Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:15][C:16]=3[CH3:17])[C:9](=[O:26])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:27]1([C@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>COCCO.O>[CH3:17][C:16]1[CH:15]=[C:14]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[NH:13][C:12]=1[CH:11]=[C:10]1[C:3]2[C:2]([NH:35][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:34])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:26]
Reactant: C[C@@H](N)c1ccccc1
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Solvent: COCCO
Solvent: O
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(NC(C)c3ccccc3)c21
Temperature: 115 °C
Yield: 83.1 %

Procedure:
A mixture of 4-chloro-5-[3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (37 mg, 0.1 mmol) and (R)-(+)-1-phenylethylamine (121 mg, 1 mmol) in 2-methoxyethanol (0.5 mL) was heated at 110-120° C. for 1.5 hours. The reaction was diluted with water and filtered. The precipitate was washed with water, little ethanol, ethyl acetate, hexane and dried to give 38.1 mg (81%) of the title compound as a yellow solid. MS 459 [M++1].
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:11](OC(=O)C)[CH:10]=[CH:9][C@H:8]([C:16](=[NH:19])[NH:17][OH:18])[O:7]1)(=O)C.[CH2:20]([O:22][C:23]([C:25]#[C:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])[CH3:21]>CCO>[OH:4][CH2:5][C@H:6]1[O:7][C@@H:8]([C:16](=[NH:19])[NH:17][O:18]/[C:26](=[CH:25]/[C:23]([O:22][CH2:20][CH3:21])=[O:24])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CC(=O)OC[C@H]1O[C@@H](C(=N)NO)C=C[C@@H]1OC(C)=O
Solvent: CCO
Product: CCOC(=O)/C=C(/ONC(=N)[C@H]1CCC[C@@H](CO)O1)C(=O)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To ((2R,3S,6R)-3-acetoxy-6-(N-hydroxycarbamimidoyl)-3,6-dihydro-2H-pyran-2-yl)methyl acetate (2.33 g, 13.4 mmol) in EtOH (15 mL) was added diethylacetylenedicarboxylate (3.20 mL, 20.1 mmol) and the reaction mixture was stirred at 60° C. for 3 h. The solvent was removed in vacuo to afford 2.40 g (52% yield) of the title compound as an amber oil. LCMS (+ESI, M+H+) m/z 345.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20]>CS(C)=O>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(C(=O)OCC)CC2)cc1
Yield: 69.9 %

Procedure:
Ethyl 4-fluorobenzoate (0.93 ml, 6.3 mmol), anhydrous potassium carbonate (0.96 g, 7.0 mmol), ethoxycarbonyl piperazine (0.92 ml, 6.3 mmol)and dry DMSO (30 ml) were heated under dry conditions at 90° C. for 72h. The mixture was partitioned between ethyl acetate and water, dried (sodium sulphate) and evaporated to dryness under reduced pressure. The product was purified by flash column chromatography on silica eluting with 10%MeOH/chloroform to afford the title compound as an oil (1.35 g, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[C:8]([O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 12 h

Procedure:
A mixture of 4-methylsalicyclic acid (20 g), benzylbromide (33 ml) and potassium carbonate (36.3 g ) in DMF (100 ml) was stirred for 12 hours. The mixture was poured into water (300 ml) and extracted three times with diethylether (100 ml each time). The combined organic extracts were washed with water and dried. Removal of the solvent gave benzyl 2-benzyloxy-4-methylbenzoate acid as a yellow liquid, yield 45 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:18](=[C:8]1/[CH2:9][CH2:10][CH2:11][CH2:12][C:5]2[C:6]/1=[N:7][C:2]([CH3:1])=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=2)/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)/C(=C/c1ccccc1)CCCC2
Yield: 33.3 %

Procedure:
Ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.07 g, 4.40 mmol) and benzaldehyde (583.6 mg, 5.50 mmol) were dissolved in acetic anhydride (2.0 ml), and the solution was mixed with zinc chloride (40.0 mg, 0.30 mmol) at room temperature and then heated under reflux for 36 hours. After cooling, acetic anhydride was evaporated under reduced pressure, and the thus obtained residue was mixed with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:6-1:5) to obtain the title compound (471.4 mg, 33.4%) as pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: COCCOCCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COCCOCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.66 g) in 2-propanol (20 mL) were added 4-{[2-(2-methoxyethoxy)ethyl]amino}-1,3-thiazol-2(5H)-one (1.60 g) and piperidinium acetate (0.710 g). The reaction mixture was stirred at 80° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.88 g).
Reaction SMILES: [ClH:1].CC(C)([O:5][C:6](=[O:45])[CH2:7][NH:8][C@@H:9]([C:23]([N:25]1[CH2:44][CH2:43][CH2:42][C@H:26]1[C:27]([NH:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([NH2:41])=[N:36][CH:35]=[CH:34]2)=[O:28])=[O:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.FC(F)(F)C(O)=O>ClCCl>[ClH:1].[C:6]([CH2:7][NH:8][C@@H:9]([C:23]([N:25]1[CH2:44][CH2:43][CH2:42][C@H:26]1[C:27]([NH:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([NH2:41])=[N:36][CH:35]=[CH:34]2)=[O:28])=[O:24])[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([OH:45])=[O:5]
Reactant: CC(C)(C)OC(=O)CN[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@H](NCC(=O)O)C(c3ccccc3)c3ccccc3)ccc12

Procedure:
To a solution of N-[2-(1,1-dimethylethoxy)-2-oxoethyl]-β-phenyl-D-phenylalanyl-N-[(1-amino-6-isoquinolyl)methyl]-L-prolinamide hydrochloride c (4.6 g, 7.1 mmol) in dichloromethane (25 ml) was added trifluoroacetic acid (4.6 ml). After standing over-night the solution was evaporated to dryness, dissolved in dichloromethane and excess hydrochloric acid in diethyl ether added. The product was precipitated by addition of anhydrous diethyl ether then collected by filtration and dried under vacuum to give 2.8 g. A further 0.8 g was obtained by precipitation from the mother liquors.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:7]([NH:9][C@H:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][C:12]([O:14]CC)=[O:13])=[O:8])([O-:3])=[O:2].O.[OH-].[Na+].Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:7]([NH:9][C@H:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Temperature: 45 °C

Procedure:
15.4 g of ethyl (S)-3-(3,5-dinitrobenzamido)-3-phenylpropionate from reaction a were dissolved in 100 ml of tetrahydrofuran, and the resulting solution was admixed with 50 ml of water. With vigorous stirring, the slightly cloudy reaction mixture was heated to 45° C., and the pH was adjusted to 13-13.5 with 32% aqueous sodium hydroxide solution and kept constant for the course of the reaction. After the reaction ended (HPLC monitoring >99 area % conversion), the pH of the solution was adjusted to 7-8 by adding 6 N hydrochloric acid, then the organic solvent was distilled off under reduced pressure. The aqueous solution was diluted to 350 ml with water, and the pH was adjusted to 1-2 with 6 N hydrochloric acid with vigorous stirring. The precipitated product was filtered off with suction and washed twice with water. After drying at 40° C. under reduced pressure, a yield of 13.67 g was determined. The HPLC purity was 99.8 area %.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1nc2c(C)cccc2cc1C=O
Yield: 90.1 %

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline 3-carbaldehyde (0.206 g, 1 mmol), 2-methoxyphenyl boronic acid (0.167 g, 1.1 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.058 g, 0.05 mmol, 0.05 eq), and sodium carbonate (0.530 g, 5 mmol, 5 eq) in acetonitrile (7.5 mL) and water (2.5 mL). After purification, 2-(2-methoxyphenyl)-8-methylquinoline-3-carbaldehyde (0.250 g, 90%) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.86 (1 H, s), 8.88 (1 H, s), 8.13 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=7.1 Hz), 7.56-7.74 (3 H, m), 7.22-7.30 (2 H, m), 3.78 (3 H, s), 2.80 (3 H, s) Mass Spectrum (ESI) m/e=278.0 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]1([C:14](=[O:16])[NH2:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]1([C:14](=[O:16])/[N:15]=[CH:20]/[N:21]([CH3:23])[CH3:22])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Product: CN(C)/C=N/C(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a round bottom flask was added (1-carbamoyl-cyclopropyl)-carbamic acid benzyl ester (935 mg, 4 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL). The reaction mixture was stirred at 100° C. for 1 h. The solvent was concentrated in vacuo. The residue was dissolved in EtOAc/sat. NaHCO3. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered, concentrated and dried under high vacuum to afford 1.11 g of (1-{[1-dimethylamino-meth-(E)-ylidene]-carbamoyl}-cyclopropyl)-carbamic acid benzyl ester as a light brown oil, m/z 290.9 [M+1]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1/[CH:15]=[CH:16]/[C:17]([OH:19])=O.CN(C)C=O.Cl.[CH3:26][NH:27][O:28][CH3:29].CCN(C(C)C)C(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1/[CH:15]=[CH:16]/[C:17]([N:27]([O:28][CH3:29])[CH3:26])=[O:19]
Reactant: CNOC
Reactant: O=C(O)/C=C/c1cc(F)ccc1Br
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)/C=C/c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (2.0 M in dichloromethane, 2.08 mL, 4.16 mmol) was added to a suspension of (E)-3-(2-bromo-5-fluorophenyl)acrylic acid (678 mg, 2.77 mmol) in dichloromethane (8 mL). N,N-dimethylformamide (11 □L, 0.14 mmol) was added, and the resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo, and 4-dimethylaminopyridine (3 mg, 0.025 mmol), N,O-dimethylhydroxylamine hydrochloride (270 mg, 2.77 mmol), Hunig's base (1.44 mL, 8.28 mmol), and dichloromethane (8 ml) were added. The mixture was stirred at 25° C. for 10 h, then transferred to a separatory funnel with dichloromethane (100 mL), and the organic layer was extracted sequentially with water (7 mL), 0.5 M sodium carbonate (7 mL), 1 M hydrochloric acid (7 mL), and half-saturated brine (7 mL), and then dried over sodium sulfate and concentrated. Purification of the concentrate by flash column chromatography (33% to 40% EtOAc/hexane) afforded the title compound as a white solid. MS m/z: 288 & 290 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[C:17](=[C:19]([CH2:23][CH2:24][CH3:25])[N:20]([CH3:22])[N:21]=3)[N:18]=2)[C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1.N[C:28](N)=[S:29].C([BH3-])#N.[Na+].[O-2].[Ca+2].CI>CN(C)C=O.C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC[PH+](CC)CC.CC[PH+](CC)CC.Cl[Ni]Cl>[CH2:9]([O:8][C:5]1[C:4]([C:13]2[NH:14][C:15](=[O:26])[C:16]3[C:17](=[C:19]([CH2:23][CH2:24][CH3:25])[N:20]([CH3:22])[N:21]=3)[N:18]=2)=[CH:3][C:2]([S:29][CH3:28])=[CH:7][N:6]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: NC(N)=S
Reactant: CCCc1c2nc(-c3cc(I)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Agent: Cl[Ni]Cl
Agent: CC[PH+](CC)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCc1c2nc(-c3cc(SC)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound of example 141 (500 mg, 1.07 mmol) and thiourea (90 mg, 1.18 mmol) were suspended in N,N-dimethylformamide (3 ml), degassed at 70° C., and treated with bis(triethylphosphine)nickel(II) chloride (20 mg, 0.05 mmol). Sodium cyanoborohydride (80 μl of 1M solution in THF, 0.08 mmol) was added, and the resultant black reaction mixture heated for ¾ h before further bis(triethylphosphine)nickel(II) chloride (60 mg, 0.16 mmol) and sodium cyanoborohydride (160 μl of 1M solution in THF, 0.16 mmol) were added and the reaction mixture heated for a further 6 h. The green reaction mixture was allowed to cool to room temperature and calcium oxide (90 mg, 1.6 mmol) added. After 1 h, methyl iodide (150 ?l, 2.4 mmol) was added and the mixture stirred for a further 1 h. The reaction mixture was diluted with ethyl acetate (20 ml) and citric acid (10% aq, 20 ml), the organic phase separated and washed with further citric acid (2×20 ml), brine (20 ml) and dried (MgSO4) to afford crude 5-[2-isobutoxy-5-(methylsulfanyl)-3-pyridinyl]-2-methyl-3-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O[SiH](OCC)OCC)C>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1C=CC=CC=1>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:11]
Reactant: CN(C)C(=O)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Solvent: c1ccccc1
Product: CN(C)Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
N,N-dimethylbenzamide (0.49 g, 3.0 mmol), triethoxysilane (1.4 mL, 7.5 mmol), titanium (IV) isopropoxide (0.04 mL, 0.15 mmol), and C6H6 (0.5 mL) were added to a flask open to the air and capped with a CaSO4 drying tube. The reaction mixture was heated to 60° C. for 16 hours. The solvent was removed in Vacuo and the contents were added to a mixture of 1 M NaOH (20mL) and THF (10mL). This mixture was stirred for 3 hours at room temperature and then poured into ethyl ether and washed with 1 M NaOH (5×50mL). The ether extracts were dried over MgSO4, filtered and the solvent was removed in vacuo to produce 0.30 g of N,N-dimethyl benzylamine as a yellowish oil (74% yield).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:22][CH2:23][CH2:24][OH:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)(Cl)Cl>[CH2:41]([O:40][C:38](=[O:39])[N:26]([C@@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)CCN[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a stirred solution of the material from Step 5 (8 g, 18.11 mmol) in a 2:1 mixture of chloroform and saturated aqueous NaHCO3 (271 mL) was added benzyl chloroformate (2.59 mL, 118.11 mmol). The reaction mixture was stirred at room temperature for 1 hour, partitioned and extracted with chloroform. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes (10 to 70%) to yield 7 g of the title compound. LCMS (M+1)=576
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[N:29][CH:30]=1.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]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:27]4[CH:28]=[N:29][CH:30]=[C:25]([Cl:24])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Oc1cncc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cncc(Cl)c4)ncnc32)CC1
Yield: 15.5 %

Procedure:
4-[4-(5-Chloro-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (10 mg, 16%) was prepared using the procedure described for the preparation of Example 96, by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol) with 5-chloro-3-pyridinol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 25 mg, 0.19 mmol) in the presence of potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL). Mass spectrum (ES) MH+=431. HRMS Calcd. for C20H24ClN6O3 (MH+): 431.1593. Found: 431.1593.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:20].[Na+].I>C(C(C)=O)C>[CH2:1]([C:8]1[C:9]([I:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Clc1ccc2cc(Cc3ccccc3)c(Cl)nc2c1
Agent: I
Agent: [Na+]
Solvent: CCC(C)=O
Product: Clc1ccc2cc(Cc3ccccc3)c(I)nc2c1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 3-benzyl-2,7-dichloroquinoline (3.0 g, 10.4 mmol) and sodium iodide (15.6 g, 104 mmol) in 30 mL of methyl ethyl ketone was heated to 80° C. To this was added hydroiodic acid (1.13 ml, 13.2 mmol). The reaction mixture was heated at 80° C. for 1.5 hours and then cooled to ambient temperature. The reaction was quenched with H2O. Excess ethyl acetate was added to the reaction mixture and the organic layer was washed with saturated NaHCO3, saturated Na2S2O3, brine, dried over MgSO4, filtered and the solvent was removed in vacuo to yield 3.9 g (10.3 mmol, 99%) of 3-benzyl-7-chloro-2 iodo-quinoline 23 as a tan solid.
Reaction SMILES: [OH:1][N:2]1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[OH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:31]1[CH2:36][CH2:35][N:34]([S:37]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]2[C:46](O)=[O:47])(=[O:39])=[O:38])[CH2:33][CH2:32]1.NO>CN(C)C1C=CN=CC=1.CN(C)C=O.C(Cl)Cl.C(Cl)Cl.CO>[OH:1][NH:2][C:46]([CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][N:40]1[S:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:25]2[C:24]3[C:28](=[CH:29][CH:30]=[C:22]([OH:21])[CH:23]=3)[NH:27][CH:26]=2)[CH2:36][CH2:35]1)(=[O:39])=[O:38])=[O:47]
Reactant: O=C(O)C1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NO)C1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(O)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
N-Hydroxysuccinimide (0.181 g, 1.57 mmol), 4-dimethylaminopyridine (96 mg, 0.78 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.33 g, 1.73 mmol) were added to a solution of 1-[4-(5-hydroxyindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (0.32 g, 0.78 mmol) [prepared as described in Step 2 above] in 30% dimethylformamide/methylene chloride (5.5 ml). After stirring at RT for 2 h, the reaction was diluted with methylene chloride (50 ml) and washed with 1M HCl, brine and dried over MgSO4. The organics were evaporated in vacuo and the residue was dissolved in 50% ethyl acetate/methanol (13.4 ml). This solution was added to a solution of 50% aqueous hydroxylamine (6.7 ml, 109 mmol) in methanol (6.7 ml) at -30° C. with vigorous stirring. After 10 min., the reaction mixture was quenched with 1M HCl (final pH=3) and then concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with brine and dried over MgSO4. The organics were evaporated in vacuo and the residue was chromatographed (SiO2, 10% methanol/methylene chloride) to give N-hydroxy-1-[4-(5-hydroxyindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide (22%) as a white solid.