Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6]C)[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]>C(O)(=O)C.O>[CH3:1][C@@:2]1([OH:18])[C@H:9]([CH3:10])[O:8][C@@H:5]([OH:6])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@](C)(O)[C@H](C)O1
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H]1O[C@@H](O)C[C@H](NC(=O)C(F)(F)F)[C@]1(C)O
Yield: 99.8 %

Procedure:
A solution of 1 g (3.7 mmoles) of methyl 2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (IV-A) in 20 ml of acetic acid and 80 ml of water was reacted at 100° C. for 2 hours. The solution was evaporated and 2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-α-L-lyxo-hexopyranose (V-A) (0.95 g; 95%) was obtained as a white solid; m.p. 181°-182° C. [α]D23° =-127° (c=1.0 in methanol). The PMR spectrum (CDCl3 +DMSO-d6) showed, inter alia, absorptions at: 1.05 (s, CH3 --C-4), 1.16 (d, CH3 -C-5), and 5.27δ(C-l-H). A solution of 0.75 g (2.9 mmoles) of compound V-A in a mixture of 10 ml of triethylamine and 20 ml of anhydrous methylene dichloride was treated under stirring with 2.20 g of p-nitrobenzoyl chloride and 0.220 g of 4-dimethylaminopyridine and then heated at 45° C. for 90 minutes. The solution was evaporated to form a residue which was dissolved in 100 ml of chloroform, washed with 10% sodium bicarbonate solution and then with water. The chloroform solution was then dried over sodium sulphate and concentrated to a residue which was chromatographed on a silica gel column. Elution with a 95:5 chloroform: acetone mixture gave 1,4-di-O-p-nitrobenzoyl-2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-L-lyxo-hexopyranose (VI-A, 1.55 g; 95%): m.p. 168°-170° C.; [α]D23° =-35° (c=1 in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[C:13]3([C:14]([OH:16])=[O:15])[C:10]([CH3:17])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[CH2:25](N(CC)CC)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.CO.C(N(CC)CC)C.O1CCCC1>[CH3:25][O:15][C:14]([C:13]12[O:12][CH2:11][C:10]1([CH3:17])[CH2:9][CH2:8][CH:7]2[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1)=[O:16]
Reactant: CC12CCC(Cc3ccc(Cl)cc3)C1(C(=O)O)OC2
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C12OCC1(C)CCC2Cc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
In 2 ml of toluene, 50 mg of Compound 13-1 synthesized in Production Example 26 was dissolved. To the solution thus obtained, 0.06 ml of triethylamine was added, and the resulting mixture solution was then cooled. To the solution thus cooled, 0.02 ml of thionyl chloride was added, and the resulting mixture solution was stirred for 1 hour while being allowed to reach room temperature. After the reaction, triethylamine hydrochloride generated was removed by filtration from the reaction solution, and the solvent was then distilled away under a reduced pressure to obtain 73 mg of crude product. To the crude product, 2 ml of tetrahydrofuran, 0.05 ml of triethylamine, and 0.05 ml of methanol were added, and the resulting mixture was stirred at room temperature for 0.5 hour. After the reaction, an aqueous solution of diluted sulphuric acid was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away under a reduced pressure to obtain 58 mg of Compound 7-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2)CC1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (2.70 g, 0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jone's oxidant in water (8.00M, 1.90 mL) at 0° C. The solution was stirred at rt for 1 hour and then filtered, concentrated. The residue was dissolved in AcOEt, and the solution was washed with water and brine successively, dried over MgSO4, and concentrated. The crude product was purified using Combiflash eluting with 50% AcOEt in hexanes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[Se:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[C:10]2[Se:9][C:13]([CH:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[OH:8])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1
Reactant: c1cc[se]c1
Reactant: O=Cc1ccncc1
Product: OC(c1ccncc1)c1ccc(C(O)c2ccncc2)[se]1

Procedure:
2,5-bis(4-pyridylhydroxymethyl)selenophene was prepared by a reaction of 9.04 mL (0.09 mol) 4-pyrdinecarboxaldehyde with 3.5 mL (0.04 mol) selenophene by a procedure similar to that described above. The 2,5-bis(4-pyridylhydroxymethyl)selenophene was obtained in 20% yield. 1H NMR (DMSO-d6) δ 8.48 (d, J=3.4 Hz, 4H), 7.36 (d, J=3.4 Hz, 2H), 7 6.87 (s, 2H), 6.93 (s, 2H), 6.44 (brs, 2H), 5.82 (s, 2H); HRMS (FAB) (M+) calcd. for C16H15O2N2Se: 347.0299; found, 347.0301.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:17][C:18]1[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: FC(F)(F)c1ccc(CBr)o1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(C(F)(F)F)o1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 110 °C
Yield: 78.3 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 2-bromomethyl-5-trifluoromethyl-furan (144 mg, 0.63 mmol) in N,N-dimethylformamide (5 mL) was heated at 110° C. for 2 days. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (50 mL), washed with water (2×25 mL) and brine (25 mL), dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 2-3% methanol/dichloromethane to give (4S,7R)-1,7,8,8-tetramethyl-2-(5-trifluoromethyl-furan-2-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (136 mg, 78%) as a white solid. APCI-MS (M+H) 355.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:50]1[CH2:55][CH2:54][CH2:53][C@@H:52]([C:56]([OH:59])([CH3:58])[CH3:57])[CH2:51]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:50]3[CH2:55][CH2:54][CH2:53][C@@H:52]([C:56]([OH:59])([CH3:58])[CH3:57])[CH2:51]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(O)[C@@H]1CCCNC1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1Cl
Yield: 72.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z 379 (M+1); HRMS, calcd for C19H23ClN2O4: 378.1346, found 378.1340.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][C:17]([CH:37]4[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]4)=[N:16][C:15]=23)[CH:2]=1.C([Sn](CCCC)(CCCC)[C:50]([O:52][CH2:53][CH3:54])=[CH2:51])CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[N:13][N:14]3[C:19]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])=[C:18]([C:50]([O:52][CH2:53][CH3:54])=[CH2:51])[C:17]([CH:37]4[CH2:38][CH2:39][S:40](=[O:44])(=[O:43])[CH2:41][CH2:42]4)=[N:16][C:15]=23)[CH:2]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCS(=O)(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C2CCS(=O)(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A mixture of 3-(quinolin-3-yl)-5-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-2b, 210 mg, 0.28 mmol), tributyl(1-ethoxyvinyl)stannane (310 mg, 0.84 mmol) and Pd(Ph3P)4 (31 mg, 0.028 mmol) in anhydrous dioxane (5.0 mL) was heated under argon at 100° C. for 24 h, cooled and concentrated. The residue purified by Biotage (CH2Cl2/EtOAc, 20:1 to 4:1) to give 169 mg (83%) of the title compound as a light brown solid. LC/MS RT=2.58 min (5 min method). Mass calculated for, M+H 724.33, observed 724.33.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][CH:4]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:23]([NH:25][C:26]2[C:27]([CH3:41])=[C:28]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:29]=[CH:30][CH:31]=2)=[O:24])=[CH:18][CH:17]=1.[Cl-].[NH4+]>CN(C=O)C.C1CCCCC1.C(OCC)(=O)C>[CH:42]1([CH:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:5]3[C:6](=[O:13])[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:3]=[CH:4]3)=[CH:17][CH:18]=2)[C:23]([NH:25][C:26]2[C:27]([CH3:41])=[C:28]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:29]=[CH:30][CH:31]=2)=[O:24])[CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(Cn2cnc3ccccc3c2=O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15 mg (0.39 mmol, content 60%) of sodium hydride were added to a solution of 34 mg (0.23 mmol) of quinazolin-4(3H)-one in 5 ml of DMF, and the mixture was stirred under an atmosphere of argon at 0° C. for 30 min. 100 mg (0.19 mmol) of tert-butyl 3-[3-({[4-(bromomethyl)phenyl](cyclopentyl)acetyl}amino)-2-methylphenyl]propanoate, dissolved in 1 ml of DMF, were then added to the reaction solution, and the latter was slowly warmed to toom temperature. After the reaction had gone to completion (monitored by TLC; cyclohexane/ethyl acetate 2:1), 1 ml of saturated ammonium chloride solution was added and the reaction mixture was purified directly by preparative HPLC. This gave 28 mg (0.05 mmol, 25% of theory) of the racemic title compound.
Reaction SMILES: [N:1]1[C:11]2[C:10](=O)[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].[K+].[Br-]>C(O)(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][N:23]=[C:10]2[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:11]2=3)=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)c2ncccc2N1
Reactant: NNc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Br-]
Solvent: CC(=O)O
Product: O=C1CCC(=NNc2ccc(F)cc2)c2ncccc2N1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
183 mg (1.04 mmol) 5H-Pyrido[3,2-b]azepine-6,9(7H,8H)-dione and 186 mg (1.14 mmol) (4-fluorophenyl)hydrazine hydrochloride, and 90 mg (1.1 mmol) sodium acetate were suspended in glacial acetic acid (11 ml) and stirred for 1 hour at 70° C. After cooling to room temperature, the mixture was poured into a 5% aqueous sodium acetate solution. The mixture was extracted with 4×20 ml ethyl acetate. The combined organic layers were dried over sodium sulfate, and evaporated to dryness. Recrystallization from ethanol afforded a yellow solid. Yield: 170 mg (58%);m.p. 232-233° C.; IR (KBr): 3286 cm−1 (NH), 3119/3061 cm−1 (CH-arom.) 2956/2888 cm−1 (CH-aliph.), 1674 cm−1 (C═O); 1H-NMR (DMSO-d6, 400 MHz): δ (ppm)=2.54-2.58 (m, 2H, part of AA′XX′-system, azepine-CH2), 3.01-3.04 (m, 2H, part of AA′XX′-system, azepine-CH2), 7.03-7.07 (m, 2H, arom. H), 7.16-7.20 (m, 2H, arom. H), 7.33-7.40 (m, 2H, arom. H), 8.40 (dd, 1H, 4.4/1.6 Hz, arom. H), 9.35 (s, 1H, NH), 9.77 (s, 1H, NH); C15H13FN4O (284.30).
Reaction SMILES: [C:1](=[O:32])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=1)OC1C=CC=CC=1.[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][NH:33][C:1](=[O:32])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(COC(=O)Oc2ccccc2)cc1
Reactant: NCc1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)NCc2ccccn2)cc1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
A mixture of 0.50 g of product from Example 94 and 0.184 g of 2-(aminomethyl)pyridine is heated in a sealed tube at 100° C. for 80 minutes. The crystalline reaction product is dissolved in methylene chloride, washed with 5% potassium hydroxide and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 50% ethyl acetate/hexane) to give 0.481 g of the desired product as colorless plates.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.COC[O:20][C:21]1[C:22](=[O:39])[N:23](COC)[CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)[CH:26]=1>>[OH:20][C:21]1[C:22](=[O:39])[NH:23][CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2ccc(C)cn2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: Cc1ccc(CSc2c[nH]c(=O)c(O)c2)nc1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 3-(methoxymethoxy)-1-(methoxymethyl)-5-{[(5-methylpyridin-2-yl)methyl]sulfanyl}pyridin-2(1H)-one (Intermediate 28).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15]C(=O)C)=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-].[Li+].Cl>C(O)CO>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: CC(=O)Oc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: OCCO
Product: Oc1ccc2c(c1)Cc1cc(Br)ccc1-2
Yield: 67.3 %

Procedure:
A mixture of 2-bromo-7-acetoxyfluorene (69 g), lithium hydroxide (9 g) and ethylene glycol (350 mL) was heated for one hour while refluxing. The reaction mixture was poured into 6M-hydrochloric acid (300 mL) to terminate the reaction, and the product was extracted with ethyl acetate (350 mL). The ethyl acetate layer was washed with a saturated sodium carbonate aqueous solution and dried on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off under reduced pressure was recrystallized from chloroform to obtain 2-bromo-7-hydroxyfluorene (40 g) of colorless needle crystal. The melting point was 183-184° C.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:18]([O:21][CH:22]([C:31]1[CH:35]([OH:36])[O:34][C:33](=[O:37])[CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:20])[CH3:19]>O1CCCC1.O>[C:18]([O:21][CH:22]([C:31]1[CH:35]([O:36][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:34][C:33](=[O:37])[CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:20])[CH3:19]
Reactant: CCCCCCCCC(OC(C)=O)C1=CC(=O)OC1O
Reactant: CCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCC(OC(C)=O)C1=CC(=O)OC1OC(=O)CCCCCCC
Temperature: 0 °C

Procedure:
Octanoyl chloride (83.6 μl, 0.49 mmol), followed by triethylamine (68.2 μl, 0.49 mmol), was added to 4-(1-acetoxynonyl)-5-hydroxy-2(5H)-furanone (132.6 mg, 0.47 mmol) in tetrahydrofuran (6 ml) at 0°. Stirring was continued for 14h while the ice bath attained room temperature. The mixture was diluted with water (10 ml) and extracted with dichloromethane. Evaporation of the dried (magnesium sulfate) extract gave a yellow oil, which was flash chromatographed on silica using 30% ethyl ether/petroleum ether. Fractions with Rf 0.38 on evaporation gave the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl.O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (125 g, 0.579 mol, content: 89.9%, water: 8.7%) and trimethylcetylammonium chloride (0.137 g) was stirred in toluene (240 ml) and diisopropyl ether (170 ml), and 36% conc. hydrochloric acid (15.6 g) was added. At this time, the amount of water in the reaction system was calculated as 2.0 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (15.5 g) in diisopropyl ether (70 ml) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 500 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (720 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (93.8 g, yield: 92.0%) and 2-keto-L-gulonic acid (0.3 g, residual ratio: 0.3%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH:11]([CH2:13][C:14](O)=[O:15])[CH3:12].C(N(CC)CC)C>CS(C)=O>[CH3:12][N:11]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:14](=[O:15])[CH2:13]1
Reactant: CNCC(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CC(=O)Nc2ccccc21

Procedure:
5.2 g of o-fluoro-nitrobenzene, 3.2 g of sarcosine and 5.2 ml triethylamine was stirred in 25 ml DMSO at 70° C. for 4 days. The mixture was then evaporated in vacuo and the residue was partitioned between water and methylene chloride. The organic phase was evaporated in vacuo. The residue was dissolved in 100 ml 96% ethanol and was hydrogenated at normal pressure using 0.5 g Pd/C. After completion of hydrogen uptake, the mixture was filtered and evaporated in vacuo. The residue was washed with water with disodium carbonate, ether and water. Yield of title compound: 1.3 g M.p. 132° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].C(O)[C:7]1[CH:12]=[CH:11]C=[CH:9][CH:8]=1>C([O-])(=O)C.[Hg+]>[CH:1]([O:3][CH2:4][C:5]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1)=[CH2:2]
Reactant: C=COCC
Reactant: OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Hg+]
Product: C=COCc1ccccc1

Procedure:
Ethyl vinyl ether was mixed in benzyl alcohol, to which was then added mercury acetate, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate and the ethyl acetate extract was washed with water, followed by distillation in vacuo to obtain benzyl vinyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C:9]=2[CH2:16][OH:17])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:4][CH:3]=1
Reactant: OCC1=C(c2ccc(Cl)cc2)CCC(F)(F)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC1=C(c2ccc(Cl)cc2)CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 321D (1.38 g) in dichloromethane (25 mL) was added Dess-Martin periodinane (2.489 g) and the reaction stirred for 1 hour at room temperature. The reaction was quenched with 1N aqueous NaOH solution (75 mL) and the product was extracted into dichloromethane (2×100 mL). The combined organics were washed with brine (75 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveris 80 g) eluting with a gradient of 1% to 10% ethyl acetate/hexanes over 40 minutes gave the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@:25]3([CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][C@:25]1([C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)[CH2:31][O:32][Si:33]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:35])[CH3:36])[CH:40]([CH3:41])[CH3:42]
Reactant: CC(C)[Si](OC[C@@]1(c2nnc3ccc(F)cn23)CCCN1C)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC[C@@]1(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCCN1C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of Intermediate A (170 mg, 1.03 mmol) in DMF (4 mL) was added NaH (60% in oil, 103 mg, 2.59 mmol) and the mixture stirred at RT for 20 min, before Intermediate 85i (350 mg, 0.862 mmol) was added. This mixture was stirred at 60° C. for 4 h. The cooled mixture was diluted with EtOAc, washed with water (3×), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound as a clear viscous oil (230 mg, 48%). LCMS (Method 1): Rt 2.28 min, m/z 550 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:24](=[O:27])[CH2:25][CH3:26])[C:20](=[O:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([C:20](=[O:23])[CH2:21][CH3:22])[C:24](=[O:27])[CH2:25][CH3:26])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: CCC(=O)C(CCCCCCBr)C(=O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)C(CCCCCCOc1ccc(S(N)(=O)=O)cc1)C(=O)CC

Procedure:
A mixture of 18.2 g, of 4-hydroxybenzenesulfonamide, 33.6 g of 4-(6-bromohexyl)-3,5-heptanedione, 18.3 g. of powdered anhydrous potassium carbonate and 175 ml. of acetone was stirred at reflux for 24 hours. The reaction mixture was cooled, filtered to remove salts, and concentrated in vacuo. The solid residue was recyrstallized from an acetone-ether mixture to give 4-[6-(4-aminosulfonylphenoxy)hexyl]-3,5-heptanedione, m.p. 86°-87° C. (light yellow solid).