Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]([CH3:29])([CH3:28])[C:26]#N)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:30]S(O)(=O)=O>O1CCCC1.O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:25]([CH3:29])([CH3:28])[CH:26]=[O:30])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C#N)c1cccc(OCc2ccccc2)c1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Temperature: 16.5 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Diisobutylaluminum hydride (300 mL, 0.3 mol of a 1.0 M solution in hexanes) was added dropwise to a cooled (15° C., ice-bath) solution of nitrile II (59.9 g, 0.24 mol) in anhydrous tetrahydrofuran (250 mL). The reaction temperature was maintained at 15-18° C. during the addition. The reaction was then allowed to warm to room temperature and stirred for an additional 2 hours. The reaction was hydrolyzed by addition of a cold solution of conc. H2SO4 (35.5 mL) in water (117.5 mL) with the temperature maintained at <30° C. The resultant mixture was stirred for a further 2 hours, then filtered, and the filtrate extracted with diethyl ether (2×250 mL), washed with water (300 mL), brine (300 mL), dried and concentrated under reduced pressure to give crude aldehyde III as a light-yellow oil (59.82 g, 98%) which was used without further purification. M+1=255.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P([O-])(O)(O)=O.[Na+].C1C[O:30][CH2:29]C1>CN(C)C=O>[CH2:9]([N:16]1[CH:20]=[N:19][C:18]([CH:29]=[O:30])=[N:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(Cn2cncn2)cc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: O=P([O-])(O)O
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=Cc1ncn(Cc2ccccc2)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a continuously stirred mixture of 0.156 moles of lithium diisopropylamide in 150 ml of THF cooled at -70° C. was added dropwise a solution of 1-benzyl-1,2,4-triazole prepared above in 200 ml of THF. After the mixture was stirred for one hour longer, there was added in one portion 16.5 ml of dry dimethylformamide. The mixture was stirred in the cold for 0.5 hour and then at room temperature for 3.5 hours whereupon there was added dropwise a saturated aqueous solution of 21.5 grams of sodium dihydrogenphosphate. After the mixture was extracted well with dichloromethane, the combined extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and evaporated to give a crude product. The crude product was flash column chromatographed over silica gel and eluted with dichloromethane/ethyl acetate (2:1) to provide 24.6 grams of pure 1-benzyl-3-formyl-1,2,4-triazole as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:21][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][C:17]=1[F:20])[N:10]([CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]1)[C:11](=[O:22])[CH:12]=[N:13]2
Reactant: NC1CCN(CCn2c(=O)cnc3cc(F)c(F)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5cc(F)c(F)cc54)CC3)nc2N1
Yield: 61.7 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,7-difluoro quinoxalin-2(1H)-one (Intermediate 150, 190 mg, 0.62 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (110 mg, 0.62 mmol), and sodium triacetoxy borohydride (390 mg, 1.90 mmol) were reacted as described according to Example 69 to give 180 mg (62%) of the free base of the product as a colorless solid.
Reaction SMILES: C1[O:18][CH2:17][CH2:16]OCCOCCOCCOCCOC1.FC(F)(F)COP(CC(OC)=O)(=O)OCC(F)(F)F.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:48][C:49]1[C:54]([CH:55]=O)=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[F:63])[N:52]=[C:51]([S:64][CH3:65])[N:50]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOCC>[F:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[C:53]1[C:54]2[CH:55]=[CH:16][C:17](=[O:18])[NH:48][C:49]=2[N:50]=[C:51]([S:64][CH3:65])[N:52]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CSc1nc(N)c(C=O)c(-c2ccccc2F)n1
Agent: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1nc(-c2ccccc2F)c2ccc(=O)[nH]c2n1
Reaction time: 0.5 h
Yield: 108.8 %

Procedure:
A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (81 uL, 0.38 mmol, 1.2 eq) in anhyd THF (20 mL) was cooled to −78°, potassium bis(trimethylsilyl)amide (0.96 mL, 0.48 mmol, 1.5 eq) as a 0.5 mol solution in toluene was added. This solution was stirred for additional 30 min at −78° and 4-amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (85 mg, 0.32 mmol) in dry THF (1 mL) was added dropwise. The reaction mixture was then stirred for 8 h at −78° and warmed to 23°, and stirred 16 h. Saturated aq NH4Cl (5 mL), followed by Et2O (20 mL), was added. The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was purified by Flash chromatography to afford 100 mg (91% yield) of 4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR δ 2.62 (s, 3H), 6.55 (d, 1H, J=9.9 Hz), 7.26 (m, 3H), 7.52 (m, 2H), 8.99 (br s, 1H). LC MS (m/e)=288 (MH+). Rt=1.75 min.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.O[C@@H]([C@H](O)C(O)=O)C(O)=O.[C:23]1([C@H:29]2[CH2:31][C@@H:30]2[NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:32]([C@H:30]1[CH2:31][C@@H:29]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[C:5]=[O:11]
Reactant: N[C@H]1C[C@@H]1c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C=N[C@H]1C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triphosgene (0.33 eq.) was added to a stirred, cooled 0° C., 0.053 M mixture of (2S,3S)-2,3-dihydroxysuccinic acid and (1S,2R)-2-phenylcyclopropanamine (1:1) (prepared according to: Newman in “Optical resolution procedures for chemical compounds” Chapter 1 Amines and related com. Pages 120-122) in a 1:1 mixture of DCM and sat. aq. NaHCO3 solution, and the reaction mixture was stirred at 0° C. for 1 h. The reaction was poured into a separatory funnel and layers were separated. Aqueous layer was extracted with DCM (×3). Combined organic layers were dried and evaporated to give the title compound as colorless oil in quantitative yield. 1H NMR (300 MHz, CDCl3, 300K) δ 7.30 (2H, t, J=7.0 Hz), 7.21 (1H, t, J=7.0 Hz), 7.05 (2H, d, J=7.0 Hz), 2.92 (1H, ddd, J=7.4, 4.3, 3.3 Hz), 2.20 (1H, ddd, J=9.8, 6.8, 3.3 Hz), 1.33-1.20 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:20][C:21](O)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:20][C:21](=[O:22])[N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH2:31][CH2:32]1
Reactant: COc1ccccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1ccccc1C1(CC(=O)N2CCN(c3ccccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Yield: 86.9 %

Procedure:
With 800 mg of [5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid, which is the compound described in Preparation 1.1 of the brochure Publication No. WO03/008407, and 433 mg of 1-pyridin-2-ylpiperazine as starting materials, 1.00 g of the title compound (colorless solid) was obtained by a similar method to Step 45-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14].[OH-].[Na+].Cl>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:12]/[C:13]([C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: COc1ccc(C=O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-hydroxy-4-methoxybenzaldehyde (1.1 g, 7.3 mmol) and 3,4,5-trimethoxyacetophenone (1.54 g, 7.3 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with chloroform (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, the solvent concentrated under vacou. The product was purified by crystallisation from methanol. 1H-NMR (CDCl3): 7.8 (d, 1H), 7.4 (d, 1H), 7.2-7.3 (m, 3H), 7.1 (dd, 1H), 6.9 (d, 1H), 5.8 (s, 1H) 4.0 (s, 9H) 3.9 (s, 3H); Mass Spectrum m/e (M+1) 329.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[S:8][C:4]=2[CH:3]=1.N(OCCC(C)C)=O.[I:24]CI>O1CCCC1.[Cu]I>[I:24][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[S:8][C:4]=2[CH:3]=1
Reactant: ICI
Reactant: N#CCCCc1nc2ccc(N)cc2s1
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: N#CCCCc1nc2ccc(I)cc2s1

Procedure:
1.1 g of 4-(6-amino-1,3-benzothiazol-2-yl)butane nitrile synthesized according to a method described in JP-A 5–194440, 2 mL isoamyl nitrite, 0.96 g of copper (I) iodide and 2 mL diiodomethane were heated in tetrahydrofuran at 80° C. for 1 hour. After the solvent was removed, the residue was purified by NH silica gel column to give 888 mg of the title compound as colorless crystals.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:6]1=[O:31])(=O)C.Cl>C(OCC)(=O)C>[OH:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:6]1=[O:31]
Reactant: COc1ccc([C@H]2SC=C(c3ccccc3)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2SC=C(c3ccccc3)N(CCN(C)C)C(=O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.3 %

Procedure:
A mixture of 0.5 g (0.001 mol) of rac-cis-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-4[2-(dimethylamino)ethyl]-3-phenyl-1,4-thiazepin-5(4H)-one and 5 mL of ethyl acetate saturated with hydrogen chloride was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ammonium hydroxide. The ethyl acetate solution was washed with brine, dried (MgSO4) and removal of the solvent gave 0.3 g (67%) of rac.-cis-6,7-dihydro-6-hydroxy-7-(4-methoxyphenyl)-4-[2(dimethylamino) ethyl]-3-phenyl-1,4-thiazepin-5(4H)-one. Analytical sample was crystallized from ethyl acetate, mp 159°-160°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.Cl.[CH3:29][NH:30][CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:29][N:30]([CH3:31])[C:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1cccc(C(=O)O)c1)c1ccccc1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 21 from (Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone, dimethylamine-hydrochloride, TBTU, HOBt and triethylamine in DMF.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C([NH:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[O:40])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])/[C:37](=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)/[S:36][C:35]1=[O:40]
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCc1ccc(C=O)cc1
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: CCCc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1

Procedure:
The title compound 30e was prepared from 4-propylbenzaldehyde (92 mg, 0.62 mmol), compound 29 (250 mg, 0.62 mmol) and piperidine (7.0 μL, 0.062 mmol) in a manner similar to that described for 30a in 38.0% (95 mg) yield as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][CH3:24])[C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([NH:12]C(=O)C)[CH:10]=2)[N:5]([CH:19]([CH3:21])[CH3:20])[C:4]1=[O:22])[CH3:2].Cl>C(O)C>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[N+:16]([O-:18])=[O:17])[N:5]([CH:19]([CH3:20])[CH3:21])[C:4](=[O:22])[C:3]2([CH2:23][CH3:24])[CH2:1][CH3:2]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc([N+](=O)[O-])c(NC(C)=O)cc21
Agent: Cl
Solvent: CCO
Product: CCC1(CC)C(=O)N(C(C)C)c2cc([N+](=O)[O-])c(N)cc21
Yield: 98.8 %

Procedure:
N-(3,3-diethyl-1-isopropyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2.2 g, 6.60 mmol) was dissolved in ethanol (50 ml). After addition of hydrochloric acid (25%, 3.2 ml, 33.0 mmol) the mixture was heated under reflux for 3 h. Most of the solvent was evaporated and water was added. The mixture was weakly alkalized by addition of aqueous NaOH solution. The mixture was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was evaporated to yield 1.9 g 5-amino-3,3-diethyl-1-isopropyl-6-nitro-1,3-dihydro-indol-2-one (6.52 mmol, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38](Cl)=[O:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(Cl)Cc1ccccc1F
Product: O=C(Cc1ccccc1F)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-fluorophenyl-acetyl chloride according to the procedure of Example 61. MS (ES) m/z 526.8.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13].[CH2:15]([OH:18])[C:16]#[CH:17].[OH-].[K+].[NH4+].[Cl-]>C1COCC1.O>[CH3:13][C:12]([OH:14])([CH2:11][CH2:10][C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])[C:17]#[C:16][CH2:15][OH:18]
Reactant: CC(=O)CCC1=C(C)CCCC1(C)C
Reactant: C#CCO
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(CCC(C)(O)C#CCO)C(C)(C)CCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanone (107 g, 0.55 mol) and propargyl alcohol (34 g, 0.61 mol) was added dropwise during 1.5 h to a mechanically stirred slurry of powered KOH (Fluka, 230 g, 4.1 mol) in THF (tetrahydrofuran 800 ml) maintained at 20° C. After a further 3 h, the brown mixture was poured into a cold solution of NH4Cl (250 g, 4.7 mol) in H2O (800 ml) and the phases separated. Extraction of the aqueous phase with ether and concentration of the combined organic phase afforded a reddish brown solid which was recrystallized from petroleum ether (80/100) to furnish 4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-hexyn-1,4-diol as a pale yellow powder (110 g, 80% yield).
Reaction SMILES: [CH:1](=[N:8][C@H:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:25]([CH2:28][C:29](Cl)=[O:30])=[N+:26]=[N-:27]>C(Cl)Cl>[C:14]([O:13][C:11]([C@@H:9]([N:8]1[C@@H:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:28]([N:25]=[N+:26]=[N-:27])[C:29]1=[O:30])[CH3:10])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: [N-]=[N+]=NCC(=O)Cl
Reactant: C[C@H](N=Cc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@H](N=[N+]=[N-])[C@@H]1c1ccccc1
Reaction time: 14 h
Yield: 41.1 %

Procedure:
To 75 ml. of a solution of N-benzylidene-1(S)-t-butoxycarbonylethylamine (5.07 g., 21.7 mmol) and triethylamine (4.84 g., 47.8 mmol) in methylene chloride, there was gradually added dropwise 75 ml. of a solution of azidoacetyl chloride (5.19 g., 43.5 mmol) in methylene chloride at -78° C. After stirring at -78° C. to room temperature for 14 hours, the reaction mixture was washed with water and then with a saturated saline solution, followed by drying over anhydrous magnesium sulfate. After removal of the solvent by distillation, the residue was subjected to silica gel column chromatography, using hexane-ethyl acetate (3:1) as an eluent, to give 1-(1(S)-t-butoxycarbonylethyl)-3(S)-azido-4(R)-azetidin-2-one (2.68 g., yield: 39%) and 1-(1(S)-t-butoxycarbonylethyl)-3(R)-azido-4(S)-phenylazetidin-2-one (2.82 g., yield: 41%).
Reaction SMILES: C1CN([P+]([O:17][N:18]2[N:26]=[N:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1CC[N:42]2[C:37](=[N:38][CH2:39][CH2:40][CH2:41]2)CC1>C(#N)C>[N:18]1([O:17][C:39]2[C:40]3[N:18]=[CH:19][CH:20]=[CH:21][C:41]=3[N:42]=[CH:37][N:38]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]=[N:26]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: C1CCC2=NCCCN2CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: c1cnc2c(On3nnc4ccccc43)ncnc2c1
Reaction time: 2.5 h
Yield: 136.7 %

Procedure:
A mixture of this material (10 g, 68.0 mmol) and PyBOP (38.9 g, 74.8 mmol) in acetonitrile (250 mL) was treated with DBU (12.2 mL, 81.6 mmol) and stirred for 2.5 h. The reaction mixture was filtered, and the precipitate was washed with diethyl ether (3×50 mL) and dried under vacuum. The title compound (13.51 g, 75%) was obtained as a cream-coloured solid. δH (DMSO-d6) 9.28 (dd, J 4.2, 1.6 Hz, 1H), 8.82 (s, 1H), 8.59 (dd, J 8.6, 1.5 Hz, 1H), 8.24-8.18 (m, 2H), 7.88-7.85 (m, 1H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 1H). LCMS (ES+) 265 (M+H)+, RT 1.23 minutes.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2cccc(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 87 (1.5 g, 3.37 mmol) in EtOAc (30 mL) for 1 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue crystallized from dichloromethane and Et2O to give 1.05 g of the product 88. 1H NMR (DMSO-d6) δ 9.28 (t, 1H), 8.68 (s, 1H), 8.15 (s, 1H), 7.35-7.10 (m, 3H), 7.10-6.80 (m, 7H), 6.80-6.50 (m, 4H), 5.03 (s, 1H), 4.80-4.45 (m, 2H); MS: m/z 346 (M++1).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH2:23][OH:24])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].ClCCl>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=[O:24])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1c(CO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a 100 ml dichloromethane solution of 13.8 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(hydroxymethyl)quinolin-4(1H)-one was added 67.0 g of manganese dioxide at room temperature, followed by overnight stirring. After completion of the reaction and subsequent filtration using celite, the filtrate was evaporated under a reduced pressure. By crystallizing the resulting solid from ethyl acetate, 13.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[Br:12][CH2:13][CH:14](OC)OC.OS(O)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]2[CH2:9][O:10][CH:14]([CH2:13][Br:12])[O:8][C:6]=2[CH:7]=1
Reactant: OCc1c(O)cc(Br)cc1F
Reactant: COC(CBr)OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc2c1COC(CBr)O2

Procedure:
Preparation according to Preparation 9. 5-bromo-3-fluoro-2-(hydroxymethyl)phenol (0.79 g, 3.6 mmol), 2-bromo-1,1-dimethoxyethane (4.2 ml, 36 mmol), dry THF (10 ml) and concentrated H2SO4 (1.5 ml).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: COc1cccc(B(O)O)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Yield: 83.7 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 13.04 mmol) with 3-methoxyphenylboronic acid (2.97 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.512 g, 0.652 mmol) and potassium carbonate (4.51 g, 32.62 mmol) generally according to the reaction conditions described for Intermediate 37 gave 4.48 g (84%) of (±)-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 141-142° C.; Anal. calcd. for C23H22O5S: C, 67.3; H, 5.4. Found: C, 66.51; H, 5.41.