Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: OCc1cncn1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cncn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of [1-(4-fluorophenyl)-1H-imidazol-5-yl]methanol (2.50 g), activated manganese dioxide (10 g) and tetrahydrofuran (150 ml) was stirred at room temperature for 3 hrs. The reaction mixture was filtered, and the organic layer was concentrated to give 1-(4-fluorophenyl)-1H-imidazole-5-carbaldehyde (2.20 g, 89%) as crystals. Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 131-133° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[C:5](=[O:16])[CH:4]=1>C(Cl)Cl.O=[Mn]=O>[Cl:15][C:11]1[CH:10]=[C:9]([N:6]2[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][C:5]2=[O:16])[CH:14]=[CH:13][CH:12]=1
Reactant: O=c1cc(CO)ccn1-c1cccc(Cl)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccn(-c2cccc(Cl)c2)c(=O)c1
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxymethyl-1-(3-chlorophenyl)-1H-pyridin-2-one (2.39 g, 10.14 mmol) in CH2Cl2 (250 ml) was added MnO2 (4.41 g, 50.71 mmol) and stirred for 18 hours. The suspension was filtered through celite and the pad washed with additional CH2Cl2 (200 ml). The combined filtrates were evaporated in vacuo and chromatographed (silica gel, 5-20% EtOAc: CH2Cl2 gradient elution) to afford the title compound.
Reaction SMILES: [FH:1].[CH:2]1[N:6]([CH:7]2[O:11][CH:10]([CH2:12][OH:13])[CH:9]([OH:14])[CH:8]2[OH:15])[C:5]2[N:16]=[C:17](N)[N:18]=[C:19]([NH2:20])[C:4]=2[N:3]=1.C(ON=O)(C)(C)C.C(=O)(O)[O-].[Na+].C(=O)=O>N1C=CC=CC=1.O.C(OCC)(=O)C.C(OCC)(=O)C.CO>[F:1][C:17]1[N:18]=[C:19]([NH2:20])[C:4]2[N:3]=[CH:2][N:6]([C:5]=2[N:16]=1)[C@@H:7]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:9]([OH:14])[C@H:8]1[OH:15]
Reactant: F
Reactant: Nc1nc(N)c2ncn(C3OC(CO)C(O)C3O)c2n1
Agent: *CC*
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: -20 °C

Procedure:
A 2 L polyethylene bottle was equipped with a magnetic stirrer, thermometer, dry ice/acetone bath and a stream of argon gas. Anhydrous pyridine (750 mL) was added and the solution was cooled to −20° C. To this was added 70% hydrogen fluoride in pyridine (500 mL). 2,6-diaminopurine riboside (1,2-aminoadenosine, 105 g, 0.372 mol, R.I. Chemical, Orange, Calif., Reliable Biopharmaceuticals, St. Louis, Mo.) was suspended in the liquid. Tert-butylnitrite (90 mL, 0.76 mol) was added in one portion and the reaction was stirred at 9-11° C. until the reaction was complete as judged by TLC (3 h, Rf 0.20, starting material; Rf 0.40, product, ethyl acetate-methanol 4:1). Sodium bicarbonate (3 kg) was suspended with manual stirring in water (2 L) in a 20 L bucket. The reaction solution was slowly poured (to allow for evolution of carbon dioxide) into the aqueous layer with vigorous stirring. Ethyl acetate was added periodically in small portions to reduce foaming. The resulting suspension was extracted with ethyl acetate (5×1 L). The organic layers were combined and concentrated to a solid. The solid was mostly dissolved in warm methanol (300 mL). The solution was cooled in a ice water bath and the resulting solid was collected, rinsed with methanol (2×100 mL) and dried under vacuum (1 mm Hg, 25° C., 24 h) to give 76 g of product as a gold solid, mp 214-215° C. The mother liquor was concentrated to a solid and recrystallized from water (600 mL) to give in three crops an additional 18.3 g of similar quality product for a total of 90.3 g (85%). H-NMR (DMSO-d6) δ 3.4-3.8 (m, 2, 5′ and 5″-H), 3.95 (m, 1, 4′-H), 4.14 (m, 1, 3′-H), 4.53 (m, 1, 2′-H), 5.04 (t, 1, 5′-OH), 5.23 (d, 1, 3′-OH), 5.50 (d, 1, 2′-OH), 5.80 (d, 1, 1′-H), 7.89 (br s, 2, NH2), 8.37 (s, 1, 8-H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.NN.Cl>CCO>[NH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Br:1])[CH:9]=1
Reactant: N#Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1Br
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CN)cc1Br
Yield: 75.8 %

Procedure:
To a suspension of 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (8.0 g, 23.5 mmol) in EtOH (150 mL) was added hydrazine hydrate (85%, 2.76 g). The mixture was refluxed for 3 h. At room temperature 2 N HCl (60 mL) was added (pH=3), and the mixture was filtered and rinsed with water (50 mL×4). The filtrate was evaporated to about 150 mL and filtered again. After addition of NaHCO3 to adjust the pH=9, the filtrate was extracted with CH2Cl2 (100 mL×3). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After removing the solvent, 1N HCl in MeOH (50 mL) was added and the solvent was evaporated to afford crude material as a white solid. Recrystallization from MeOH-Et2O yielded 4.3 g of the product, 4-(aminomethyl)-2-bromobenzonitrile (yield: 75.8%). 1H NMR (400 MHz, D2O) δ 4.21 (S, 2H), 7.43 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H); 13C NMR (100 MHz, D2O): δ42.3, 115.5, 118.0, 125.6, 128.4, 133.4, 135.5, 139.9; HPLC: retention time: 4.709 min; purity: 99.7%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12](Cl)([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[CH:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Cl)(c1ccccc1)C(F)(F)C3
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(c1ccccc1)C(F)(F)C3
Yield: 78.6 %

Procedure:
Into a 500 ml Parr bottle, the product from step (d) (5.9 g, 14.56 mmol) dissolved in EtOH (150 ml) was added. To the solution, 5% Pd—C (3 g) was added. The reaction mixture was shaken over hydrogen (50 psi) for 16 hours. The reaction mixture was filtered through celite and the volatiles were evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 20% EtOAc in hexanes) gave the sub-title compound as a colorless oil (4.25 g). 1H NMR (300 MHz, CHCl3) δ 7.28-7.26 (m, 3H); 7.10 (s, 2H); 7.01-6.98 (m, 2H); 4.64 (d, J=20.1 Hz, 1H); 4.11-4.01 (m, 2H); 3.66-3.60 (m, 1H); 3.54-3.31 (m, 4H); 3.13-3.06 (m, 1H); 2.89-2.85 (m, 2H); 2.67-2.47 (m, 2H); 1.26-1.22 (m, 3H); MS: ESI (positive): 372 (M+1).
Reaction SMILES: ClC1C=C(C=CC=1Cl)C[O:6][C:7](=[O:26])[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)[OH:9].[OH-].[Li+].Cl.CCOC(C)=O>C1COCC1.CO>[Cl:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[Cl:24])[CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([OH:9])[C:7]([OH:26])=[O:6])=[CH:11][CH:12]=1
Reactant: O=C(OCc1ccc(Cl)c(Cl)c1)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-acetic acid 3,4-dichloro-benzyl ester (9.4 g) was dissolved in 120 mL of THF-methanol (4:1) and 2N lithium hydroxide solution (39 mL) added. The resulting reaction mixture was stirred at room temperature 16 h. The mixture was poured onto 1N HCl and EtOAc and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residual oil was taken up in minimal DCM and hexanes added to give a solid. The solid was filtered and washed with hexanes to afford the desired product [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid in pure form (6.1 g). 1H NMR (400 MHz, DMSO d6): 7.69 (d, 1H), 7.63 (d, 1H), 7.41 (m, 1H), 7.31 (m, 2H), 6.96 (m, 2H), 5.10 (s, 2H), 4.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([NH2:15])[N:7]=1.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]=2[NH2:15]
Reactant: BrCc1cccc(CBr)c1
Reactant: COCCOc1nc(N)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1nc(N)c2ncn(Cc3cccc(CBr)c3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.6 %

Procedure:
2-(2-Methoxy-ethoxy)-9H-purin-6-ylamine (1 g, 4.78 mmol) (1), α,α′-dibromo-m-xylene (2.52 g, 9.56 mmol) and anhydrous potassium carbonate (1.32 g, 9.56 mmol) were combined in DMF (10 mL) and stirred at ambient temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (120 mL), washed with water (2×), brine, dried with Na2SO4, and evaporated under vacuum. The crude product was purified by chromatography on silica gel with 0-10% methanol in ethyl acetate as eluent. Evaporation of the appropriate fractions gave 9-(3-Bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-6-ylamine (2) (1.1 g, 2.80 mmol, 59%). MS: 392/394 (MH+).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[NH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:14][CH2:13]1.C(Cl)Cl>CCOCC>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][N:12]([NH:11][C:8]([NH:7][C:3]3[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:13][CH2:14]2)=[CH:21]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc(NC(=O)NN2CCN(CCc3c[nH]c4ccccc34)CC2)c1
Reaction time: 2 h

Procedure:
3.34 g of m-tolylisocyanate are added dropwise to a stirred solution of 6.13 g of 3-[2-(4-aminopiperazin-1-yl)ethyl]indole in 100 ml. of dry methylene chloride while maintaining the reaction temperature below 35° C. After 2 hours a fine precipitate appears, 50 ml. of ether are added and stirring is continued for 3 additional hours. More ether is added and the product is filtered and washed with ether. The solid product is recrystallized from an ethanol and water mixture to give white flakes, m.p. 186°-188° C. of 1-[1-(indol-3-ylethyl)piperazin-4-yl]-3-m-tolylurea.
Reaction SMILES: [C:1]12([C:8]([CH3:10])=[O:9])[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=O>[O-2].[Zn+2]>[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=[CH:10][C:8]([C:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)=[O:9]
Reactant: CC(=O)C12CCC(CC1)C2
Reactant: CC(C)=CC=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(C)=CC=CC(=O)C12CCC(CC1)C2
Yield: 88 %

Procedure:
100 Parts of methyl norbornyl ketone, 50 parts of 3,3-dimethyl-acrolein and 15 parts of zinc oxide are heated for 5 hours at 180° C and a pressure of 55 atmospheres. 85.7 Parts of (4-methyl-1,3-pentadienyl)-norbornyl ketone is obtained having a boiling point of 110° C at 0.01 mm analogously to Example 9. The yield is 88% of theory at a conversion of 80% of theory based on 3,3-dimethylacrolein.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:33][C:34]2[NH:35][CH:36]=[CH:37][N:38]=2)[CH2:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>O>[NH:38]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:33][N:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:23][CH:22]=1)[CH2:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: COC(=O)CCN(CCCCN1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Solvent: O
Product: Cn1ccnc1CN(Cc1ccc(CN(CCCCN2CCCCC2)CCC(=O)O)cc1)Cc1ncc[nH]1
Yield: 103.6 %

Procedure:
The compound (333 mg) obtained in Example 62-3 was dissolved in water (0.5 ml) and concentrated hydrochloric acid (6.0 ml) and the whole was refluxed under heating for 2 hours. After completion of the reaction, the solvent was distilled off, thereby obtaining a hydrochloride (336 mg) of the subject compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C.[Cl:22][C:23]1[C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(O)C(N)(CO)CO>C(Cl)Cl>[Cl:22][C:23]1[C:28]([C:29]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccc(-c2ncc[nH]2)cc1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2ncc[nH]2)cc1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A slurry of 4-imidazolylphenylamine (15.9 mg, 0.100 mmol), polymer-supported DIPEA (0.100 g, 0.362 mmol, 3.62 mmol/g loading) in CH2Cl2 (2 ml) was treated with a 2-chloropyridine-3-carbonyl chloride solution (0.10 M, 0.200 mmol, 2.0 ml, 2.0 eq) in CH2Cl2. The mixture was vortexed at RT for 14 h. Afterwards, the excess acid chloride was removed by treating the reaction mixture with polymer-supported trisamine resin (0.100 g, 0.375 mmol, 3.75 mmol/g loading). The slurry was shaken at RT for an additional 18 h. The reaction mixture was filtered, rinsed with CH2Cl2 (1 ml), and the filtrate was concentrated under reduced pressure. The resulting brown oil was used directly in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[F:13][C:14]([F:32])([C:28]([F:31])([F:30])[F:29])[C:15]([S:18][C:19]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[NH:21][N:20]=1)([F:17])[F:16].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(OCC)(=O)C>[F:32][C:14]([F:13])([C:28]([F:29])([F:30])[F:31])[C:15]([S:18][C:19]1[N:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[N:21]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[N:20]=1)([F:16])[F:17]
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1nc(SC(F)(F)C(F)(F)C(F)(F)F)n[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2nc(SC(F)(F)C(F)(F)C(F)(F)F)nc2C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 29.7 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.43 g), 3-heptafluoropropylsulfanyl-5-trifluoromethyl-1H-(1,2,4)-triazole (0.70 g), tetrabutylammonium iodide (0.09 g), 18-crown-6 (0.06 g) and potassium carbonate (0.48 g) were refluxed in acetonitrile (10 ml) for 2 hours. After cooling, the reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 3-heptafluoropropylsulfanyl-1-(3-methyl-4-nitrobenzyl)-5-trifluoromethyl-1H-(1,2,4)-triazole (0.30 g).
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:5])[CH3:4].ClCCl>CCCCCC.C(OCC)(=O)C>[C:3]([O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([Br:1])[CH:11]=[C:10]1[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(=O)c1cccn1CCOC(C)=O
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1cc(Br)cn1CCOC(C)=O
Reaction time: 2.5 h
Yield: 56.3 %

Procedure:
Three ml. (58.3 mmole) of bromine is added in a dropwise manner to a stirred solution of 14.77 g. (58.3 mmole) of ethyl 1-(2-acetoxyethyl)pyrrole- 2-glyoxalate in 200 ml. anhydrous dichloromethane and cooled to -75° C. After the addition, the reaction is left at -75° C. for 2.5 hours and then the temperature is allowed to increase to room tempearture. The solvent is removed in vacuo, dichloromethane is added to the residue and the solution is washed successively with water, 10% sodium bicarbonate solution and water. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuo. The crude product thus obtained (18.3 g) is subjected to column chromatography on Florisil (1 Kg) using hexane-ethyl acetate (9:1) as the eluting solvent. There is thus obtained upon removal of the solvent, 10.9 g (56%) of ethyl 1-(2-acetoxyethyl)-4-bromopyrrole-2-glyoxalate as an oil having the following physical constants:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:21]2[C:16](=[N:17][C:18]([NH2:22])=[N:19][CH:20]=2)[N:15]([CH3:23])[N:14]=1.[Cl:24]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>S(=O)(=O)(O)O>[Cl:24][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:13]2[C:21]3[C:16](=[N:17][C:18]([NH2:22])=[N:19][CH:20]=3)[N:15]([CH3:23])[N:14]=2)[CH:5]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1nn(C)c2nc(N)ncc12
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(C(F)(F)F)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 88) (526 mg, 1.62 mmol) is dissolved in concentrated sulfuric acid (98%, 15 ml) and trichloroisocyanuric acid (126 mg, 0.54 mmol) is added. The reaction mixture is stirred at room temperature for 3 days, poured onto ice water (100 ml) and stirred for 30 minutes. The resulting precipitate is collected by filtration and dried under vacuum to afford the title compound as the sulfate salt.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1.O>CN(C=O)C>[CH3:1][S:2][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: Clc1cc(-c2ccccc2)ncn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(-c2ccccc2)ncn1
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a suspension of sodium methanethiolate (0.88 g) in dry DMF (15 ml) at 0° C. was added dropwise over 20 minutes a solution of 4-chloro-6-phenylpyrimidine (2.18 g) in dry DMF (25 ml). Ater stirring for a further 15 minutes, the temperature was allowed to rise to room temperature. After 2 hours the reaction mixture was poured into water and extracted with ether (×3). The combined ether extracts were washed with water (×2), dried, filtered and evaporated to give 4-methylthio-6-phenylpyrimidine (2.16 g, 87% pure by GC analysis) as a yellow liquid which was used directly in the next stage.
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Na+].[I-].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:59])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:53][C@@H:54]([OH:58])[C:55]([OH:57])=[O:56])[NH:26][C:27]([C:29]3[N:30]=[N:31][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1.CC#N>CC(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:59])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:53][C@@H:54]([OH:58])[C:55]([O:57][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[O:56])[NH:26][C:27]([C:29]3[N:30]=[N:31][NH:32][N:33]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1
Reactant: CCCC(=O)OCCl
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCCC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn[nH]n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A mixture of chloromethyl butyrate (6.8 μL, 54.5 μmol) and NaI (8.2 mg, 54.5 μmol) in acetone (0.5 mL, 7 mmol) was stirred at 60° C. for 1 hour, then it was added to a mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(2-trityl-2H-tetrazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (12.3 mg, 18.2 μmol) and DIPEA (4.8 μL, 27.2 μmol) in acetone (0.5 mL). The resulting mixture was stirred at 40° C. for 2 hours, concentrated and partitioned between EtOAc (10 mL) and water (2 mL). The organic layer was dried over MgSO4, filtered, and concentrated. 4.0 M HCl in 1,4-dioxane (40.0 μL, 160 μmol) in MeCN (0.2 mL, 4 mmol) was added and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was concentrated and the residue was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (1.3 mg). MS m/z [M+H]+ calc'd for C23H24ClFN6O6, 535.14. found 535.1.
Reaction SMILES: C[O:2][C:3]([C:5]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:10][CH2:9][N:8]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][N:8]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:12])[CH2:9][CH2:10]2)(=[O:20])=[O:19])=[CH:26][CH:25]=1)[C:29]#[C:30][CH3:31]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)N3CCCC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)N3CCCC3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4-carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4-carboxylic acid methyl ester (250 mg, 0.52 mmol) in 4 ml of tetrahydrofuran:methanol (1:1) and 1N sodium hydroxide (1.03 ml, 1.03 mmol), 150 mg of (62%) of the acid was isolated. HR-MS: m/z Calculated for C24H25NO7S 472.1425; Found 472.1426.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1>CCCCCC>[C:5]([CH:10]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:12][CH2:11]1)(=[O:8])[CH2:6][CH3:7]
Reactant: C1=CCCCC1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: CCC(=O)C1CCC(c2ccccc2)CC1
Temperature: -60 °C
Reaction time: 3.5 h
Yield: 120.1 %

Procedure:
In a 2,000 mL (inside volume) three-necked flask equipped with a reflux condenser, 600 mL of hexane and 160 g of anhydrous AlCl3 were mixed and cooled to −60° C., to which were then added 110 g of propionyl chloride and 82.2 g of cyclohexene. The temperature of the mixture was raised to −40° C. while stirring the mixture for 3.5 h. The solvent was then removed by decantation and the residues were washed with cold hexane. The thus obtained 1-propionyl-2-chlorocyclohexane was added with 500 mL of benzene and an additional amount (60 g) of AlCl3. The mixture was then stirred at 45° C. for 3.5 h. The reaction liquid was cooled to room temperature and then poured onto ice. An oil layer was separated and concentrated to obtain 130 g of (4-propionylcyclohexyl)benzene. This was mixed with 1,200 mL of diethylene glycol, 225 g of potassium hydroxide and 310 g of 80% by mass hydrazine hydrate. After refluxing the resulting mixture for 1 h, the contents in the flask were heated to 220° C. to distil off volatile matters therefrom. The mixture was further refluxed for 1 h, cooled to room temperature and then poured in water. An oil layer was then extracted with hexane, washed with water, 5% by mass sulfuric acid and 80% by mass sulfuric acid and then dried. The obtained oil layer was purified by distillation to obtain 85 g of (4-n-propylcyclohexyl)-benzene. As a result of gas chromatography, it was confirmed that the (4-n-propylcyclohexyl)benzene purity was 98.0% and the cis/trans molar ratio was 1.36.