Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[C:28]([OH:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[C:28]([OH:36])[CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)c(O)c4)C3)nc3scnc23)cc1OC
Reaction time: 16 h
Yield: 14 %

Procedure:
To a stirred solution of methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-hydroxybenzoate in 5 mL of THF and 5 mL of methanol was added a solution of 1N NaOH (5 mL) at room temperature. After the addition, the reaction was stirred at this temperature for 16 hours. The solvent was evaporated and the residue was diluted with water and adjusted to pH=2 by HCl (aq.). The suspension was filtered and dried. The crude was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)-2-hydroxybenzoic acid (15 mg, 14% over two steps). 1H NMR (300 MHz, DMSO): δ 9.72 (s, 1H), 8.85 (s, 1H), 8.76 (d, 1H, J=6.0 Hz), 7.86 (s, 1H), 7.84 (s, 1H), 7.43-7.37 (m, 3H), 6.92 (d, 1H, J=8.4 Hz), 4.56 (brs, 1H), 3.77-3.73 (m, 11H), 2.27-2.23 (m, 1H), 2.09-2.07 (m, 1H). LC-MS: 537 [M+H]+, tR=1.37 min. HPLC: 99.62% at 214 nm, 99.22% at 254 nm, tR=3.53 min.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C>[N:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccncc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3 g of 4-pyridylacetonitrile hydrochloride in 50 ml of DMF is cooled to 0° C., 2.6 g of 60% sodium hydride in oil are added portionwise and the mixture is left stirring at RT for 1 hour 30 minutes. The reaction mixture is cooled on an ice bath, 2.7 ml of 1,5-dibromopentane are added dropwise and this mixture is left stirring at RT for 48 hours. The reaction mixture is poured into saturated NH4CO solution and extracted with ether, the organic phase is washed three times with water and dried over MgSO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H gel, eluting with DCM and, then with a DCM/MeOH mixture (98/2; v/v). 2.5 g of the expected product are obtained; m.p.=79° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[NH:19][C:18](=[O:31])[N:17]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50]Br)=[CH:45][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:50][CH2:49][C:46]4[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=4)[C:18](=[O:31])[N:17]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(=O)n(CCc2ccccc2)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Chlorophenyl)-3-methoxycarbonylmethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (49 mg) was dissolved in N,N-dimethylformamide (1 ml), and potassium carbonate (20 mg) and 2-phenethyl bromide (0.03 ml) were added to the solution. Then, the mixture was stirred at 50° C. overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by distillation to give 52 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)Cl.CO>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N+:6]=1[O-:17]
Reactant: Nc1ccc(F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(F)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a stirred solution of 5-fluoropyridin-2-amine (500 mg, 4.46 mmol) in DCM/MeOH (20 mL) in an ice-bath was added MCPBA (1199 mg, 5.35 mmol). The reaction was slowly warmed to room temperature and stirred overnight. The red-orange color solution was loaded to a SCX resin, which was then washed with methanol, eluted with 2 N ammonia in methanol to collect the product. Evaporation of the solvent gave the title compound as yellow-brownish solid (420 mg) without further purification. LCMS m/z=129.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:18]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1>>[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[C:18]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccco1
Yield: 29.2 %

Procedure:
Using the general method of Example 47, furoyl chloride (15.8 μL, 0.16 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.05 g, 0.16 mmole) to provide 0.019 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamide as a white solid. 1H NMR (300 MHz, CDCl3) δ8.58 (dd, J=4.4, 1.5 Hz, 1H), 8.06 (dd, J=8.6, 1.6 Hz, 1H), 7.41 (dd, J=8.5, 4.4 Hz, 1H), 7.33 (m, 1H), 7.08 (dd, J=3.5, 0.6 Hz, 1H), 6.84 (m, 1H), 6.47 (dd, J=3.5, 1.7 Hz, 1H), 4.86 (apparent t, J=7.7 Hz, 2H), 3.59 (apparent q, J=6.5 Hz, 2H), 2.92 (apparent t, J=7.8 Hz, 2H), 1.7-2.1(m, 6H), 1.51 (m, 2H); 1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C22H26N6O2 (M+) 406.2117, found 406.2121.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([CH3:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>O>[Cl:18][CH:12]1[NH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][CH:10]=[C:11]1[CH3:15]
Reactant: Cc1cnc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC1=CN=C(c2ccc(Cl)cc2)NC1Cl
Yield: 92 %

Procedure:
2-(4-Chloro-phenyl)-5-methyl-3H-pyrimidin-4-one (570 mg, 2.58 mmol) was suspended in phosphorus oxychloride (2 ml) and heated to reflux for 2 hours. The mixture was cooled before being stripped to dryness in vacuo. The resulting crude product was solubilised in water (10 ml) and ethyl acetate (10 ml) and the biphasic mixture separated. The aqueous layer was further extracted with ethyl acetate (10 ml) before the combined organics were dried with magnesium sulphate, filtered and stripped to dryness in vacuo to give 6-Chloro-2-(4-chloro-phenyl)-5-methyl-1,6-dihydro-pyrimidine as a white solid (567 mg, 2.38 mmol, 92% yield).
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([Cl:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([Cl:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1nn2c(N)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.35 g (0.935 mmol) of 3-benzenesulphonyl-5,7-dichloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at RT for 12 hrs. The DMF was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/AcOEt 15:1) and crystallization from EtOH yielded 0.28 g (84%) of 3-benzenesulphonyl-5-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[OH:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH:17]([NH:1][C:2]2[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:16][CH2:15]1
Reactant: CC1(O)CCC(=O)CC1
Reactant: COC(=O)c1cccc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2CCC(C)(O)CC2)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of methyl 3-amino-2-methylbenzoate (1.5 g, 9.1 mmol) and 4-hydroxy-4-methylcyclohexanone (1.51 ml, 11.8 mmol) in 10 ml of dichloroethane was added acetic acid (3.2 mL, 55 mmol) and the reaction mixture stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (5.78 g, 27.3 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was neutralized with sat. NaHCO3, extracted with DCM, dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to afford the title compound which was carried forward as a mixture of cis and trans isomers (1.4 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:10][C:7]1[CH:8]=[C:2]([CH3:1])[CH:3]=[C:4]([F:9])[C:5]=1[NH2:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N)c(F)c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)c(N)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A stirred solution of 4-methyl-2-fluoroaniline (15 g, 0.12 mol) in acetic acid (120 ml) at 15° C. under argon was treated portionwise over 20 minutes with solid N-bromosuccinimide (24 g, 0.135 mol), then allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was treated with water (500 ml) and extracted with ethyl acetate (2×300 ml). The combined extract was washed with water (2×500 ml), then excess 10% Na2CO3 solution (400 ml). The ethyl acetate solution was dried (Na2SO4) and concentrated under vacuum to leave the title compound as a dark red oil (24.0 g, 98%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][CH2:9][S:10][CH3:11])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([NH:1][C@H:2]([CH2:8][CH2:9][S:10][CH3:11])[CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CSCC[C@@H](N)C(O)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A solution of Example 1C (2.68 g, 12.5 mmol), triethylamine (3.47 ml, 75.0 mmol), and 2-(tert-butyoxycarbonyloxyimino)-2-phenylacetonitrile (3.22 g, 13.0 mmol) in 30% aqueous dioxane was heated to 50° C. for 6 hours, cooled to ambient temperature, and concentrated. The residue was diluted with aqueous sodium hydroxide (0.25M, 50 mL) and extracted twice with ethyl acetate. The aqueous layer was acidified to pH 3 with 1M H3PO4 and extracted five times with chloroform. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product (1.62 g). MS (ESI) m/e 278 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5](=O)[CH2:6][CH2:7][CH3:8])[CH3:3].C([O-])(=O)C.[NH4+].C([BH3-])#[N:16].[Na+]>CO>[CH3:1][CH:2]([CH2:4][CH:5]([NH2:16])[CH2:6][CH2:7][CH3:8])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CCCC(=O)CC(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(N)CC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
To a solution of 2-methylheptan-4-one (4.24 g, 33.07 mmol), in methanol (60 mL), were added ammonium acetate (25.50 g, 330.71 mmol) and sodium cyanoborohydride (2.08 g, 33.07 mmol). The reaction mixture was stirred at room temperature for about 24 hours. The solvent was removed under reduced pressure and the residue was diluted with water and basified with 15% NaOH aqueous and extracted with ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 3.3 g of 2-methylheptan-4-amine (77%). MS (M+H, 130).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH2:9][O:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:22]([OH:25])[C:23]#[CH:24]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:25][CH2:22][C:23]#[C:24][C:2]1[CH:21]=[CH:20][C:5]([C:6]([O:8][CH2:9][O:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([C:4]#[C:5][CH2:6][OH:7])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(OCOC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCOC(=O)c1ccc(C#CCO)cc1)c1ccc(C#CCO)cc1
Reaction time: 240 h
Yield: 167.9 %

Procedure:
Bis (triphenylphosphine)palladium dichloride (17.0 mg, 0.02 mmol) and cuprous iodide (2.0 mg, 0.01 mmol) are added to a suspension of methylene bis (p-bromobenzoate) (0.500 g, 1.21 mmol) prepared as described in Example 14 and propargyl alcohol (0.16 ml, 2.66 mmol) in triethylamine (10 ml) with good stirring, at 20° C., under a dry N2 atmosphere. After 10 days at 20° C., the triethylamine is removed under reduced pressure, water (20 ml) is added and the mixture is extracted with dichloromethane (3×15 ml). The dichloromethane phases are washed with hydrochloric acid (0.5M, 10 ml), dried (MgSO4) and the dichloromethane removed under reduced pressure to give 0.37 g (85%) of the crude product. 1H NMR (60 MHz, CDCl3): δ 3.67 (2H, s, OH), 4.47 (4H, s, CH2 --O), 6.18 (2H, s, O--CH2 --O), 7.2-7.5 (4H, Ar), 7.8-8.0 (4H, Ar).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:9]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(CCCc1ccccc1)CCCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC1CCNCC1)C(CCCc1ccccc1)CCCc1ccccc1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid (1-benzyl-piperidin-4-yl)-amide (23) (0.5 g; 1.07 mmol) is combined with ethanol (25 mL) and 20% Pd(OH)2 on carbon (0.2 g) in a hydrogenation bottle. The mixture is hydrogenated at 50 psi for 18 hours then filtered through a celite pad and washed with ethanol. The combined filtrate plus wash is concentrated in vacuo affording the desired product (0.38 g) as an oil. ESMS: MH+ 379.4 (base).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[K+]>CC(N(C)C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Yield: 45.8 %

Procedure:
Following a procedure similar to that described in Example 40(a), 2.00 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 3.74 g of (S)-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine and 0.983 g of potassium t-butoxide were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.65 g (yield 45%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[C:5]([CH:11]=[CH:12][N:13](C)C)=[C:4]([N+:16]([O-])=O)[CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]2[CH:11]=[CH:12][NH:13][C:6]=2[CH:7]=1
Reactant: CN(C)C=Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)cc2[nH]ccc12
Reaction time: 8 h

Procedure:
2-(4-fluoro-2,6-dinitrophenyl)-N,N-dimethylethenamine (18 g, 0.071 mol) was dissolved in ethanol (1000 mL), and charged with 10% palladium on carbon (2.0 g). The mixture was hydrogenated at room temperature overnight. The mixture was filtrated through celite and washed with ethanol. The filtrate was combined and evaporated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=2:1) to afford the title compound. LC/MS m/z=151.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1O)[CH3:2].O.[ClH:19].[H][H]>[Pd].C(O)C>[ClH:19].[CH2:1]([C:3]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1(c2c[nH]cn2)Cc2ccccc2C1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCC1(c2c[nH]cn2)Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-(2-ethyl-2,3-dihydro-1-hydroxy-1H-inden-2-yl)-1H-imidazole (5 kg), water (40 kg), 30% HCl (34 kg), ethanol (22 kg) and 10% palladium on charcoal (0.5 kg) are charged. The mixture is stirred under 2.2 bar overpressure of hydrogen at 80±3° C. for 12 hours. The reaction mixture is filtered at 73±2° C., the filter cake is washed with water (7 kg) and the filtrates are combined. The reaction mixture is heated to boil and 50 l of the solvent is distilled off. The solution is cooled to 0±2° C. during 2 h. The solution is seeded during the cooling procedure with atipamezole HCl at 100±5° C., 90±5° C., 80±5° C. and at 70±5° C., until the crystallization starts. The mixture is agitated for two hours at 0±2° C. The crystalline compound is recovered by centrifugation and washed with HCl-water mixture (0.34 kg HCl and 10 kg of water) and then with 18 kg of acetone. The product is dried under reduced pressure raising the temperature gradually to 85±3° C. The yield is 4.8 kg (89%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(O)(=O)C.[Na].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2c(ccc(Br)c2F)C1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1c(Br)ccc2c1CCC(N1CCOCC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To 6-bromo-5-fluoro-tetralin-2-one (1 g, 4.11 mmol) and morpholine (0.36 mL, 4.11 mmol) in dichlormethane is added glacial acetic acid (0.52 mL, 9.05 mmol). The reaction mixture is cooled with an ice bath and sodium triacetoxyborhydride (1.74 g, 8.23 mmol) is added. The reaction mixture is stirred at r.t. overnight. Morpholine (0.2 mL) is added and stirred again at r.t. overnight. The reaction mixture is basified with potassium carbonate solution (20%) and stirred for 15 min. The organic layer is separated and the aq. layer is washed two times with dichlormethane. The organic layers are dried and concentrated. The crude product is purified by reversed phase HPLC Yield 57%, m/z 314/316 [M+H]+, rt 0.68 min, LC-MS Method X011_S03.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=Cc1ccc(OC2CCNCC2)cc1
Product: O=Cc1ccc(OC2CCN(C(=O)NCc3ccccc3)CC2)cc1
Yield: 80 %

Procedure:
The title compound (0.2 g, 80%) was prepared as a white solid from 4-(piperidin-4-yloxy)benzaldehyde (0.25 g) and benzyl isocyanate (0.084 ml), in a similar manner to that described in preparation 14.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>ClCCl>[C:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:38])[CH:36]=[CH2:37]
Reactant: C=CC(=O)Cl
Reactant: CN(CCCCCCO)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCN(C)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 23 °C
Reaction time: 72 h
Yield: 67.5 %

Procedure:
A stirred mixture of 4'-[(6-hydroxyhexyl)-methylamino]-4-methylsulfonylstilbene (App-Ex. 4, 20.0 g, 52 mmol), triethylamine (6.3 g, 62 mmol) and dry dichloromethane (DCM) was treated dropwise with acryloyl chloride (5.6 g, 62 mmol) in 50 mL of DCM at 23° C. under nitrogen. The resulting solution was stirred at 23° C. for 72 hours, and then filtered. The filtrate was washed successively with saturated NaCl, with saturated NHCO3, and with water. The organic layer was dried (MgSO4), and the solvent was removed at reduced pressure to deposit a yellow oil which gradually crystallized. The product was recrystallized from tetrahydrofuran (THF)/hexanes to yield 15.5 g (68%) of a yellow solid, mp 88°-90° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.N[C:14]([CH3:18])=[CH:15][C:16]#[N:17].[ClH:19]>>[ClH:19].[NH2:17][C:16]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)[N:10]=[C:14]([CH3:18])[CH:15]=1
Reactant: CC(N)=CC#N
Reactant: NNc1cccc(C(F)(F)F)c1
Agent: Cl
Product: Cc1cc(N)n(-c2cccc(C(F)(F)F)c2)n1

Procedure:
3-Trifluoromethylphenyl hydrazine (Tetrahedron, 1960, 69) (25.0 g.) was reacted with 3-amino-2-butene nitrile (12.7 g.) as described in Example XLIII to give 36.1 g. product as HCl salt, mp 222°-226°.