Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C@H:10]([OH:9])[CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 140.8 %

Procedure:
To a solution of (S)-3-benzoyloxy-1-t-butoxycarbonylpyrrolidine (21 g) in methanol (210 ml) was added 28% sodium methoxide in methanol solution (18 ml) under nitrogen at -10° C. After stirring at 0° C. for 2 hours, acetic acid (4.95 ml) was added thereto and the mixture was evaporated. The residue was extracted with ethyl acetate and the extract was washed with water and brine successively. The dried organic solvent was evaporated to give (S)-1-t-butoxycarbonyl-3-hydroxypyrrolidine (19.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]
Reactant: CCOc1ccc(C(=O)O)nc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A stirred mixture of 5-ethoxy-pyridine-2-carboxylic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solids were filtered and dissolved in CH2Cl2 (10 mL). The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2, gradient, product eluted at 3% MeOH). The product fractions were combined and concentrated to give 5-ethoxy-pyridine-2-carboxylic acid[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 77% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.98 min (95.90%); mp: 145-147° C.; 1H NMR (DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 1.88 (s, 3H), 2.01-2.07 (m, 1H), 2.54-2.71 (m, 3H), 4.19 (dd, J=6.9, 13.8 Hz, 2H), 4.61 (d, J=6.3 Hz, 2H), 7.53 (dd, J=3.0, 8.7 Hz, 1H), 7.77-7.82 (m, 3H), 7.99 (d, J=8.7 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 9.40 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ 12.70, 19.30, 26.90, 27.40, 40.60, 57.00, 62.40, 119.60, 120.00, 121.40, 121.70, 127.80, 129.60, 131.80, 135.10, 14.050, 145.90, 155.30, 162.30, 166.10, 166.20, 170.40, 170.50; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.5H2O: C, 60.13; H, 5.05; N, 12.19. Found: C, 59.95; H, 4.91; N, 12.04.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCc1nc([N+](=O)[O-])ccc1Br
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 31.9 %

Procedure:
A mixture of 3-bromo-2-ethyl-6-nitropyridine (2.31 g, 10.0 mmol), 2-chloropyridin-4-ol (2.59 g, 20.0 mmol) and K2CO3 (4.15 g, 30.0 mmol) in DMA (20 mL) was sparged with Ar and heated at 105° C. overnight. The mixture was cooled to RT, treated with EtOAc, washed successively with 10% K2CO3 (1×), 5% LiCl (1×) and brine (1×), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (892 mg, 25%). MS (ESI) m/z: 280.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]([F:11])=[C:4](F)[C:3]=1[F:13].[CH3:14][O-:15].[Na+].[Na]>CO>[CH3:14][O:15][C:4]1[C:3]([F:13])=[C:2]([F:1])[C:7]([CH2:8][OH:9])=[C:6]([F:10])[C:5]=1[F:11]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(F)c(F)c(CO)c(F)c1F

Procedure:
Pentafluorobenzyl alcohol (1.98 g) was added to a stirred solution of sodium methoxide (obtained by dissolving sodium (0.4 g) in methyl alcohol (10 ml) at the ambient temperature, and the mixture heated at the reflux temperature for 3.5 hours. After cooling the mixture, the solvent was removed by evaporation under reduced pressure and the residue partitioned between water and diethyl ether. After separating the ethereal layer and washing with water, it was dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure to yield 4-methoxy-2,3,5,6-tetrafluorobenzyl alcohol (1.8 g), identical with the product of Example 5.
Reaction SMILES: CCO.[CH2:4]1[C@H:8]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[N:11]=[CH:10]2)[O:7][C@H:6]([CH2:19][OH:20])[C@H:5]1[OH:21]>O>[CH2:4]1[C@@H:8]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[N:11]=[CH:10]2)[O:7][C@@H:6]([CH2:19][OH:20])[C@@H:5]1[OH:21]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: O
Solvent: CCO
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@@H](O)[C@H](CO)O1

Procedure:
mp 189-190° C. (EtOH 95) (identical to commercial 2′-deoxy-D-adenosine) 1H NMR (200 MHz, DMSO-D6):δ 8.35 and 8.14 (2s, 2H, H2 and H8), 7.34 (s1, 2H, NH2), 6.35 (dd, 1H, H1′, J 6.1 Hz, J 7.85 Hz), 5.33 (d, 1H, OH2′, J 4.0 Hz), 5.28 (dd, 1H, H3′, J 4.95 Hz; J 6.6 Hz), 4.42 (m, 1H, OH5′), 3.88 (m, 1H, H4′), 3.63-3.52 (m, 2H, H5′a and H5′b), 2,71 (m, 1H, H2′a), 2.28 (m, 1H, H2′b). (identical to commercial 2′-deoxy-D-adenosine) αD+26° (c 0.5 water) (commercial 2′-deoxy-D-adenosine −25° (c 0.5 water)). UV λmax 260 nm (ε 14100) (H2O). Mass analysis (FAB+, GT) m/z 252 (M+H)+, 136 (BH2)+
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][F:10])[CH:8]=1.[OH-].[Na+].[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=[C:17]([F:19])[F:18]>CC(C)=O.O>[F:18][C:17]([O:11][C:5]1[CH:4]=[C:3]([CH2:2][F:1])[CH:8]=[C:7]([CH2:9][F:10])[CH:6]=1)([F:19])[CH:16]([F:20])[C:15]([F:22])([F:21])[F:14]
Reactant: Oc1cc(CF)cc(CF)c1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: FCc1cc(CF)cc(OC(F)(F)C(F)C(F)(F)F)c1

Procedure:
490 g of 3,5-bis-fluoromethyl-phenol were placed in 1000 ml of acetone together with 50 g of 50% by weight aqueous sodium hydroxide solution, and hexafluoropropene was introduced at 25° C. up to the saturation point. The batch was then diluted with 11 of water and the organic phase was separated off, dried and distilled to give 673 g of 3,5-bis-fluoromethyl-phenyl 1,1,2,3,3,3-hexafluoropropyl ether with a boiling point of 65° to 70° C. at 22 mbar and a refractive index nD2 of 1.3560.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:44][C:43]1[CH:42]=[CH:41][C:40]([O:39][CH2:38][CH2:37][CH2:36][Cl:35])=[CH:47][CH:46]=1)[C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCOc1ccc(CBr)cc1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Reaction time: 0.33 h

Procedure:
A solution consisting of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole No. 7 (6.5 g, 15.5 mmol) in DMF (60 mL) was cooled to 0° C. and treated with addition of sodium hydride (0.68 g, 17.0 mmol) and stirred for 20 minutes. A solution of 4-(3-chloropropoxy)-benzyl bromide No. 163 in DMF (10 mL) was then added slowly. The reaction was allowed to come to rt and stirred for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water, brine and dried over magnesium sulfate and concentrated. The concentrate was treated with methanol and 5 g of the desired product precipitated as a white solid with a melting point of 130-132° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH:18]=1
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1
Yield: 57 %

Procedure:
A suspension of 3-cyano-4-fluoronitrobenzene (831 mg, 5 mmol), of 4-methylimidazol (821 mg, 10 mmol) and of potassium carbonate (1382 mg, 10 mmol) in acetonitrile (10 mL) was stirred over the weekend at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1N aqueous NaOH solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was crystallized from ethanol/water to yield the title compound (650 mg, 57%) as an off-white solid. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=8.95 (s, 1H), 8.62 (d, 1H), 8.16 (s, 1H), 7.93 (d, 1H), 7.49 (s, 1H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[C:19](O[K])(C)(C)C.CI>ClCCl>[CH3:1][N:2]([CH3:18])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:8][CH2:7][C:6]([CH3:19])([CH:9]=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)O[K]
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C=O)CC1
Solvent: CI
Solvent: ClCCl
Product: CN(C)C1(c2cccc(F)c2)CCC(C)(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the title compound of step 1 (2.73 g, 10.95 mmol) in abs. dichloromethane (50 mL) was mixed with tert-BuOK (1.47 g, 13.14 mmol) and methyl iodide (747 μl, 12 mmol) at 0° C. in argon. After 30 min the batch was heated to RT and then stirred overnight (solid separated out). The reaction mixture was mixed with saturated NaCl solution (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic phases were dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with ethyl acetate/MeOH 20:1.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([S:9][CH3:10])=[C:7]([Cl:11])[CH:6]=[CH:5][C:4]=1[C:12](=[O:19])[CH2:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15].[C:20]([O:23][C:24](=O)C)(=O)[CH3:21]>C(O)(=O)C>[CH3:1][S:2][C:3]1[C:8]([S:9][CH3:10])=[C:7]([Cl:11])[CH:6]=[CH:5][C:4]=1[C:12](=[O:19])[C:13](=[CH:24][O:23][CH2:20][CH3:21])[C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CSc1c(Cl)ccc(C(=O)CC(=O)C2CC2)c1SC
Solvent: CC(=O)O
Product: CCOC=C(C(=O)c1ccc(Cl)c(SC)c1SC)C(=O)C1CC1
Yield: 100.9 %

Procedure:
A mixture of 1-[2,3-bis(methylsulphenyl)-4-chlorophenyl]-3-cyclopropylpropan-1,3-dione (3.45 g) and acetic anhydride (3.37 g) in acetic acid was stirred and heated at reflux for 3 hours. It was cooled and evaporated to dryness. The residue was dissolved in toluene and re-evaporated to give 1-[2,3-bis(methylsulphenyl)4-chlorophenyl]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (4.1g) as a brown oil which was not further purified.
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>ClCCl>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:9][C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2])=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 76 %

Procedure:
Tert-octylamine (51.7 g, 0.4 mol) and triethylamine (61.2 ml, 0.44 mol) in 260 ml of dichloromethane were introduced into a reactor. It was heated to 70° C. then 4-nitrobenzoyl chloride (77.9 g, 0.42 mol) was added in small portions over 50 minutes. It was heated under reflux for 4 hours. The reaction mixture was poured over ice water; it was extracted with dichloromethane, dried and the solvent was evaporated off. The beige precipitate obtained was recrystallized from a mixture of isopropyl ether and ethanol (ratio 10:1). After drying under vacuum, 84.6 g (yield: 76%) of 4-nitro-N-(tert-octyl)benzamide were obtained in the form of an off-white powder and used as is in the next step.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:32][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:32])[NH2:2]
Reactant: [Li]O
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Agent: OO
Solvent: CO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (709 mg, 1.60 mmol, 1.00 equiv) in 6 mL of MeOH was added LiOH.H2O (135 mg, 3.21 mmol, 2.01 equiv) and H2O2 (30%, 1 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and quenched with saturated aqueous NaHSO3 solution and extracted with 3×50 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (524 mg, 71%) as a white solid. MS: m/z 461 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:4].[Cl:18][S:19](O)(=[O:21])=[O:20]>CCOC(C)=O>[F:17][C:2]([F:1])([F:16])[C:3]([NH:5][C:6]1[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1cccc2cccnc12)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S(=O)(=O)Cl)c2cccnc12)C(F)(F)F
Temperature: 80 °C
Yield: 31 %

Procedure:
Under N2 at 25° C., 2,2,2-trifluoro-N-(quinolin-8-yl)acetamide (5.0 g, 20.8 mmol) was added to chlorosulfonic acid (15 ml) and then heated at 80° C. for 19 h. The mixture was then poured into ice-water (200 ml), followed by addition of EtOAc (300 ml). The organic layer was passed through a short bed of silica gel followed by EtOAc (700 ml) and then evaporated and triturated with Et2O to give the product as a light tan solid (2.2 g, 31%). 1H NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 9.19 (dd, J=8.8, 1.4 Hz, 1H), 9.05 (dd, J=4.2, 1.4 Hz, 1H), 8.84 (d, J=8.5 Hz, 1H), 8.48 (d, J=8.5 Hz, 1H), 7.85 (dd, J=8.8, 4.2 Hz, 1H).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:29]([N+:30]([O-:32])=[O:31])=[C:28]2[C:33]3[C:24](=[CH:25][CH:26]=[CH:27]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=3[CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:15]2[C:29]([N+:30]([O-:32])=[O:31])=[C:28]3[C:33]4[C:24](=[CH:25][CH:26]=[CH:27]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=4[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1c(Br)cc2c3c(cccc13)-c1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1c(-c2cccc3ccccc23)cc2c3c(cccc13)-c1ccccc1-2
Temperature: 25 °C
Yield: 61.8 %

Procedure:
Under an argon atmosphere, 8.53 g of 1-naphthalene boronic acid, 14.7 g of 2-bromo-3-nitrofluoranthene, 1.04 g of tetrakistriphenylphosphine palladium(0), 70 mL of 1,2-dimethoxyethane, 70 mL of toluene, and 70 mL of a 2 M aqueous solution of sodium carbonate were charged in a flask, and the resultant mixture was refluxed for 8 h under heating and stirring. After cooling to room temperature, the reaction solution was extracted with toluene and then the aqueous layer was removed. The organic layer was washed with a saturated saline, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 10.4 g of 2-(1-naphthyl)-3-nitrofluoranthene.
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:25]4[CH:26]=[CH:27][C:28]([CH2:31][C:32]5[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=5)=[CH:29][CH:30]=4)[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:41][CH:42]=1
Reactant: [H][H]
Reactant: CCCCC1CCC(c2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)(c2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1CCC(c2ccc(Cc3ccc(N)cc3)cc2)(c2ccc(Cc3ccc(N)cc3)cc2)CC1
Yield: 41.9 %

Procedure:
1,1-Bis[4-(4-nitrobenzyl)phenyl]-4-butylcyclohexane 38.0 g was dissolved in 500 ml of tetrahydrofuran, a Pd--C catalyst (5% purity, water content 55.9%) 4.0 g was added, and the mixture was cooled with water at atmospheric pressure and contacted with hydrogen gas with stirring. After the absorption of hydrogen stopped, the catalyst was filtered off and the solution was concentrated. The concentrate was recrystallized with mixture solvent of ethanol 87% and methanol 13% to obtain 1,1-bis[4-(4-aminobenzyl)phenyl]-4-butylcyclohexane 14.22 g which is a diamino compound of the present invention. The melting point was 58.5°-60.1° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].C(C(CCCC)C=O)C.C=O>>[CH2:6]([C:3]([CH2:1][CH3:2])([CH2:4][OH:5])[CH2:10][OH:11])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C=O)(CC)CO
Agent: C=O
Agent: CCCCC(C=O)CC
Product: CCCCC(CC)(CO)CO

Procedure:
Disclosed is a continuous process for the manufacture of 2-ethyl-2-(hydroxymethyl)hexanal wherein 2-ethylhexanal, formaldehyde and a tertiary amine are continuously fed to a reaction zone and crude product comprising an aqueous phase and an organic phase containing 2-ethyl-2-(hydroxymethyl)hexanal and 2-ethylhexanal is continuously removed from the reaction zone Also disclosed are processes for (1) the azeotropic distillation of the organic phase of the crude product whereby unreacted 2-ethylhexanal is recovered and (2) the catalytic hydrogenation of the refined, organic phase of the crude product to produce 2-butyl-2-ethyl-1,3-propanediol.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([N:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](=[O:34])[O:32][CH3:33])[CH:26]=[CH:25]2>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.C1(C)C=CC=CC=1>[C:6]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([N:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](=[O:34])[O:32][CH3:33])[CH:26]=[CH:25]2)(=[O:8])[CH3:7]
Reactant: COC(=O)N(c1ccccc1)c1ccc2cccc(Br)c2n1
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: Cc1ccccc1
Product: COC(=O)N(c1ccccc1)c1ccc2cccc(C(C)=O)c2n1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of Pd(PPh3)4 (60.8 mg, 0.053 mmol, Strem Chemicals, Newburyport, Mass.), tributyl(1-ethoxyvinyl)stannane (391 μl, 1.158 mmol, Sigma Aldrich), methyl (8-bromoquinolin-2-yl)(phenyl)carbamate (Example 46a; 376 mg, 1.053 mmol), and toluene (5.2 mL) were stirred under N2 at 100° C. for 20 h. Purification by column chromatography (silica gel: 0 to 10% EtOAc/hexanes followed by 70% EtOAc/hexanes) provided methyl (8-acetylquinolin-2-yl)(phenyl)carbamate, which was used without further purification in the next step. m/z (ESI, +ve) 349.1 (M+H)+.
Reaction SMILES: [CH:1]([C@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=1)[CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH:1]([C@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=1)[CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(=O)[C@@H](C/C=C/C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COCCCOc1cc(C[C@@H](C/C=C/C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of (2S,7S)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropyloxy)-benzoyl]-8-methylnon-4-enoic acid (90 mg; 0.21 mmol) in trifluoroacetic acid (1 ml) was added triethylsilane (250 μl; 1.5 mmol). After stirring the solution at RT for 1 day, a second portion of triethylsilane (250 μl; 1.5 mmol) was added, and the solution was stirred at RT for a further 2 days and then added to water. The aqueous layer was extracted 3× with tert-butyl methyl ether and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel; hexane/acetone 4:1) to obtain (2S,7R)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnon-4-enoic acid (53 mg, 0.126 mmol, 61% yield).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[CH:24](O)=O.N>CO.O>[CH3:24][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1
Reactant: O=CO
Reactant: c1ccc(-c2sc3ccccc3c2N2CCNCC2)cc1
Agent: C=O
Agent: N
Solvent: CO
Solvent: O
Product: CN1CCN(c2c(-c3ccccc3)sc3ccccc23)CC1

Procedure:
A mixture of 7.0 g (24 mmole) of 3-(piperazino)-2-phenyl-benzo(b)thiophene, 3.5 milliliters of formalin at 35% (41 mmole) and 3.5 milliliters of formic acid at 98-100% (92 mmole) is refluxed for 1 hour. After cooling, it is poured into water, made alkaline with ammonia and extracted with CH2Cl2. By evaporating the organic phase dried over K2CO3, 7.2 g (98% of theory) of 3-(4'-methylpiperazino)-2-phenyl-benzo(b)thiophene are obtained: beige crystals, mp 118°-120° (methanol).