Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2ncn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.31) (190 mg, 0.56 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (153 mg, 0.56 mmol) according to general procedure II. Obtained as a brown solid (192 mg, 64%). MS (ISN) 527.1 [(M−H)−]; mp 149° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[CH3:18][C:19]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Cc1cccc(CBr)c1C
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: Cc1cccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)c1C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,3-dimethylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[NH2:17].[N:18]([O-])=O.[Na+]>>[Cl:1][C:2]1[C:3]2[N:17]=[N:18][N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(Cl)c(N)c(NCc2ccccn2)n1
Reactant: O=N[O-]
Agent: [Na+]
Product: Nc1nc(Cl)c2nnn(Cc3ccccn3)c2n1

Procedure:
A solution of 6-chloro-N4-pyridin-2-ylmethyl-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. 1HNMR (CDCl3): δ 8.60–8.59 (m, 1H), 7.71–7.67(m, 1H), 7.29–7.25 (m, 1H), 7.22–7.20 (m, 1H), 5.81 (s, 2H), 5.48 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][C:6]=1[C:7]([O:9]CC(F)(F)F)=O.[NH2:27][CH:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1)[CH3:29]>>[F:26][C:2]([F:1])([F:25])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:15][C:6]=1[C:7]([NH:27][CH:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1)[CH3:29])=[O:9]
Reactant: CC(N)C1CCCCN1
Reactant: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: CC(NC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F)C1CCCCN1

Procedure:
Starting with 2,2,2-trifluoroethyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate and 2-(1-aminoethyl)piperidine and using the procedure illustrated in Examples 21 and 22, the product 2,5-bis(2,2,2-trifluoroethoxy)-N-[1-(2-piperidyl)ethyl]-benzamide, m.p. 95° -97° C., is obtained as white needles.
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:12])[CH2:10]Br)[N:8]=1)[CH3:3].C(=O)([O-])O.[K+].Cl.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([NH2:32])[CH3:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]>CC(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([NH:32][CH2:10][CH:9]([OH:12])[C:7]2[N:8]=[C:4]([N:2]([CH3:3])[CH3:1])[S:5][CH:6]=2)[CH3:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]
Reactant: CN(C)c1nc(C(=O)CBr)cs1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CC(C)NCC(O)c2csc(N(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g of 2-(N,N-dimethylamino)-4-bromoacetyl-thiazole in 250 ml of acetone are heated to reflux with 10 g of potassium hydrogen carbonate and 9.5 g of 2-(4-carbomethoxyphenyl)-1-methylethylamine-hydrochloride for 3 hours. After the reaction mixture has been cooled the inorganic products are removed by filtration, and the filtrate is concentrated in a rotary evaporator. The resulting oil residue is taken up in 150 ml of absolute methanol and, at 0°-5° C., 1.75 g of sodium borohydride are added in small portions. The mixture is then stirred at 0°-5° C. for one hour and at room temperature for 24 hours. Then ice-water are added to the reaction mixture, and it is acidified with concentrated hydrochloric acid, made alkaline with ammonia, while cooling in ice, and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol=8:2 as eluant.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18]O)[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2.C(N(CC)C(C)C)(C)C.F.F.F.C(N(CC)CC)C.[F:48]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[NH4+].[Cl-]>C1COCC1.COC(C)(C)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:48])[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Agent: F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (21.0 g, 0.519 mol, 1.0 equiv.) was dissolved in dry THF (105 mL) under a nitrogen atmosphere and the solution was cooled at 0° C. N,N-diisopropylethylamine (40.7 mL, 0.234 mol, 4.50 equiv.), triethylamine trihydrofluoride (14.0 mL, 0.0857 mol, 1.65 equiv.) and perfluorobutanesulfonyl fluoride (22.4 mL, 0.125 mol, 2.40 equiv.) were added while maintaining temperature under 5° C. The reaction was stirred for 3 h at 0° C. then slowly warmed to RT and stirred for 11 h. To the reaction mixture was charged sat.NH4Cl (100 mL) followed by 2-methoxy-2-methylpropane (100 mL). The organic phase was isolated and washed with aq. HCl (1.0 M, 100 ml), concentrated and redissolved in 2-methoxy-2-methylpropane (301 ml). The organic phase was then washed with aq.HCl (1M, 63 mL), sat aq.NaHCO3 (100 mL). The last aqueous layer was extracted with 2-methoxy-2-methylpropane. The combined organic phase was washed with 18% aq.NaCl (63 mL) and concentrated under reduced pressure to afford title compound (19.40 g) as a foam. 1H NMR (500 MHz, DMSO) δ ppm 8.02 (s, 2H), 7.61-7.51 (m, 1H), 7.51-7.38 (m, 3H), 7.39-7.18 (m, 2H), 4.72-4.49 (m, 2H), 4.48-4.37 (m, 1H), 4.41 (d, J=9.1 Hz, 21H), 3.04 (s, 2H); 13C NMR (125 MHz, DMSO) δ ppm 150.92 (dd, JCF=245.5, 13.3 Hz), 148.11 (dd, JCF=248.2, 13.4 Hz), 132.40, 128.99, 128.63, 125.16, 124.94, 117.61, 83.64 (d, JCF=170.2 Hz), 79.51 (d, JCF=18.4 Hz), 76.17, 66.27, 23.67.
Reaction SMILES: [CH3:1][O:2][C:3]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:7])[CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.ClCCl>CC(C)=O.C(OCC)C>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH3:7])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(C)(CCO)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(C)(CCOS(=O)(=O)c1ccc(C)cc1)c1ccc(-c2ccccc2)cc1
Reaction time: 14 h
Yield: 87.4 %

Procedure:
To a solution of 3-methoxy-3-(4phenylphenyl)butan-1-ol (2.04 g, 8.0 mmole, prepared in Example 8, Part B above) and triethylamine (1.51 g, 15 mmole) in acetone (10 mL) at 0° was added in one portion a solution of p-toluenesulfonyl chloride (2.85 g, 15 mmole) in acetone (4 mL). The resultant suspension was warmed to 20° C. and stirred at that temperature for 14 hours, then diluted with diethyl ether (40 mL). The resultant precipitate (triethylamine hydrochloride) was removed by filtration and the filtrate was evaporated to dryness to give a crude product, which was purified by column chromatography on silica gel, eluting with a 1:1 v/v hexanes:dichloromethane mixture to give the desired product (2.87 g, 87% yield) of colorless solid. Less pure fractions were combined to provide an additional 0.147 g of colorless solid which was crystallized from hexanes (10 mL), furnishing colorless fine matted needles weighing 0.070 g; melting point 69-70.5° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8](=[O:15])[CH2:7]1)=[O:5])C.[OH-].[Na+]>CCO>[O:15]=[C:8]1[C:9]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:14][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)C1CC(=O)c2ccsc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CC(C(=O)O)Cc2sccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.6 %

Procedure:
Ethyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate (1.5 g, 6.7 mmol) was dissolved in EtOH (20 mL). 1M NaOH (aq.) (7 mL) was added portion-wise and the mixture was stirred at room temperature for 1 hr 45 min. The mixture was concentrated in vacuo and the residue was treated with 2M HCl (aq.). The product was extracted into ethyl acetate (×3) and this was back extracted with water and saturated brine. The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to yield crude 4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylic acid (1.27 g, 100%). This was dissolved in THF (15 mL) and BH3.DMS (4.8 mL, 2M in THF, 8.7 mmol) was added drop-wise at 0° C. The mixture was warmed to room temperature and stirred for 18 hr. Methanol was added and the reaction mixture was concentrated in vacuo. The crude residue was dissolved in ethyl acetate and washed with 1M NaOH (aq.) solution, water and brine. The organic extract was dried (MgSO4) and concentrated in vacuo to give the title compound (1.2 g, quant.).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[C:29]1([CH2:28][O:7][C:8]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCCCC2)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
K2CO3 (203 mg, 1.47 mmol) was added to a stirred solution of methyl 2-hydroxy-5-(1-piperidinylsulfonyl)benzoate (may be prepared as described in Description 67; 400 mg, 1.34 mmol) in acetone (20 ml), followed by the addition of (bromomethyl)benzene (251 mg, 1.47 mmol). The mixture was heated at reflux for 16 h, and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated to yield the title compound as a colourless oil. 300 mg.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:5][C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[N:6][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N=C(N)c1ccccc1F
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2ccccc2F)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=363.0 (M+H+), was prepared from 2-fluorobenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[Se:16][C:17]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[CH:18][CH:19]=3)=[C:11]([F:25])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[Se:16][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:18][CH:19]=3)=[C:11]([F:25])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCCC=Cc1ccc(-c2ccc(-c3ccc(CC)cc3)cc2F)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCc1ccc(-c2ccc(-c3ccc(CC)cc3)cc2F)[se]1

Procedure:
17.1 g (43.0 mmol) of 2-(4′-ethyl-3-fluorobiphenyl-4-yl)-5-(pent-1-enyl)-selenophene are hydrogenated in 170 ml of ethyl acetate, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane:toluene=98:2→95:5). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-5-pentylselenophene is obtained as a colourless solid (m.p. 52° C.).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:11])/[CH:7]=[C:8](\Cl)/[CH3:9])[CH:2]([CH3:4])[CH3:3].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:5][C:6](=[O:11])/[CH:7]=[C:8](\[N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)/[CH3:9])[CH:2]([CH3:4])[CH3:3]
Reactant: c1nc[nH]n1
Reactant: C/C(Cl)=C/C(=O)OCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C/C(=C/C(=O)OCC(C)C)n1cncn1

Procedure:
0.1 Mol (17.7 g) of 3-chlorocrotonic acid isobutyl ester in 100 ml acetonitrile, 012 mol (8.3 g) of 1,2,4-triazole and 0.12 mol (16.5 g) of anhydrous potassium carbonate were refluxed for 5 hours. After removal of the solvent under reduced presure, the reaction mixture was cooled, water was added and the resulting mixture was extracted with methylene chloride. After distillation of the methylene chloride under reduced pressure, the 3-(1,2,4-triazol-1-yl)-crotonic acid isobutyl ester was obtained in the form of a weakly yellow oil.
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].C(N(CC)CC)C.Cl[CH2:26][CH:27]([OH:34])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH3:33].S(=O)(=O)(O)O>CN(C)C=O>[CH2:30]([O:29][CH2:28][CH:27]([OH:34])[CH2:26][N:6]1[C:4](=[O:5])[C:3]([CH2:2][CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH2:31][CH2:32][CH3:33]
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Reactant: CCCCOCC(O)CCl
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCC(O)CN1C(=O)NC(=O)C(CC)(c2ccccc2)C1=O
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A solution of phenobarbital (69.6 g, 0.3 mole) in dimethylformamide (60 ml) containing triethylamine (20.2 g, 0.2 mole) was stirred with 1-chloro-3-n-butoxy-2-propanol (33.2 g, 0.2 mole) for 6 hours at 70° C. The reaction mixture was then poured into 3% sulphuric acid (500 ml) and the precipitated product was extracted with toluene (200 ml) at 70° C. The toluene layer was separated, washed with 3% aqueous sulphuric acid (200 ml) and left overnight at 4° C. The precipitated phenobarbital was filtered off and filtrate extracted with 5% aqueous sodium carbonate (5×100 ml). The organic layer was then extracted with 1M aqueous sodium hydroxide (2×200 ml), the aqueous layers collected, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid. The precipitated product was extracted with toluene (150 ml), the organic layer was separated, dried and evaporated under reduced pressure to give the title compound (38.5 g, 53%); purity by HPLC 96.5% .
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:20])[NH:7][C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4].[Cl:21][C:22]([Cl:28])([S:26]Cl)[CH:23]([Cl:25])[Cl:24]>O.ClCCl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[C:3]([C:5]1[C:6](=[O:20])[N:7]([S:26][C:22]([Cl:28])([Cl:21])[CH:23]([Cl:25])[Cl:24])[C:8](=[O:19])[N:9]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH:10]=1)#[N:4]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(SC(Cl)(Cl)C(Cl)Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 1.60 g (0.04 mol) of NaOH in 45 ml of water is added 9.64 g (0.04 mol) of 5-cyano-1-(2,6-dimethylphenyl)uracil, obtained as in Example 1. After dissolution, 50 ml of ice cold dichloromethane is added, followed by a solution of 9.36 g (0.04 mol) of 1,1,2,2-tetrachloroethanesulfenyl chloride (prepared by the method of U.S. Pat. No. 3,395,180) in 15 ml of dichloromethane. The mixture is stirred for 30 min at 4°, after which time 50 mg of triethylbenzylammonium chloride is added and stirring is continued for another 30 min at 4°. The aqueous layer is separated and discarded. The dichloromethane solution is dried and stripped at aspirator pressure. The unreacted sulfenyl chloride is then removed by trituration with pentane/dichloromethane (4:1). The resultant crude product is purified by slurrying at 30° in 60 ml of ethanol-free chloroform, allowed to cool to RT and filtered. To the filtrate is added hexane to the cloud point, and the mixture is then filtered to yield 5-cyano-1-(2,6-dimethylphenyl)-3-(1,1,2,2-tetrachloroethanesulfenyl)uracil, m.p. 180°-183°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C@@H:17]([NH:19]C(=O)OC(C)(C)C)[CH3:18])[CH2:12][CH2:11]2)=[C:6]([Cl:28])[N:5]=[C:4]([CH3:29])[N:3]=1.C(O)(C(F)(F)F)=O.CO.O>C(Cl)Cl>[NH2:19][C@@H:17]([CH3:18])[C:16]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][CH2:8][C:7]2[C:2]([NH2:1])=[N:3][C:4]([CH3:29])=[N:5][C:6]=2[Cl:28])[CH2:11][CH2:12]1)=[O:27]
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(Cl)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)N)CC2)c(Cl)n1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Dissolve tert-butyl N-[(1S)-2-[4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5-yl)ethyl]-1-piperidyl]-1-methyl-2-oxo-ethyl]carbamate (15.78 g, 37.05 mmol) in DCM (185 mL), add TFA (185 mL) in a dropwise manner over 3 min, and stir overnight. Analyze the reaction by LCMS (low pH) to show complete conversion. Slowly add MeOH (400 mL) due to exothermic mixing. Prewash three SCX columns (50 g) with water (20 mL) and then MeOH (20 mL). Divide the reaction mixture into three equal portions and load equally onto the SCX columns Wash each column with water (40 mL) and MeOH (40 mL) collecting the washes in a vacuum flask. Elute the desired material from the SCX columns with 2 N ammonia in MeOH (60 mL) into a clean vessel. Combine the product containing solutions, concentrate under reduced pressure, azeotrope with DCM-hexanes (1:1), three times, and place under vacuum to obtain the title compound as a white foam (10.29 g, 84%). LC-ES/MS m/z (35Cl/37Cl) 326.2/328.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([CH2:10][CH3:11])[C:3]([F:9])([F:8])[C:4]([OH:7])([F:6])[F:5].[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>>[C:14]([Cl:16])(=[O:15])[C:13]([O:7][C:4]([F:6])([F:5])[C:3]([F:8])([F:9])[C:2]([F:12])([F:1])[CH2:10][CH3:11])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(F)(F)C(F)(F)C(O)(F)F
Product: CCC(F)(F)C(F)(F)C(F)(F)OC(=O)C(=O)Cl
Yield: 52.8 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step hexafluoroamyl alcohol was reacted with 100% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce hexafluoroamyl chlorooxalate having an assay of 91.3% and in a corrected yield of 52.8%. In the second step hexafluoroamyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product as described below:
Reaction SMILES: [C:1]([CH:6]=[CH:7][CH2:8][O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@:16]3([OH:34])[CH2:17][CH2:18][C@@H:19]2[C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[CH2:11]1)(OCC)=[O:2].O>O1CCCC1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@:16]3([OH:34])[CH2:17][CH2:18][C@@H:19]2[C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[CH2:11]1
Reactant: CCOC(=O)C=CCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](OCCCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 82 %

Procedure:
To a solution of 0.40 g of 3β-(3-carbethoxyprop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 30 ml of anhydrous tetrahydrofuran, 2 ml of sodium bis(2-methoxyethoxy)aluminum hydride (solution 3.4M in toluene) were added at room temperature. The solution was kept at reflux temperature for 8 hrs, then 10 ml of water were added and the organic solution was evaporated to dryness under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography using n-hexane/ethyl acetate 70/30 as eluant to give 0.30 g of 3β-(4-hydroxybutoxy)-17β-(3-furyl)-5β-androstan-14β-ol, as a white pasty solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16](OC)=[O:17].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][CH2:16][OH:17]
Reactant: COC(=O)CCc1cnoc1-c1ccc(F)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of methyl 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionate (1.05 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 8.7 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propan-1-ol (640 mg, yield 68%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 1.29 (1H, br s), 1.75–1.95 (2H, m), 2.55–2.65 (2H, m), 3.6–3.75 (2H, m), 6.9–7.1 (2H, m), 7.5–7.65 (1H, m), 8.25 (1H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.P(Br)(Br)([Br:14])=O>>[Br:14][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: Oc1ccnc2cccnc12
Reactant: O=P(Br)(Br)Br
Product: Brc1ccnc2cccnc12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A flask was charged with 1,5-naphthyridin-4-ol (1 g, 6.7 mmol) and phosphorousoxybromide (5 g, 17 mmol). The mixture was heated to 150° C., stirred for 1 hour, and then cooled to room temperature. The mixture was poured into ice-water and extracted with toluene. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was re-crystallized from petroleum ether to give 4-bromo-1,5-naphthyridine.