Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])=[CH:28][CH:27]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-fluorophenyl isocyanate (0.139 ml, 1.22 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 265 mg (85.2%) of the desired product as a solid.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH:8]=1.C1(C(=[N:33][C:34]2[CH:35]=[C:36]([CH:43]=[CH:44][N:45]=2)[C:37](N(OC)C)=[O:38])C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:33][C:34]1[CH:35]=[C:36]([C:37]([C:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH:8]=2)=[O:38])[CH:43]=[CH:44][N:45]=1
Reactant: Ic1cn(C2COC2)c2ccncc12
Reactant: CON(C)C(=O)c1ccnc(N=C(c2ccccc2)c2ccccc2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Nc1cc(C(=O)c2cn(C3COC3)c3ccncc23)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropyl magnesium chloride (8.16 mL, 1.28 mmol, 2M in diethyl ether) was added to 3-iodo-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 53, 4.45 g, 14.8 mmol) in THF (90 mL) at 0° C., under nitrogen. The mixture was stirred at 0° C. for 1 hour then a solution of 2-[(diphenylmethylene)amino]-N-methoxy-N-methylisonicotinamide (Preparation 51, 5.12 g, 14.8 mmol) in THF (30 mL) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred at this temperature for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with DCM/MeOH 95:5 (7×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-5% MeOH in DCM followed by a second purification by silica gel column chromatography eluting with 30-50% EtOAc in DCM. The residue was dissolved in THF (90 mL) and 0.5M HCl (90 mL) was added followed by stirring at room temperature for 30 minutes. The reaction was quenched by the addition of 1N NaOH to pH 6-7 and the mixture eluted through an SCX cartridge washing through with MeOH followed by ammonia in MeOH (300 mL, 2M solution). The filtrate was concentrated in vacuo, azeotroping with toluene. The residue was dissolved in DCM:MeOH 90:10 (20 mL) and poured into diethyl ether (1000 mL) to precipitate a white solid. After filtering the white solid was dried to afford the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[O:10][C:11](=O)OC1C=C(Br)C=CC=1OC.[OH-].[Na+]>CO>[Br:9][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: COc1ccc(Br)cc1OC(=O)Oc1cc(Br)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Br)ccc1O
Temperature: 25 °C
Yield: 195.4 %

Procedure:
A suspension of (20.7 g, 47.9 mmol, 1.0 eq) bis(2-methoxy-5-bromophenyl)carbonate in 250 ml methanol and 60 ml (120 mmol, 2.5 eq) of 2N NaOH was refluxed for 2 hours. The reaction mixture was cooled to room temperature, concentrated to a volume of ca 100 ml, and poured into 1 L of H2O. The pH was adjusted to 2 using 1N HCl. The acidic mixture was transferred to a separatory funnel, and extracted three times with ether. The ether extracts were combined and washed once with H2O, once with brine, and then dried over anhydrous sodium sulfate. Filtration, concentration and drying afforded 19.0 g of a white solid, which was recrystallized from petroleum ether to yield 17.63 g, 91% yield, of white prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21](=[O:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[C:11]([CH:21]([OH:23])[CH3:22])=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC=O
Reactant: Fc1cccc2ccc(Cl)nc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cc2cccc(F)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-8-fluoroquinoline (182 mg, 1.0 mmol) was dissolved in THF (2 mL) and cooled to −78° C. To this solution was added Lithium diisopropylamide (1M solution in THF, 1.1 mL, 1.1 mmol, 1.1 eq). The reaction was allowed to stir at −78° C. for 20 min, after which time acetaldehyde (113 μl, 2.0 mmol, 2 eq.) was added via syringe. After 30 minutes, the reaction was quenched with water and diluted with ethyl acetate. The layers were separated and washed with brine. The crude reaction mixture was purified by column chromatography (8:2 hexanes:ethyl acetate) to afford 1-(2-chloro-8-fluoroquinolin-3-yl)ethanol. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (br s, 1H), 7.64 (td, J=7.8, 5.1 Hz, 1H), 7.41 (ddd, J=10.2, 7.4, 1.2 Hz, 1H), 5.39 (qdd, J=6.3, 3.9, 0.8 Hz, 1H), 2.22 (d, J=3.9 Hz, 1H), 1.62 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:11](=[O:24])[N:10]2[CH2:25][C:26]([O:28]CC)=[O:27])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+:31].[OH-].Cl>C1COCC1.O>[C:18]([O:17][C:15]([N:13]1[CH2:14][C@@H:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[N:10]([CH2:25][C:26]([O-:28])=[O:27])[C:11](=[O:24])[C:12]1([CH3:23])[CH3:22])=[O:16])([CH3:21])([CH3:19])[CH3:20].[Li+:31]
Reactant: CCOC(=O)CN1C(=O)C(C)(C)N(C(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)[O-])C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (5R)-5-(3,5-difluorophenyl)-4-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-3-oxopiperazine-1-carboxylate from Step C (1.18 g, 2.77 mmol) in THF (18 mL) and H2O (2 mL) was added 1 N aqueous LiOH (3.04 mL, 3.04 mmol) and the resulting mixture was stirred at ambient temperature for 5 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=343 (M−C4H7).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[C:21]([Cl:22])=[CH:20][C:14]2[O:15][C:16]([F:19])([F:18])[O:17][C:13]=2[CH:12]=1>>[Cl:22][C:21]1[C:11]([Cl:10])=[CH:12][C:13]2[O:17][C:16]([F:19])([F:18])[O:15][C:14]=2[C:20]=1[N+:1]([O-:4])=[O:2]
Reactant: FC1(F)Oc2cc(Cl)c(Cl)cc2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)c(Cl)cc2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
A precooled mixture of 140 ml of 100% strength nitric acid and 200 ml of 100% strength sulphuric acid is added dropwise at 5° to 10° C. (internal temperature) with good stirring to 219 g (0.96 mol) of 5,6-dichloro-2,2-difluorobenzo[1.3]dioxole. The reaction mixture is then subsequently stirred at room temperature for 6 h. It is added to ice-water and extracted with ether, and the extract is dried and concentrated. 233 g (89% of theory) of 5,6-dichloro-4-nitro-2,2-difluoro-benzo(1.3)dioxole having a melting point of 29°-30° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:12][C:11]#[N:13])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CC#N
Reactant: O=Cc1ccc(F)c(Br)c1
Product: N#CCC(O)c1ccc(F)c(Br)c1

Procedure:
Addition of acetonitrile to 3-bromo-4-fluorobenzaldehyde following the method used in Example 16 gave 3-(3-bromo-4-fluorophenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (4.2 g, 70%): 1H NMR (400 MHz, DMSO-d6) δ 7.71 (dd, J=6.8, 2.0 Hz, 1H), 7.44 (ddd, J=8.4, 5.2, 2.4 Hz, 1H), 7.35 (t, J=8.8 Hz, 1H), 6.08 (bs, 1H), 4.90 (s, 1H), 2.90 (ABd, J=16.8, 5.2 Hz, 1H), 2.83 (ABd, J=16.8, 6.4 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:8].[Na+]>O>[OH:8][C:2]1[CH:3]=[CH:4][C:5]([C:7]2([C:5]3[CH:4]=[CH:3][C:2]([OH:8])=[C:1]([CH3:7])[CH:6]=3)[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[C:6]3[C:1]2=[CH:2][CH:3]=[CH:4][CH:5]=3)=[CH:6][C:1]=1[CH3:7]
Reactant: Cc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C2(c3ccc(O)c(C)c3)c3ccccc3-c3ccccc32)ccc1O
Temperature: 80 °C
Yield: 43.7 %

Procedure:
A reaction was carried out in the same manner as in Example 3. To an obtained reaction mixture liquid, 135 g of toluene, 23 g of water, and 17.9 g of 29% sodium hydroxide aqueous solution were added, and the reaction mixture liquid was neutralized by stirring at 80° C. Thereafter, an aqueous phase was separated and removed. An organic phase was further washed twice with 23 g of water. From the organic phase, toluene and 91.5 g of 2-methyl phenol were distilled away by concentration under reduced pressure. Thereafter, 161 g of toluene was added to a concentrated liquid, and the mixture liquid was cooled to 10° C. Then, precipitated crystals were subjected to filtration and drying to obtain 37.0 g of 9,9-bis(4-hydroxy-3-methylphenyl)fluorene (yield: 82.5%, LC purity: 98.7%). Obtained 9,9-bis(4-hydroxy-3-methylphenyl)fluorene was dissolved by heat at 230° C. for 2 hours. The 9,9-bis(4-hydroxy-3-methylphenyl)fluorene thus dissolved show a hue of 4 in Gardner. The total amount of toluene used in the production was 8 parts by weight relative to 1 part by weight of the 9,9-bis(4-hydroxy-3-methylphenyl)fluorene.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[S:4][N:3]=1.[ClH:20]>ClCCl.CCO>[ClH:20].[CH3:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[S:4][N:3]=1
Reactant: Cc1nsc(C2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1nsc(C2CCCNC2)n1
Temperature: 35 °C

Procedure:
The Boc-protected intermediate 11a (0.87 g, 3.07 mmol) was stirred in dichloromethane (10 mL) and treated with 10 mL of a 2.53 M solution of HCl in EtOH. After warming to 35° C. for 2 hours, the mixture was concentrated under vacuum. The product was precipitated from IPA:MTBE (1:10). The product was recrystallized from IPA:MTBE three times to afford a high purity sample (42 mg) of white solid. MS (ESI) m/z 184 [M+1]+. NMR (CDCl3) δ 1.68-1.91 (m, 3H), 2.13-2.20 (d, 1H), 2.58 (s, 3H), 2.87-2.95 (dt, 1H), 3.14 (t, 1H), 3.25-3.28 (d, 1H), 3.54-3.59 (d, 1H), 3.65-3.73 (m, 1H), 9.10 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])/[C:7](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:26])/[C:7](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:8][CH2:9][N:50]1[C:46](=[O:56])[C:47]2[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:49]1=[O:51])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc(/C=C(\CCO)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(/C=C(\CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Yield: 87.5 %

Procedure:
To an anhydrous THF (3.0 mL) solution of (E)-4-hydroxy-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester (100 mg), triphenylphosphine (87.8 mg), phthalimide (49.3 mg) and diisopropyl azodicarboxylate (77.0 μL) were added one by one. After agitating reaction solution at room temperature for 1.5 hours, reaction solution was concentrated under reduced pressure as it was, the residue was purified by silica gel chromatography (elution solvent: ethyl acetate), and 119 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:27](=[O:29])[CH3:28])[CH2:15]1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc2c1cnn2CC1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(Cn2ncc3c([N+](=O)[O-])cccc32)C1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of 4-nitro-1-(piperidin-3-ylmethyl)-1H-indazole (0.050 g, 0.139 mmol), triethylamine (0.097 mL, 0.699 mmol) in DCM (1 mL) was treated with acetic anhydride (0.0158 mL, 0.168 mmol) at ambient temperature and stirring continued for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate, extracted with DCM, dried (phase separator silicone treated filter paper) and concentrated to provide 1-(3-((4-nitro-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone (0.022 g, 52% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[S:9][CH:10]=[C:11]([CH3:13])[N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: Cc1csc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)n1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1csc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)n1

Procedure:
The title compound was prepared from 2'-methyl-4'-(4-methylthiazol-2-yl)biphenyl-4-carboxylic acid (D40) and 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8), following the procedure of Example 1. The oxalate salt crystallised from acetone as a buff powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C@@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][O:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1cc(Cl)cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Clc1cc(Cl)cc(CO[C@H]2OCCN[C@H]2c2ccccc2)c1
Temperature: 110 °C
Reaction time: 60 h
Yield: 19.6 %

Procedure:
A solution of 0.33 g (0.77 mmole) of 4-benzyl-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine (from Example 44, Step B) and 0.22 g (1.54 mmole) of 1-chloroethyl chloroformate in 4.5 mL of 1,2-dichloroethane was placed in a pressure vial which was lowered into an oil bath which was heated to 110° C. After stirring for 60 hr the solution was cooled and concentrated in vacuo. The residue was dissolved in 7 mL of methanol and the resulting solution was heated at reflux for 30 min. The mixture was cooled and treated with several drops of concentrated aqueous ammonia and the solution was concentrated. The residue was partly purified by flash chromatography on 67 g of silica eluting with 1.5 L of 100:1 methylene chloride: methanol, and the rich cuts were purified by flash chormatography on 32 g of silica eluting with 50:50 hexanes: ethyl acetate and then 50:50:5 hexanes:ethyl acetate:methanol to give 0.051 g (20%) of an oil, which by 1H NMR was pure cis morpholine.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[O:58])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (0.70 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloro-perbenzoic acid (70%, 0.38 g) in dichloromethane (10 ml) and the mixture was stirred at −78° C. for 1 hour. To the reaction system was added an aqueous sodium thiosulfate solution, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The resultant was concentrated under reduced pressure, the residue was separated and purified with column chromatography (basic silica gel, ethyl acetate→ethanol:ethyl acetate 1:19), followed by recrystallization (ethyl acetate-diisopropyl ether) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocin-5-carboxamide (490.1 mg) as yellow crystals (Compound 47).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:34][C:33]4[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: C/C(=C\c1ccc(C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and 4-nitro-benzaldehyde there can be obtained 4-nitrobenzyl p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoate of melting point 183°-184° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(Cl)Cl.C(OCC)C>[C:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
N-Boc-3-pyrrolodinol (17.192 g, 0.092 mole) in 50 mL anhydrous methylene chloride was added to a solution of (60 g, 0.276 mole) of pyridinechlorochromate in 300 mL anhydrous methylene chloride which was surrounded by a water bath at room temperature. After stirring at room temperature for 4 hours an additional (60 g, 0.276 mole) of pyridinechlorochromate was added and the reaction was stirred over night. The reaction had gone to completion by the next morning and was diluted with 400 mL diethyl ether and filtered through a pad of celite 521 filter aid using excess diethyl ether to wash through. Evaporation gave a black oil which was flash chromatographed over silica gel eluting with 40% ethyl acetate in hexane to provide the title compound (12.5 g, 71%) as an oil. Mass Spec FD+MI=184.9, (MW=185) 1H NMR (300 MHz CDCl3) δ 1.49 (9H, s); 2.56-2.61 (2H, t); 3.75-3.80 (4H, t).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=S)[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=S)sc3c(=S)[nH]c(N)nc32)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncc2sc(=S)n([C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)c2n1
Yield: 67.7 %

Procedure:
5-Amino-2,3-dihydro-2-thioxo-3-(2,3,5-tri-O-acetyl-β-D-xylofuranosyl)thiazolo[4,5-d]pyrimidin-7-thione (65 mg, 0.14 mmol) is dissolved in MeOH (5 mL). To this was added K2CO3 (19 mg, 0.137 mmol), and the resultant mixture was stirred for 3 h whereupon it was quenched with HOAc (140 μL, 2.4 mmol), and the solvent was removed by rotary evaporation. The crude product is submitted to HPLC purification (MeCN—H2O) yielding 30 mg (62%) of white solid: 1H NMR (400 MHz, d6-DMSO) δ 8.50 (s, 1H), 6.90 (br s, 2H), 6.45 (d, J=5.2, 1H), 5.67 (d, J=8.0, 1H), 5.49 (d, J=8.4, 1H), 5.03 (m, 1H), 4.49 (t, J=5.2, 1H), 4.02 (m, 2H), 3.72 (m, 2H). Analysis calc'd for C10H12N4O4S2.0.4H2O: C, 37.12; H, 3.99; N, 17.32; S, 19.82. Found: C, 37.53; H, 3.80; N, 17.04; S, 19.42.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([F:25])[CH:17]=1.[OH-].[Na+].O>O1CCCC1>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[C:18]([F:25])[CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
1-(3,5-Dimethylpyridin-2-yl)piperazine (2.42 g) described in Preparation Example 79 was dissolved in tetrahydrofuran (32 mL), 4-bromo-2-fluorobenzoyl chloride (3.0 g) and 1N aqueous sodium hydroxide solution (15 mL) were added, and the mixture was stirred at room temperature. The reaction mixture was poured into water under cooling, 4N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine added 4N aqueous sodium hydroxide solution and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (4.39 g).