Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]([CH3:61])[C:55]([CH3:60])([C:57](O)=[O:58])[CH3:56])=[O:53])([CH3:50])([CH3:49])[CH3:48].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:47]([O:51][C:52]([N:54]([CH3:61])[C:55]([CH3:60])([C:57]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:58])[CH3:56])=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)C(C)C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a mixture of #86 (80.3 mg, 0.122 mmol, 1 eq.) in dichloromethane (4 mL, 0.03 M) was added N-(tert-butoxycarbonyl)-N,2-dimethylalanine (29.1 mg, 0.134 mmol, 1.1 eq.) followed by diisopropylethylamine (64 μL, 0.365 mmol, 3 eq.) and HATU (71.7 mg, 0.183 mmol, 1.5 eq.) After stirring overnight, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (6 mL) and washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine. The organic solvent was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in dichloromethane and filtered; the filtrate was concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) to afford #87 (58 mg, 50%) as a white solid. LC-MS: m/z 857.7 [M+H+], 879.7 [M+Na+], retention time=0.99 minute; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8 Hz) and 8.87 (br d, J=9 Hz), total 1H], [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.3 Hz), total 1H], [7.63 (d, J=3.2 Hz) and 7.66 (d, J=3.2 Hz), total 1H], 7.13-7.31 (m, 5H), [6.95 (br d, J=8 Hz) and 7.06 (br d, J=8 Hz), total 1H], 5.35-5.42 and 5.51-5.58 (2 m, total 1H), 3.15, 3.19, 3.20 and 3.26 (4 s, total 6H), 2.94 and 3.03 (2 br s, total 3H), 2.83 and 2.84 (2 s, total 3H), [1.05 (d, J=6.7 Hz) and 1.11 (d, J=6.7 Hz), total 3H].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]([C:11]2[CH:12]=[C:13]([CH:39]=[CH:40][CH:41]=2)[CH2:14][N:15]2[C:19](=[O:20])[C:18]3([CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[N:17]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:16]2)=[O:10])[CH2:4][CH2:3]1.Cl>O1CCOCC1>[O:20]=[C:19]1[C:18]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:17]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:16][N:15]1[CH2:14][C:13]1[CH:12]=[C:11]([CH:41]=[CH:40][CH:39]=1)[C:9]([O:8][CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: CN1CCC(OC(=O)c2cccc(CN3CN(c4ccccc4)C4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(OC(=O)c2cccc(CN3CN(c4ccccc4)C4(CCNCC4)C3=O)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(3-((1-methylpiperidin-4-yloxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.01 g, 0.18 mmol) was added 4M solution of HCl in dioxane (2 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain 1-methylpiperidin-4-yl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][CH2:22][CH2:21]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][CH3:16])=[CH:26][C:25]=3[CH3:27])[CH2:21][CH2:22]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 164-165° C.; 1H NMR (300 MHz, CDCl3): δ 6.67 (s, 1H), 6.66 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 4.82-4.80 (m, 1 H), 4.39 (t, J=7.9 Hz, 2 H), 3.79 (s, 3 H), 3.05 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.84-1.73 (m, 2 H), 1.70-1.59 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C19H25N3O2Cl (M+H)+: 362.1635; found m/z 362.1648.
Reaction SMILES: Br[C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[C:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1sc2ccccc2c1Br
Reactant: Cc1ccccc1B(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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1c(C=O)sc2ccccc12
Temperature: 130 °C

Procedure:
A mixture of 3-bromobenzo[b]thiophene-2-carbaldehyde (500 mg, 2.07 mmol), 2-methylphenylboronic acid (394 mg, 2.90 mmol), Pd(PPh3)4 (243 mg, 0.21 mmol), Cs2CO3 (2.02 g, 6.21 mmol) in dioxane (12 mL) and water (4 mL) was degassed with a stream of nitrogen then heated at 130° C. in a sealed tube using microwave irradiation for 45 min. The reaction mixture was extracted with EtOAc, and the organic fraction washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-70% DCM in cyclohexane) affording the title compound (quantitative yield). LCMS (Method C): RT 4.16 min
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].I[CH2:42][CH3:43]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH2:42][CH3:43])[CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Reactant: CCI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)C1c1ccccc1C
Yield: 63.9 %

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.3 g, 0.54 mmol) prepared in example 24b was reacted with LiH (86 mg, 10.9 mmol) (Aldrich) and iodoethane (2 mL, 25 mmol) in N,N-dimethyl-formamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white foam (Yield: 0.2 g, 63%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][N:39](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[NH2:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:38]#[N:39])=[CH:25][CH:24]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1nc2n(c1-c1ccc(C3(N)CCC3)cc1)-c1cccnc1Nc1ccccc1-2
Temperature: 160 °C
Yield: 8 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), Pd(PPh3)4(20 mg, 0.02 mmol), and zinc cyanide (33 mg, 0.27 mmol) in DMF (0.9 mL) was heated at 160° C. for 2 hour. After cooling to room temperature, the mixture was purified by HPLC to give the titled compound as a white solid (4 mg, 8%). 1HNMR (CD3OD) 400 MHz δ: 8.45 (s, 1H), 8.18 (dd, J=4.9, 1.4 Hz, 1H), 7.92 (dd, J=7.4, 1.1 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.43 (t, J=7.4 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.08 (dd, J=8.0, 1.7 Hz, 1H), 6.78 (dd, J=8.0, 4.6 Hz, 1H), 2.83-2.75 (m, 2H), 2.63-2.56 (m, 2H), 2.30-2.20 (m, 1H), 2.04-1.94 (m, 1H); LCMS: 405 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][C@@H:33]([NH:36]C(=O)OC(C)(C)C)[CH2:32]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>O1CCOCC1>[ClH:44].[ClH:44].[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][C@@H:33]([NH2:36])[CH2:32]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(CCN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)c(-c3ccc(C(F)(F)F)cc3)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(CCN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)c(-c3ccc(C(F)(F)F)cc3)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a cooled solution of tert-butyl(R)-1-(2-((trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-ylcarbamate (400 mg, 0.67 mmol) in dioxane (8 mL) at 0° C., HCl in 1,4dioxane (4 mL) was added and stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion, the solvent was evaporated, residue was triturated with Et2O to get (R)-1-(2-((trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopropylamino)ethyl)pyrrolidin-3-amine dihydrochloride (380 mg, 95%) as a white solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:33]([NH2:35])=O)=[N:15][N:16]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:17]=2[O:18][CH2:19][O:20][CH3:21])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([C:33]#[N:35])=[N:15][N:16]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:17]=2[O:18][CH2:19][O:20][CH3:21])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2c(C(N)=O)nn(C(C)(C)Cc3ccc(C)cc3)c2OCOC)cc1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2c(C#N)nn(C(C)(C)Cc3ccc(C)cc3)c2OCOC)cc1
Temperature: 0 °C

Procedure:
171 mg of 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxamide was dissolved in 2 mL of methylene chloride and mixed with 0.3 mL (2 mmol) of triethylamine. The reaction solution was cooled to 0° C. in an ice bath, and after dropwise addition of 0.080 mL (0.72 mmol) of trichloroacetyl chloride at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was mixed with methylene chloride and washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product (crude yield 266 mg).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20](Cl)=[O:21])[CH:18]=3)[NH:6][C:5]=2[C:4](=[O:23])[N:3]1[CH2:24][CH2:25][CH3:26].[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>C1COCC1>[O:21]=[C:20]([N:38]1[CH2:37][CH2:36][N:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:41])([F:42])[F:27])[CH:30]=2)[CH2:40][CH2:39]1)[CH2:19][N:17]1[CH:18]=[C:14]([C:7]2[NH:6][C:5]3[C:4](=[O:23])[N:3]([CH2:24][CH2:25][CH3:26])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=3[N:8]=2)[CH:15]=[N:16]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CCCn1c(=O)c2[nH]c(-c3cnn(CC(=O)Cl)c3)nc2n(CCC)c1=O
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC(=O)N4CCN(c5cccc(C(F)(F)F)c5)CC4)c3)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a solution of [4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-acetyl chloride (100 mg, 0.26 mmol) in THF (10 ml) was added TEA (53 mg, 0.53 mmol) and 1-(3-Trifluoromethyl-phenyl)-piperazine (66 mg, 0.29 mmol) at 0° C. and the mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC to obtain 8-(1-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (30 mg, 21%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([Si:21]([O:24][CH2:25][CH2:26]I)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.O>[Si:21]([O:24][CH2:25][CH2:26][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (977 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added tert-butyl(2-iodoethoxy)dimethylsilane (839 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (591 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=4)=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[NH2:39][CH2:40][CH2:41][OH:42]>CN(C)C=O>[CH3:32][O:31][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][NH:39][CH2:40][CH2:41][OH:42])[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=2)=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=1
Reactant: NCCO
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCNCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-5,6,5′-trimethyl-[2,2′]bipyridine (compound 466) (33 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (101 mg) and 2-aminoethanol (0.13 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (25 mg, yield 71%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>CN(C)C=O.CC(C)=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[O:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc2nc3cscc3c(=O)n2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (0.7 g., 0.003 mol) and 1,1'-carbonyldiimidazole (0.94 g., 0.006 mol) in dimethylformamide (25 ml) is heated at 100° C. with stirring under nitrogen for 1.5 hours. 5-Aminotetrazole monohydrate (0.3 g., 0.003 mol) is added and the resulting mixture is heated at 100° C. for 2 hours. The reaction mixture is cooled and diluted with acetone. The precipitate is filtered off, washed with boiling dimethylformamide, and dried to give the product (0.46 g.), mp 280° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:22][CH2:23][CH:24]1[CH2:26][CH2:25]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH:24]1([CH2:23][NH:22][C:18]([CH:16]2[CH2:15][C:14]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:2]([Cl:1])[CH:3]=3)([OH:21])[CH2:17]2)=[O:19])[CH2:26][CH2:25]1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: NCC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(NCC1CC1)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added aminomethylcyclopropane (0.112 ml, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (101 mg, 43% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C20H27Cl N2 O2, 362.9, found, 363.2 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.44-7.38 (m, 2H), 7.28 (dd, J=7.9, 2.6 Hz, 1H), 6.40 (br apt t, J=5.4 Hz, 1H), 3.69 (s, 2H), 3.10-3.04 (m, 2H), 2.76-2.68 (m, 3H), 2.57-2.42 (m, 6H), 1.78-1.69 (m, 4H), 0.94-0.84 (m, 1H), 0.48-0.40 (m, 2H), 0.18-0.12 (m, 2H); 100 MHz 13C NMR (CDCl3) δ 176.7, 146.1, 135.3, 133.9, 130.8, 126.3, 123.6, 74.0, 56.7, 54.3, 44.9, 41.1, 40.7, 33.1, 23.7, 10.8, 3.7.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([C:23]([CH2:27][CH3:28])([OH:26])[CH2:24][CH3:25])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH2:30]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:23]([CH2:27][CH3:28])([OH:26])[CH2:24][CH3:25])[C:20]([NH:30][CH3:29])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CCC(O)(CC)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Solvent: CO
Product: CCC(O)(CC)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)NC
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of 361 mg (0.91 mmoles) of (3S, 5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]-3-(1-ethyl-1-hydroxypropyl)dihydrofuran-2(3H)-one (prepared as described in Preparation 21) in 10 ml of methanol was saturated with gaseous methylamine by passing the gas through the solution whilst ice-cooling, and then the flask containing the reaction mixture was stoppered tightly and allowed to stand at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from hexane, to give 372 mg (yield 96%) of the title compound as white crystals, melting at 152°-155° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)Cl.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[CH2:27]([O:26][C:24]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC1CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred mixture of 175.4 parts of ethyl 4-piperidineacetate, 116.6 parts of sodium carbonate and 2250 parts of trichloromethane there were added dropwise 119.4 parts of ethyl chloroformate. After stirring for 4 hours at room temperature, the reaction mixture was diluted with 400 parts of water. The organic layer was separated, dried, filtered and evaporated, yielding 277 parts (100%) of ethyl 1-(ethoxycarbonyl)-4-piperidineacetate (interm 18).
Reaction SMILES: CO.[CH:3]([O:8]C)([O:6][CH3:7])OC.OS(O)(=O)=O.[C:15]([C:23]1C(=O)[O:25][C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][C:28]=1[OH:29])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:30]1([C:26]2[O:25][C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][C:28](=[O:29])[C:27]=2[C:3]([O:6][CH3:7])=[O:8])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(OC)OC
Reactant: O=C(c1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Yield: 84 %

Procedure:
A 200 ml flask was fitted with a N2 inlet, a magnetic stirring bar and a condenser. 50 mls of methanol, 8.0 gms of trimethyl orthoformate, 5.2 gms of concentrated H2SO4 and 5.0 gms of 3-benzoyl-4-hydroxy-6-phenyl-pyr-2-one were added. The resulting mixture was then refluxed for 3 days, cooled, poured into water and extracted with methylene chloride (300 mls). The organic extracts were combined and washed with water. Removal of the solvent provided 4.4 gms of 2,6-diphenyl-3-methoxycarbonyl-pyr-4-one (85%). Recrystallization from methylene chloride/ether provide material with a melting point=150°-1°.