Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[CH2:22](Br)[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O.CO>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:21])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:24][C:23]#[CH:22])[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: C#CCN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1
Reaction time: 5 h

Procedure:
To a solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (800 mg, 2.6 mmol) in acetone (20 ml) was added propargyl bromide (80% solution, 0.290 ml, 2.6 mmol) and potassium carbonate (720 mg, 5.2 mmol). The solution was heated to reflux and stirred for 5 hours. Thin layer chromatography (10:1 dichloromethane:methanol) showed formation of product. The solution was cooled and filtered. The filtrate was concentrated and purified by preparative chromatography (dichloromethane:methanol) to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ynylpiperazinyl)propan-2-ol (M+1=346.2).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.O[CH2:14][C:15]1([CH2:28][CH2:29][CH2:30][OH:31])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1>[CH2:14]1[C:15]2([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19][CH2:20]2)[CH2:28][CH2:29][CH2:30][O:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCCOC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.9 %

Procedure:
Diethyl diazenedicarboxylate (390 μL, 2.46 mmol) was added to a solution of 1,1-dimethylethyl 4-(hydroxymethyl)-4-(3-hydroxypropyl)-1-piperidinecarboxylate (Description 137, 560 mg, 2.05 mmol) and triphenylphosphine (646 mg, 2.46 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at room temperature for 24 hours. Further triphenylphosphine (646 mg, 2.46 mmol) and diethyl diazenedicarboxylate (390 μL, 2.46 mmol) were added and the mixture was stirred at room temperature for 24 hours. Methanol (5 mL) was added and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25), to give the title compound (78 mg, 15%). m/z (ES+) 256 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:6](OC)=[O:7])#[N:2].C(O)C.[BH4-].[Li+]>O1CCCC1>[F:13][C:11]1[CH:12]=[C:3]([CH:4]=[C:5]([CH2:6][OH:7])[CH:10]=1)[C:1]#[N:2]
Reactant: COC(=O)c1cc(F)cc(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(CO)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
(Step 2) To a mixed solution of methyl 3-cyano-5-fluorobenzoate (0.55 g) obtained in Step 1 in tetrahydrofuran:ethanol=10:1 (22 ml) was added lithium tetrahydroborate (0.10 g) at 0° C. After stirring at 55° C. for 1 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 3-fluoro-5-(hydroxymethyl)benzonitrile (0.29 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH2:13][OH:14])[C:9]=1[CH3:15].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[CH3:15]
Reactant: Cc1c(CO)c[nH]c1-c1ccccc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: Cc1c(C=O)c[nH]c1-c1ccccc1F

Procedure:
By a similar operation as in Reference Example 15 and using [5-(2-fluorophenyl)-4-methyl-1H-pyrrol-3-yl]methanol (1.17 g), tetra-n-propylammonium perruthenate (101 mg), N-methylmorpholine N-oxide (1.01 g) and molecular sieves 4A powder (572 mg), the title compound was obtained as pale-pink crystals (yield 0.67 g, 58%).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:9][CH:8]=1.O.[OH-].[Li+].Cl>C1COCC1.O.O>[C:13]12([C:10]3[CH:9]=[CH:8][C:7]([O:6]/[CH:5]=[CH:4]/[C:3]([OH:23])=[O:2])=[CH:12][CH:11]=3)[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:22]1)[CH2:14]2
Reactant: COC(=O)C=COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 12 h
Yield: 96.9 %

Procedure:
3-(4-Adamantan-1-yl-phenoxy)-acrylic acid methylester (569 mg, 1.82 mmol) was dissolved in THF/H2O mixed solution (3:1, 20 ml), to which lithium hydroxide monohydrate (153 mg, 3.65 mmol) dissolved in purified water (5 ml) was added, followed by stirring for 12 hours. The reaction solution was treated with 10% HCl solution and extracted with ethylacetate and NaCl solution. The organic layer was dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc=3:1) to give the target compound as a white solid (526 mg, yield: 96.7%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:16](=[O:18])[CH3:17])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[CH3:15][N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N(C)C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(acetyl-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (525 mg, 2.05 mmol) in AcOEt (5 ml) was added HCl 3N (4 ml). The reaction mixture was stirred at RT for 16 hrs. Solvent were removed under reduced pressure to gine the expected N-methyl-N-piperidin-4-yl-acetamide as its hydrochloride salt (395 mg, quant.).
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([CH2:17][CH2:18][CH3:19])[C:13]=1[N+:14]([O-])=O)([C:3](OCC)=[O:4])=[O:2]>C(O)(=O)C.[Zn]>[CH2:23]([O:22][C:20]([C:11]1[S:10][C:9]2[NH:8][C:1](=[O:2])[C:3](=[O:4])[NH:14][C:13]=2[C:12]=1[CH2:17][CH2:18][CH3:19])=[O:21])[CH3:24]
Reactant: CCCc1c(C(=O)OCC)sc(NC(=O)C(=O)OCC)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCc1c(C(=O)OCC)sc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A suspension of ethyl 2-ethoxalylamino-3-nitro-4-propylthiophene-5-carboxylate (4.2 g, 11.7 mmol) and zinc dust (3.83 g, 58.6 mmol) in 57 ml of 80% aqueous acetic acid was stirred under a nitrogen atmosphere in a water bath for 1 hour. The reaction mixture was decanted from the residual zinc and poured into ice water. The precipitate was filtered off, washed with water and dried. Recrystallization from ethanol (300 ml) afforded 1.67 g (62%) of the title compound. M.p.305°-307° C. 1H-NMR (DMSO-D6,δ): 0.93 (t, 3H), 1.28 (t, 3H), 1.49 (hex, 2H), 2.96 (t, 3H), 4.26 (q, 2H), 12.06 (s, 1H), 12.54 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6]2.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:15])=[O:14]
Reactant: COc1ccc2c(c1)CCC2
Reactant: O=S(=O)(O)Cl
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCC2

Procedure:
50 g (0.34 mole) of 5-methoxyindane are reacted with 75 ml of chlorosulfonic acid analogously to Example 1a to give 6-chlorosulfonyl-5-methoxyindane.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>CC(O)(C)C>[CH2:16]([O:15][C:7]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)=[O:14])[CH3:17]
Reactant: O=C1C=CCC1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C(=O)OCC)[C@@H]1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
Under an atmosphere of argon, 12.6 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Tsdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 152 μL (1.0 mol) of diethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 233 mg (96% yield) of the title compound. After this was converted into an ethylene ketal derivative by the same procedure as in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 96% ee.
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH2:9]1[O:18][C:17]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2[O:10]1>>[CH2:9]1[O:18][C:17]2[CH:16]=[CH:15][C:13]([NH:14][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7])=[CH:12][C:11]=2[O:10]1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc2c(c1)OCO2
Product: CC(C)[C@H](Nc1ccc2c(c1)OCO2)C(=O)O

Procedure:
Following the procedure of Example 1, the m-phenoxybenzyl ester of α-bromoisovaleric acid is reacted with 3,4-methylenedioxyaniline (3 equivalents) at about 75° for about 14 hours to yield the m-phenoxybenzyl ester of N-(3,4-methylenedioxyphenyl)valine, MS m/e 419 (M+, 13.2), 192 (100).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[CH2:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:13][SiH:14]([CH3:18])[O:15][CH2:16][CH3:17]>[Pt]>[C:1]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][Si:14]([CH3:18])([CH3:13])[O:15][CH2:16][CH3:17])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOCCOC(=O)C(=C)C
Reactant: CCO[SiH](C)C
Agent: [Pt]
Product: C=C(C)C(=O)OCCOCCC[Si](C)(C)OCC
Temperature: 50 °C
Reaction time: 24 h

Procedure:
The reaction vessel was a flask equipped with a stirring device, a thermometer, a dropping funnel and fitted with a reflux condenser and a drying tube. The flask charged with about one mole of allyloxyethyl methacrylate and about 1×10-5 moles of a platinum catalyst. The mixture heated to about 50° C. and maintained at 50° C. for 15 minutes. The temperature of the reaction mixture was cooled down to 20° C. with a water bath. When the temperature had reached 20° C., 1.1 moles of dimethylethoxysilane was added to the mixture with the temperature being held at 20° C. during dimethylethoxysilane addition, and stirred for 24 hours. Fractionation of the resulting gave methacryloxyethoxypropyl dimethyl ethoxysilane which had a vacuum boiling point of about 115° C. at 4 mm Hg.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[C:3](=[O:33])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:32])[CH:9]=1)=O.P(Cl)(Cl)(Cl)=O>O>[C:2]([C:3]1[O:33][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH3:32])[CH:9]=2)=[N:5][CH:4]=1)([CH3:34])([CH3:1])[CH3:35]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(C(=O)NCC(=O)C(C)(C)C)cc2C)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(C)(C)C)o3)cc2C)cc1
Temperature: 90 °C
Yield: 80.6 %

Procedure:
To methyl 4-((1-(4-((3,3-dimethyl-2-oxobutyl)carbamoyl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoate (200 mg) was added phosphoryl chloride (0.5 ml) at room temperature. The reaction mixture was heated at 90° C. for 1 hr, and water was added at room temperature. The filtrate was extracted with ethyl acetate, and the extract was washed with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (155.4 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])=[C:12]([F:23])[C:11]2[C:7](=[C:8]([CH3:25])[N:9]([CH3:24])[N:10]=2)[CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[F:23][C:12]1[C:11]2[C:7](=[C:8]([CH3:25])[N:9]([CH3:24])[N:10]=2)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: COC(=O)c1cc2c(C)n(C)nc2c(F)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(C(=O)O)c(Nc3ccc(I)cc3F)c(F)c2nn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of 7-fluoro-6-(2-fluoro-4-iodophenylamino)-2,3-dimethyl-2H-indazole-5-carboxylic acid methyl ester (137 mg, 0.30 mmol) in a mixture of THF (10 ml) and H2O (5 ml) was added a solution of LiOH (1.50 mL, 1M in H2O, 1.50 mmol). After stirring at room temperature for 4 h, the reaction was concentrated, acidified with 1 M HCl solution, and extracted with EtOAc (2×20 ml). The organic solution was dried over MgSO4 and concentrated to give 126 mg (96%) the title compound as an orange solid.
Reaction SMILES: C(OC1C=CC(C(C)(C)CO[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=CC=1)C.BrC1C=C(C(C)(C)COCC2C=CC=C(OC3C=CC=CC=3)C=2)C=CC=1OCC>C1C=CC=CC=1>[O:20]([C:16]1[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Agent: CCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1Br
Solvent: c1ccccc1
Product: Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
The reaction mixture was cooled to room temperature and the gas was released. 100 ml of benzene was charged in the autoclave to dissolve an oil. An insoluble matter was filtered out. After washing with 20 ml of benzene, a resulting mother wash solution was shaken well and then left to stand to obtain a benzene layer. The benzene layer was washed with 100 ml of water three times. Benzene was distilled off under reduced pressure to obtain an oily product. According to gas chromatographic analysis by the internal standard method, the oily product contained 98.5% of intended 3-phenoxybenzyl 2-(4-ethoxyphenyl)-2-methylpropyl ether and 0.3% of starting material 3-phenoxybenzyl 2-(3-bromo-4-ethoxyphenyl)-2-methylpropyl ether. The amounts of 3-phenoxytoluene and 4-ethoxyneophy alcohol formed by ether bond cleavage were each less than 0.2%.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:17][C:15]=4[CH:16]=3)[CH2:8][CH2:7]2)=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)=[CH:17][C:15]=4[CH:16]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C(C1CC1)N1CCC(c2cc3cc(C4CCCCC4)ccc3o2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1cc2oc(C3CCN(CC4CC4)CC3)cc2cc1C1CCCCC1

Procedure:
A solution of 19.0 g of 1-(cyclopropylcarbonyl)-4-(5-cyclohexyl-2-benzofuranyl)-piperidine in 150 ml of tetrahydrofuran is added dropwise to a solution, boiling under reflux, of 13.5 g of lithium aluminium hydride in 200 ml of tetrahydrofuran. The reaction mixture is then refluxed for a further 15 hours; it is afterwards cooled, and the unreacted lithium aluminium hydride is decomposed at -10° by means of 15 ml of water, 15 ml of 10% sodium hydroxide solution and 45 ml of water. The reaction solution is thereupon filtered with suction, the filter residue is washed with 100 ml of chloroform, and the combined filtrates are concentrated in vacuo. The residue is dissolved in 500 ml of 2N hydrochloric acid, and the acid solution is washed with ether. The aqueous solution is subsequently brought to pH 12 by the addition of 10% sodium hydroxide solution, and extracted with one liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered with suction and concentrated by evaporation to obtain crude 1-(cyclopropylmethyl)-4-(5-cyclohexyl-2-benzofuranyl)-piperidine. This is converted with hydrogen chloride in ethyl acetate into the hydrochloride, and this is recrystallised from ethyl acetate, whereupon it melts at 220°.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([C@@H:35]2[CH2:40][CH2:39][C:38](=[N:41][O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:37][NH:36]2)=[O:34])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([C@@H:35]2[CH2:40][CH2:39][C@@H:38]([NH:41][O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:37][NH:36]2)=[O:34])[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)[C@@H]1CCC(=NOCc2ccccc2)CN1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: -20 °C
Reaction time: 9 h
Yield: 81.7 %

Procedure:
(+)-Camphorsulfonic acid (0.350 g, 1.51 mmol) and tetrahydrofuran (1 ml) was added to 4-[({(2S)-5-[(benzyloxy)imino]piperidin-2-yl}carbonyl)amino]piperidine-1-carboxylic acid benzyl ester (0.113 g, 0.25 mmol), and the obtained mixture was cooled down to −20° C. Borane-tetrahydrofuran complex (0.95M, 1.3 ml, 1.24 mmol) was added to the mixture, and after 9 hours of stirring, saturated sodium hydrogen carbonate aqueous solution (5 ml) was added. The reaction mixture was extracted with ethyl acetate (10 ml), and the organic layer was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (95.3 mg) as brown oil (crude yield: 84%). The diastereo selectivity was (2S,5R)/(2S,5S)=93.2/6.8 (86.4% de).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:14](C)=O)[CH:4]=1.FC(F)(F)[C:19]([O:21][C:22](=O)[C:23](F)(F)F)=O>ClCCl>[CH3:19][O:21][C:22]1[CH:23]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:14][S:14][C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:4]=1
Reactant: COc1ccnc(-c2sccc2S(C)=O)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1ccnc(-c2sccc2SSc2ccsc2-c2cc(OC)ccn2)c1

Procedure:
The product of step (d) above (1.61 g) and trifluoroacetic anhydride (1.79 ml) were heated under reflux in dichloromethane (50 ml) producing a copious white precipitate during 1.5 hour. The solvent was evaporated off and the residue was heated under reflux with methanol (10 ml) and triethylamine (10 ml) for 0.5 hour. Evaporation to dryness in vacuo, aqueous work-up, extraction in ethyl acetate and chromatography gave the sub-title compound as a gum. MS (FAB) 445 (M+1), (5%), 222 (100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[I-:13].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:13])[C:5]([OH:7])=[O:6]
Reactant: [I-]
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
25.00 g (180.0 mmol) of 3-hydroxybenzoic acid, 7.20 g (180.0 mmol) of sodium hydroxide pellets, 27.13 g (180.0 mmol) of sodium iodide and 500 ml of methanol are introduced into a one-litre three-necked flask under a stream of nitrogen. The mixture is cooled to 0° C. and 374.30 g (180.0 mmol) of an aqueous sodium hypochlorite solution are added dropwise over one hour and fifty minutes. The reaction medium is stirred for two hours at 0° C., a sodium thiosulphate solution is then added, the mixture is acidified at pH 5, extracted with ethyl ether, the organic phase is washed with water to neutral pH, dried over magnesium sulphate and filtered and the solvents are evaporated off. 43.80 g (92%) of the expected compound are collected in the form of a beige-coloured powder with a melting point of 198° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[C:10]1([C:16](=[N:23][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[CH:29]=[O:30])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].[Cl-].[NH4+]>CO>[C:10]1([C:16](=[N:23][C:24]2[CH:31]=[C:28]([CH:29]([C:9]3[C:5]4[CH:4]=[N:3][CH:2]=[N:1][C:6]=4[NH:7][CH:8]=3)[OH:30])[CH:27]=[N:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: c1ncc2cc[nH]c2n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Product: OC(c1cncc(N=C(c2ccccc2)c2ccccc2)c1)c1c[nH]c2ncncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of 7H-pyrrolo[2,3-d]pyrimidine (Preparation 202, 953 mg, 8.0 mmol), 5-[(diphenylmethylene)amino]nicotinaldehyde (Preparation 106, 3340 mg, 11.7 mmol) and KOH (1350 mg, 24 mmol) in MeOH (16 mL) was stirred for 16 hours at room temperature. The reaction was neutralized with saturated aqueous ammonium chloride solution and the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to obtain a crude residue. The crude material was purified by column chromatography on silica gel (EtOAc:MeOH=100:0 to 80:20,) to give the desired compound as a solid in 62% yield, 2003 mg.
Reaction SMILES: [I:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH2:7]1[CH2:11][O:10][CH2:9]C1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC1COC1>CN(C=O)C.CCOC(C)=O.O>[I:1][C:2]1[CH:6]=[CH:5][N:4]([CH:7]2[CH2:9][O:10][CH2:11]2)[N:3]=1
Reactant: C1CCOC1
Reactant: Ic1cc[nH]n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: IC1COC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Ic1ccn(C2COC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-iodo-1H-pyrazole (503 mg, 2.6 mmol) was added as a solution in DMF (1 mL) to a 1.0 M THF solution of NaHMDS (2.9 mL, 2.9 mmol) that had been pre-cooled in an ice water bath. Additional portions of DMF (2×1 mL) were used to ensure complete transfer. 3-iodooxetane (0.41 mL, 4.7 mmol) was added in one portion and the reaction mixture was allowed to warm to r.t. After 1 h, the reaction mixture was heated to 45° C. and allowed to stir for an additional 75 h. The mixture was cooled and diluted with EtOAc, and water. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with water and were dried over Na2SO4, filtered and concentrated to afford a crude residue that was purified by silica gel chromatography (0-30% EtOAc in hexanes) to provide 3-iodo-1-(oxetan-3-yl)-1H-pyrazole 7.53 (414 mg). Regiochemistry was confirmed as drawn via NOE studies. LCMS-ESI+ (m/z): [M+H]+ calcd for C6H8IN2O: 251.0; found: 251.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.S(=O)(=O)(O)O.[C:11](O)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)O
Reactant: c1cn[nH]c1
Agent: O=S(=O)(O)O
Product: CC(C)(C)n1cccn1
Temperature: 195 °C
Yield: 72.8 %

Procedure:
As in Example 2, the column was charged with 30 g of glass rings of diameter 3 mm, 16.4 g (0.24 mol) of pyrazole and 1.02 g (0.01 mol) of 96% by weight sulfuric acid, heated to 195° C. and reacted over the course of 7 hours with 703 g (9.5 mol) of tert-butanol vaporized at 180° C. 21.7 g of N-tert-butylpyrazole were obtained, boiling point 103° C., with a content of 99.4% (GC), which corresponds to a yield of 72.5%.