Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:23])([F:22])[C:8]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1([CH3:21])[OH:20])([OH:13])[C:9]([F:12])([F:11])[F:10].[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>O1CCCC1>[C:24]([O:20][C:15]1([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[C:8]([OH:13])([C:9]([F:11])([F:10])[F:12])[C:7]([F:22])([F:23])[F:6])(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: CC1(O)CCCCC1C(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(C)CCCCC1C(O)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a flame-dried, nitrogen-purged 250 mL 3-neck roundbottom flask with 50 mL pressure-equalizing addition funnel and magnetic stirbar was charged 85 mL n-butyl lithium (136 mmol, 2 equiv., 1.6 M in hexanes). A degassed solution of 12-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan2-yl)-1-methylcyclohexanol (X) (.about.68 mmol, 1 eq.) in 50 mL anhydrous tetrahydrofuran was charged to the addition funnel and added to the reaction mixture dropwise at 0° C. over 30 minutes. The reaction mixture was warmed for 15 minutes on a hot water bath to ensure the reaction was complete. The reaction vessel was cooled to 0° C. and 7.46 g methacryloyl chloride (71.4 mmol, 1.05 eq.) was added dropwise and allowed to stir for 15 minutes. The addition funnel was replaced with a reflux condenser and the reaction heated to reflux for 20 hours. After the reaction was complete, it was cooled to 0° C. and quenched with dilute HCl solution until the pH was less than 5.0. The reaction solution was neutralized with saturated aqueous sodium bicarbonate until the pH was greater than 8. The product was extracted into ethyl ether and the organic phase washed sequentially with aqueous sodium bicarbonate, water, and brine and then dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. The crude product mixture was purified via silica gel column chromatography (20:1 hexane:ethyl acetate eluent) to afford 3.08 of 2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1-methylcyclohex-1-yl methacrylate (XII) as a colorless liquid (1 isomer) of only 66% purity. After standing in the refrigerator overnight, 2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1-methylcyclohex-1-yl methacrylate (XII) crystallizes out of the mixture a white crystalline solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][O:20][CH3:21].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][O:20][CH3:21])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(C)=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 2.00 g) and 1-bromo-2-methoxyethane (1.5 g) were dissolved in DMF (20 ml), and sodium hydride (259 mg) was added. After stirring at RT for 3 h, the mixture was left to stand overnight. Then the DMF was drawn off and the residue was taken up in EA. The EA phase was washed with water, dried, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA 0-40% within 60 min). 1.17 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:22](=[O:23])[O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Br)nc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)nc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-aminopyridine (3.0 g, 17.3 mmol) in THF (44 mL) cooled to 0° C. was added pyridine (1.8 mL, 21.7 mmol) followed by phenylchloroformate (2.3 mL, 18.2 mmol). A precipitate formed and the reaction was stirred at 0° C. for 1 h. The reaction was stirred at RT overnight and quenched with 1N HCl. The mixture was extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated to give the title compound as a biege solid (4.81 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-])=O>O1CCCC1.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>[NH2:19][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:10]=1[NH:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(NCc2ccccc2Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1NCc1ccccc1Cl
Yield: 70 %

Procedure:
The procedure of Example 2(ii) was followed. From 3.06 (10 mmol) of 4-[(2-chlorophenyl)methyl]amino-3-nitrobenzoic acid in 30 mL of tetrahydrofuran, 25 mL of 5% sodium bicarbonate solution and excess sodium sulfite was obtained 1.93 g (70%) of 3-amino-4-[(2-chlorophenyl)-methyl]aminobenzoic acid; mp 180°-181° C. (from ethyl acetate/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([C:14]1[C:22](O)=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH2:12][OH:13].C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:14]2=[CH:15][C:16]3[O:20][CH2:19][O:18][C:17]=3[CH:21]=[C:22]2[O:13][CH2:12]1
Reactant: O=C1Nc2c(Br)cccc2C1(CO)c1cc2c(cc1O)OCO2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1Nc2c(Br)cccc2C12COc1cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a suspended mixture of 7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (4.70 g, 12.4 mmol) in anhydrous tetrahydrofuran (120 mL) was added tributylphosphine (3.8 mL, 15.5 mmol), followed by additional of di-tert-butyl azodicarboxylate (3.58 g, 15.5 mmol) in anhydrous tetrahydrofuran (25 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and at ambient temperature for 16 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (150 mL) and extracted with ethyl acetate (3×200 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give 7′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (2.4 g, 53%) as a colorless solid: mp 240° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ10.88 (s, 1H), 7.34 (dd, J=8.1, 1.0 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 6.93 (dd, J=8.1, 7.5 Hz, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 5.93 (dd, J=2.9, 0.8 Hz, 2H), 4.77 (d, J=9.4 Hz, 1H), 4.65 (d, J=9.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ178.1, 155.3, 148.2, 141.6, 141.1, 134.2, 131.4, 123.8, 122.8, 119.4, 103.1, 102.0, 101.3, 93.1, 79.9, 58.8; MS (ES+) m/z 360.2 (M+1), 362.2 (M+1); MS (ES−) m/z 358.2 (M−1), 360.2 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[OH:25][CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:35]=[CH:36][C:37]([C:40]3([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)=[CH:3][CH:4]=1)[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: COc1cccc(SCC(O)c2c(C)noc2-c2ccc(Br)cc2)c1
Product: COc1cccc(SCC(O)c2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-methoxy-phenylsulfanyl)-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: CCOC(=O)CBr
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: CCOC(=O)Cn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 17 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and ethyl bromoacetate was used in place of methyl iodide. As a result, 61.3 mg (yield: 17%) of Compound 6 was obtained as pale yellow crystals.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:31]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:32])[C:3]1=[O:20]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(NC(=O)C23CC4CC(CC(C4)C2)C3)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and adamantane-1-carboxylic acid chloride were mixed in methylene chloride. The pH was adjusted to 8.5 with triethylamine and the reaction stirred 10 mins at 25° C. The mixture was flash chromatographed on silica gel (5% Et2O in Et2O in Ch2Cl2CH2CL2) and the title compound obtained by trituration with ethyl acetate: (mp 256°-257° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][OH:20])(=[O:12])=[O:11])=[C:5]([CH3:21])[CH:4]=1.[OH-].[Na+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:21])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
n-Bu4NCl (7.52 g, 27.1 mmol) was added to a solution of (1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol (27.2 g, max. 73.8 mmol) in toluene/MC (150 ml/150 ml) and the mixture was cooled to 0° C. A 35% strength aqueous NaOH solution (300 ml) was then added. Bromoacetic acid tert-butyl ester (17.8 ml, 122 mmol) was then added dropwise to the reaction mixture and the mixture was stirred at room temperature for 3 hours. The organic phase was separated off, washed with water (3×300 ml), dried over Na2SO4 and concentrated in vacuo. Purification was carried out by chromatography on silica gel (heptane/ethyl acetate 3:1). The yield was 26.8 g (85% over 2 stages).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]([CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([O:42]C)=[O:41])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:25][C:26](=[O:28])[OH:27])=[O:22])=[O:18])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].Cl>CO.O>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]([CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([OH:42])=[O:41])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:25][C:26](=[O:27])[OH:28])=[O:22])=[O:18])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCN(CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1CCCCC1)C(=O)OC)C(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1CCCCC1)C(=O)O)C(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[N-[N-(4-(N-BOC-piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl(b-benzyl ester)]-b-cyclohexylalanine, methyl ester (1.79 g) is dissolved in methanol (40 ml) and 10% palladium/carbon (0.25 g) is added. The mixture is shaken under hydrogen at 50 psi for about 18 hours. The mixture is filtered through a Celite pad and the filtrate evaporated in vacuo to give N-[N-[N-(4-(N-BOC-piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-b-cyclohexylalanine, methyl ester. The ester is dissolved in methanol (20 ml) and 1N aqueous sodium hydroxide solution (10 ml) is added. The mixture is stirred at room temperature for about 4 hours, diluted with water (25 ml), and acidified to pH 2 with 1N HCl. The mixture is extracted with ethyl acetate (3×100 ml) and the ethyl acetate solution dried over magnesium sulfate, filtered and evaporated in vacuo to give N-[N-[N-(4-(N-BOC-piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-b-cyclohexylalanine.
Reaction SMILES: Cl.CN.C([N:7]([CH2:11]C)[CH:8]([CH3:10])C)(C)C.BrCC[O:16][C:17]1[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][CH:22]=1>O1CCCC1>[CH3:11][NH:7][CH2:8][CH2:10][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1cccc(OCCBr)c1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNCCOc1cccc(C(F)(F)F)c1
Yield: 45.2 %

Procedure:
A mixture of methylamine hydrochloride salt (380 mg, 5.57 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (1.44 g, 11.15 mmol) and 3-(2-bromoethoxy)benzotrifluoride (300 mg, 1.11 mmol). The reaction mixture was allowed to stir at reflux for 2 d. At this time, the reaction was quenched by the addition of water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 methylene chloride/methanol) afforded methyl-[2-(3-trifluoromethyl-phenoxy)-ethyl]-amine (110 mg, 45%) as yellow solid. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4]>O.[OH-].[Na+].C(O)C>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.68 g (92.3 mmol) of sodium borohydride, dissolved in 30 ml of water to which 5 ml of 5N NaOH have been added, is added dropwise and with stirring to a solution of 13.86 g (92.3 mmol) of 4-formylbenzoic acid in 200 ml of absolute ethanol. The reaction medium is left thus for 5 hours with stirring at room temperature. The ethanol is then removed by evaporation under vacuum and the residue is taken up with water and then acidified with 5N hydrochloric acid: the precipitate obtained is separated by filtration on a sinter.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[CH3:13][C:14]1[C@@H:31]([O:32][C:33]([C@H:35]([OH:52])[C@@H:36]([NH:43][C:44]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:45])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:30][C@:26]2([OH:53])[C:27]([CH3:29])([CH3:28])[C:15]=1[C@@H:16]([O:71][C:72]([CH3:74])=[O:73])[C:17]([C@@:19]1([CH3:70])[C@H:24]([C@@H:25]2[O:54][C:55]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[O:56])[C@:23]2([O:65][C:66]([CH3:68])=[O:67])[CH2:63][O:64][C@@H:22]2[CH2:21][C@@H:20]1[OH:69])=[O:18]>ClCCl>[C:72]([O:71][C@@H:16]1[C:15]2[C:27]([CH3:28])([CH3:29])[C@@:26]([OH:53])([CH2:30][C@H:31]([O:32][C:33](=[O:34])[C@H:35]([O:52][C:8]([O:10][CH2:11][Cl:12])=[O:9])[C@@H:36]([NH:43][C:44](=[O:45])[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:14]=2[CH3:13])[C@@H:25]([O:54][C:55](=[O:56])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:24]2[C@:23]3([O:65][C:66](=[O:67])[CH3:68])[CH2:63][O:64][C@@H:22]3[CH2:21][C@H:20]([O:69][C:8]([O:10][CH2:11][Cl:12])=[O:9])[C@@:19]2([CH3:70])[C:17]1=[O:18])(=[O:73])[CH3:74]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C(=O)[C@]2(C)[C@@H](OC(=O)OCCl)C[C@H]3OC[C@@]3(OC(C)=O)[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)C[C@H](OC(=O)[C@H](OC(=O)OCCl)[C@@H](NC(=O)c3ccccc3)c3ccccc3)C(C)=C1C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.9 %

Procedure:
Pyridine (0.026 g, 23.0 mmol, 2.0 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8](0.02 g, 23.0 mmol, 2.0 eq) in dry dichloromethane under an argon atmosphere at 0° C. At 0° C., a solution of paclitaxel [4114] (0.10 g, 11.7 mmol, 1.0 eq) in dry dichloromethane was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After 2 h the reaction mixture was diluted with dichloromethane (25 ml), washed with a 10% solution of NaHCO3 (15 ml), brine (10 ml), and then dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum gave a white solid, [312], (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4-(((chloromethoxy)carbonyl)oxy)-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate, (0.11 g, 90%)
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:37])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:25][C@H:24]([CH2:26][O:27]C(=O)C4C=CC=CC=4)[C@@H:14]([O:15]C(=O)C4C=CC=CC=4)[C@@H:13]3[F:36])[C:6]=2[N:7]=1.O(C)[Na]>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:37])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:14]([OH:15])[C@@H:13]3[F:36])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=S)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)[nH]1
Agent: CO[Na]
Solvent: CO
Product: Nc1nc2c(sc(=S)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-amino-3-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-7-oxothiazolo[4,5-d]pyrimidine-2(3H,6H)-thione (0.18 g, 0.33 mmol), NaOCH3 (0.055 g) and anhydrous MeOH (60 mL) was stirred at room temperature for 16 h with the exclusion of moisture. The reaction mixture was neutralized with Amberlite IR-120(H+) ion-exchange resin. The resin was removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in MeOH (5 mL), adsorbed onto silica gel (5 g) and loaded on top of a prepacked (in CH2Cl2) silica gel column (2.8×15 cm). The column was flash eluted with CH2Cl2 :MeOH (9:1), the homogeneous product was isolated and crystallized from aqueous EtOH; 0.068 g (0.178 mmol, 54%), mp 240-242° C. (dec). Ir (KBr): ν3210-3410 (OH, NH2), 1685 (C=O), and 1630 (C=S) cm-1 ; Uv, λmax (nm) (ε×10-3): pH 1, 352 (6.5), 291 (3.2), 264 (5.1), 244 (5.4), 216 (5.5); pH 7, 356 (6.2), 264 (5.1), 244 (5.5); pH 11, 356 (6.1), 264 (5.1), 244 (5.6). 1H nmr (DMSO-d6): δ3.74 (m, 3H, C5'H2 and C4'H), 4.72 (t, 1H, C5'OH), 4.90 (m, 1H, C3'H), 5.25 (q, 1H, C2'H), 5.58 (d, 1H, C3'OH), 6.93 (s, 2H, NH2), 7.10 (t, J1',2' =7.6 Hz, 1H, C1'H), 11.53 (s, 1H, NH). Anal. Calc'd for C10H11FN4O4S2.C2H5OH (380.41): C, 37.88; H, 4.50; N, 14.73; S, 16.85; F, 4.99. Found: C, 37.72; H, 4.17; N, 14.93; S, 16.54; F, 5.16.
Reaction SMILES: O[C:2]1([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:2]1([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: Oc1ccc(C2(O)CCCCC2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(C2=CCCCC2)nc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a suspension of 6-(1-hydroxy-cyclohexyl)-pyridin-3-ol (2.5 g, 12.9 mmol) in toluene (130 mL) was added p-toluenesulfonic acid monohydrate (8.12 g, 42.7 mmol). The mixture was refluxed with azeotropic removal of water for 2 hours. The reaction mixture was cooled to room temperature, neutralized with aqueous NaHCO3 and extracted three times with EtOAc. The organic phase was washed with brine, dried (Na2SO4), passed through a silica gel pad and concentrated to provide the title compound as a solid (2.2 g).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]([O:21][CH3:22])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=[O:29].O>CCCCCC.O1CCCC1.C(OCC)(=O)C>[CH3:22][O:21][CH:8]([O:7][CH3:6])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=1[CH:28]([OH:29])[C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1cc(C(OC)OC)cc(OC)c1OC
Reactant: COc1ccc(C=O)cc1OC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
136 ml of a 1.6M n-butyl lithium solution in hexane are added to a solution of 48.5 g of 3,4,5-trimethoxybenzaldehyde dimethyl acetal in 485 ml of tetrahydrofuran under stirring at 0° C. for about 20 minutes. The mixture is further stirred at 0° C. for 30 minutes, and 33.2 g of 3,4-dimethoxybenzaldehyde are added thereto. After stirring the mixture at 0° to 10° C. for 2 hours, 780 ml of water and 780 ml of ethyl acetate are added thereto. After shaking the mixture, the organic layer is separated therefrom, washed with water and evaporated under reduced pressure to remove solvent. 81.0 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal are thereby obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][CH:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH:20]([CH3:19])[CH:21]([CH3:23])[CH3:22])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)C(C)N
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Product: CC(C)C(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 111.2 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) and 1,2-dimethyl-propylamine (0.11 g, 1.32 mmol) were treated substantially as described in Part D of Example 9 to produce 0.26 g (100%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1,2-dimethyl-propyl)-amine. MS (AP) m/z 354.2 [(M+H)+, 100].