Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11]CC1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11]
Reactant: BrCCCCCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCOCCCCCCBr
Yield: 98 %

Procedure:
A solution of [(2-[(6-bromohexyl)oxy]ethoxy)methyl]benzene (1.5 g) in EtOAc (20 ml) and EtOH (20 ml) was hydrogenated over 10% palladium on carbon (200 mg). After 2 h the mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (1.05 g). TSP+ve 242 (MNH4)+, 244 (MNH4)+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:10]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C:35]2[CH:44]=[C:43]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=[CH:42]3)[CH:36]=2)[CH:29]=1)(=[O:7])[CH3:6].[C:45](OC(=O)C)(=[O:47])[CH3:46].Cl>C(Cl)Cl>[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:10]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C:35]2[CH:36]=[C:37]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=[CH:38]3)[C:44]=2[C:45](=[O:47])[CH3:46])[CH:29]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3C(C)=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
Aluminum chloride (0.24 g) was added to a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.20 g) in methylene chloride (20 ml) at 0° C. and the mixture was stirred for 30 minutes. Next, acetic anhydride (0.17 ml) was added dropwise to the reaction mixture at 0° C. and the mixture was refluxed with stirring for 30 minutes and further 16 hours. The reaction mixture was added to 10% aqueous solution of hydrochloric acid under cooling with ice and was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (2S,3S,4R,5R,6R)-2-[3-[(1-acetylazulen-2-yl)methyl]phenyl]-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.09 g).
Reaction SMILES: NC1(N)[C:10]2[C:5](=[CH:6]C=CC=2)[CH2:4]C1.[NH2:12][C:13]1[C:14]([CH3:25])=[C:15]2[C:19](=[C:20]([NH2:22])[CH:21]=1)[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16]2>>[NH2:12][C:13]1[C:14]([CH3:25])=[C:15]2[C:19](=[C:20]([NH2:22])[C:21]=1[C:5]([CH3:10])([CH3:6])[CH3:4])[C:18]([CH3:23])([CH3:24])[CH2:17][CH2:16]2
Reactant: Cc1c(N)cc(N)c2c1CCC2(C)C
Reactant: NC1(N)CCc2ccccc21
Product: Cc1c(N)c(C(C)(C)C)c(N)c2c1CCC2(C)C

Procedure:
The diaminoindane derivative of claim 2 wherein the derivative if 5,7-diamino-1,1,4-trimethylindane.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])=[N+]=[N-]>O>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCNC(=O)COCC(=O)O
Solvent: O
Product: NCCOCCOCCOCCOCCOCCNC(=O)COCC(=O)O

Procedure:
23-Azido-5-oxo-6-aza-3,9,12,15,18,21-hexaoxatricosanoic acid (9.0 g, 21 mmol) was dissolved in water (50 mL) and reduced using H2(g)-Pd/C (10%). The reaction was run until ESI-MS analysis showed complete conversion to the desired product (MH+ calculated: 397.2. found 397.6). The crude product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[OH:23]>>[OH:23][C:17]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:9]
Reactant: Cc1cccc(N)c1O
Reactant: Cc1cc(C(=O)O)c(Br)s1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2cccc(C)c2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-6-methylphenol, N-(2-hydroxy-3-methylphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:67]([OH:73])[CH:68]1[O:72][CH2:71][CH2:70][CH2:69]1>O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([O:73][CH2:67][CH:68]3[CH2:69][CH2:70][CH2:71][O:72]3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: OCC1CCCO1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(OCC2CCCO2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 200 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 246 mg of tripotassium phosphate, 111 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 60 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, 4 ml of tetrahydrofurfurylalcohol and 2 ml of 1,4-dioxane were added, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 1 hour. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 77 mg of the objective compound as pale yellow powder.
Reaction SMILES: [OH:1][OH:2].[C:3](Cl)(=[O:7])[CH:4]([CH3:6])[CH3:5]>O>[C:3]([O:1][O:2][C:3](=[O:7])[CH:4]([CH3:6])[CH3:5])(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: OO
Reactant: CC(C)C(=O)Cl
Solvent: O
Product: CC(C)C(=O)OOC(=O)C(C)C

Procedure:
In Example A, the procedure of WO 01/32613 was repeated. First, a solution of Na2O2 was prepared by combining 108.3 g of demineralized water, 18.5 g of NaOH-33 solution, and 3.7 g of the aqueous H2O2. A second reactor was charged with 33.3 g of demineralized water, 27.7 g of the PVA solution, and 16.3 g of isobutanoyl chloride while controlling the temperature between 5–10° C. Next, the Na2O2 solution was dosed while the system was homogenized. No diisobutanoyl peroxide was obtained and only an aqueous phase formed.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:16][O:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:22][CH:23]=1
Reactant: C=Cc1ccc(OC)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-methoxy-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C@H:16]([NH:18][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1OCCC1=CO
Agent: [Na]
Product: C[C@@H](NC=C1CCOC1=O)c1ccccc1
Yield: 70.9 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and (R)-1-phenylethylamine (55 mmol) and proceeding according to the abovementioned method A1, (R)-3-(1-phenylethylamino)methylenedihydrofuran-2-one (7.70 g, efficiency: 71%) is produced in the form of a white powder.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCCC>[CH:10]1([NH:16][C:17]([NH:9][CH:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCCCC1
Reactant: O=C=NC1CCCCC1
Solvent: CCCCCC
Product: O=C(NC1CCCCCCC1)NC1CCCCC1
Yield: 88 %

Procedure:
Cyclooctylamine, 0.382 g (3.00 mmol), 0.40 mL (0.39 g, 3.1 mmol) of cyclohexylisocyanate in 20 mL of hexane, on standing for one day provides 0.664 g (88%) of 1-cyclohexyl-3-cyclooctylurea as white needles, mp 194.0-194.5° C. An infrared spectrum [3344 (s, NH), 3334 (s, NH), 1624 (vs, C=O), 1564 (vs. amide II) cm-1 ] and mass spectrum [FAB-MS m/z calcd. for C15H28N2O: 252, obsd: 253 (M+H+)] confirms the identity of this material.
Reaction SMILES: C(O)(=O)C(O)=O.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:14]([C:16]1[CH:36]=[CH:35][C:19]2[N:20]([CH3:34])[C:21]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15].O.C(=O)([O-])[O-].[K+].[K+].N1([C:56]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[O:57])C=CN=C1>C(#N)C>[CH3:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][O:58][C:56](/[N:33]=[C:31](\[NH2:32])/[C:28]1[CH:27]=[CH:26][C:25]([NH:24][CH2:23][C:21]2[N:20]([CH3:34])[C:19]3[CH:35]=[CH:36][C:16]([C:14]([N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:15])=[CH:17][C:18]=3[N:22]=2)=[CH:30][CH:29]=1)=[O:57]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)n1ccnc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-6a (100 g) was added to acetonitrile (1200 ml) and water (800 ml) at 25-35° C. and then cooled to 12-18° C. Potassium carbonate (117 g) was added to the reaction mixture and stirred for 15 minutes at 12-18° C. A solution of hexyl 1H-imidazole-1-carboxylate compound of formula-4 (60 g) in acetonitrile (150 ml) was slowly added to the reaction mixture over a period of 25 minutes at 12-18° C. and stirred for 14 hours at 15-20° C. After completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes. Filtered the solid, washed with acetonitrile followed by aqueous acetonitrile and then dried to get title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Further the obtained solid, recrystallized from ethylacetate and ethanol.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:34][C:35]4[CH:44]=[C:43]5[C:38]([CH:39]=[CH:40][CH:41]=[N:42]5)=[C:37]([F:45])[CH:36]=4)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)[CH3:23])[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:34][C:35]3[CH:44]=[C:43]4[C:38]([CH:39]=[CH:40][CH:41]=[N:42]4)=[C:37]([F:45])[CH:36]=3)=[N:18][CH:19]=[C:20]([C@H:22]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)[CH3:23])[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cc(F)c4cccnc4c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cnc2Nc2cc(F)c3cccnc3c2)n1
Temperature: 75 °C
Yield: 58.1 %

Procedure:
A glass microwave reaction vessel was charged with (R)—N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)-5-fluoroquinolin-7-amine (82 mg, 0.105 mmol) and trifluoroacetic acid (1 mL, 13.46 mmol, Aldrich). The reaction mixture was stirred and heated in an oil bath at 75° C. for 14 h. The solvent was removed in vacuo. The residue was treated with 10% MeOH/CH2Cl2 (40 mL). The reaction mixture was washed with sat. NaHCO3 (10 mL), saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 5% MeOH/CH2Cl2 to give (R)—N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)-5-fluoroquinolin-7-amine (33 mg, 0.061 mmol, 58.2% yield). 1H NMR (300 MHz, CDCl3) δ 1.47 (d, J=6.72 Hz, 3H) 2.52-2.72 (m, 7H) 2.78 (s, 3H) 3.25 (t, J=4.17 Hz, 4H) 3.60 (q, J=6.53 Hz, 1H) 5.49 (s, 2H) 7.12-7.24 (m, 1H) 7.39-7.54 (m, 1H) 7.83 (d, J=8.33 Hz, 1H) 8.48 (d, J=2.19 Hz, 1H) 8.77 (d, J=2.05 Hz, 1H) 8.96 (d, J=2.34 Hz, 1H) 9.25 (d, J=1.90 Hz, 1H) 12.51 (s, 1H). m/z (ESI, +ve ion) 538.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:32]=2[O:31][CH2:30]1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([O:38][C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH2:27][CH3:28])=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2ccc3c(c2)OCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 1,3-benzodioxol-5-ol (0.21 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.44 g, 86%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si](C(C)(C)C)(C)C)[C@H:9]1[C@@H:21](O)[C:22]([F:25])([F:24])[F:23])=[O:7])(C)(C)C.[N:27]([C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([Cl:38])[C:31]=1[F:39])=C=O>>[Cl:38][C:32]1[C:31]([F:39])=[C:30]([N:27]2[C@H:21]([C:22]([F:23])([F:24])[F:25])[C@@H:9]3[C@H:10]([OH:13])[CH2:11][CH2:12][N:8]3[C:6]2=[O:7])[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]
Reactant: N#Cc1ccc(N=C=O)c(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Product: N#Cc1ccc(N2C(=O)N3CC[C@@H](O)[C@H]3[C@H]2C(F)(F)F)c(F)c1Cl

Procedure:
The title compound was prepared from (2R,3R)-3-(tert-butyl-dimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxyethyl)]pyrrolidine-1-carboxylic acid tert-butyl ester (66A) and 2-chloro-4-isocyanato-3-fluorobenzonitrile (73C) following procedures analogous to those found in Example 72. LCMS: m/z 364[M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20].[NH:21]1[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]1.CC(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH2:15][N:21]2[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:20]
Reactant: O=C(O)C1CNC1
Reactant: CC[C@@H](Nc1cccc(C=O)c1)c1ccc(Cl)c(C)c1
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@@H](Nc1cccc(CN2CC(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of INT 7 (700 mg, 2.43 mmol) and azetidine-3-carboxylic acid (248 mg, 2.92 mmol) in MeOH (24 mL) was added HOAc (0.14 mL, 2.43 mmol) followed by PS—CNBH3 (2.5 mmol/g, 1.95 g, 4.86 mmol). The reaction mixture was stirred at room temperature for 3 days. The mixture was filtered over Celite. The filtrate was concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to give the title compound Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])=[C:20]([C:33]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[O:34])[CH:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.CN(C)C=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[O:26])=[C:20]([C:33]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[O:34])[CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)N4CCOCC4)c(C(=O)N4CCN(C)CC4)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)N4CCOCC4)c(C(=O)N4CCN(C)CC4)c3)cc12
Reaction time: 2 h
Yield: 21.1 %

Procedure:
Crude morpholine-4-carboxylic acid [4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(4-methyl-piperazine-1-carbonyl)-phenyl]-amide (0.637 mmol) was dissolved in methanol (1.0 mL) and dimethylformamide (1.0 mL) and 50% w/v aqueous potassium hydroxide (1.0 mL) was added. After 2 hours, the reaction was quenched by addition of acetic acid (1.0 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford morpholine-4-carboxylic acid [4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(4-methyl-piperazine-1-carbonyl)-phenyl]-amide (74.5 mg, 21.0%, 4 steps). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.18 (s, 3H), 2.31 (br m, 4H), 3.38 (t, J=4.5 Hz, 1H), 3.61 (t, J=5.0 Hz, 1H), 3.82 (s, 3H), 7.05 (dt, J=7.5, J=1.0 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.29 (dd, J=1.5, J=9.0 Hz 1H), 7.54 (d, J=2.0 Hz, 1H), 7.60 (dd, J=1.5 Hz, J=7.0 Hz, 1H), 7.60 (d, J=9.0, 1H), 7.72 (m, 2H), 8.14 (d, J=1.5 Hz, 1H), 8.53 (d, J=2.0, 1H), 8.60 (s, 1H), 11.9 (s, 1H). MS: m/z 556 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.Cl.[CH2:18]([NH2:20])[CH3:19]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:20][CH2:18][CH3:19])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Product: CCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(ethylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, ethylamine hydrochloride, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [OH-].[Li+].C(O)C.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=1)[C:15](=[O:29])[CH2:14][CH2:13]2>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=1)[C:15](=[O:29])[CH2:14][CH2:13]2
Reactant: COC(=O)c1ccc(CN2C(=O)CCc3c(CC4SC(=O)NC4=O)ccc(OC)c32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(C(=O)O)cc1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
35 ml of an aqueous 1 N-lithium hydroxide solution was added to a mixed ethanol (200 ml) and THF (200 ml) solution of 4.0 g of 5-[8-methoxy-1-(4-methoxycarbonylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, hydrochloric acid was added to the residue, and the insoluble matter thus formed was collected by filtration. The collected insoluble matter was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→1:3), and recrystallized from ethyl acetate, giving 3.75 g (97% yield) of 5-[8-methoxy-1-(4-carboxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [OH:1][C:2]1([C:9]#[N:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:12].C(=O)([O-])[O-].[Ba+2].S([O-])([O-])(=O)=O.[Ba+2]>C(O)C.O>[OH:1][C:2]1([C:9](=[O:12])[NH2:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: CN1CCC(O)(C#N)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O
Solvent: CCO
Product: CN1CCC(O)(C(N)=O)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
The compound 4-hydroxy-4-cyano-1-methylpiperidine (36.4 g, 0.26 mole) was gradually added to sulfuric acid (80 ml), under external cooling. The mixture was maintained at room temperature for 41 hours, then was added to powdered ice (30 g). The resulting solution was neutralized with barium carbonate (376 g) to pH 8-9 and after addition of water the resulting barium sulfate was separated and washed with methanol. The filtrate was concentrated under reduced pressure. The product, 4-hydroxy-4-carbamoyl-1-methylpiperidine (28.16 g, 0.18 mole, 69% yield), crystallized from ethanol as a white solid (mp. 180° C.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)([Cl:37])=[O:36]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:35]([Cl:37])=[O:36])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)([CH3:16])[C:13]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(F)cc2)C(C)(c2ccc(F)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(F)cc2)C(C)(c2ccc(F)cc2)N1C(=O)Cl

Procedure:
rac-(4S*,5R*)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was then reacted with phosgene in the presence of triethylamine to give rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride.