Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[CH:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[CH:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
DIPEA (3.47 mL, 19.88 mmol) was added to a stirred slurry of crude 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g, 13.3 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.01 g, 13.25 mmol) in acetonitrile (80 mL) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and purified by BIOTAGE® Horizon (160 g SiO2, 10-20% EtOAc/hexanes). The fractions containing the desired product were allowed to stand for 3 d. Some fractions had crashed large crystals (collected 240 mg, pure desired product by 1H NMR). All fractions containing the desired product were collected and concentrated to a yellow solidified foam which was slurried with Et2O (˜40 mL). The white solid that formed was collected by filtration and rinsed with Et2O to yield (1R,3S,5R)-3-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.24 g). LC-MS retention time 2.760 min; m/z 472, 474.02 (1:1) (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 mHz, MeOD) d ppm 8.61 (br s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.71 (dd, J=8.6, 1.8 Hz, 1H), 5.75-5.66 (m, 1H), 5.61-5.46 (m, 1H), 4.34-4.26 (m, 1H), 3.46 (br s, 1H), 2.69-2.59 (m, 1H), 2.55-2.44 (m, 1H), 1.73 (br s, 1H), 1.54-1.43 (m, 9H), 0.88 (br s, 1H), 0.59-0.53 (m, 1H).
Reaction SMILES: CON(C)[C:4](=[O:19])[CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1>>[CH3:28][C:24]1[CH:23]=[C:22]([C:4](=[O:19])[CH2:5][CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:27]=[CH:26][N:25]=1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C(=O)CC(c2ccccc2)c2ccccc2)ccn1

Procedure:
In analogy to example 55, step 2, the title compounds was prepared from N-methoxy-N-methyl-3,3-diphenyl-propionamide and 4-bromo-2-methylpyridine as a colorless oil, MS (ESI+): m/z=302.15 ([M+H]+).
Reaction SMILES: [CH2:1]([CH2:9][SiH](Cl)Cl)[CH2:2]C1C=CC=CC=1.ClS(O)(=O)=O.[Cl:18][S:19]([C:22]1[CH:33]=[CH:32][C:25]([CH2:26][CH2:27][CH2:28][SiH:29]([Cl:31])Cl)=[CH:24][CH:23]=1)(=[O:21])=[O:20].C([Mg]Cl)C=C>>[Cl:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH2:27][CH2:28][SiH:29]([CH2:9][CH:1]=[CH2:2])[Cl:31])=[CH:32][CH:33]=1)(=[O:20])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(CCC[SiH](Cl)Cl)cc1
Reactant: Cl[SiH](Cl)CCCc1ccccc1
Agent: C=CC[Mg]Cl
Agent: O=S(=O)(O)Cl
Product: C=CC[SiH](Cl)CCCc1ccc(S(=O)(=O)Cl)cc1

Procedure:
Phenethylmethyldichlorosilane (Gelest, Inc., Tullytown, Pa., USA) is chlorosulfonated with chlorosulfonic acid as described in Chem. Abstr. 103 P71494v. This yields [4-(chlorosulfonyl)phenethyl] methyldichlorosilane which is reacted with allyl-magnesium chloride to form [4-(chlorosulfonyl)phenethyl] methyl allylchlorosilane. This product is reacted with octadecyl methylchlorosilane (boiling point of 175° to 177°/0.5 mm, from reaction of octadecylmagnesium bromide with methyldichlorosilane) under chloroplatinic acid catalysis to form 1-(octadecyl methylchlorosilyl)-3-{methyl [4-(chlorosulfonyl)phenethyl] chlorosilyl}propane. This material is reacted with dimethylamine to form 1-(octadecyl methyl dimethylaminosilyl)-3-{methyl [4-(chlorosulfonyl)-phenethyl] dimethylaminosilyl}propane.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#N.S(=O)(=O)(O)[OH:27]>C1C=CC=CC=1.C(OCC)C>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:27]
Reactant: N#CCCCCCCOC1CCCCO1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CCCCCCCOC1CCCCO1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (19.4 g.) in dry benzene (50 ml.) was added dropwise at 10° C. to a stirred solution of 7-(2-tetrahydropyranyloxy)heptanenitrile (20.6 g.) in dry diethyl ether (200 ml.). The solution was stirred at 10° C. for 30 minutes and was then added to 2 N aqueous sulphuric acid (300 ml.) at 0° C. The mixture was heated at 30° C. for 30 minutes, and then saturated with sodium chloride and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with aqueous sodium bicarbonate, and then aqueous sodium chloride, and dried over sodium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 7-(2-tetrahydropyranyloxy)heptanal (12.7 g.), b.p. 78°-106° C./0.1 mm.Hg, nD25 1.456.
Reaction SMILES: [CH3:1][C@H:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][C@@H:3]1[NH2:11].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O.[CH3:50][N:51]([CH2:53][C@@H:54]([NH:62][CH2:63][C:64]1[CH:65]=[C:66]([CH:78]=[CH:79][CH:80]=1)[CH2:67][N:68]1[CH:72]([C:73](O)=[O:74])[CH2:71][CH2:70][S:69]1(=[O:77])=[O:76])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:52].C(N(CC)C(C)C)(C)C>CN(C)C=O.C[C@H]1C2C(C)(C)C(C2)C[C@@H]1N.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O>[CH3:1][C@@H:2]1[C@@H:3]([NH:11][C:73]([CH:72]2[CH2:71][CH2:70][S:69](=[O:77])(=[O:76])[N:68]2[CH2:67][C:66]2[CH:78]=[CH:79][CH:80]=[C:64]([CH2:63][NH:62][C@H:54]([CH2:53][N:51]([CH3:50])[CH3:52])[CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:65]=2)=[O:74])[CH2:4][C@H:5]2[CH2:6][C@@H:7]1[C:8]2([CH3:10])[CH3:9]
Reactant: CN(C)C[C@H](Cc1ccccc1)NCc1cccc(CN2C(C(=O)O)CCS2(=O)=O)c1
Reactant: C[C@H]1C2CC(C[C@@H]1N)C2(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN[C@@H](Cc3ccccc3)CN(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Temperature: 25 °C
Yield: 244.9 %

Procedure:
(+)-Isopinocampheylamine (Aldrich; 29 mg, 0.19 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (available from Aldrich; 58.4 mg, 0.18 mmol), N-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 24.3 mg, 0.18 mmol) were added to a cooled (0° C.) solution of 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (100 mg 80% pure, 0.18 mmol) in dry N,N-dimethylformamide (3 mL) under argon. N,N-Diisopropylethylamine (70 μL, 0.4 mmol) was then added. The solution was then stirred at room temperature. After 30 minutes more (+)-isopinocampheylamine (6 mg, 0.04 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (available from Aldrich; 6 mg, 0.002 mmol) and N-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 3 mg, 0.002 mmol) were added. After 90 minutes all of the starting material had been consumed. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1N NaOH (3×15 mL), and brine (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give the crude product (132 mg). This material was combined with the crude product from an identical experiment using 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (250 mg). The combined lots were chromatographed, eluting with 0-10% methanol/dichloromethane to give 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicylo[3.1.1]hept-3-yl)amide (256 mg, 60%) as a tan foam.
Reaction SMILES: [CH2:1]([C:4]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)([CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[C:12]([CH3:27])[CH:11]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl.[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][NH2:43].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][NH:43][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([C:4]([CH2:1][CH:2]=[CH2:3])([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=3)=[C:12]([CH3:27])[CH:11]=2)[CH2:5][CH:6]=[CH2:7])=[CH:36][CH:35]=1
Reactant: COC(=O)CCN
Reactant: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Yield: 72.4 %

Procedure:
To a mixture of 4-[1-allyl-1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoic acid (0.349 g, 0.705 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.112 g, 0.804 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.121 g, 0.898 mmol) in DMF (7.0 mL) is added N,N-diisopropylethylamine (0.38 mL, 2.2 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.180 g, 0.938 mmol) and stirred overnight. The reaction mixture is poured into water (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts are washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide 0.296 g (72%) of the title compound as a white foam. MS (ES): 580.4 [M+H]+.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](Br)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:9]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)c2ccccc2)CC1
Yield: 68.3 %

Procedure:
To 1370 ml of acetonitrile were added ethyl benzoylacetate (49.9 g, 0.26 mol), 1,2-dibromomethane (48.8 g, 0.26 g) and anhydrous potassium carbonate (143.6 g, 1.04 mol) and the mixture was stirred under reflux for 18 h. After cooling, the reaction mixture was filtrated and concentrated. The residual solution (56.3 g) was purified by silica gel column chromatography (ethyl acetate/hexane=1/5) to give the title compound (38.7 g) as a colorless oil (yield 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: Oc1c(F)cc(F)cc1I
Reactant: C#Cc1ccc(OC)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 2,4-Difluoro-6-iodo-phenol (1.0 g, 3.9 mmol), 4-Methoxyphenylacetylene(0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH and filtered to give 86 as a solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])C.CC(C[AlH]CC(C)C)C.CO.Cl>C1(C)C=CC=CC=1>[F:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[CH:13]=1
Reactant: CCOC(=O)CCCc1cc(F)ccc1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(F)cc1CCCC=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of ethyl-4-(5′-fluoro-2′-methoxyphenyl)butyrate (2.25 g, 9.4 mmol) in dry toluene (30 mL) under Ar(g) was added DIBAL solution (1 M in toluene, 11 mL, 11 mmol) at −78° C. Then the reaction was stirred at this temperature for 2 h. Methanol (2 mL) was then added to the reaction mixture and the reaction was allowed to warm to 0° C. The reaction mixture was poured into a separatory funnel containing HCl solution (1 N, 100 mL). The organic function was extracted with ethyl acetate (3×60 mL) and the combined organic layers were washed with brine (80 mL) and dried over sodium sulfate. The crude product that obtained by removal of the solvent in vacuo was purified by flash column chromatography (10% EtOAc in hexane, Rf=0.10) to give the product (1.30 g, 70%).
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:19](OC(OCC)OCC)C.C(OC(=O)C)(=O)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>C(O)(C)C>[F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:19][NH:39][CH:36]1[CH2:38][CH2:37]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: NC1CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To 10.2 g (38.5 mmol) of the 2-(2,3,4,5-tetrafluorobenzoylacetic acid, ethyl ester was added 8.4 g (57.0 mmol) of triethylorthoformate and 9.3 g (91.5 mmol) of acetic anhydride. The mixture was heated to 150° C. for two hours and was then placed under high vacuum at 75°-85° C. for one hour. The residue dissolved, without purification, in 100 ml of isopropyl alcohol and treated with 2.4 ml of cyclopropylamine. The reaction was allowed to stand overnight. It was concentrated and purified by column chromatography (silica gel 70-200, using hexane:chloroform:isopropyl alcohol, 80:15:5). The product off the column was recrystallized from pentane to give 6.16 g of 2-(2,3,4,5-tetrafluoro-benzoyl)-3-cyclopropylaminoacrylic acid, ethyl ester, mp 63°-64° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH3:12]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O1CCOCC1>[NH2:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: N
Reactant: Brc1cncc2ccccc12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cncc2ccccc12
Temperature: 165 °C
Reaction time: 21 h

Procedure:
A suspension of 4-bromoisoquinoline (25.0 g), copper(II) sulfate pentahydrate (30.4 g, Nacalai Tesque), 28% aqueous ammonia (100 ml) and 1,4-dioxane (100 ml) was stirred in a sealed tube at 165° C. for 21 hours. The reaction mixture was cooled to room temperature, the insoluble matters were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate (150 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the title compound (13.2 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br)([O-:24])=[O:23]>CN(C)C=O.C(OCC)(=O)C.O>[OH:1][CH2:2][CH:3]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[N+:22]([O-:24])=[O:23])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(CO)N(Cc1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.3 %

Procedure:
To a solution of 15.0 g (51.85 mmol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 125 ml of N,N-dimethylformamide, cooled in an ice bath, was added portionwise 2.29 g (57.03 mmol) of NaH (60% in oil). The mixture was stirred at 0° C. for 20 minutes and then a solution of 12.32 g (57.03 mmol) of 2-nitrobenzyl bromide in 25 ml of dry N,N-dimethylformamide was added dropwise. The solution was stirred at room temperature for 48 hours and diluted with 500 ml of ethyl acetate and water. The organic layer was separated and the aqueous layer extracted with 250 ml of ethyl acetate. The combined organic layer and extract was washed with 200 ml each of H2O, 1 N NaHCO3, brine and dried with Na2SO4. The solvent was removed and the residual solid was triturated with ethyl acetate, cooled and filtered to give 13.5 g (61%) of white crystals, having a m.p. 127-129° C. From a small scale run (3.0 g) there was obtained 2.32 g of white crystals, having a m.p. 127-129° C. Anal. for C18H20N2O8S: Calc'd: C.50.9; H,4.8; N,6.6; Found: C,50.9; H,4.8; N,6.5.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@@H:21]4[CH2:23][O:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>O1CCCC1>[NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@@H:21]([OH:22])[CH2:23][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@@H]1CO1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C[C@H](O)COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1C#N
Temperature: 50 °C
Reaction time: 120 h
Yield: 91.1 %

Procedure:
After dissolving 4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2S)-oxiran-2-yl)methoxyquinoline (72 mg, 0.196 mmol) in tetrahydrofuran (2.0 ml) under a nitrogen atmosphere, diethylamine (0.4 ml) was added and the mixture was stirred at 50° C. for 5 days. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent-ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (78.6 mg, 0.178 mmol, 91.1%) as light yellow crystals.
Reaction SMILES: [N+:1]([CH2:3][CH2:4]C(S(C1C=C(C=CC=1)N)(=O)=O)C)#[C-:2].[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24])([O-:19])=[O:18].CCOC(C)=O>CO>[CH3:4][C:3]1[N:1]=[CH:2][O:24][C:23]=1[C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: [C-]#[N+]CCC(C)S(=O)(=O)c1cccc(N)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ncoc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 3-{[1-(isocyanoethyl)ethyl]sulfonyl}aniline (60 g, 0.287 mol) in dry MeOH (800 mL), was added dry powdered K2CO3 and stirred at rt for 1 h. The reaction mixture was re-cooled to 0° C. and 3-nitro benzaldehyde (43 g, 0.287 mol) added. The reaction mixture was warmed to rt, followed by heating at 55° C. overnight with stirring. The excess solvent was removed under reduced pressure, the residue was dissolved in water (100 mL) and extracted with EtOAc (3×350 mL). The combined organic layers were washed with brine, water, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica get (60-120 mesh) column chromatograph using 15% EtOAc in petroleum-ether to yield product as yellow solid. Yield 50 g (86%).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([N:28]2[CH2:29][CH2:30][C:25]([OH:24])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26][CH2:27]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCC(O)(c2ccccc2)CC1

Procedure:
Following the procedures set out in Example 1, 1 part of 3,3,3-triphenylpropionyl chloride and 2 parts of 4-hydroxy-4-phenylpiperidine are reacted to provide 1-(3,3,3-triphenylpropionyl)-4-hydroxy-4-phenylpiperidine. 0.23 Parts of this amide is reacted with 0.05 parts of lithium aluminum hydride in 3.0 parts by volume of ethyl ether to provide 1-(3,3,3-triphenylpropyl)-4-hydroxy-4-phenylpiperidine. This compound has the following structural formula ##STR31##
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)C=CC=3)=[O:20])[CH2:8][C:7]=2[CH:31]=1.C(C(O)=O)(=[O:39])C1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(C1C=CC2[N:67](CC3N=CN(C(OC(C)(C)C)=O)C=3)[CH2:66][C@@H:65]([CH2:81][C:82]3[CH:87]=CC=CC=3)N(S(C)(=O)=O)CC=2C=1)#N>CN(C=O)C.C(Cl)Cl>[ClH:1].[ClH:1].[ClH:1].[NH:17]1[CH:18]=[C:14]([CH2:13][N:12]2[C:6]3[CH:5]=[CH:4][C:3]([C:81]4[CH:65]=[CH:66][N:67]=[CH:87][CH:82]=4)=[CH:31][C:7]=3[CH2:8][N:9]([C:19](=[O:20])[C:21]([C:30]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:39])[CH2:10][CH2:11]2)[N:15]=[CH:16]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(C(=O)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccncc3)cc2C1)c1ccccc1

Procedure:
Example 297 was prepared as a yellow solid from 7-bromo-1,4-benzodiazepine (see Example 11) and benzoylformic acid by the following sequence: Example 252, in 10:1 methylene chloride:DMF and with chromatography with 50% EtOAc/hexanes; treatment with trifluoracetic anhydride and workup as described in Compound A of Example 296; Compounds B, C and D of Example 296.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH:23]2[CH2:25][CH2:24]2)[CH2:18][CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH:23]1([N:19]2[C:20]3[C:15](=[CH:14][C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=4)=[CH:22][CH:21]=3)[C:16]([CH3:27])([CH3:26])[CH2:17][CH2:18]2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCN(C2CC2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Following general procedure L and using 4-(1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-ylethynyl)-benzoic acid ethyl ester (Compound 61, 0.005 g, 0.13 mmol), 5 mL of ethanol and 5M sodium hydroxide solution (2 mL) followed by recrystallization from hot ethyl acetate, the title compound was obtained as a solid (0.030 g, 64%).