Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@H]1CC[C@H](c2ccccn2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 18.5 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.30 g, 4.69 mmol), (1S,3S)-3-(2-pyridyl)cyclopentylamine (913 mg, 5.63 mmol) and triethylamine (1.30 mL, 9.33 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1S,3S)-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (364 mg, 19%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Br)ccc1CO
Product: Cc1cc(Br)ccc1CCl
Temperature: 25 °C
Yield: 78.9 %

Procedure:
(4-Bromo-2-methyl-phenyl)-methanol (40.0 g, 199 mmol) was added to thionyl chloride (106.6 g, 0.896 mole, 65.3 mL). The mixture was heated to reflux, for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and added carefully to saturated aqueous NaHCO3 (500 mL). The EtOAc layer was separated, and the aqueous layer was extracted with EtOAc (250 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo yielding the title compound (34.19 g, 157 mmol, 79%) as a slightly colored oil that solidified to a white solid upon standing. 1H NMR (CDCl3, 300 MHz) δ ppm 2.38 (s, 3H); 4.57 (s, 2H); 7.12 (d, 1H); 7.28 (s, 1H); 7.55 (d, 1H)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH2:22][C:23](OCC)=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].CO>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([CH2:22][CH2:23][OH:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reaction time: 0.33 h
Yield: 112.1 %

Procedure:
Ethyl [6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]acetate (3.0 g) was dissolved in tetrahydrofuran (40 mL), and cooled in an ice bath. Sodium tetrahydroborate (884 mg, 23.4 mmol) was added followed by methanol (4.8 mL, 120 mmol), in portions. The reaction mixture was stirred for 20 min, removed the ice bath, and stirred at 21° C. for 0.5 hour. HPLC & LCMS showed no remaining ester, and showed conversion to the desired M+H 349; and also showed several over reduction products (at least one of which has no UV absorbance). The reaction mixture was quenched with water and evaporated. The reaction mixture was diluted with aqueous bicarbonate and EtOAc, and stirred for 0.5 hour. The EtOAc layer was washed with brine, dried (Na2SO4), and evaporated to give 3.0 g oil. The product was purified by chromatography on a 120 g silica gel column, using solvent A=hexane; solvent B=3% iPA/EtOAc; flow 60 mL/min; A, 3 min; Gradient to 50% B in 30 min, then 50% B for 15 min; detector set at 254 nm; collected 47 mL fractions; retention time, 34 min. evaporated to yield 1.5 g, a light yellow viscous oil, 56% yield. 1H NMR (300 MHz, DMSO-D6): δ7.10 (s, 1H); 5.20 (m, 1H, OCH); 4.71 (t, 1H, OH); 3.85 (s, 4H, OCH2); 3.72 (q, 2H, OCH2); 2.85 (t, 2H, CH2); 1.5-2.0 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[O-:13][CH2:14][CH3:15].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:13][CH2:14][CH3:15]
Reactant: CC[O-]
Reactant: Clc1ncnc2ccc(Br)cc12
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
The suspension of 6-bromo-4-chloro-quinazoline (4.87 g, 20 mmol), sodium ethoxide (95%, 14.32 g, 200 mmol) in anhydrous ethyl alcohol (150 ml) was stirred at room temperature for 4 hr. After the reaction, solvent was evaporated. Then, ice water was added, followed by addition of 3 N HCL aq to adjust the pH to 9, and precipitate formed. The solid was collected and washed with H2O three times, then dried. Flash chromatography (Merck silica gel 60, 230-400 mesh, 10%-50% ethyl acetate in hexane for 30 min) afforded 6-Bromo-4-ethoxy-quinazoline (2.13 g, 55%) as a light yellow solid. LC-MS m/e 254 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:27][OH:28])=[N:11][CH:12]=[C:13]([C:25]=1[OH:26])[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:10]([CH:27]=[O:28])=[N:11][CH:12]=[C:13]([C:25]=1[OH:26])[C:14]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1cnc(CO)c(OCc2ccccc2)c1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
After manganese dioxide (49 g) was added to a suspension of the compound 10 (9.8 g, 25.6 mmol) in chloroform (49 ml), the mixture was stirred at room temperature for 1 hour. After the reaction solution was stirred at 60° C. for 20 minutes, Celite filtration was performed, and this was washed with chloroform heated at 50° C. The filtrate was distilled off under reduced pressure to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-6-formyl-4-hydroxy-nicotinic acid amide 12 (8.2 g, 84%) as a pale yellow crystal.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]([NH:17]C(=O)C(F)(F)F)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(CCOCOCc2ccccc2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1ccc(CCOCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
To a solution of 4′-[2-(benzyloxymethoxy)ethyl]-2,2,2-trifluoroacetanilide (9.7 g) in methanol (50 ml) were added water (30 ml) and potassium carbonate (3.3 g), and the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 4-[2-(benzyloxymethoxy)ethyl]aniline (6.2 g).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[Na+:38]>O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[Na+:38]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A suspension of the product of Example 49H in water (3 mL) was treated with 0.997N sodium hydroxide solution (0.410 mL) and stirred at 25° C. for 1 hour. The solution was lyophilized to give 209 mg (74%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 m, 1 H) 0.70 (s, 9 H) 0.81 m, 1 H) 1.38 (s, 3 H) 1.71 m, 1 H) 2.16 (m, 1 H) 2.90 (s, 3H) 7.28 m, 3 H) 7.44 m, 3 H) 8.05 (d, J=7.35 Hz, 1 H) 9.87 (s, 1 H) 15.44 (s, 1 H); MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.B.O1CCCC1>O1CCCC1.O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1=O
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@H]1O
Yield: 92.2 %

Procedure:
(S)-(−)-CBS-oxazaborolidine (1.0 M in tetrahydrofuran, 1.06 mL, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (53.1 mL, distilled from sodium/benzophenone ketyl). To this solution was simultaneously added a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(2-methyl-3-oxo-cyclohex-1-en-1-yl)-3-methyl-phenyl]-methanone of Example 4 (2.18 g, 5.31 mmol) in anhydrous tetrahydrofuran (20 mL) via syringe pump (1.6 mL/min.) and borane-tetrahydrofuran (1.0 M in tetrahydrofuran, 3.19 mL, 3.19 mmol) at a rate such that enone addition was complete upon addition of approximately 2/3 of borane-tetrahydrofuran. Upon completion of borane-tetrahydrofuran addition, the reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide, 1N hydrochloric acid, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica, 50% ethyl acetate in hexane) to afford the title compound (2.02 g) as a white solid. Analytical HPLC (Chiralpak AD, 4.6×250 mm, 50% ethanol in hexane, 0.5 mL/min.) indicated an enantiomeric excess of 96.4%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH:27]1([CH2:34]O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([CH2:34][I:25])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: OCC1CCCCCC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICC1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of triphenylphosphine (24.59 g; 92.8 mmol) and imidazole (6.40 g; 93.1 mmol) in methylene chloride (100 mL) cooled to 0° C. and Iodine (23.52 g; 92.7 mmol) was added portionwise over a 10 minute period. A solution of cycloheptane methanol (9.14 g; 71.3 mmol) dissolved in methylene chloride (50 mL) was then added over a 5 minute period. The cooling bath was removed and the mixture allowed to warm to room temperature and stirred overnight. The mixture was diluted with methylene chloride, washed with water and the organic layer dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed (eluent:hexanes) to give 15.35 g (93%) of cycloheptylmethyl iodide as an oil.
Reaction SMILES: Cl.[C:2]([C:6]1[S:7][C:8]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:32]=[C:31]([CH3:33])[N:30]([CH3:34])[N:29]=5)[C:24](=[O:35])[N:23](COCC[Si](C)(C)C)[N:22]=4)[C:16]=3[CH3:44])[CH2:11][C:9]=2[N:10]=1)([CH3:5])([CH3:4])[CH3:3].C1(OC)C=CC=CC=1>CO>[C:2]([C:6]1[S:7][C:8]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:32]=[C:31]([CH3:33])[N:30]([CH3:34])[N:29]=5)[C:24](=[O:35])[NH:23][N:22]=4)[C:16]=3[CH3:44])[CH2:11][C:9]=2[N:10]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Agent: Cl
Solvent: COc1ccccc1
Solvent: CO
Product: Cc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)[nH]n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
Hydrogen chloride gas was bubbled into 2-tert-butyl-5-(3-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 110c (186 mg, 0.30 mmol) and anisole (0.163 mL, 1.50 mmol) in methanol (20 mL) at 0° C. for 5 min. The resulting mixture was allowed to warm to room temperature and continue stirring for 16 h. The reaction mixture was concentrated. The residue was purified by reverse phase HPLC: C-18 column eluted with 20 to 60% Acetronitrile in water with 1% ammonium hydroxide over 14 min to afford 2-tert-butyl-5-(3-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 110 (40 mg, 30%). M+1 490.1. 1H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 9.09 (s, 1H), 7.77 (s, 1H), 7.50 (dd, J=5.6, 3.6, 1H), 7.41-7.32 (m, 2H), 5.97 (s, 1H), 4.97 (s, 2H), 3.62 (s, 3H), 2.17 (d, J=19.6, 6H), 1.47 (s, 9H).
Reaction SMILES: CCOCC.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[CH2:17]([OH:20])[C:18]#[CH:19].Cl>[OH-].[Na+]>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:20][CH2:17][C:18]#[CH:19])([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCCBr
Reactant: C#CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C#CCOCCCCCCCC(=O)O
Temperature: 60 °C
Yield: 124.2 %

Procedure:
An ether solution of 8-bromooctanoic acid (15.1 g, 65 mmol) was reacted with 325 mmol propargyl alcohol dissolved in aqueous NaOH solution containing 975 mmol NaOH. After heating at 60° C. for 24 hours, the reaction was stopped by neutralizing the base with hydrochloric acid. Ether extraction provided 16 g of opaque white liquid, which was further purified by distillation under reduced pressure (160°-163° C./0.075 mm Hg). The sample was analyzed with 1H-NMR in CDCl3, and the observed chemical shift peaks were at δ=1.34 (br singlet, 6H, --(CH2)--), 1.61 (pentate center, 4H, --(CH2)--), 2.35 (t, 2H, CH2 --COO), 2.42, (d, J=2.6 Hz, 1H, C≡CH), 3.51 (t, J=6.6 Hz, 2H, --CH2 --O), and 4.14 (d, J=2.6 Hz, 2H, O--CH2 --C≡C). Observed IR (KBr) peaks were at 1709 (COOH), 2120 (--C≡C--) and 3298 (--C≡CH) cm-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH3:29])[CH:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][C:24]=1[CH3:29]
Reactant: Cc1cc(Br)ccc1Cl
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: Cc1cc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)ccc1Cl
Yield: 15 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 4-bromo-1-chloro-2-methylbenzene (308 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 60 mg (yield 15%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>ClCCl>[Cl:24][C:19](=[O:21])[CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH2:12][CH2:13]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a stirred mixture of 29 parts of 1-[(phenylmethoxy)carbonyl]-4-piperidinepropanoic acid and 520 parts of dichloromethane were added dropwise 14.9 parts of thionyl chloride. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was evaporated, yielding 28.3 parts (91.5%) of (phenylmethyl) 4-(3-chloro-3-oxopropyl)-1-piperidinecarboxylate as a residue (int. 34).
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH2:19][CH2:18]3)[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27]>C(O)C>[CH2:2]([O:4][N:5]=[C:25]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][CH2:19][CH2:18]3)[CH2:12][C:11]=1[OH:24])[CH2:26][CH3:27])[CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 1578.4 %

Procedure:
Ethoxyamine hydrochloride (0.42 g; 4.1 mmole) and then aqueous 1% sodium hydroxide (17.0 ml) were added to a solution of 3-hydroxy-5-(5-indanyl)-2-propionylcyclohex-2-en-one (1 10 g; 3.87 mmole) in anhydrous absolute ethanol (200 ml). The mixture was stirred at room temperature for a period of 4 hours and then the ethanol was removed by evaporation under reduced pressure using a rotary evaporator. The residue was treated with dichloromethane and the organic phase was washed twice with dilute aqueous hydrochloric acid and twice with water. The organic phase was dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(ethoxyimino)propyl]-3-hydroxy-5(5-indanyl)-cyclohex-2-en-1-one (1 20 g; 94.8%) as a pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21]CC3C=CC=CC=3)=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[C:1]1([CH2:7][N:8]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Yield: 33.6 %

Procedure:
A solution of {5-{(1R)-2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-[(phenylmethyl)oxy]phenyl}formamide (1.40 g) in EtOAc (15 ml) and EtOH (15 ml) was hydrogenated over 10% palladium on carbon (140 mg). When hydrogen uptake had ceased the mixture was filtered through celite, the solvent evaporated in vacuo and the residue purified on a silica SPE bond elut cartridge (70 g) using a gradient of 0% to 5% MeOH in DCM (Gradmaster™). The appropriate fractions were evaporated in vacuo to give the title compound (380 mg). LCMS RT=2.17 min.
Reaction SMILES: [C:1]([O:5][CH:6]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:25]([SH:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C(O)C>[CH2:25]([S:37][CH2:3][CH2:2][C:1]([O:5][CH:6]([CH2:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C=CC(=O)OC(CSCc1ccccc1)CSCc1ccccc1
Reactant: CCCCCCCCCCCCS
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCSCCC(=O)OC(CSCc1ccccc1)CSCc1ccccc1

Procedure:
A solution of 16.5 grams of 1,3-bis-(benzylthio)-2-propyl acrylate, 9.45 grams of dodecanethiol, and 1 milliliter of "Triton B" in 75 milliliters of ethanol was heated under reflux for 11 hours. The reaction mixture was allowed to cool and was then poured into water. The oil which precipitated was separated by extraction with hexane and the hexane solution was stripped on a rotary evaporator. The residue, which weighed 22.5 grams, was identified as 1,3-bis-(benzylthio)-2-propyl 3-(dodecylthio)propionate by means of its NMR spectrum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)=[CH:3][C:4]=2[CH3:17])[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: Cc1cc(Br)cnc1N1CCN(C(C)C)CC1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2cnc(N3CCN(C(C)C)CC3)c(C)c2)c1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1-(5-bromo-3-methyl-pyridin-2-yl)-4-isopropyl-piperazine and 3-acetylaminophenylboronic acid. 1H NMR (300 MHz, CDCl3) δ 8.35 (d, 1H), 7.77 (s, 1H), 7.58 (d, 1H), 7.46 (d, 2H), 7.35 (t, 1H), 3.32 (t, 4H), 2.92-2.75 (m, 5H), 2.30 (s, 3H), 2.19 (s, 3H), 1.14 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: O=C(Cl)CF
Reactant: Cc1ccc(F)cc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 95.7 %

Procedure:
4.5 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-5-fluoroaniline, 1.85 g of pyridine and 2.26 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 5.2 g of N-(2-fluroacetamido-5-nitrobenzoyl)-2-methyl-5-fluoroaniline are obtained as colorless needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:36](=[O:37])[O:38][CH2:39][CH3:40])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 2 ml of dimethylformamide, 178 mg of ethyl chloroformate and 271 mg of potassium carbonate were added to the solution, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was evaporated, and the resulting residue was purified by silica gel column chromatography using ethyl acetate:hexane (2:8) as the eluent to give 169 mg of ethyl N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]carbamate.