Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]([CH3:13])[CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:13][CH:12]1[CH2:11][CH:10]([C:14]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:16])[CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC1CC(C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(C(=O)NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 135.9 %

Procedure:
To a solution of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-3-pyrrolidinecarboxylic acid (0.9 g, 3.93 mmol) in CH2Cl2 (15 mL) at room temperature was added Hunig's base (0.89 mL, 5.10 mmol, 1.3 equiv) and benzylamine (0.56 mL, 5.10 mmol, 1.3 equiv) in one portion. The resulting mixture was chilled in an ice bath, followed by addition of HATU (1.64 g, 4.32 mmol, 1.1 equiv) in one portion, and the reaction mixture was stirred in the ice bath for 30 minutes. The mixture was filtered through celite, and rinsed with CH2Cl2. The filtrate was washed with water and dried over Na2SO4, followed by filtration and concentration in vacuo. The resulting residue was purified by silica gel column chromatography resulting in 1.70 g of the title compound as an oil. The ratio of cis/trans isomers could not be determined. LC-MS (ES) m/z=319 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:3]=1.[C:17]([NH:20][NH2:21])(=[O:19])[CH3:18]>CCO>[C:17]([NH:20][N:21]=[CH:8][C:7]1[C:2]([F:1])=[N:3][C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:5][CH:6]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)NN
Reactant: CN1CCN(c2ccc(C=O)c(F)n2)CC1
Solvent: CCO
Product: CC(=O)NN=Cc1ccc(N2CCN(C)CC2)nc1F
Reaction time: 72 h

Procedure:
2-Fluoro-6-(4-methyl-1-piperazinyl)pyridine-3-carboxaldehyde (3.35 g, 0.015 mole) was dissolved in 20 mL of EtOH and treated with acetylhydrazine (2.2 g, 0.030 mole). This reaction mixture was stirred for 72 hours and then the product was filtered off and recrystallized from EtOAc to give 2.85 g, mp 210°-212° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14](O)[CH2:15][OH:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:16][CH2:15][CH2:14][O:7]2)=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2OCCO2)c(C(F)(F)F)c1
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of commercially available 4-fluoro-2-(trifluoromethyl)benzaldehyde (15 g, 78 mmol) in toluene (90 mL) was added ethylene glycol (21.77 mL, 390 mmol) and TsOH (0.743 g, 3.90 mmol). The mixture was then heated (under a Dean-Stark trap attached to a reflux condenser) in an oil bath at 140° C. for 4 h, about 1.4-1.5 mL of water was collected, which was close to the expected volume. TLC (20% EtOAc-hexane) showed a major, new more polar spot. The mixture is diluted with EtOAc (100 mL) and washed with water (50 mL). The organic phase is washed with water (1×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (330 g ISCO column) eluting with 0-10% EtOAc-hexane gradient. The cleanest fractions with product afforded 9.83 g (51% yield): MS (ESI): m/z 237 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].Cl[CH2:7][C:8]1[N:9]([CH2:35][CH2:36][CH3:37])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:34])(=[O:33])[NH:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:22][CH:21]=3)[N:14]=2)=[CH:11][N:12]=1.O>C(O)(C)C>[CH:2]([O:3][CH2:7][C:8]1[N:9]([CH2:35][CH2:36][CH3:37])[C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([S:26](=[O:34])(=[O:33])[NH:27][CH2:28][CH2:29][O:30][CH2:31][CH3:32])=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][N:12]=1)([CH3:4])[CH3:1]
Reactant: CC(C)[O-]
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CCl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1COC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.1 %

Procedure:
Sodium isopropoxide (87 mg, 1.05 mmol) was added to a stirred suspension of 4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Method 116; 100 mg, 0.21 mmol) in isopropanol (20 ml). The reaction was stirred for 48 hours at ambient temperature, and was then poured into water (80 ml) and extracted with EtOAc (3×30 ml). The extracts were combined washed with brine (2×40 ml), dried and the volatiles removed by evaporation. The residue was purified by reverse phase HLPC (C18 column) eluting with aqueous ammonia/water/acetonitrile (5:90:5 decreasing in polarity to (5:0:95) to give the title compound (18 mg, 17%) as a brown gum. M/z 503.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[F:5][C:6]([F:16])([F:15])[C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.C([Li])CCC.CCCCCC>>[F:14][C:7]([F:13])([C:6]([F:5])([F:15])[F:16])[C:8]([CH:2]([CH3:3])[C:1]#[N:4])=[O:10]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CCC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C#N)C(=O)C(F)(F)C(F)(F)F

Procedure:
Propionitrile (13.2 g, 0.24 mole), ethyl pentafluoropropionate (23.05 g, 0.12 mole) and a solution of n-butyllithium in n-hexane (168 ml, 0.264 mole) were reacted according to the same procedure as described in Example 1 to give 22.72 g (crude yield 94.1%) of the crude title compound. The yield calculated as the pure product was 84.1%. When the resulting compound was dissolved in CDCl3 and its NMR was measured, the ratio of the keto form/the enol form was found to be 71/29, b.p. 63°-65° C./28 mmHg.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[N:8]=2)[CH2:3]1.[ClH:45].[C:46]([Cl:54])(=[O:53])[C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1>C1COCC1.CN1C(=O)CCC1>[ClH:54].[ClH:45].[OH:44][C:41]1[CH:42]=[CH:43][C:38]([CH:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:46](=[O:53])[C:47]4[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=4)[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[CH:39][CH:40]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)c5ccncc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising N-((1S,2R,3S,4R)-4-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 22 step 4) (20 mg, 33 μmol) in THF (0.5 ml) and NMP (0.5 ml) is treated with TEA (13 mg, 0.13 mmol) followed by isonicotinoyl chloride hydrochloride (16 mg, 83 μmol). After stirring at room temperature for 2 hours, the solvent is removed in vacuo and purification by C-18 reverse phase column chromatography eluting with acetonitrile:water:HCl (0.1%) (gradient of 0 to 100% acetonitrile) yields the title compound. (MH+ 708.4)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([N:32]([CH2:36][Si](C)(C)C)[CH2:33]OC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:36][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled solution of (4S)-4-benzyl-3-[(2E)-3-(4-chlorophenyl)prop-2-enoyl]-1,3-oxazolidin-2-one, from preparation 23 (5 g, 14.62 mmol) and N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (5.24 mL, 20.47 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (60 L, 0.73 mmol). The reaction mixture was stirred at 0° C. for 20 minutes and then warmed to room temperature and stirred for 24 hours. Sodium hydrogen carbonate solution (80 mL) was added and the reaction mixture was stirred for 10 minutes. The phases were separated and the organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to give a yellow oil. Purification by column chromatography on silica gel using ethyl acetate:pentane (10:50-50:50) as eluent afforded the desired product (which is the second-eluting diastereomer) as a white crystalline solid, 733 mg (11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:12]2[CH2:17][C:16]([CH3:18])=[CH:15][CH2:14][NH:13]2)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH2:19](I)[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:19]([N:13]1[CH2:14][CH:15]=[C:16]([CH3:18])[CH2:17][CH:12]1[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([CH3:11])[CH3:10])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COc1ccc(C(C)(C)C2CC(C)=CCN2)cc1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN1CC=C(C)CC1C(C)(C)c1ccc(OC)cc1
Yield: 75.1 %

Procedure:
A mixture of 1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]-4-methylpyridine (2.9 g), pentyl iodide (2.34 g), potassium carbonate (3 g) and dimethylformamide (20 ml) was heated to reflux for 4 hours while stirring. After cooling and adding water, the reaction product was extracted with benzene. The extract was washed twice with water, dried over potassium carbonate and distilled to remove benzene to obtain 2.8 g of 1,2,3,6-tetrahydro-1-pentyl-2-[1-(4-methoxyphenyl)-1-methylethyl]-4-methylpyridine as a viscous mass. To the mass was added 20 ml of 47% hydrobromic acid and the mixture was heated to reflux for 10 hours while stirring, after cooling, made alkaline with a concentrated ammonia water under cooling and extracted with chloroform. The extract was dried over sodium sulfate and distilled to remove chloroform. The residue was fed to a column chromatograph on silica gel and eluted with chloroform. Chloroform was distilled off from the eluate to obtain 2.2 g of 1,2,3,4,5,6-hexahydro-8-hydroxy-3-pentyl- 2,6-methano-1,1,6-trimethyl-3-benzazocine as a viscous mass. The product was treated as in Example 1-(5) to obtain the corresponding hydrochloride as colorless fine needles having a melting point above 230° C. (sublimable) after the recrystallization from methanol-ethyl ether.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Na+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][CH2:22][C:21](=O)[C:20]=2[CH:25]=1.O>C1COCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([CH2:4][C:3]([N:2]([CH3:1])[CH3:12])=[O:11])=[CH:21][C:20]=2[CH:25]=1
Reactant: COP(=O)(CC(=O)N(C)C)OC
Reactant: O=C1COc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Cc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl [2-(dimethylamino)-2-oxoethyl]phosphonate (5 g) was added to a stirred suspension of sodium hydride (1.02 g of a 60% dispersion in oil) in dry THF (100 ml) at 0° under nitrogen. After stirring for 15 minutes 5-bromo-3-(2H)-benzofuranone (5.0 g) in THF (20 ml) was added dropwise and stirred at room temperature for 3 h. Water (50 ml) was added and the mixture extracted with ethyl acetate (3×50 ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography using 50% ethyl acetate/hexane as eluant to yield the title compound as a pale yellow solid m.p. 92°-94° C.
Reaction SMILES: [CH3:1][C:2]#[N:3].[H-].[Na+].[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:25](OC)=[O:26])=[CH:13][C:14]=1[O:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH3:17])=[O:9]>O1CCOCC1>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:25](=[O:26])[CH2:1][C:2]#[N:3])=[CH:13][C:14]=1[O:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH3:17])=[O:9]
Reactant: COC(=O)c1cc(OC(C)c2ccccc2Cl)c(C(=O)OC)s1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C(=O)CC#N)cc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Yield: 5.7 %

Procedure:
MeCN (231 mg, 5.62 mmol, 1.0 Eq.) was added to a suspension of NaH (225 mg, 60% dispersion in mineral oil, 5.62 mmol, 1.0 Eq.) in anhydrous dioxane (30 mL) at ambient temperature under nitrogen. After stirring for 25 minutes 3-[1-(2-Chlorophenyl)-ethoxy]-thiophene-2,5-dicarboxylic acid dimethyl ester (1.94 g, 5.62 mmol, 1.0 Eq.) was added and the reaction heated at reflux overnight. The reaction was cooled to ambient temperature, quenched with water and partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic extracts dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (50% EtOAc/Petroleum ether) to give the sub-title compound as a white solid (115 mg, 0.32 mmol, 6%); 1H NMR (400 MHz, d-6 DMSO) δ 1.61 (3H, d), 3.82 (3H, s), 4.62-4.74 (2H, m). 5.88 (1H, q), 7.35 (1H, t), 7.40 (1H, t), 7.48 (1H, d), 7.73 (1H, d), 7.91 (1H, s).
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 521D (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 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: C(N(CC)CC)C.[Br:8][C:9]1[S:13][C:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=1.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>C(Cl)Cl>[Br:8][C:9]1[S:13][C:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[CH:11][CH:10]=1
Reactant: C=C(C)C(=O)Cl
Reactant: OCCCCCCOCc1ccc(Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Triethylamine (2.10 g, 20.8 mmol) is added dropwise to a solution of 6-(5-bromothiophen-2-yl)methoxyhexanol (3.10 g, 10.62 mmol) and methacryloyl chloride (1.20 g, 11.54 mmol) in DCM (30 mL) at −10° C. This mixture is allowed to warm to room temperature and stirred overnight before it is quenched by the addition water (50 mL) The organic layer is separated and the liquid phase is extracted with DCM (2×30 mL). The organic layers is combined, washed with brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure. The product is purified by column chromatography on silica, eluting with petroleum ether (40-60° C.)/ethyl acetate (90:10) to afford the product as a pale yellow oil (3.27 g, 86%). NMR and MS showed the expected signals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:20][CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:13]2[C:21](O)=[O:22])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O=S(Cl)[Cl:26]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:20][CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:13]2[C:21]([Cl:26])=[O:22])(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)C1C2CCCCC2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1C2CCCCC2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
N-(3,5-Dichlorobenzenesulfonyl)-octahydroisoindole-1-carboxylic acid (1 gm, 2.64 mmol) was dissolved in CH2Cl2 (5 mL) containing DMF (1 drop) and SOCl2 (770 μL, 10.56 mmol). The reaction mixture was refluxed under nitrogen for ˜1 hr. The reaction mixture was monitored by TLC for the formation of the acid chloride. The reaction mixture was then concentrated in vacuo and azeotroped with toluene (1×5 mL) to afford N-(3,5-dichlorobenzenesulfonyl)-octahydroisoindole-1-carboxylic acid chloride which was used without further purification in the subsequent step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F:30]C1C=C(OCC2C=CC3C(=CC=CC=3)N=2)C=CC=1C(=O)CC1C=CN=CC=1>>[F:30][C:29]1[CH:28]=[C:15]([CH:14]=[CH:13][C:12]=1[C:8]1[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:11][NH:10][N:9]=1)[O:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1F
Product: Fc1cc(OCc2ccc3ccccc3n2)ccc1-c1n[nH]cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline but substituting 1-{2-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl}-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.5 Hz, 2H), 8.22 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.74 (m, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.55 (m, 1H), 7.25 (m, 1H), 7.18 (d, J=6.2 Hz, 2H), 6.85 (d, J=10.9, 2H), 5.38 (s, 2H): MS: (M+H m/z=397.2).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][C:32]=1[O:33]CC1C=CC=CC=1)[CH2:12][N:13]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][C:16]=2[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:14]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:15]2[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[N:13]([CH2:12][C:11]3[CH:10]=[C:9]([OH:8])[C:32]([OH:33])=[CH:31][CH:30]=3)[N:14]=2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(-c2nn(Cc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c3c2CCNCC3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of 1-(3,4-bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-carboxylic acid tert-butyl ester (Example 154, 0.1 mmol) in CH2Cl2 (5 mL) was cooled to 0° C., and 1 M BBr3 in CH2Cl2 (0.5 mL) was added. The mixture was allowed to warm to RT and was stirred at RT for 1 h. The precipitate that had formed was collected by filtration, washed with water, and dried under vacuum to provide the title compound (25 mg). MS (ESI): exact mass calculated for C20H20ClN3O2, 369.12. found, m/z 370.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.42 (m, 4H), 7.39-7.37 (m, 2H), 6.63 (d, J=8.1 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 6.45 (dd, J=8.1, 2.1 Hz, 1H), 5.18 (s, 2H), 3.29-3.25 (m, 4H), 3.06-3.04 (m, 2H), 2.97-2.95 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[CH2:20]([N:22]=[C:23]=[S:24])[CH3:21]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:23](=[S:24])[NH:22][CH2:20][CH3:21])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Br)cc1F
Reactant: CCN=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=S)SC1C2=C(CCCC2)C(=O)N1c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
In 20 ml of dichloromethane was dissolved 3.4 g of 2-(4-bromo-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.0 g of ethyl isothiocyanate, together with one drop of triethylamine, was added to the solution, followed by stirring at room temperature for 5 hours. The dichloromethane was distilled off under reduced pressure, and the resulting crystals were washed with cold ethanol and dried, thereby producing 3.8 g (yield of 88%) of the subject compound. Recrystallization from ethanol yielded white crystals, m.p. 130°-131° C.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Cl[C@:11]1(CO)[O:16][C:14]([C:17](=[O:19])C)(O)[C@:13](C(=O)C)([OH:20])[C@:12]1(C(=O)C)[OH:24].CO.N>C(Cl)(Cl)Cl>[CH:9]1[C:8]2[N:7]=[CH:6][N:5]([C@@H:11]3[O:16][C@H:14]([CH2:17][OH:19])[C@@H:13]([OH:20])[C@H:12]3[OH:24])[C:4]=2[N:3]=[CH:2][N:1]=1
Reactant: CC(=O)C1(O)O[C@](Cl)(CO)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Reactant: c1ncc2[nH]cnc2n1
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OC[C@H]1O[C@@H](n2cnc3cncnc32)[C@H](O)[C@@H]1O

Procedure:
Nebularine was prepared by the use of the thallous salt of purine in the procedure of Brown et al., J. Biol. Chem. 204, 1019 (1953), in place of the chloromercuri salt used therein. The thallous salt of purine is condensed with chlorotriacetylribofuranose and the resulting acetyl derivative hydrolyzed to the product with methanol-ammonia. Other experimental conditions were identical. Crystalline nebularine was obtained after chromatography of the crude product on silica-gel with chloroform.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1([C:14]([OH:16])=[O:15])[CH:11]2[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:13][CH:5]1[CH2:6]3)[CH2:10]2.[C:17]1([N:27]2[C:31]([C:32]3[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=3[O:40][CH3:41])=[CH:30][C:29]([C:42](Cl)=[O:43])=[N:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.Cl>O.O1CCCC1>[C:17]1([N:27]2[C:31]([C:32]3[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=3[O:40][CH3:41])=[CH:30][C:29]([C:42]([NH:3][C:4]3([C:14]([OH:16])=[O:15])[CH:11]4[CH2:10][CH:9]5[CH2:8][CH:7]([CH2:6][CH:5]3[CH2:13]5)[CH2:12]4)=[O:43])=[N:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)Cl)nn1-c1cccc2ccccc12
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1cccc2ccccc12
Reaction time: 0.17 h

Procedure:
0.107 g of sodium hydroxide in 1.36 ml of water and 0.51 ml of tetrahydrofuran are cooled to 0° C. 0.52 g of 2-amino-2-adamantanecarboxylic acid is added in a single portion, and 0.53 g of 1-(1-naphthyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarbonyl chloride, dissolved in 3 ml of tetrahydrofuran, is then added dropwise. The mixture is left for 10 minutes, and the same amount of the above acid chloride, in 3 ml of tetrahydrofuran, is added again; simultaneously, 1.32 ml of 2N sodium hydroxide are added. The reaction mixture is left for 4 days at room temperature; successively, ice-cold water is added and concentrated hydrochloric acid is added to pH 1, and the precipitate is filtered off. The crystals are washed with diisopropyl ether.