Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(C([N:13]1[CH:16]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:14]1=[O:37])O)(O)=O.S(Cl)(Cl)=O>C(Cl)Cl>[C:18]([S:17][CH:16]1[NH:13][C:14](=[O:37])[CH2:15]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C(O)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1CC(SC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A cooled (ice bath) solution of the triethylamine salt of 1-(1'-carboxy-1'-hydroxymethyl)-4-tritylthio-2-azetidinone (1.04 g, 2.0 mmol) in methylene chloride (5 ml) was treated dropwise, under N2, with thionyl chloride (0.16 ml, 2.2 mmol) in methylene chloride (2 ml). The solution was stirred at room temperature for 20 min and concentrated. The residue was diluted with benzene and filtered over a Celite/charcoal bed. The filtrate was evaporated in vacuo to give 870 mg (quantitative) of the title compound as an amorphous solid. It was used in the next step without further purification. ir νmax : 1775 cm-1 ; 1Hmr (CDCl3)δ: 9.22 (1H, bs), 7.27 (15H, m), 5.3 and 5.2 (1H, 2d, J=2 Hz), 4.6 (1H, m) and 2.8 ppm (2H, m).
Reaction SMILES: C([O:3][C:4](=[O:21])/[CH:5]=[CH:6]\[CH:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[K+]>CO>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7]/[CH:6]=[CH:5]\[C:4]([OH:21])=[O:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C\C=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C\C=C(c1ccccc1)c1ccccc1
Yield: 96.9 %

Procedure:
A solution of (Z)-5,5-diphenyl-2,4-pentadieneoic acid ethyl ester (3.5 g) in methanol (20 mL) was treated with a 4N potassium hydroxide solution (5 mL) and the mixture was stirred at reflux for 30 minutes. Most of the methanol was removed under reduced pressure. Then the residual solution was poured over ice containing 3N hydrochloric acid (10 mL). The resulting solid was collected by filtration washed with water, dried and crystallized from dichloromethane-hexane to furnish 3.05 g of (Z)-5,5-diphenyl-2,4-pentadienoic acid mp 175°-176.5° C. Anal. Calculated for C17H14O2 : C, 81.57; H, 5.63 Found: C, 81.51; H. 5.77.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[N:28](COCC[Si](C)(C)C)[CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14](O)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Cl.[F:40][C:41]([F:46])([F:45])[C@@H:42]([NH2:44])[CH3:43]>>[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:44][C@@H:42]([CH3:43])[C:41]([F:46])([F:45])[F:40])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ccnc21
Reactant: C[C@H](N)C(F)(F)F
Agent: Cl
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1)C(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 34, Step 3 starting from 5-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylic acid and (2S)-1,1,1-trifluoropropan-2-amine hydrochloride. LCMS (M+H)+: m/z=496.1. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (br, 1H), 8.99 (s, 1H), 8.83 (d, J=9.3 Hz, 1H), 8.69 (d, J=1.4 Hz, 1H), 8.47 (s, 1H), 8.32 (d, J=5.6 Hz, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.67 (dd, J=3.3, 2.6 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 7.09 (dd, J=3.4, 1.7 Hz), 4.83 (d, J=10.0 Hz, 2H), 4.80 (m, 1H), 4.57 (d, J=9.6 Hz, 2H), 3.78 (s, 2H), 1.36 (d, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([O:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[O:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:7]1)=[O:4].[N+](C1C=CC=CC=1)([O-])=O.[F:43]C(F)(F)C([O-])=O.[Na+].FOC(F)(F)F>FC(Cl)(Cl)Cl>[F:1][C:2]([F:32])([F:33])[C:3]([O:5][C@H:6]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@:20]2([F:43])[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[O:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH2:7]1)=[O:4]
Reactant: C[C@]12CC[C@H](OC(=O)C(F)(F)F)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(F)(F)F)CC[C@@H]12
Reactant: O=C([O-])C(F)(F)F
Agent: FOC(F)(F)F
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: C[C@]12CC[C@@]3(F)[C@@H](CC[C@H]4C[C@@H](OC(=O)C(F)(F)F)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)C(F)(F)F
Yield: 39.4 %

Procedure:
A well-stirred solution of 3β, 17β-di(trifluoroacetoxy)-5α-androstane (2.5 g, 5.15 mmole, prepared by treatment of 5α-androstane-3β,17β-diol with trifluoroacetic anhydride in pyridine), nitrobenzene (800 mg, 6.5 mmole) and sodium trifluoroacetate (10 g, 73.5 mmole) in fluorotrichloromethane (45 ml) was treated with trifluoromethyl hypofluorite (8.5 mmole) at -20° for 2.5 hours, air being admitted to the reaction vessel during this time. Thereafter the solution was purged with nitrogen and the solvent was removed in vacuo. The residue was dissolved in chloroform and the resulting solution was washed with aqueous sodium bicarbonate and water and was then dried, whereafter the product was chromatographed on silica gel (125 g). Elution with chloroform:hexane (3:7) gave unreacted starting material (308 mg), while subsequent elution with chloroform:hexane (7:13) gave 3β,17β-di(trifluoroacetoxy)-9α-fluoro-5α-androstane (1.02 g), which crystallised from hexane as prisms (917 mg) m.p. 140°-142°; [α] D24 -22° (c 1.47, CHCl3). (Found C,55.10; H,5.78; F,26.35%;m/e 502. C33H29O4F7 requires C,54.97; H,5.82; F,26.47%; M+ 502).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N+:9]([O-:16])[CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])=[C:4]([C:19]([O:21]C)=O)[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].BrC1C=CC2OC3C(=NC=CC=3[N+]([O-])=O)C(=O)C=2C=1>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][C:7]3[C:8](=[N+:9]([O-:16])[CH:10]=[CH:11][C:12]=3[N+:13]([O-:15])=[O:14])[C:19](=[O:21])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(Br)ccc1Oc1c[n+]([O-])ccc1[N+](=O)[O-]
Agent: CC(C)[N-]C(C)C
Agent: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])ccnc12
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc[n+]([O-])c12
Temperature: -78 °C
Reaction time: 3 h
Yield: 5.9 %

Procedure:
To a solution of 3-(4-bromo-2-(methoxycarbonyl)phenoxy)-4-nitropyridine 1-oxide (369 mg, 1.000 mmol) in 20 mL of dry THF at −78° C. was added dropwise lithium diisopropylamide (2M, 1.99 mL, 1.999 mmol) and the reaction was stirred at −78° C. for 3 h. The reaction was quenched at this temperature with 15 mL of 1 M HCl in ether and the whole was allowed to warm up to rt. The reaction was extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (hexane to H/CH2Cl2=1:1 to CH2Cl2) gave 8-bromo-4-nitro-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide (20 mg, 0.059 mmol, 5.94% yield) as an offwhite solid and 8-bromo-4-nitro-10H-chromeno[3,2-b]pyridin-10-one as an light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[Li+].[OH-].Cl>C1COCC1>[CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3cccc(OC)c3)c(C)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)c1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A THF solution (2 mL) of ethyl (2E)-3-[4-({3-methyl-6-(methyloxy)-2-[3-(methyloxy)phenyl]-1-naphthalenyl}oxy)phenyl]-2-propenoate (249) (0.030 g, 0.06 mmol, 1 equiv) was treated with 1 M aqueous LiOH (0.260 mL). After 2 h at 50° C., the mixture was acidified with 3M aqueous HCl to pH ca. 1 and extracted with EtOAc (3×5 mL). The pooled organic portions were dried (Na2SO4) and concentrated. Radial chromatography (SiO2, 1 mm plate, 80:20; hexanes/EtOAc) afforded the title compound (250) as a white foam (0.024 g, 85%). 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J=9.2 Hz, 1H), 7.63 (d, J=15.9 Hz, 1H), 7.55 (s, 1H), 7.27 (d, J=8.3 Hz, 2H), 7.16 (dd, J=7.9, 7.9 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.03 (dd, J=9.1, 2.2 Hz, 1H), 6.77 (dd, J=8.1, 1.9 Hz, 1H), 6.71 (d, J=7.4 Hz, 1H), 6.64-6.60 (m, 3H), 6.22 (d, J=15.9 Hz, 1H), 3.92 (s, 3H), 3.62 (s, 3H), 2.25 (s, 3H). TLC (98:2; CHCl3/MeOH): Rf=0.05.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:18]([CH3:26])[CH:17]=2)[O:13][N:12]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:52]1[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][N:52]2[CH2:55][CH:54]([C:56]([O:58][CH3:59])=[O:57])[CH2:53]2)[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:18]([CH3:26])[CH:17]=2)[O:13][N:12]=1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(C)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(CN2CC(C(=O)OC)C2)ccc1-c1noc(-c2ccc(CC(C)C)c(C)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {6-ethyl-5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.15 g, 0.42 mmol) that was obtained in Example 29 (29a), carbon tetrabromide (0.28 g, 0.84 mmol), triphenylphosphine (0.22 g, 0.84 mmol), methyl 3-azetidinecarboxylate hydrochloride (96 mg, 0.63 mmol), and N,N-diisopropylethylamine (0.22 ml, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1) as the eluent to afford the title compound (0.13 g) in a yield of 71% as a colourless oily product.
Reaction SMILES: N1C=C(C(N)=O)C=N1.[CH:9]1([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:26]([C:31]([F:34])([F:33])[F:32])=[N:27][N:28]([CH3:30])[CH:29]=2)=[O:24])=[CH2:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)C.[Pd]>[CH:9]1([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:26]([C:31]([F:33])([F:34])[F:32])=[N:27][N:28]([CH3:30])[CH:29]=2)=[O:24])[CH3:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C=C(c1ccccc1NC(=O)c1cn(C)nc1C(F)(F)F)C1CCCC1
Agent: [Pd]
Agent: NC(=O)c1cn[nH]c1
Solvent: CCO
Product: CC(c1ccccc1NC(=O)c1cn(C)nc1C(F)(F)F)C1CCCC1
Yield: 97.1 %

Procedure:
A mixture of N-[2-(1-cyclopentylideneethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide trifluoromethyl)-1H-pyrazole-4-carboxamide and N-[2-(1-cyclopentylethenyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (2.5 g), each prepared using the methods described above, were shaken on a Parr Shaker with 5% Pd/C in ethanol (75 mL) under 60 lbs of H2 overnight. Contents were filtered and concentrated in vacuo leaving a white solid (2.44 g). The solid was recrystallized from EtOAc/hexanes to give the desired compound as a white solid (1.3 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl>C(OCC)(=O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccccc3)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(-c2ccc(N3CCNCC3)nc2)cc1

Procedure:
A mixed solution of tert-butyl 4-(5-phenylpyridin-2-yl)piperazine-1-carboxylate (800 mg, 2.36 mmol), 2N methanol solution of hydrogen chloride (5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 4 hours, and the solvent was distilled away under reduce pressure. To the residue was added 1N aqueous solution of sodium hydroxide (10 ml), and the titled compound 520 mg (92.1%) was collected by filtration as a solid product.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[CH2:22][C:23]([OH:25])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:38][NH:39][O:40][CH3:41].CN1CCCCC1>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[CH2:22][C:23]([N:39]([O:40][CH3:41])[CH3:38])=[O:25])=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOc1cc(C(CC(=O)O)NC(=O)OC(C)(C)C)ccc1OC
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CCOc1cc(C(CC(=O)N(C)OC)NC(=O)OC(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of carbonyldiimidazole (0.96 g, 5.9 mmol), 3-(tert-butoxycarbonylamino)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (2.0 g, 5.9 mmol) and methylene chloride (25 mL) was stirred at room temperature for 1 hr and then cooled to 5° C. A solution of N,O-dimethylhydroxyamine hydrochloride (0.86 g, 8.85 mmol) and 1-methylpiperidine (0.87 g, 8.85 mmol) in methylene chloride (10 mL) was added slowly. The mixture was stirred at room temperature for 1 hr and then quenched with water (20 mL). The organic layer was separated and then was washed with 1N citric acid, water, and brine. The organic layer was dried and concentrated in vacuo to give an oil. This oil was purified by chromatography (silica gel, methylene chloride:ethyl acetate 8:2) to afford 3-(tert-butyloxycarbonylamino)-3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-N-methylpropanamide as a white solid (1.76 g, 78%); 1H NMR (CDCl3) δ6.86-6.78 (m, 3H), 6.07 (b, 1H), 5.01 (m, 1H), 4.10 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.50 (s, 3H), 3.10 (s, 3H), 3.02 (m, 2H), 2.84-2.75 (dd, J=5.3 and 15.2 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.41 (s, 9H); 13C NMR (CDCl3) δ171.81, 155.18, 148.39, 148.19, 134.82, 118.12, 111.41, 111.18, 79.27, 64.26, 61.19, 55.90, 51.25, 37.80, 31.87, 28.33,14.73.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:4]([Cl:11])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
945 mg of 2,6-dichloropurine, 15 ml of DMF (dimethylformamide) and 288 mg of NaH are mixed and left at ambient temperature for 2 hours. 1.06 ml of 2-chloromethoxyethyltrimethylsilane are then added. The mixture is stirred for 18 hours at ambient temperature. The DMF is evaporated off. The product is taken up in methylene chloride. Washing is carried out with a saturated sodium bicarbonate solution and then once with H2O and, finally, with a saturated NaCl solution. Drying over Na2SO4 and evaporation to dryness are carried out. Purification is carried out by chromatography on silica with a CHCl3-AcOEt: 5-5 mixture for eluent. 876 mg of expected product are obtained, in the form of a yellow-colored oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]1=[O:14]
Reactant: O=C(O)CCCC(=O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=C1CCCC(=O)C1c1ccccc1Cl
Temperature: 120 °C
Yield: 63.2 %

Procedure:
A 500 ml one-neck round bottom flask was charged with 10.0 g (0.0416 mol) of 6-(2'-chlorophenyl)-5-keto-hexanoic acid and 100 ml of 72% sulfuric acid. The reaction mixture was stirred and heated to 120° C. for 51/2 hrs. (oil bath) then poured into 600 ml of ice water. A tacky, white solid formed, and this was extracted into 300 ml of methylene chloride. The CH2Cl2 solution was washed six times with water, dried over anhydrous MgSO4, and stripped to leave 8.87 g of a tacky, white solid. This material was recrystallized from ethyl acetate to give 5.85 g (63%) of 2-(2'-Chlorophenyl)-1,3-cyclohexanedione as a white, crystalline solid, m.p. 148.5°-149° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.CCCCCC>ClCCl.C(OCC)C>[CH2:12]([O:19][C:20]([NH:22][CH2:23][CH:24]=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
This compound was prepared according to a modified literature procedure (Tetrahedron Lett. P184, 25, 5303). Under an atmosphere of argon, dry dichloromethane (30 ml) was added to powdered (3 Å) molecular sieves (2.13 g) which were previously dried for 2 hours. Solid pyridinium chlorochromate (5.50 g, 25.5 mmol) was then added and the mixture stirred at r.t. under argon for 10 minutes. A solution of 2-benzyloxycarbonylaminoethanol (prepared according to a literature procedure (Tetrahedron, 1991, 47, 2591)) (1.42 g, 7.28 mmol) in dry dichloromethane (30 ml) was added dropwise to the stirred mixture. After 2.5 hours t.l.c. (ethyl acetate/hexane 1:1) indicated complete conversion of the starting material (Rf 0.26) to product (Rf 0.61). The reaction mixture was diluted with diethyl ether (80 ml) and stirred for 10 minutes. The solution was then filtered through a silica plug, eluting with diethyl ether. The residual molecular sieves and pyridinium chlorochromate were collected and crushed in a mortar and pestle with diethyl ether and the resulting solution was filtered through the plug eluting with further diethyl ether. The resulting filtrate was concentrated in vacuo and the ensuing oil purified by flash column chromatography (ethyl acetate/hexane 1:1) to afford the title compound as a colourless oil (777 mg, 55%). δH (CDCl3, 200 MHz): 4.16 (2H, d, J 5.0, CH2CHO), 5.05 5.19 (3H, m, ArCH2, NH), 7.30 7.48 (5H, m, ArH), 9.68 (1H, s, CHO).
Reaction SMILES: [CH3:1][N:2]([S:12]([CH3:15])(=[O:14])=[O:13])[C:3]1[NH:7][N:6]=[N:5][C:4]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+]>C1COCC1>[CH3:1][N:2]([S:12]([CH3:15])(=[O:14])=[O:13])[C:3]1[NH:7][N:6]=[N:5][C:4]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1nn[nH]c1N(C)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(c1[nH]nnc1C(=O)O)S(C)(=O)=O
Yield: 20.7 %

Procedure:
Methyl 5-[methyl(methylsulfonyl)amino]-1H-1,2,3-triazole-4-carboxylate (0.36 g) was stirred in THF (5 mL) with 2 N aqueous sodium hydroxide solution (1.7 mL) for 18 h. The mixture was concentrated in vacuo. To the aqueous residue was added dilute acetic acid and this was extracted with ethyl acetate (2×15 mL). The extracts were washed with water and brine then dried and evaporated to leave the subtitle compound (0.07 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[Ti:12]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])(C)C>>[O:7]([Ti:12]([O:13][C:14]1[CH:15]=[CH:24][CH:22]=[CH:23][CH:16]=1)([O:17][C:18]1[CH:19]=[CH:20][CH:18]=[CH:19][CH:20]=1)[O:21][C:22]1[CH:23]=[CH:16][CH:14]=[CH:15][CH:24]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Reactant: Oc1ccccc1
Product: c1ccc(O[Ti](Oc2ccccc2)(Oc2ccccc2)Oc2ccccc2)cc1

Procedure:
To the bottom of an Oldershaw type reaction-distillation column (hereinafter referred to as “reaction-distillation column for synthesizing a catalyst”) having an inner diameter of 32 mm and equipped with a bottom flask having a volume of 1L was charged 300 ml of phenol, and heated by an oil bath. While maintaining the whole refluxing state, and after stabilization of the temperature distribution in the reaction-distillation column for synthesizing a catalyst, phenol was fed with a flow amount of 342.4 g/h, and tetraisopropoxy titanium (TIPT) with 21.6 g/h. The ratio of the molar number of the phenol fed and the molar number of of the Ti atom in TIPT (phenol/Ti) was 48. The distilled liquid from the top was taken out while maintaining the reflux ratio of 5. With regard to the bottom, the liquid was continuously taken out from the bottom portion of the reaction-distillation column for synthesizing a catalyst so that the liquid surface maintained 330 ml. With this state, it was maintained until the system became a steady state, and when the bottom liquid was analyzed, 10.8% by weight of tetraphenoxy titanium (TPT), 89.2% by weight of phenol and 114 ppm of isopropanol (IPA) were detected. Also, the composition of the distillate was 71.8% by weight of phenol and 28.2% by weight of isopropanol. The taken out amounts at that time were the bottom liquid of 295.4 g/h and the top distillate of 68.6 g/h. Also, the bottom temperature was 190° C., and the top temperature was 164° C. As a result, the conversion of TIPT to TPT (TPT yield) was 99.8%. The reaction conditions and the results are shown in Table 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:38]([F:39])=[CH:37][C:17]3[N:18]=[C:19]([CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:16]3[CH:15]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:38]([F:39])=[CH:37][C:17]=3[N:18]=[C:19]2[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1

Procedure:
4.2 g of 4-[3-(4-chloro-benzyl)-6-fluoro-2-phenoxymethyl-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (7.6 mmol) were stirred in 50 ml trifluoroacetic acid (651 mmol) for 2 h at rt. The reaction mixture was diluted with 500 ml water and the pH adjusted to 8 with solid sodium bicarbonate and then to 9-10 with ammonium hydroxide, extracted with ethylacetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo, leading to 3.34 g of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole as a light yellow solid (99%). MS(ISP): 451.2 (M+H)+.