%) of 3 as a light brown oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[CH:10](O)[C:9]=2[CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[Cl:3][CH:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:15]=2[CH:14]=[CH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]1=2
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2C=Cc2ccccc21
Solvent: c1ccccc1
Product: ClC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In this preparation 25 ml. of thionyl chloride is added dropwise, with vigorous stirring, to a slurry of 5 g. of 5H-dibenzo[a,d]cyclohepten-5-ol in 50 ml. of anhydrous benzene containing five drops of pydridine, at about 0°C. The resulting mixture is continually stirred and allowed to heat to room temperature and then allowed to stand for 4 hours. The resulting mixture is then evaporated under vacuum to remove solvent and excess reagent affording a crystalline residue of 5-chloro-5H-dibenzo[a,d]cycloheptene which is then further dried under vacuum.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[OH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([N:11]([CH3:12])[C:27](=[O:28])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:1]
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C(O)c1ccccc1)N(C)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A dry 1 L round-bottomed flask equipped with a magnetic stirrer was charged (+)-pseudoephedrine (13.92 g, 84.26 mmol, 1.0 equiv), triethylamine (13.39 mL, 96.06 mmol, 1.14 mmol), and tetrahydrofuran (340 mL). The solution was cooled to 0° C. and phenylacetyl chloride (14.33 g, 92.69 mmol, 1.1 equiv) was added via cannula over a 20 minute interval as a solution in tetrahydrofuran (90 mL). After 30 minutes, the reaction was quenched with saturated sodium bicarbonate. The amide was extracted from brine (1 L) with ethyl acetate (400 mL, 130 mL, 130 mL), and the organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, a solid was obtained. The solid was recrystallized from 2:1:1 ether/dichloromethane/hexanes (500 mL), affording the phenylacetamide (17.90 g, 75% yield) as a white powder: mp 145°-146° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.5 (m, 10H), 4.55 (br, 1H), 4.48 (t, 1H, J=7.1 Hz), 4.11 (m, 1H), 3.95 (m, 1H), 3.83 (m, 1H), 3.78 (s, 2H), 3.31 (d, 2H, J=1.3 Hz), 2.76 (s, 3H), 2.12 (s, 3H), 0.95 (d, 3H, J=7.0 Hz), 0.42 (d, 3H, J=6.7 Hz); 13C NMR (75.5 MHz, CDCl3) δ173.1, 172.2, 142.2, 141.4, 135.5, 134.5, 128.7, 128.64, 128.58, 128.3, 128.1, 127.5, 126.73, 126.68, 126.6, 126.3, 76.2, 75.3, 58.6, 41.8, 41.4, 33.3, 27.0, 15.0, 14.3; FTIR (neat film) cm-1 3393 (br, m), 1618 (s), 1494 (m), 1453 (m), 1402 (m); HRMS (FAB) Calcd for C18H22NO2 (MH+): 284. 1652. Found: 284.1646.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:31])[C:28]([F:32])=[CH:27][C:26]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:36]1(=O)[CH2:40][CH2:39][C:38](=[O:41])[CH2:37]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][CH:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([C:36]4[CH2:40][CH2:39][C:38](=[O:41])[CH:37]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:31])[C:28]([F:32])=[CH:27][C:26]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)c(I)cc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: O=C1CCC(=O)C1
Product: Cc1cc(F)c(I)cc1[C@@H]1C(O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]21

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-5-iodo-2-methylphenyl)octahydropyrano[3,4-c]pyrrole and cyclopentane-1,3-dione according to the procedures used for example 3. MS: (MH)+698.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Fe]>[CH2:1]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C=CCCCCCCC
Reactant: Oc1ccccc1
Agent: [Fe]
Product: CCCCCCCCCc1ccccc1O

Procedure:
The alkylation reaction, example 11 from DE-A-1 271 682 was reworked analogously. In a 1 liter three-neck flask equipped with a thermometer, a magnetic stirring mechanism and a reflux condenser, 252.5 g (2.0 mole) nonene, 235.3 g (2.5 mole) phenol and 5.0 g catalyst from Example 2 and Example 3 were heated to 90° C. After 3 hours reaction time, the catalyst was filtered off. The filtrate was fractionated using a 10 cm Vigreaux column. In the boiling range from 159° C. to 181° C. the alkylation product nonyl phenol was obtained.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[C:7]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=O)[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1.C1C=CC=CC=1>ClCCCl>[F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[C:7]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[S:34])[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4]1
Reactant: O=c1ccccn1C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)C(n1ccccc1=S)=CC(CF)(CF)O2
Yield: 69.5 %

Procedure:
A mixture of 0.13 g of 2,2-bisfluoromethyl-6-nitro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran, 83 mg of a Lawesson's reagent, 1 ml of benzene and 1 ml of 1,2-dichloroethane was refluxed for 3 hours and the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, CH2Cl2), and then, recrystallized from a mixture of ethyl acetate and hexane to obtain 0.05 g of 2,2-bisfluoromethyl-6-nitro-4-(1,2-dihydro-2-thioxo-1-pyridyl)-2H-1-benzopyran represented by the following formula having a melting point of 209°-210° C.