Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O.O.NN.[OH-].[K+].Cl>C(O)CO.O.CCOCC>[F:14][C:10]1[CH:9]=[C:8]([CH2:6][CH2:5][CH2:4][C:3]([OH:15])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CCC(=O)c1cccc(F)c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Solvent: CCOCC
Product: O=C(O)CCCc1cccc(F)c1
Yield: 75.3 %

Procedure:
A solution of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methyl ester (28.27 g, 134.49 mmol), hydrazine monohydrate (26.1 mL, 26.93 g, 537.96 mmol) and KOH (22.64 g, 403.47 mmol) in ethylene glycol (150 mL) was heated to reflux under argon and refluxed for 2 hours. The reaction mixture was cooled and diluted with 1.5 liters of water, 500 mL of Et2O was added, and the mixtures was acidified by addition of 6 M HCl with stirring, after which an additional 500 mL of Et2O was added. The organic layer was removed and the aqueous layer was extracted twice with 250 mL of 500 mL of Et2O/EtOAc (3:1). The combined organic layers were washed with water, saturated brine, and then dried over MgSO4. The solvent was evaporated under reduced pressure to yield a brownish oil, which was eluted through silica gel using hexanes/EtOAc (9:1). Removal of solvent under reduced pressure yielded 18.44 g (101.21 mmol, 75.26%) of 4-(3-fluoro-phenyl)-butyric acid as an oil. MS: 183 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:26][NH:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]=3[N:22]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1.[CH2:33](N)[CH3:34].C(=O)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:33]([N:25]1[CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[N:22]=[C:17]([NH:16][C:6]3[CH:7]=[CH:8][C:9]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:4]([O:3][CH3:2])[CH:5]=3)[N:18]=[CH:19][C:20]=2[CH2:26]1)[CH3:34]
Reactant: CCN
Reactant: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CNC3)ccc1-n1cnc(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1Cc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc2C(c2ccccc2)C1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(8-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-amine hydrochloride (75 mg, 0.17 mmol) in tetrahydrofuran (3.3 mL) was added at room temperature NN,-diisoprpyl ethyl amine (43 mg, 0.33 mmol). After stirring for 5 minutes at room temperature acetaldehyde (8.1 mg, 0.18 mmol), acetic acid (20 mg, 0.33 mmol) and sodium triacetoxyborohydride (106 mg, 0.50 mmol) were added. The reaction was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (95:5 v/v) as eluent to yield the title compound (45 mg, 61%) as a yellow gum. MS ISN (m/e): 439.6 (100) [(M−H)−]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.24 (s, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.20-7.34 (m, 5H), 7.02 (d, 1H), 6.79 (s, 1H), 6.70 (d, 1H), 4.24 (m, 1H), 3.76 (d, 1H), 3.54 (d, 1H), 3.33 (s, 3H), 3.20 (dd, 1H), 2.60 (m, 3H), 2.67 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:20].[CH3:30][N:31]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[C:32]1[C:39](Cl)=[O:40]>CO.C(Cl)Cl.[Pd]>[CH3:30][N:31]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[C:32]1[C:39]([NH:15][C:13]1[CH:14]=[C:10]([C:8]([NH:7][C:5]2[CH:4]=[C:3]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:20])[N:2]([CH3:1])[CH:6]=2)=[O:9])[N:11]([CH3:18])[CH:12]=1)=[O:40]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Reactant: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])cn3C)cn2C)cc1C(=O)NCCN1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-N-[2-(4-morpholinyl)ethyl]-1H-pyrrole-2-carboxamide (0.343 g, 0.85 mmol; see Preparation 1(iv) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (200 mg) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (160 g, 0.85 mmol) in DCM (10 mL) was then added and allowed to stir for 1 h at RT, the solvent was removed under reduced pressure, the crude product obtained was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][OH:21])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][OH:21])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCN2CCO
Yield: 100.2 %

Procedure:
A solution of ethyl 6-(benzyloxy)-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (1.40 g, 3.89 mmol) in a mixture of ethyl acetate (300 ml) and ethanol (75 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (200 mg) and under one atmosphere of hydrogen for four hours to give 1.05 g (100% yield) of the title compound as light yellow needles; mp 155-156° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.44 (3H, t, J=7.1 Hz, CH3), 3.46 (2H, m, CH2), 3.75 (2H, t, J=8.3 Hz, CH2), 3.92 (2H, m, CH2), 4.20 (2H, t, J=8.3 Hz, CH2), 4.43 (2H, q, J=7.1 Hz, OCH2), 10.20 (1H, s, OH). Anal. Calcd for C11H15N3O5: C, 49.06; H, 5.61; N, 15.60. Found: C, 49.09, H, 5.73; N, 15.58.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=1)(=[O:8])[CH3:1]
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 78.8 %

Procedure:
MeMgBr (3 M solution in diethyl ether, 4 mL, 12 mmol) was added dropwise at −78° C. to a solution of N,5-dimethoxy-N-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (2.09 g, 5.85 mmol) in THF (50 mL). After stirring for 1 h, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with AcOEt three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/MeOH (1/0-10/1) and recrystallized from hexane/AcOEt to give the title compound (1.44 g, 79% yield) as off-white crystals: mp 155-156° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.71 (3H, s), 3.98 (3H, s), 7.68-7.76 (2H, m), 7.83-7.88 (2H, m), 7.94 (1H, s). Anal. Calcd for C14H11F3N2O3: C, 53.85; H, 3.55; N, 8.97. Found: C, 53.79; H, 3.59; N, 9.02.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(C)=CC=1.BrBr.O>C(O)(=O)C.[Co]>[CH3:13][O:8][C:6](=[O:7])[CH3:5].[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)cc1
Agent: [Co]
Agent: BrBr
Agent: O=C(O)c1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: COC(C)=O

Procedure:
In a process for the synthesis of terephthalic acid, comprising the oxidation of para-xylene in acetic acid solution, at a temperature of from 100° to 230° C. and at a pressure from 1 to 30 kg/cm2, and in the presence of a catalytic system based on manganese, bromine and cobalt, whereby water is formed and methyl-acetate is by-produced during the oxidation, whereby solid terephthalic acid is separated from the mother liquor and whereby one withdraws from the oxidation zone a liquid which is obtained by condensing the vapors released during the oxidation and which are mainly consisting of acetic acid and water, the improvement for the recovery of the acetic acid solvent, the catalyst and the methyl acetate, comprising:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH2:12].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:25]=1[CH2:26][NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[NH:36][C:37]1[N:42]=[C:41](SC#N)[C:40]([N+:46]([O-:48])=[O:47])=[CH:39][N:38]=1>CS(C)=O.C1COCC1.CCOC(C)=O>[CH3:22][O:23][C:24]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:25]=1[CH2:26][NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[NH:36][C:37]1[N:42]=[C:41]([NH:12][C@H:7]2[C:6]3[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[O:10][CH2:9][CH2:8]2)[C:40]([N+:46]([O-:48])=[O:47])=[CH:39][N:38]=1
Reactant: N[C@@H]1CCOc2c(F)cccc21
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cccc43)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
(R)-8-Fluorochroman-4-amine (HCl salt, 0.45 g, 2.2 mmol) was dissolved in 1 mL DMSO with 1.7 mL N,N-diisopropylethyl amine (9.7 mmol) in 40 mL anhydrous THF. To this solution was added 0.93 g (2.0 mmol) 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile. The slightly cloudy mixture was stirred at room temperature for 16 hrs under Argon balloon till HPLC showed the completion of reaction. The mixture became clear then. The reaction mixture was diluted with EtOAc, washed with brine twice, and then dried over Na2SO4. Solvents were removed under vacuum to give 1.1 g dark red solid as the crude product.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:32])=O>>[CH3:1][N:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:3][CH2:4][C:5]([Cl:32])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CN(CCC(=O)O)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Product: CN(CCC(=O)Cl)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step B (3 mmol), dissolved in thionyl chloride, is stirred at 60° C. under a stream of nitrogen for one hour. The thionyl chloride is evaporated off under reduced pressure and the residue is dried using a vane pump to yield the title product.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].[I:16][CH2:17]I>C1COCC1>[CH3:6][O:7][C:8]([C:10]1([CH2:17][I:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: ICI
Reactant: COC(=O)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C1(CI)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113.8 %

Procedure:
To a −78° C. of Diisoprpyl amine (132 mmol, 18.65 mL) in THF (100 mL) was added n-BuLi (120 mmol, 75 mL). Cold bath was removed and put back after 30 minutes. Cyclohexane carboxylic acid methyl ester 1261-A (15.57 g, 109 mmol) was added dropwise in THF (50 mL). After 1 h, Diiodomethane (109 mmol, 8.78 mL) was added while keeping temperature below 10° C. After addition, reaction was warmed to RT and stirred overnight. After 18 h, reaction was quenched with NH4Cl and extracted with EtOAc. Washed with brine, dried over MgSO4, filtered and concentrated down to provide 35 g of product 1261-B.
Reaction SMILES: I[C:2]1[C:10]2[CH2:9][O:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11].[F-].[Cs+].[CH3:14]B(O)O>O1CCOCC1.CCOC(C)=O.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:14][C:2]1[C:10]2[CH2:9][O:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: CB(O)O
Reactant: Nc1ccc2c(c1I)COC2
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc2c1COC2
Temperature: 80 °C

Procedure:
To a solution of 4-iodo-1,3-dihydro-2-benzofuran-5-amine (563 g, 2.16 mmol) in 1,4-dioxane (15 mL) under N2 was added CsF (1.15 g, 7.56 mmol), MeB(OH)2 (387 g, 6.47 mmol) and PdCl2(DPPF) (176 mg, 0.216 mmol). The mixture was heated at 80° C. for 4 h. The mixture was cooled to room temperature and then diluted with EtOAc (40 mL) and water (40 mL). The mixture was filtered through Celite. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-methyl-1,3-dihydro-2-benzofuran-5-amine. LCMS calc.=150.1; found=149.9 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 6.92 (d, J=7.8 Hz, 1H); 6.66 (d, J=7.9 Hz, 1H); 5.11 (s, 4H); 3.63 (br s, 2H); 2.08 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:40])[NH:12]2
Reactant: CC(=O)O
Reactant: Fc1ccccc1-c1cccc2[nH]ccc12
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccccc2F)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To the suspension of 4-(2-fluoro-phenyl)-1H-indole (1.30 g, 6.15 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (74 mL) was added pyridinium tribromide (5.90 g, 18.46 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (0.59 g, 42%) as a tan solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=[O:12].Cl>CO>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH3:16])([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C)(C)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccccc1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A 5 N aqueous solution of sodium hydroxide (10 mL) was added to a solution of methyl 2-(2-fluorophenyl)-2-methylpropionate (1.357 g) in methanol (10 mL), and the reaction solution was stirred at 80° C. for 3 hours. The reaction solution was returned to room temperature, made acidic with 5 N hydrochloric acid, and then extracted with ethyl acetate. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.15 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:17]1[CH:29]=[CH:28][C:20]([C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.Cl[CH2:46][C:47]#[N:48].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O1CCCC1>[C:47]([CH2:46][N:6]1[C@H:5]([CH3:8])[CH2:4][N:3]([C@H:9]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:28][CH:29]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[C@@H:2]([CH3:1])[CH2:7]1)#[N:48]
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: N#CCCl
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(CC#N)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-4-((αR*)-α-((2S*,5R*)-2,5-Dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide, tert-butyldimethylsilyl ether (0.51 g, 1.0 mmol, Example 81, infra) was combined with 2-chloroacetonitrile (0.07 mL, 1.1 mmol, Eastman Kodak, Rochester, N.Y.) and sodium carbonate in anhydrous tetrahydrofuran. The reaction mixture was chilled in an ice bath and sodium iodide (0.16 g, 1.1 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed and the residue was redissolved in dichloromethane and washed with water. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethanol (0-3%) in dichloromethane. The product was dissolved in 20 mL of acetonitrile and stirred for 3 hours with tetraethylammonium fluoride hydrate (0.18 g). The solvent was evaporated and the residue was purified by chromatography on silica gel with ethanol (0-3%) in dichloromethane. Crystallization of the product from acetonitrile gave 37 mg of solid, mp 190°-192° C. Calc for C26H34N4O4:C, 71.86; H, 7.88; N, 12.89. Found: C, 71.83; H, 7.94; N, 12.95. NMR (200 MHz, CDCl3): δ0.93 (d, J=6 Hz, 3H); 1.15 (d, J=4.7 Hz, 3H); 1.0-1.2 (br m, 6H); 1.79 (t, J=11 Hz, 1H); 2.2-2.4 (m, 5H); 3.2-3.6 (br m, 4H); 3.36 & 3.76 (ABq, J=17.4 Hz, 2H); 5.15 (s, 1H); 6.55 (s, 1H); 6.57 (d, J=8.6 Hz, 1H); 6.73 (d, J=8 Hz, 1H); 7.13 (t, J=7.6 Hz, 1H); 7.28 & 7.42 (ABq, J=8.2 Hz, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][C:18](=[O:22])[NH:19]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][C:18](=[O:22])[NH:19]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)NC(=O)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc2c(c1)NC(=O)C2
Reaction time: 72 h
Yield: 83.6 %

Procedure:
A mixture of 6-(1-t-butoxycarbonylpyrrol-2-yl)oxindole (560 mg, 1.9 mmol), (prepared as described for the starting material in Example 63), and 10% palladium-on-charcoal catalyst (50 mg) in ethyl acetate (30 ml) was stirred under hydrogen at 1 atmosphere pressure for 3 days. The catalyst was removed by filtration through diatomaceous earth, the solvent was removed by evaporation and the residue triturated with ether/isohexanes (1/5) and collected by filtration to give 6-(1-t-butoxycarbonylpyrrolidin-2-yl)oxindole (480 mg, 85%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](OC)([O:13]C)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>O.ClCCl.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:17]=1
Reactant: COc1ccc2c(c1)CCCC(OC)(OC)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2c(c1)CCCC(=O)C2
Yield: 80.2 %

Procedure:
A solution of 2,6,6-trimethoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene (387 mg) and p-toluenesulfonic acid monohydrate (31 mg) was stirred in 5 mL of 1:1 water:acetone. The mixture was diluted with 50 mL of dichloromethane and 50 mL of saturated sodium hydrogen carbonate. The aqueous layer was re-extracted with 50 mL more dichloromethane and the combined organics were dried over sodium sulfate. Evaporation of the solvent gave 250 mg of 2-methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one, which was converted to 2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamine by using Procedure X.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:25])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.I[CH2:27][CH3:28].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([O:25][CH2:27][CH3:28])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=3)[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CCI
Reactant: O=c1[nH]c2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(Cl)nccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a mixture of 8-chloro-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (437 mg), iodoethane (0.19 ml) and N,N-dimethylformamide (10 ml) was added potassium carbonate (326 mg) at room temperature, and the mixture was stirred at 80° C. for 15 hr, and allowed to be cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (116 mg).
Reaction SMILES: Br[CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[NH3:20]>>[NH2:20][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=c1cc(-c2ccncn2)nc2n1CCOCC2Br
Reactant: N
Product: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A suspension of 18.7 g (57.89 mmol) of (+/−)-9-bromo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4-a-diaza-benzocyclohepten-4-one in 520 mL of ammonia (7N solution in MeOH) in sealed tubes was stirred at 100° C. for 4 hours. The cooled solution was evaporated to remove solvent. After an acido-basic work-up and extraction with dichloromethane, the mixture was washed with saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated. The residue was organised in diethyl ether to afford 6.70 g (44%) of product as a yellow solid.
Reaction SMILES: [C:1]([NH:11][S:12]([NH:15][CH:16]([CH2:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23]O>[Pd]>[CH3:23][O:18][C:17](=[O:19])[CH:16]([NH:15][S:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])(=[O:14])=[O:13])[CH2:20][CH2:21][CH3:22]
Reactant: CO
Reactant: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Product: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)OC
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-(N-carbobenzyloxyaminosulfonyl)aminopentanoic acid (46.7 g) , methanol (350 mL) and 10% palladium on carbon (3.0 g) was hydrogenated at 55 psi for about 2 hours. The catalyst was removed by filtration through CELITE®, the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 50% ethyl acetate/hexane to afford 25.6 g (90%) of 2-(aminosulfonylamino) pentanoic acid methyl ester (Formula XIV: R=CH3 ; R1 =H; R2 =propyl; R3 =H), m.p. 63°-64° C.