Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.Cl>CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:16]1([OH:18])[CH2:17][O:14][CH2:15]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)COC1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
Tetrahydrofuran (110 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (7.18 mL, 48.6 mmol) was then added and stirred under N2 and then cooled to 0° C. oxetan-3-one (2.5 g, 34.7 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.347 mL, 0.347 mmol) was added dropwise slowly via syringe and allowed to warm up to RT for 1 hr. The reaction was then cooled back down to 0° C. and added 30 mL of 1N HCl and stirred at RT for overnight. The reaction was then diluted with EtOAc and separated with water. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give the product 3-(trifluoromethyl)oxetan-3-ol (2.00 g, 40.6% yield) as an orange thin oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.82-4.74 (m, 2H), 4.70-4.60 (m, 2H), 3.23 (br. s., 1H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]2[CH2:24][CH2:23][O:22][C:20]2=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][O:26][CH2:27]Cl>C1COCC1>[C:13]1([C:19]2([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][O:22][C:20]2=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OCCC1c1ccccc1
Reactant: COCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCC1(c2ccccc2)CCOC1=O
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Butyl lithium (62.5 mL of 1.6M solution in hexanes) was treated dropwise with a solution of diisopropylamine (14.0 mL) in THF (200 mL) at −20° C. and the resulted mixture was stirred for additional 30 min at the same temperature. After that the mixture was cooled to −90° C., treated dropwise with a solution of 2-phenyl-γ-butyrolactone (11.0 g) in THF (50 mL) and then stirred for 45 min at the same temperature. Next the reaction mixture was treated dropwise with a solution of chloromethyl methyl ether (8.05 g) in THF (50 mL), stirred for additional 10 min, then allowed to slowly warm-up to room temperature and stirred at this temperature for 16 h. Subsequently the reaction mixture was quenched by pouring onto a mixture of ice and 10% aqueous phosphoric acid. The formed organic phase was separated and the aqueous phase was extracted with chloroform. The combined organic phases were washed with saturated aqueous solution of potassium bicarbonate, then water, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.5 g (82%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]([C@:15]12[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C@@H:20]1[NH:19][CH2:18][CH2:17][CH2:16]2)[CH3:14]>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:19]3[C@@H:20]4[C@:15]([CH2:13][CH3:14])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[CH2:22][CH2:21]4)[CH2:16][CH2:17][CH2:18]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC[C@@]12CCCN[C@H]1CCc1ccccc12
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: CO
Solvent: ClCCl
Product: CC[C@@]12CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CCc1ccccc12
Yield: 44 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10b-ethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 44% of theory; TLC: rf=0.42 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=360 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH:19]=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.[C:29]([S:33]([NH2:35])=[O:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:1][C:2]1([CH3:28])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH:18]([NH:21][S:22]([C:24]([CH3:26])([CH3:27])[CH3:25])=[O:23])/[CH:19]=[N:35]/[S:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:34])=[CH:11][CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(C=O)NS(=O)C(C)(C)C)cc2)O1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2ccc(CCCC(/C=N/S(=O)C(C)(C)C)NS(=O)C(C)(C)C)cc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-formyl-butyl}-amide in THF (20 ml) is added tert-butyl sulfinamide (323 mg, 2.7 mmol) followed by titanium ethoxide (1.0 ml, 4.8 mmol). The yellow solution formed is stirred at room temperature overnight. The solution is quenched with 1N NaOH (50 ml) and EtOAc (50 ml) and stirred for 30 minutes at room temperature. The resultant mixture is filtered through Celite™ (filter material) and the organic phase separated and dried (MgSO4). Concentration gives 2-Methyl-propane-2-sulfinic acid (4-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-1-{[(E)-2-methyl-propane-2-sulfinylimino]-methyl}-butyl)-amide as a mixture of diastereomers as a yellow oil; [M+H]+ 515.38
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][C:33]([CH3:36])([CH3:35])[NH2:34])[CH2:23][CH3:24])[CH3:21].C(#N)C>C(OCC)(=O)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][C:33]([NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])([CH3:35])[CH3:36])[CH2:23][CH3:24])[CH3:21]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CC(C)(C)NC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 62 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-l-yl]-1,1-dimethyl-ethanamine in a yield of 62% of theory. Colourless crystals, m.p. 160°-162° C. (acetonitrile and ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25](O)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([NH:35][C@H:36]([C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([NH:35][C@H:36]([C:41]([N:43]1[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Product: CN1CCN(C(=O)[C@H](CC(N)=O)NC(=O)CCc2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Yield: 0.1 %

Procedure:
Condensation of 3-(2,4-dibenzyloxyphenyl) propionic acid (961 mg) and 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-methylpiperazine (1.0 g) was carried out in the same manner as in Example 12 (i) to obtain colorless crystalline 1-[3-(2,4-dibenzyloxyphenyl) propionyl-L-asparaginyl]-4-methylpiperazine (1.39 mg). Melting point: 121°-123° C.
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3]([Cl:6])(Cl)Cl.N1C=CC=CC=1.[CH3:19][NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1>O1CCCC1>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:20]([CH3:19])[C:3]([Cl:6])=[O:2])=[N:22][CH:23]=1)#[N:26]
Reactant: CNc1ccc(C#N)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C(=O)Cl)c1ccc(C#N)cn1

Procedure:
To a solution of bis(trichloromethyl) carbonate (50 mg, 0.17 mmol) in tetrahydrofuran (2.0 mL) was added pyridine (0.04 mL, 0.510 mmol) dropwise under ice-cooling. After stirring under ice-cooling for 30 min, 6-(methylamino)nicotinonitrile (68 mg, 0.510 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. The precipitated solid was filtered off. The filtrate containing (5-cyanopyridin-2-yl)(methyl)carbamic chloride (I-28) was directly used for next step.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCCCCC>O1CCCC1>[OH:22][C:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCCC1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a solution of 4-bromobenzoic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (54 mL) at −78° C. was added n-butyllithium (19.1 mL of 1.6 M in hexanes, 30.6 mmol) dropwise while maintaining the internal temperature below −65° C. The mixture was stirred at −78° C. for 30 min. Cyclohexanone (1.55 mL, 14.9 mmol) was added dropwise while maintaining the reaction temperature below −65° C. The mixture was stirred at −78° C. for 10 min then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and 1N HCl (25 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was stirred with 1:1 dichloromethane/hexane (20 mL) to provide a white solid, which was filtered and discarded. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-5% methanol/dichloromethane) to provide an off-white solid. The solid was stirred with hexane, filtered, and dried to provide 4-(1-hydroxycyclohexyl)benzoic acid (375 mg, 11%). ESI-MS m/z calc. 220.1. Found 221.3 (M+1)+; Retention time: 1.18 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 4.84 (s, 1H), 1.81-1.46 (m, 9H), 1.35-1.17 (m, 1H).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:47])[CH:30]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.C(N)CCC>>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:47])[CH:30]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C@H:20]1[OH:21]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Solvent: CCCCN
Product: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1C(=O)O
Yield: 87.7 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-[N-tert-butoxycarbonyl-β-(4-fluorophenyl)-D,L-alanylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (400 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9yl)-3-[N-tert-butoxycarbonyl-β-(4-fluorophenyl)-D,L-alanylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (543 mg) prepared in Example 9 with n-butylamine (5.0 ml) according to a similar manner to that of Example 23, mp. 149°-154° C. (dec.).
Reaction SMILES: CS([C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=O)=O.[CH3:25][Mg]Br.[Cl-].[NH4+].O>CCOCC>[CH3:25][C:5]1[N:12]=[C:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CC(C)[Si](OCc1ccc(C#N)c(S(C)(=O)=O)n1)(C(C)C)C(C)C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N
Yield: 95 %

Procedure:
To a solution of 2-(methylsulfonyl)-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (0.80 g, 2.2 mmol) that was obtained in Example 24 (24b) in ether (10 ml) was added a 3.0 M solution of methylmagnesium bromide in ether (1.5 ml, 4.4 mmol) at −78° C. with stirring, and the resulting mixture was stirred at the same temperature for 1 hour. After stirring, a saturated aqueous solution of ammonium chloride (1 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and 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 (0:10 to 1:9) as the eluent to afford the title compound (0.64 g) in a yield of 95% as a white crystalline solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(Sc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(Sc2ccccc2)cc1
Reaction time: 1 h

Procedure:
The 1-hydroxymethyl-4-phenylthiobenzene (3.0 g) is dissolved in methylene chloride (15 ml), and thereto is added with stirring thionyl chloride (1.5 ml) under ice cooling. The mixture is stirred for one hour, and the reaction mixture is washed with ice water (10 ml×3), and thereto is added methylene chloride (50 ml). The mixture is washed in order with 5% aqueous sodium hydrogen carbonate solution (5 ml×3) and saturated aqueous sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-chloromethyl-4-phenylthiobenzene (3.0 g).
Reaction SMILES: C([O:4][C@H:5]1[C:14]2[N:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:11]3[C@@H:18]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[O:19][C:20]4([CH2:24][CH2:23][CH2:22][CH2:21]4)[C:10]=3[C:9]=2[C@@H:8]([OH:35])[CH2:7][C:6]1([CH3:37])[CH3:36])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:15]([C:12]1[C:11]2[C@@H:18]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=3)[O:19][C:20]3([CH2:21][CH2:22][CH2:23][CH2:24]3)[C:10]=2[C:9]2[C@@H:8]([OH:35])[CH2:7][C:6]([CH3:36])([CH3:37])[C@@H:5]([OH:4])[C:14]=2[N:13]=1)([CH3:17])[CH3:16]
Reactant: CC(=O)O[C@H]1c2nc(C(C)C)c3c(c2[C@@H](O)CC1(C)C)C1(CCCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCCC1)[C@@H](O)CC(C)(C)[C@H]2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13 mg (3′R,6′R,9′S)-9′-hydroxy-4′-isopropyl-7′,7′-dimethyl-3′-(4-(trifluoromethyl)phenyl)-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline]-6′-yl acetate are dissolved in 1 ml methanol and treated with 14 mg potassium carbonate. Three drops water are added and the mixture is stirred for 3 hours at room temperature. Then the solvent is evaporated in vacuo and the residue is partitioned between water and dichloromethane. The organic phase is dried with sodium sulphate and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (hexane/ethylacetate 4:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[F:11][C:12]([F:16])([F:15])[CH2:13]O.C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[F:11][C:12]([F:16])([F:15])[CH2:13][O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: OCCOC1CCCCO1
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: FC(F)(F)COCCOC1CCCCO1
Reaction time: 6 h

Procedure:
According to the procedure of Tet. Let., 35, 5997-6000 (1994), combine 1-hydroxy-2-tetrahydropyran-2-yloxyethane (J. Chem. Soc. Chem. Commun., 1766 (1990)) (5.0 mmol), 1,1-diethylazodicarboxylate (10 mmol), 2,2,2-trifluoroethanol (100 mmol), and tributylphosphine (10 mmol) in benzene (100 mL). After 6 hours, concentrate in vacuo to give a residue. Chromatograph on silica gel to give 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluorethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH2:16]O)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:12][C@H:11]2[CH3:26])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:41]1[CH:45]=[N:44][N:43]=[N:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@@H:14]([CH2:16][C:45]3[NH:44][N:43]=[N:42][N:41]=3)[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:12][C@H:11]2[CH3:26])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1C(=O)COc1ccc(Cl)cc1
Reactant: c1nnn[nH]1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@H](Cc2nnn[nH]2)CN1C(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 13 %

Procedure:
To a solution of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)-5-((hydroxy)methyl)piperazine (0.17 g, 0.42 mmol) in CH2Cl2 (50 mL) at 0° C. was added triethylamine (excess) and methane sulfonyl chloride (0.050 mL, 0.5 mmol). The resultant mixture was stirred at 0° C. until consumption of alcohol was observed by TLC analysis. The mixture was concentrated of volatiles in vacuo. Residue was taken up in anhydrous DMF (5 mL) and K2CO3 (excess) added, followed by tetrazole (0.050 g, 0.71 mmol). The resulting mixture was stirred at ambient temperature for 3 days and filtered. The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate. This was washed with water then brine, then dried over MgSO4 and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 25 mg of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)-5-((tetrazolyl)methyl)piperazine as a white solid: NMR (CDCl3) 7.3 (m, 5), 7.0 (m, 4), 4.84.1 (m, 5), 3.8 (m, 3), 3.2 (m, 2), 2.8 (dd, 1), 2.5 (dd, 1), 1.4 (d, 3) ppm, MS (ESI) 458.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CCOC(C)=O>[Cl:20][C:19]([Cl:22])([Cl:21])[CH2:18][O:17][C:15](=[O:16])[NH:11][C:7]1[N:8]([CH3:10])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1nc(C(C)(C)C)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine (0.5 g, 3.26 mmol) in EtOAc (10 mL) was treated with aqueous NaOH (1M, 5.87 mmol), followed by 2,2,2-trichloroethyl chloroformate (0.54 mL, 3.92 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc (10 mL) and water (2×10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to afford the title compound as a pale orange gum (0.915 g, 86%). LCMS (Method 3): Rt 3.88 min, m/z 328/330 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:14]([OH:16])=[O:15]>C(O)(=O)C.Br>[Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:14]([OH:16])=[O:15]
Reactant: COc1ccc2c(C(=O)O)cccc2c1Br
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c(Br)c(O)ccc12
Yield: 73 %

Procedure:
A mixture of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid (33.35 g, 0.11 moles, described in example 1b) in glacial acetic acid (460 ml) and 47% aqueous HBr(417 ml) was heated at reflux for 9 hr. The resulting precipitate was collected, washed with water and dried over P2O5 under reduced pressure. The precipitate was recrystallized from ethanol-water to give 21.45 g of 5-bromo-6-hydroxy-1-naphthalenecarboxylic acid; mp>225° C.; NMR (DMSO-d6)δ 8.0 (m, 5H), 11.0 (broad, 1H), 12.6 (broad, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([N:8]([CH2:22][C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[O:24])[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO.C1COCC1>[Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([N:8]([CH2:22][C:23]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[O:24])[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(OC)cc2)c2cccc(Cl)c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
220 mg of methyl 4-{[(3-chloro-2-methylphenyl)amino]sulfonyl}benzoate was dissolved in 1.10 mL of DMF, and 168 mg of 2-bromo-N-(4-methoxybenzyl)acetamide and 100 mg of potassium carbonate were added thereto, followed by stirring at room temperature for 7 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 4:6) to obtain 270 mg of methyl 4-[((3-chloro-2-methylphenyl)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoate. The obtained methyl 4-[((3-chloro-2-methylphenyl)-{2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoate was dissolved in 2.00 mL of methanol and 1.50 mL of THF, and 1.05 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 days. The reaction liquid was acidified by addition of 1 M hydrochloric acid, and then extracted with a mixed solvent of chloroform/methanol (5/1), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:methanol=100:0 to 90:10) to obtain 204 mg of 4-[((3-chloro-2-methylphenyl) {2-[(4-methoxybenzyl)amino]-2-oxoethyl}amino)sulfonyl]benzoic acid.