Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[CH:22]1[CH:23]=[CH:24][C:25]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=2)=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:28]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:19][CH3:20])[C:4]([OH:3])=[O:21])=[CH:12][CH:11]=2)=[CH:33][CH:34]=1)[C:25]1[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(Cc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Step A (0.1 mmol, 1 eq) in 0.7 ml of DMF in a 16×100 mm tube treated with 4-hydroxydiphenylmethane (0.11 mmol, 1.1 eq) and Cesium Carbonate (0.3 mmol, 3 eq) and stirred at room temperature overnight. The reactants were filtered and washed with DMF several times. The solvent was evaporated under vacuo and the residue reconstituted in a mixture of Ethanol (2 ml) and NaOH (1M) (1 ml) and stirred at room temperature until reaction is completed by HPLC-MS. Then HCl (1M) was added (until pH=3) and the solvent were eliminated under vacuo. The residue was reconstituted in CH2Cl2/H2O and filtered through a hidrofobic syringer. The organic layer was separated, concentrated and purified by HPLC-MS to get the title compound. MS(ES) for C28H28O4[M+NH4]+: 446.2.
Reaction SMILES: [C:1]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:19][NH2:20]>CO>[C:1]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12]([NH:19][NH2:20])=[O:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)NC[C@H](O)CC(=O)OCC
Reactant: NN
Solvent: CO
Solvent: O
Product: CCCCCC(=O)NC[C@H](O)CC(=O)NN
Temperature: 65 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A 6.50 g (24.9 mmol) of ethyl (R)-4-hexanoylamino-3-hydroxybutyrate (optical purity: 95%e.e.) was dissolved in 26 ml of methanol, and 1.87 g (37.3 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was heated to 65° C. and then stirred for 2 hours. After the mixture was cooled to room temperature, stirring was conducted overnight to give 4.09 g (66%) of the title compound as a crystal. Melting point: 172.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)Sc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 7.4 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-tert-butylthiopyridine (1.19 g, 6.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (0.15 g, 7%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][C:13]([CH3:15])=[CH2:14])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[NH:7]2.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CCCCCC>[Br:20][CH2:14][C:13]1([CH3:15])[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:16])[CH:10]=[C:11]2[CH2:12]1)[NH:7][C:6](=[O:17])[C:5]([CH3:19])([CH3:18])[CH2:4]3
Reactant: C=C(C)Cc1cc(C)c2c(c1O)CC(C)(C)C(=O)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CBr)C2
Yield: 74.2 %

Procedure:
Using 5-hydroxy-6-(2-methyl-2-propenyl)-3,3,8-trimethyl-3,4-dihydrocarbostyril (1.35 g, 5.18 mmol) and N-bromosuccinimide (968 mg, 5.44 mmol), the procedure of Example 299 was followed (reaction, post-treatment, and recrystallization from chloroform-hexane) to obtain 1.30 g of the title compound as colorless needles (74%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:24]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=2)[CH:25]=1
Reactant: O=C(c1ccc(Br)cc1C(F)(F)F)N1CCCC1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Product: O=C(c1ccc(-c2cc(Cl)ccc2OCc2ccccc2)cc1C(F)(F)F)N1CCCC1

Procedure:
The sub-title compound was prepared by the method of Example 11 step b) using the product of step b) and [5-chloro-2-(phenylmethoxy)phenyl]boronic acid. M.p. 143-4° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:6][CH:5]=1.[H][H]>CO.[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2=CCNCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCNCC2)cc1
Yield: 66 %

Procedure:
To a stirred solution of 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine, HCl (3 g, 13.3 mmol) (from step B) in methanol (20 mL) was added 10% palladium on carbon (1.4 g) and the reaction mixture was stirred at 20 psi of hydrogen for 12 h. The reaction mixture was filtered through a pad of celite, which was washed with ethyl acetate, and the combined organic fractions were concentrated to obtain a white solid (2 g, 70% yield). LCMS (ES-API), m/z 192.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.13-8.36 (m, 2H), 7.14 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 3.73 (s, 3H), 3.07-2.87 (m, 4H), 2.87-2.65 (m, 4H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:17]([O-])=[CH:16][C:15]=2[N:14]=[CH:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[C:1]([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:28])[C:15]=2[N:14]=[CH:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(OCCn1cnc2c(Cl)nc3ccccc3c21)c1ccccc1

Procedure:
A mixture of 50g (0.15 mole) of 1-(2-benzoyloxyethyl)-1H-imidazo[4,5-c]quinolin-5-oxide (from Example 116) and 200 ml of phosphorus oxychloride was heated for two hours on a steam bath. The mixture was then partially evaporated in vacuo. The mixture was poured over ice, and the solution was neutralized with sodium hydroxide. The product was separated by filtration and dissolved in dichloromethane, and the solution was washed with aqueous sodium bicarbonate solution and dried. Evaporation provided a solid which was recrystallized from a 50:50 methanol:dichloromethane solution to provide white 1-(2-benzoyloxyethyl)-4-chloro-1H-imidazo[4,5-c]quinoline, m.p. 186°-190,C. Analysis: Calculated for C19H14ClN3O2 ; % C, 64.9; % H, 4.0; % N, 12.0; Found: % C, 64.8; % H, 3.8; % N, 12.1.
Reaction SMILES: [I-].[K+].[SH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2.Cl[C:17]1[S:18][C:19]([C:22]2([OH:30])[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)=[CH:20][N:21]=1>>[OH:30][C:22]1([C:19]2[S:18][C:17]([S:3][C:4]3[CH:5]=[C:6]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]4)=[N:21][CH:20]=2)[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Reactant: CC1(C)CC(O)(c2cnc(Cl)s2)CCO1
Agent: [I-]
Agent: [K+]
Product: CN1C(=O)CCc2cc(Sc3ncc(C4(O)CCOC(C)(C)C4)s3)ccc21
Yield: 92 %

Procedure:
Using an analogous procedure to that described in Example 26 except that a catalytic amount (0.01 g) of potassium iodide was added to the reaction mixture, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with 4-(2-chlorothiazol-5-yl)-4-hydroxy2,2-dimethyltetrahydropyran to give 4-hydroxy-2,2-dimethyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-5-yl]tetrahydropyran in 92% yield as a foam;
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5]>C(N(CC)CC)C.CC(=O)CC>[C:4]([CH:3]([CH2:2][CH2:3][C:4](=[O:6])[CH3:5])[C:2](=[O:7])[CH3:1])(=[O:6])[CH3:5]
Reactant: CC(=O)CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CC(=O)CCC(C(C)=O)C(C)=O
Reaction time: 42 h
Yield: 61.6 %

Procedure:
60 g of 2,4-pentandione and 0.1 g of triethyl amine were mixed, and 28 g of 2-butanone was added dropwise at room temperature. The mixture was stirred for 42 hours and the raw product was distilled off. Re-distillation gave 31.4 g of 3-acetyl-2,6-heptandione.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1.[F:9][C:10]([F:19])([F:18])[CH2:11][CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:4]1([CH2:3][C:13]([CH2:12][CH2:11][C:10]([F:9])([F:18])[F:19])([C:14]#[N:15])[C:16]#[N:17])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1cccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cccn1
Yield: 29.9 %

Procedure:
0.76 g of 1-(chloromethyl)-1H-pyrazole hydrochloride and 0.81 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 1.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and then extracted with methyl-t-butyl ether (may be referred as MTBE, hereinafter) . The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 0.36 g of (1H-pyrazole-1-yl methyl) (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (1), hereinafter) shown by below formula.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](S(C)=O)=[N:6]2.[CH2:24]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][O:26][CH2:25]1.CN1CCCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:36][C:33]1[CH:32]=[CH:31][C:30]([N:29]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:35][CH:34]=1)=[N:6]2
Reactant: CS(=O)c1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2cc(Br)c3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 150 °C
Yield: 66.8 %

Procedure:
Into a 30 mL vial, [A] 5-Bromo-2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.14 g, 0.00034 mol), 4-(4-morpholino)aniline (0.181 g, 0.00101 mol), and N-Methylpyrrolidinone (0.22 mL, 0.0023 mol) were added. The mixture was heated at 150° C. for 3 hours. The mixture was purified via ISCO column chromatography with DCM and MeOH as eluant (0 to 15% methanol). The collected fractions afforded [5-Bromo-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine as a yellow solid (120 mg, 67%). MP 242-244° C. LCMS (E/I+) 451.23 (M+H). NMR 1H (DSMO-d6)-9.43 (s, 1H), 8.86 (s, 1H), 8.16 (d, 2H, J=7.76 Hz), 7.62 (d, 2H, J=8.93 Hz), 7.54 (t, 1H, J=7.77 Hz), 7.41 (t, 1H, J=7.16 Hz), 7.34 (s, 1H), 6.93 (d, 2H, J=8.97 Hz), 3.74 (t, 4H, J=4.29 Hz), 3.06 (t, 4H, J=4.64 Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]N1C(=O)CCC1=O>CN(C=O)C>[I:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][CH:9]=2)[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ncc2cn[nH]c2n1
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ncncc12
Temperature: 80 °C

Procedure:
520 mg (4.331 mmol) of 1H-pyrazolo[3,4-d]pyrimidine and 1.461 g (6.496 mmol) of N-iodosuccinimide were dissolved in 10 ml of DMF and the mixture was heated at 80° C. for 3 h. After cooling, the mixture was concentrated on a rotary evaporator and the residue was stirred with dichloromethane, filtered off with suction and dried under high vacuum. 569 mg (53% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][CH:4]=1)#[CH:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[N:7]([CH3:8])[C:6]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[N:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1cnc(C(=O)c2ccccc2)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C#Cc1cnc(C(O)c2ccccc2)n1C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
A solution of 200 mg (0.951 mmol) of (5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone in 1 mL of MeOH was added dropwise to a 0° C. solution of 54 mg (1.43 mmol) of NaBH4 in 5 mL of MeOH. After stirring for 2 h, 10 mL of water was added and the mixture was extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, concentrated, and chromatographed (0–80% EtOAc in hexanes) to give (5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanol as a white solid (75 mg).
Reaction SMILES: [CH:1]1([CH2:7][N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[CH2:23][NH:24]C(=O)C(F)(F)F)[CH:16]=2)C(=O)C(F)(F)F)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].O>CO>[NH2:24][CH2:23][CH:22]=[CH:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[NH:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NC/C=C/c1cccc(N(CC2CCCCC2)C(=O)C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NCC=Cc1cccc(NCC2CCCCC2)c1
Reaction time: 16 h

Procedure:
A mixture of (E)-N-(cyclohexylmethyl)-2,2,2-trifluoro-N-(3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)phenyl)acetamide (0.2 g, 0.45 mmol) and K2CO3 (0.19 g, 1.37 mmol) in MeOH:H2O was stirred at room temperature for 24 h and then at 50° C. for 16 h. The solvent was removed under reduced pressure. Purification by column chromatography (5% to 10% MeOH—CH2Cl2 gradient) gave 3-(3-aminoprop-1-enyl)-N-(cyclohexylmethyl)aniline as pale brown semi-solid. Yield (0.06 g, 54%); 1H NMR (400 MHz, DMSO-d6) δ 6.99 (t, J=8.0 Hz, 1H), 6.54-6.53 (m, 2H), 6.44 (d, J=7.2 Hz, 1H), 6.42 (d, J=16.0 Hz, 1H), 6.22-6.15 (m, 1H), 5.58 (t, J=5.8 Hz, 1H), 3.34 (d, J=5.2 Hz, 2H), 2.83 (t, J=5.8 Hz, 2H), 1.80-1.77 (m, 2H), 1.70-1.56 (m, 3H), 1.54-1.49 (m, 1H), 1.18-1.12 (m, 3H), 0.97-0.91 (m, 2H); RP-HPLC (Method 4) tR=5.30 min, 96.10% (AUC); ESI MS m/z 245.26 [M+H]+.
Reaction SMILES: C([O:3][C:4](OCC)([CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH:5]=[O:6])C.Cl>C(O)C>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[CH2:7][C:4]([CH:5]=[O:6])=[O:3]
Reactant: CCOC(C=O)(Cc1c(Cl)cccc1Cl)OCC
Agent: Cl
Solvent: CCO
Product: O=CC(=O)Cc1c(Cl)cccc1Cl

Procedure:
A mixture of 10 g of 2,6-dichlorobenzylglyoxal diethylacetal, 40 ml of ethanol and 20 ml of concentrated hydrochloric acid is refluxed for 4 hours and then is evaporated to dryness. The residue, which is a yellowish oil, consists of crude 2,6-dichlorobenzylglyoxal and is used in step (b) of this Example as set forth below.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:9]([N:16]=[C:17]=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:17]([NH:16][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:18]
Reactant: CCCCCCCN=C=O
Reactant: Nc1ccncc1N
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1cnccc1N
Yield: 43.6 %

Procedure:
A mixture of 3,4-diaminopyridine (1.09 g), heptyl isocyanate (1.41 g) and 4-dimethylaminopyridine (0.37 g) was stirred in toluene (10 ml) at 50°-60° C. for 5 hrs. The solvent was distilled off and the residue was purified by a silica gel column chromatography (chloroform:methanol=4:1) to give 1-(4-amino-3-pyridyl)-3-heptylurea (1.09 g, 37%) and crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([Cl:9])[CH:4]=1.C(=O)([O-])[O-:11].[K+].[K+]>O>[Cl:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:11])[CH:8]=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccnc(Cl)c1
Agent: [K+]
Solvent: O
Product: OCc1ccnc(Cl)c1
Temperature: 25 °C
Yield: 9.3 %

Procedure:
The crude product of 4-(chloromethyl)-2-chloropyridine (9.25 g), and potassium carbonate (9.5 g, 68.7 mmol) were suspended in water (100 mL) and heated at reflux for 2.5 h. The mixture was allowed to cool to room temperature and the phases were separated. The oily phase was further extracted with water. The combined aqueous phases were washed with hexanes and extracted with EtOAc. The combined EtOAc phases were dried over MgSO4 and concentrated in vacuo to yield 2-Chloro-4-pyridinemethanol as an off white solid (762 mg, 9.3% yield over 2 steps).
Reaction SMILES: Cl.C([N:9]([CH2:23][C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[OH:25])[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:12]=2[CH2:11]1)C1C=CC=CC=1.ClC1C=CC=CC=1>[Pd].CO>[ClH:32].[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:13]2[CH2:14][CH2:15][CH2:16][CH:10]([NH:9][CH2:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[OH:25])[CH2:11][C:12]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)c1cccc(Cl)c1)CCC2
Agent: [Pd]
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CO
Product: COc1ccc2c(c1)CC(NC[C@H](O)c1cccc(Cl)c1)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 173 %

Procedure:
A mixture of (1R)-2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanol hydrochloride (0.20 g), chlorobenzene (0.86 ml) and 10% palladium on carbon (0.01 g) in methanol (4 ml) was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The catalyst was filtered off and washed with methanol. The filtrate was evaporated in vacuo, and the residue was powdered from diisopropyl ether to afford (1R)-2-[(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-amino]-1-(3-chlorophenyl)ethanol hydrochloride (0.14 g).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COC(=O)CCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCOc1ccc(C=O)cc1OC
Yield: 62.3 %

Procedure:
A solution of vanillin (47)(40.00 g, 262.89 mmol) and methyl-4-bromobutyrate (50.00 g, 276.18 mmol) in DMF (200 mL) was allowed to stir over potassium carbonate (51.53 g, 372.40 mmol) for 16 hours. Water was added to the reaction mixture at which time the product crystallised. The resulting mixture was filtered and dried in vacuo for 16 hours to afford the keto-ester (48) as a white solid (41.3 g, 66%). MP=57-59° C. 1H NMR (250 MHz, CDCl3) δ 9.80 (s, 1H), 7.46-7.40 (m, 2H), 6.97 (d, J=8.1 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 3.92 (s, 3H), 3.70 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.20 (pent, J=6.7 Hz, 2H). 13C NMR (67.8 MHz, CDCl3) 188.2 (Cl), 173.7 (C12), 153.8 (Cquat.), 152.0 (Cquat.), 144.1 (Cquat.), 125.8 (Cmethine), 110.3 (C3), 108.5 (C6), 69.0 (C9), 57.0 (C8), 52.2 (C13), 30.6 (C11), 24.5 (C10). It was decided to adopt the numbering system shown in the figure below for the molecule for ease of peak assignment in 13C NMR.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH:16](N4CCOCC4)[CH2:15][CH2:14][C:13]=3[CH:25]=2)=[N:6][CH:7]=1.NC1C=CC2CCC([OH:51])CCC=2C=1>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH:16]([OH:51])[CH2:15][CH2:14][C:13]=3[CH:25]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)ncc2Cl)c(-n2cccn2)c1
Reactant: Nc1ccc2c(c1)CCC(O)CC2
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCC(O)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
The desired product was also isolated from Example 622, as starting material 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine of Example 622 was contaminated with a small amount of its respective alcohol, 2-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol. The product 2-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol was isolated as a lyophylate (10%); 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.23 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 8.02 (d, J=8.62 Hz, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.19 (d, J=7.95 Hz, 1H), 7.00 (d, J=8.98 Hz, 1H), 6.90 (d, J=8.20 Hz, 1H), 6.54 (s, 1H), 3.87 (s, 3H), 3.71 (bm, 1H), 2.68 (m, 1H), 2.5 (DMSO-d+H), 1.86 (m, 2H), 1.30 (m, 2H); MS (m/e) 477.43 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.O=[C:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(C(=O)OC(C)(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Yield: 75.7 %

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.51 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (100 mg, 0.51 mmol), sodium triacetoxyborohydnde (162 mg, 0.75 mmol) and acetic acid (30 mg, 0.5 mmol) in tetrahydrofuran (20 ml). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (92.3:6.7:0.33) to give the title compound (260 mg) as a solid. R 0.66 in dichloromethane:methanol:ammonia (80:20:1).