Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.C1(S)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]([O:37][C@H:38]1[C@:45]([CH3:47])([OH:46])[C@@H:44]2[CH2:48][C@@H:40]([C@@:41]([CH3:57])([CH2:49][S:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:42][O:43]2)[CH2:39]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCCCCC.C1C=CC=CC=1.CCCCCC>[C:29]([O:37][C@H:38]1[C@@:45]([CH3:47])([OH:46])[C@@H:44]2[CH2:48][C@@H:40]([C@:41]([CH3:57])([CH2:49][S:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[O:42][O:43]2)[CH2:39]1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@@]1(O)[C@@H]2C[C@H](C[C@H]1OC(=O)c1ccccc1)[C@@](C)(CSc1ccccc1)OO2
Agent: O=O
Agent: Sc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C[C@]1(O)[C@@H]2C[C@H](C[C@H]1OC(=O)c1ccccc1)[C@](C)(CSc1ccccc1)OO2
Temperature: 4 °C
Reaction time: 14 h
Yield: 6 %

Procedure:
Oxygen was bubbled through a solution of the α-benzoate 3b (690 mg, 2.70 mmol) and DBPO (8.5 mg, 0.036 mmol) in hexane-benzene (50 mL, 7:3) with simultaneous addition (syringe pump) of a solution of PhSH (99 mg, 2.0 mmol) in hexane (20 mL) during 10 h. After completion of the thiol addition, the mixture was kept under oxygen for an additional 14 h, cooled to 4° C., and Ph3P (236 mg, 0.90 mmol) was added. The reaction mixture was stirred for 2 h at 5° C. and at rt for additional 1 h. The solvents were then evaporated, and flash chromatography (hexane-EtOAc, 9:1→1:1) afforded a mixture of diastereomeric (1S,4S,5S,7R,8S)-7-benzoyloxy-4,8-dimethyl-4-phenylthiomethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 6a and (1S,4R,5S,7R,8R)-7-benzoyloxy-4,8-dimethyl-4-phenylthiomethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 6b (24 mg of ca. 94% purity, 6% yield, 6a/6b ca. 65:35), Rf 0.42 (EtOAc-heaxane, 35:65) as a pale yellow oil. 1H NMR (400 ) MHz, CDCl3, δ): 1.23 (br. s, Me11, 6a), 1.59 (br. s, Me11, 6b), total 3 H; 1.41 (s, Me10, 6b), 1.42 (s, Me10, 6a), total 3 H; 1.91-2.37 (m, total 5 H, H35 +Ha,e6 +Ha,e9, 6a+6b); 3.00 (d, 2J=12.1 Hz, H12, 6b), 3.14 (br. d, 2J=12.1 Hz, H'12, 6b), 3.39 (d, 2J=12.8 Hz, H12, 6a), 3.80 (br. d, 2J=12.8 Hz, H'12, 6a), total 2 H; 3.82 (m, He1, 6a), 3.88 (dd, 3J1e9e =4.1 Hz, 3J1e9a =1.5 Hz, He1, 6b), total 1 H; 5.26 (dd, 1 H, 3J7e6e =5.0 Hz, 3J7e6a =1.7 Hz, He7, 6b), 5.27 (dd, 1 H, 1J7e6e =5.0 Hz, 3J7e6a =1.5 Hz, He7, 6a), total 1 H; 7.09 (m, 1 H), 7.22 (m, 6 b), 7.29 (m, 6a), total 2 H; 7.41-7.47 (m,), 7.54-7.58 (m,), total 5 H; 8.13 (m, 2 H), 13C NMR (100 MHz, CDCl3, δ): Isomer 6a: 22.30 (Me11), 23.42 (C9H2), 23.47 (Me10), 28.81 (C6H2), 29.36 (C5H), 40.78 (C12H2), 73.83 (C8), 74.36 (C7H), 80.85 (C1H), 82.74 (C4), 126.36 (C16H), 128.48 (2CH), 129.00 (2CH), 129.81 (2CH), 129.90 (2CH), 130.15 (C1-benz.), 133.11 (Cp-benz. H), 136.71 (C13), 166.33 (C=O); Isomer 6b: 21.68 (Me11), 23.35 (Me10), 23.56 (C9H2), 28.68 (C6H2), 30.86 (C5H), 40.37 (C12H2), 73.68 (C8), 74.51 (C7H), 81.38 (C1H), 82,83 (C4), 126.12 (C16H), 128.52 (2CH), 128.88 (2CH), 129.06 (2CH), 129.81 (C1-benz.), 129.90 (2CH), 133.18 (Cp-benz. H), 136.25 (C13), 166.25 (C=O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>O1CCCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])[CH3:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(Br)cc1C
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1ccc(Br)cc1C
Temperature: 65 °C
Reaction time: 20 h

Procedure:
Titanium(IV) ethoxide (10.7 mL) was added to a solution of 1-(4-bromo-2-methyl-phenyl)-ethanone (4.41 g) and (R)-2-methyl-2-propanesulfinamide (2.76 g) in tetrahydrofuran (45 mL). The resulting solution was heated to 65° C. and stirred at this temperature for 20 h. Then, the solution was cooled to ambient temperature and another portion of titanium(IV) ethoxide (5.4 mL) and (R)-2-methyl-2-propane-sulfinamide (1.25 g) were added. After stirring the solution at 65° C. for another 12 h, the solution was cooled to ambient temperature and poured into brine. The resulting mixture was filtered over Celite and the organic phase of the filtrate was separated. The aqueous phase of the filtrate was extracted with ethyl acetate and the extracts were combined with the separated organic phase. The combined organic phases were washed with brine and dried (MgSO4) and the solvent was evaporated. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 9:1→1:1) to afford the title compound. Yield: 6.24 g (95% of theory); Mass spectrum (ESI+): m/z=316/318 (Br) [M+H]+.
Reaction SMILES: C(N)(C)(C)C.[Br:6]Br.[O:8]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:6][C:18]1[CH:19]=[CH:20][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:16][C:17]=1[OH:21]
Reactant: BrBr
Reactant: Oc1cccc(Oc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)N
Solvent: ClCCl
Product: Oc1cc(Oc2ccccc2)ccc1Br
Temperature: -70 °C
Reaction time: 5 h
Yield: 26.8 %

Procedure:
To a solution of t-butylamine (1.1 ml, 10.7 mmol) in 13 ml toluene, cooled to -30° C. was added bromine (0.28 ml, 5.35 mmol). The mixture was cooled to -70° C. and was treated with 3-phenoxyphenol (2.0 g, 10.7 mmol) dissolved in 2 ml CH2Cl2. The reaction was stirred to ambient temperature over 5 h, quenched with water and diluted with CH2Cl2. The organic phase was washed with water and brine and dried over Na2SO4. Column chromatography (SiO2 ; 5:95 EtOAc/Hex) afforded 380 mg (14%) of 2-bromo-5-phenoxyphenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:15].[N+:16]([O-])([O-:18])=[O:17].[K+].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: COC(=O)CCCc1ccc(F)c(C)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COC(=O)CCCc1cc(C)c(F)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
The compound obtained in (2) above (10.9 gm) was added to 6 ml of cold concentrated sulfuric acid, and to the mixture was dropwise added 5.8 gm of potassium nitrate in 15 ml of concentrated sulfuric acid, while maintaining the internal temperature below 5° C. After the addition, the mixture was stirred for a further 20 minutes. The reaction product was poured into ice-cooled water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography using a hexane-ethyl acetate (90:7) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 7.1 gm of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12](OC)=[O:13])=[CH:5][CH:4]=1)#[N:2].B([O-])=O.[Na+].[OH-].[Na+]>C1COCC1.CO>[OH:13][CH2:12][C:11]1[CH:10]=[C:9]([CH:18]=[CH:17][CH:16]=1)[CH2:8][O:7][C:6]1[CH:19]=[CH:20][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: COC(=O)c1cccc(COc2ccc(C#N)cc2)c1
Agent: O=B[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(OCc2cccc(CO)c2)cc1
Temperature: 62 °C
Reaction time: 5 h

Procedure:
20.05 kg (26.7 mol) of methyl 3-(4-cyano-phenoxymethyl)-benzoate are dissolved in 100 litres of THF and 40 litres of methanol. At 40 to 45° C., 8.51 kg of sodium boranate are added in batches. The reaction is completed by stirring the reaction mixture at 61 to 63° C. for about 5 hours. The reaction mixture is then cooled to 25° C. and 90 litres of a 15% sodium hydroxide solution are added. After stirring, the aqueous supernatant is separated off and mixed with 30 litres of a 22.5% sodium hydroxide solution. After stirring, the aqueous supernatant is separated off and from this about 100 litres of solvent are distilled off at a sump temperature of 63 to 75° C. The distillation residue is crystallised by the addition of 20 litres of isopropanol at 50 to 60° C. and 150 litres of water at 40 to 50° C. After the suspension has been cooled to 20 to 30° C. the crystals are separated off, washed with 60 to 100 litres of water and batchwise with 25 litres of cold isopropanol and dried in vacuo.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][C@H:7]2[N:18]([CH3:19])[C@@H:4]1[CH2:5][CH2:6]2)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[OH:27][NH3+:28]>CO.C(O)C>[Cl:17][C:12]1[CH:11]=[C:10]([C@H:9]2[CH2:8][C@H:7]3[N:18]([CH3:19])[C@H:4]([CH2:5][CH2:6]3)[C@@H:3]2[CH:1]=[N:28][OH:27])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: [NH3+]O
Reactant: CN1[C@H]2CC[C@@H]1[C@H](C=O)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CN1[C@H]2CC[C@@H]1[C@H](C=NO)[C@@H](c1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (1R,2R,3S)-2-formyl-3-(3,4-dichlorophenyl)tropane (6.9 g, 23 mmol) in methanol (100 ml), sodium carbonate (4 g) and hydroxylammonium chloride (2.6 g, 37 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with water. A crude product was isolated by filtration and recrystallization first in a mixture of ethanol and water (1+1) and then in 99% ethanol yielded the title compound (mixture of syn/anti isomers--approximately 1+2) as white crystals, m.p. 230°-235° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(c2cccc(Br)c2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(c2cccc(Br)c2)CCOCC1
Yield: 79.1 %

Procedure:
A stirred mixture of ethyl 4-(3-bromophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (36.5 g, 117 mmol), an aqueous solution of lithium hydroxide (6.14 g, 146 mmol, 50 ml), methanol (150 ml) and THF (150 ml) was refluxed for 1 day. The reaction mixture was partitioned between ether (100 ml) and 10% aqueous potasium hydroxide solutuion (300 ml). The ethereal layer was separated, extracted with 10% aqueous potasium hydroxide solutuion (2×100 ml) and discarded. The combined aqueous extracts were acidified with concentrated hydrogen chloride and the resulting white precipitates were collected by filtration, washed with water and dried to constant weight under vacuum at 80° C. to give the titled compound as white solids (26.4 g, 79%).
Reaction SMILES: [CH:1](=[CH:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1/[CH:20]=[C:9](\[CH3:10])/[CH:8]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CCc1cnccc1C
Reactant: CC(=O)C=Cc1ccccc1
Product: CCc1cnccc1/C=C(C)/C=C/c1ccccc1
Yield: 7.3 %

Procedure:
The procedure of Example 41 was repeated with the exception that 3.5 g of benzal acetone in place of cinnamic aldehyde and 2.26 g o±3-ethyl-4-methylpyridine were used in Example 41, to obtain 0.35 g (yield: 7.3%) of (E,E)-1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl -1,3-butadiene (hereinafter referred to as compound 57) and 0.22 g (yield: 4.7%) of (Z,E)-1-(3-ethyl-4-pyridyl)-2-methyl-4-phenyl-1,3-butadiene (hereinafter referred to as compound 58). The analytical results are shown below.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]([C:13]1[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][OH:12].N1C=CN=C1>ClCCl>[Si:5]([O:12][CH2:11][CH:10]([C:13]1[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:9])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)n1c(C(O)CO)cc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(C(O)CO[Si](C)(C)C(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
TBSCl (1.3 g, 8.9 mmol) in dichloromethane (20 mL) was added dropwise at 0° C. over 10 minutes to a solution of tert-butyl 2-(1,2-dihydroxyethyl)-1H-indole-1-carboxylate (2.0 g, 7.2 mmol) and imidazole (1.20 g, 17.4 mmol) in DCM (30 mL). After being stirred at room temperature for 1 hour, the mixture was washed with water (2×50 mL) and brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give an oil, which was further purified by prep-HPLC to afford tert-butyl 2-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)-1H-indole-1-carboxylate (500 mg, 18% yield) as an oil. LCMS (ESI) m/z: 318.3 [M-56-17]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[Cl:1]
Reactant: CON
Reactant: O=Cc1ccc(F)cc1Cl
Agent: Cl
Product: CON=Cc1ccc(F)cc1Cl
Yield: 93 %

Procedure:
Reaction of 2-chloro-4-fluoro-benzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil (93% yield). 1HNMR indicated a 9:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.99 (3H, s, OCH3), 6.99 (1H, m, aromatic), 7.12 (1H, m, aromatic), 7.87 (1H, m, aromatic), 8.41 (1H, s, CH).
Reaction SMILES: C([CH:5]([OH:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC)CCC.[OH-].[K+].[CH2:16]1[O:19][CH:17]1C.P(=O)(O)(O)O.[CH2:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:26][CH2:27][CH3:28].C(C(CCCC)C(O)=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:17]([O:19][C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:16].[CH2:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCC(O)CCCC
Reactant: CC1CO1
Agent: CCCCC(CC)C(=O)O
Agent: CCCCCCCCOCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCC(=O)OCC
Temperature: 80 °C

Procedure:
4 moles (744 grams) of Butyloctanol were charged to an autoclave, and 0.1% of Potassium Hydroxide was added as catalyst. The autoclave was purged with Nitrogen and 16 moles (928 grams) of Propylene Oxide were added at a temperature of 150–160° C. and a pressure of 30–40 psi. Upon completion, the batch was cooled to 80° C. and neutralized with Phosphoric Acid. The resultant product, PPG-4 Butyloctyl Ether, was a very pale yellow liquid. A four-neck flask was charged with 1,224 grams of the PPG-4 Butyloctyl Ether, along with 3 moles (432 grams) of 2-Ethyl Hexanoic Acid. A catalytic amount of p-Toluenesulfonic Acid was added and the reaction mixture was heated with agitation to 160° C. until an acid value of less than 5 mg KOH was obtained. The reaction mixture was cooled to 80° C., washed with a dilute Sodium Hydroxide solution sufficient to neutralize the residual acid present, followed by washing with water. The ester layer was separated and heated under vacuum until a moisture content of less than 0.2% was obtained, followed by vacuum filtration. The resultant product, PPG-4 Butyloctyl Ether Ethylhexanoate, was a clear very pale yellow liquid having an acid value of less than 0.1 mg KOH.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([OH:23])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]1[CH:45]=[C:44]([CH3:46])[O:43][N:42]=1>>[CH3:46][C:44]1[O:43][N:42]=[C:41]([CH2:40][O:22][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:31][CH:32]=4)(=[O:25])=[O:26])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:23])[CH:45]=1
Reactant: Cc1cc(CCl)no1
Reactant: O=C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Product: Cc1cc(COC(=O)[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(N4CCOCC4)nc2)C3)no1

Procedure:
The title compound was prepared by the method of Preparation 54b using (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid and 3-chloromethyl-5-methyl isoxazole. LCMS (Method F): 635 (M+H)+, Retention time 4.90 minutes.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][CH:14]=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCO
Temperature: -78 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 1-BOC-2-(S)-pyrrolidineethanal (6.80 g, 26.5 mmol) in anhydrous toluene (100 mL), cooled to -78° C. was added a 1M solution of diisobutylaluminum hydride in toluene (132.5 mL, 132.5 mmol). The reaction was stirred at -78° C. for 2 hours, and diisobutylaluminum hydride solution (26.50 mL, 26.5 mmol) was added. The mixture was stirred for 2 hours, then the reaction was quenched at -78° C. with methanol (150 mL). The mixture was poured into 1M Rochelle salt (500 mL), and the emulsified solution was extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with methanol/methylene chloride (5:95) to yield a colorless oil (3.82 g, 67%). MS (DCI/NM) m/e: 216 (M+H)+. 1HNMR (CDCl3, 300 MHz) δ: 1.47 (s, 9H), 1.58-1.76 (m, 2H), 1.82-2.05 (m, 3H), 3.31 (t, J=6.0 Hz, 2H), 3.50-3.69 (m, 2H), 4.10-4.21 (m, 1H), 4.43 (dd, J=4.0, 7.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[Br:18][C:19]1[C:20]([C:25]2[NH:29][N:28]=[CH:27][N:26]=2)=[C:21]([NH2:24])[S:22][CH:23]=1>>[Br:18][C:19]1[C:20]([C:25]2[NH:29][N:28]=[CH:27][N:26]=2)=[C:21]([NH:24][C:14](=[O:16])[CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:17])[S:22][CH:23]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: N#Cc1ccc2ccc(=O)n(CC(=O)O)c2c1
Product: N#Cc1ccc2ccc(=O)n(CC(=O)Nc3scc(Br)c3-c3ncn[nH]3)c2c1

Procedure:
N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetamide was prepared from 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (65 mg, 0.286 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (21 mg, 0.143 mmol) according to protocol A. Retention time (min)=4.143, method [7], MS(ESI) 454.9 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.01 Hz, 1H), 7.28 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[C:27]([F:29])[CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:25]5[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1cc(F)cc(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(F)cc(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3,5-difluorophenyl)methanol (153 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (56 mg) as an off-white solid.
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:8][CH:6]([CH3:7])[C:5](=[O:9])[CH2:4][C:3]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: C1COCCN1
Product: CC(C)C(=O)CC(=O)N1CCOCC1
Yield: 88.9 %

Procedure:
0.351 mol (49.6 ml) of 4-methyl-3-oxovaleric acid methyl ester and 0.369 mol (32.3 ml) morpholine were stirred for 14 hours at 110° C. in a Dean-Stark apparatus. 8 ml methanol were collected. Subsequently, the excess starting materials was distilled off for 3 h on a rotary evaporator (80° C. water bath, 2 mbar). The crude product was dissolved in 500 ml toluene and extracted with 50 ml of 1 M NaOH and 3 times with 50 ml water, and the organic phase was concentrated on a rotary evaporator to dryness. After drying, 62.2 g of the title compound were obtained.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[OH-].[K+]>C(O)C>[CH3:26][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[C:11]2[CH2:1][CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]2=[O:10])=[CH:24][CH:25]=1
Reactant: O=C1CCCc2ccccc21
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCCOc1ccc(C=C2CCc3ccccc3C2=O)cc1
Reaction time: 16 h
Yield: 75.9 %

Procedure:
A stirred solution of 50 g of α-tetralone and 70 g of 4-(3-dimethylaminopropoxy)benzaldehyde in 275 ml of ethanol is cooled to -20° C. and treated with 2.0 g of potassium hydroxide dissolved in 50 ml of ethanol. The cooling bath is removed and after standing for about 16 hours at room temperature the reaction mixture (some product has separated) is added to 1.2 liters of cold water. The material is extracted with 3:1 ether-dichloromethane (five 300 ml portions), the combined extracts are dried over magnesium sulfate, and the solvents are removed on a rotary evaporator to give a semi-solid residue. Crystallization of the residue from 300 ml of diisopropyl ether yields 86 g of product; melting point 86°-88° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11](Cl)[C@@H:10]1[OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>O1CCCC1.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:20][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@@H]1O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12

Procedure:
A solution of (±)-(1R,2R,3R)-3-tert-butoxycarbonylamino-1-chloro-1,2,3,4tetrahydro-2-naphthalenol (348 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (400 mg) in tetrahydrofuran (10 ml) was refluxed for 11/2 hours. The mixture was diluted with methylene chloride, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from cyclohexane (193 mg) to yield the title compound as a white solid, m.p. 118-119° C.