Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C@H:30]3[CH2:37][CH2:38][CH2:39][N:29]3[CH2:28]2)=[CH:23][CH:22]=1.[CH2:40]([OH:43])[C:41]#[CH:42].CO>C(N(CC)CC)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I.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>[OH:43][CH2:40][CH:41]=[CH:42][C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C@H:30]3[CH2:37][CH2:38][CH2:39][N:29]3[CH2:28]2)=[CH:23][CH:22]=1
Reactant: Brc1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: OCC=Cc1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of Pd(OAc)2 (17 mg, 0.07 mmol), Ph3P (35 mg, 0.14 mmol), CuI (15 mg), Pd(Ph3P)4 (10 mg) in 5 mL of triethylamine was added a solution of trans-1,2,3,5,6,10b-hexahydro-6-(4'-bromophenyl)pyrrolo[2,1-a]isoquinoline (440 mg, 1.34 mmol) in 15 mL of triethylamine at room temperature followed by addition of propargyl alcohol (208 mg, 3.67 mmol). The reaction mixture was teated at reflux overnight, cooled to room temperature, quenched with sat'd NaHCO3 solution (20 mL), extracted with methylene chloride (3×20 mL). The combined methylene chloride extract was dried over anhydrous MgSO4, filtered and concentrated to afford a crude product mixture. Flash chromatography with 3.5% MeOH, 0.07% Et3N in methylene chloride gave starting material 280 mg (64% recovery) and 58 mg of thick orange oil (58% conversion yield). 1H NMR (CDCl3) δ 1.73-2.05 (m, 3H, C2H2 & C1H), 2.30-2.2.44 (m, 1H, C1H), 2.579 (dt, 1H, J=9.0, 8.7 Hz, C3H), 2.869 (dd, 1H, J=5.1, 11.1 Hz, C5H), 2.90-3.03 (m, 2H, C3H & C5H), 3.480 (dd, 1H, J=7.2, 9.0 Hz, C10bH), 4.125 (t, 1H, J=4.8 Hz, C6H), 6.865 (d, 1H, J=7.5 Hz, aryl), 6.995 (d, 2H, J=8.1 Hz, C6 phenyl aryl), 7.04-7.20 (m, 3H, aryl), 7.575 (d, 2H, J=8.1 Hz, C6 phenyl aryl); 13C NMR (CDCl3) δ 22.17 (C2), 30.31 (C1), 45.48 (C3), 54.13 (C10b), 55.95 (C6), 63.67 (C5), 91.60 (4'C), 125.73 (aromatic), 126.30, 129.30, 130.97, 137.23.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[O:26][CH3:27])=[N:6]1.[OH-].[Li+].O>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:7]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:28])=[O:2])[N:6]=2)=[C:20]([O:26][CH3:27])[CH:21]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2OC)n(Cc2cccc(F)c2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)ccc1-c1nn(CC(=O)O)c(=O)n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
159 mg (0.39 mmol) of the compound from Example 147A in 4 ml methanol are treated with 1.57 ml of a 1 N solution of lithium hydroxide in water (1.57 mmol) and the resulting mixture is stirred overnight at RT. The methanol is removed on the rotary evaporator, the residue diluted with water and the resulting aqueous phase extracted twice with dichloromethane. These organic phases are discarded. The aqueous phase is then acidified with 1 N hydrochloric acid and extracted three times with dichloromethane. The extracts are combined, dried over magnesium sulphate, freed of solvent on the rotary evaporator and the residue dried under high vacuum. 144 mg (94% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[C:7]1=[NH:24].[Br:29]Br.C([O-])(O)=O.[Na+]>ClCCl>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[CH2:15][N:8]1[C:9]2[CH:14]=[CH:13][C:12]([Br:29])=[CH:11][C:10]=2[N:6]([CH2:5][C:4]2[CH:25]=[CH:26][C:27]([F:28])=[C:2]([F:1])[CH:3]=2)[C:7]1=[NH:24]
Reactant: BrBr
Reactant: N=c1n(Cc2ccc(F)c(F)c2)c2ccccc2n1Cc1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N=c1n(Cc2ccc(F)c(F)c2)c2ccc(Br)cc2n1Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Bis(3,4-difluorobenzyl)-1,3-dihydrobenzoimidazol-2-ylideneamine, prepared by Procedure A, was dissolved in dichloromethane, added bromine (2 eq) and stirred overnight at rt. Saturated aqueous NaHCO3 was added and the mixture extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated in vacuo and purified by preparative LCMS to give the title compound as the free base (solid, mp 88-89.5° C.). MS(ES+) m/z 465 ([M+1]+, 100). 1NMR (DMSO-d6) δ 5.05 (s, 4H), 6.08 (br s, 1H), 6.85-6.93 (m, 1H), 6.98-7.23 (m, 4H), 7.35-7.45 (m, 4H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Temperature: 95 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A mixture of 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.00 g, 9.88 mmole), tert-butyl 5-amino-1H-indazole-1-carboxylate (2.42 g, 10.37 mmole) in iso-propanol (130 mL) was stirred at 95° C. for 2 h. The reaction was cooled to RT and the crude product was filtered and then washed with ether, iso-propanol, and hexane and dried under vacuum to give tert-butyl 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (4.33 g, 7.20 mmole, 77% over two steps). MS 602 (M+1). HPLC retention time 6.47 mins.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Similar to the procedure of U.S. Pat. No. 4,345,072, a mixture comprising hydantoin (25 g, 0.25 mole), benzaldehyde (29.3 g, 0.275 mole), ammonium acetate (19.3 g, 0.25 mole) and glacial acetic acid (60 g) were placed in a round bottom flask fitted with stirrer, condenser, thermometer and heating mantle. The white solids became yellow on heating. All the solids dissolved when the temperature reached between 120° C. and 134° C. The mixture was refluxed for one-half hour (125° to 134° C.) and then held at 120° C. for 4 hours with stirring. Solids crystallized out on cooling to room temperature. The solid was suction filtered, water washed and then ethanol washed. After air drying, the yellow orange solid had a weight of 38.0 g for an 81% yield. The melting point of the 5-benzalhydantoin obtained was determined to be 218°-220° C. which corresponds to the melting point reported in BIOCHEM J. 29, 542 (1935).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.Cl>[CH3:11][O:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([O:1][CH2:21][O:22][CH3:23])[CH:9]=[CH:8][CH:7]=1
Reactant: COCCl
Reactant: COc1cccc(O)c1C=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCOc1cccc(OC)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (200 mg, 1.31 mmol) was placed in a 20 mL reaction vessel, and dissolved in 3.9 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), 4-dimethylaminopyridine (20 mg, 0.16 mmol), and chloromethyl methyl ether (250 μL, 3.28 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with 70 mL of ethyl acetate and 15 mL of 1N HCl, and extracted. The extract was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a pale yellow oil (224.4 mg, 87%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>>[Cl:11][C:4]1[N:3]=[C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Product: CCOC(=O)N1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1

Procedure:
2,6-Dichloro-3-nitropyridine was reacted with N-ethoxycarbonylpiperazine to give 6-chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine. The product, without purification, was heated with ethanolic ammonia in a sealed tube at 120°-125° C. to give 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (mp 132°-134° C.), which was treated with acetic anhydride in acetic acid to give 6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (mp 168°-169° C.). This compound was catalytically hydrogenated in the presence of 5% palladium-carbon in acetic acid to yield 3-amino-6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine. The obtained 3-amino derivative, without further purification, was dissolved in a mixture of ethanol and 42% tetrafluoroboric acid, and to this solution was added a solution of isoamyl nitrite in ethanol at below 0° C. with stirring. Twenty minutes later, ether was added to the solution. The resulting precipitate was collected by filtration and washed with a mixture of methanol and ether and then with chloroform to yield 6-acetylamino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-pyridine diazonium tetrafluoroborate; mp 117°-117.5° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)[Br:13]>C(Cl)Cl>[Br:13][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(Br)c(O)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.5 %

Procedure:
To the solution of 2-fluoro-4-methoxybenzaldehyde (3 g, 19.5 mmol, 1 eq., Aldrich, Milwaukee, Wis., USA) in DCM (80 mL) was added dropwise BBr3 (14.5 g, 58.7 mmol, 3 eq.) at 0° C. The mixture was stirred for 15 min, then warmed to room temperature and continued to stir for additional 3 h. The reaction was quenched by careful addition of water (50 mL), the organic layer was separated, and remaining the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography (DCM:MeOH=25:1 to 10:1) to afford 2.2 g (80.6%) of 2-fluoro-4-hydroxybenzaldehyde (24).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:20])([C:16]([F:19])([F:18])[F:17])[C:13](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:13]([C:12]([F:20])([F:11])[C:16]([F:19])([F:18])[F:17])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)C(F)(F)c1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (2.01 g; 11.4 mmoles) and 2,2,3,3,3-pentafluoro-propionic acid (1.80 mL; 17.3 mmoles) were suspended in 6N HCl (10 mL; 60 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (60 mL) and with ethyl acetate (60 mL), then sodium bicarbonate (7.59 g; 90.3 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light tan solid.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[CH2:9][C@H:8]2[O:10][C@@:7]2([CH3:11])[CH2:6][CH2:5]1)=[CH2:3].NC1C=CC=CC=1O.CC1[C@@H](O)CC(C(C)=C)CC=1>CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2]>[CH3:11][C:7]1[C:8](=[O:10])[CH2:9][CH:4]([C:2]([CH3:3])=[CH2:1])[CH2:5][CH:6]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C)O[C@@H]2C1
Agent: C=C(C)C1CC=C(C)[C@@H](O)C1
Agent: CCCCCCCC(=O)[O-]
Agent: Nc1ccccc1O
Product: C=C(C)C1CC=C(C)C(=O)C1
Temperature: 212.5 °C
Yield: 3 %

Procedure:
A mixture of 1000 parts of cis-1,2-limonene oxide, 1 part of zinc octoate (contains 18% zinc) and 0.5 parts of 2-aminophenol was refluxed at 200-225° C. for 1.5 hours in a three-necked flask equipped agitator, Dean-Stark trap, and temperature probe. This process is exothermic. Cooling should be applied to prevent a runaway reaction. After cooling 998 part of the mixture containing 87% carveol and 3% carvone was obtained. This mixture can be further processed to carvone according to example 58, or fractionated to obtain pure trans-carveol.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1.[C:18]([C:21]1[CH:22]=[CH:23][C:24]([F:30])=[C:25](B(O)O)[CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[F:30][C:24]1[CH:25]=[CH:26][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][C:23]=1[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: CC(=O)c1ccc(F)c(B(O)O)c1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)c2)cc1
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: [K+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(F)c(-c2cn(-c3ccc(OC(F)(F)F)cc3)cn2)c1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
4-Bromo-1-(4-trifluoromethoxyphenyl)-1H-imidazole (200 mg, 0.651 mmol), 5-acetyl-2-fluorophenylboronic acid (178 mg, 0.977 mmol), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.007 mmol), a 2 N aqueous solution of potassium carbonate (0.651 mL) and dioxane (8 mL) were combined and added to a microwave vessel. The reaction mixture was heated in the microwave with stirring to 150° C. for 20 min. LC-MS indicated 88% anticipated product; TLC (1:1 hexanes:EtOAc) indicated the presence of starting material plus 3 other materials. EtOAc and water were added to the reaction mixture. The aqueous layer was extracted with EtOAc and the organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography with gradient elution (100% hexanes to 100% EtOAc) resulting in 90 mg of an off-white solid. ESIMS 265.0 (M+H); mp 129° C.
Reaction SMILES: [C:1]([OH:6])(=O)[C@H:2]([CH3:4])[OH:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:37]1([CH2:40][N:41]2[C:49]([N:50]3[CH2:55][CH2:54][NH:53][C@H:52]([CH3:56])[CH2:51]3)=[N:48][C:47]3[C:42]2=[N:43][C:44]([C:63]2[CH:64]=[N:65][C:66]([NH2:69])=[N:67][CH:68]=2)=[N:45][C:46]=3[N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)[CH2:39][CH2:38]1>C(Cl)Cl.CO.CN(C)C=O>[NH2:69][C:66]1[N:65]=[CH:64][C:63]([C:44]2[N:43]=[C:42]3[C:47]([N:48]=[C:49]([N:50]4[CH2:55][CH2:54][N:53]([C:1](=[O:6])[C@@H:2]([OH:3])[CH3:4])[C@H:52]([CH3:56])[CH2:51]4)[N:41]3[CH2:40][CH:37]3[CH2:39][CH2:38]3)=[C:46]([N:57]3[CH2:62][CH2:61][O:60][CH2:59][CH2:58]3)[N:45]=2)=[CH:68][N:67]=1
Reactant: C[C@H](O)C(=O)O
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C[C@H](O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H]1C
Reaction time: 20 h
Yield: 41.6 %

Procedure:
L-Lactic acid (26.8 μl, 0.30 mmol), 1-hydroxybenzotriazole monohydrate (38.9 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (73.0 mg, 0.38 mmol), and triethylamine (53.0 μl, 0.38 mmol) were added to an N,N-dimethylformamide solution (2.0 ml) of 5-{9-(cyclopropylmethyl)-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (114.3 mg, 0.25 mmol) at room temperature. The resulting mixture was stirred for 20 hours followed by the addition of L-lactic acid (26.8 μl, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (73.0 mg, 0.38 mmol), and triethylamine (53.0 μl, 0.38 mmol) and the resulting mixture was stirred for 3 days. L-Lactic acid (26.8 μl, 0.30 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (73.0 mg, 0.38 mmol), and triethylamine (53.0 μl, 0.38 mmol) were further added, the resulting mixture was stirred for 2 days, and the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (54.3 mg, 41%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][CH:4]=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:7]1([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: Cn1nccc1C1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nccc1C1=CCCCC1
Yield: 87.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 99b by using the 1-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (11.32 g, 62.8 mmol) prepared in Example 123a, p-toluenesulfonic acid monohydrate (17.9 g, 94.1 mmol) and toluene (100 mL), to yield the title compound (8.89 g, 87%) as a colorless oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]3[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: Cc1ccc(CC(=O)O)cc1
Product: Cc1ccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 86A and 2-(4-methylphenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.42 (m, 1H), 7.90-8.03 (m, 2H), 7.71-7.73 (m, 1H), 7.53-7.68 (m, 4H), 7.25-7.27 (m, 2H), 7.15-7.17 (m, 2H), 3.64 (s, 2H), 2.29 (s, 3H); MS (APCI+) M/Z 404 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][C@H:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[H-].[Na+].Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1.O>CN(C=O)C>[CH3:12][N:9]1[CH2:8][C@H:7]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]2[CH:19]=[C:2]([O:1][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[N:26][N:25]=3)[C:3]([CH3:20])=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: Cc1cc2c(cc1O)[C@@H](c1ccccc1)CN(C)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Oc1nnnn1-c1ccccc1)[C@@H](c1ccccc1)CN(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(R)-8-Hydroxy-3,7-dimethyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (13.35g, 0.0499 mol) was dissolved in DMF (70 ml) and 50% sodium hydride in mineral oil (2.4 g, 0.0499 mol) was added with stirring under nitrogen. The solution was stirred at room temperature for one hour longer. A solution of 5-chloro-1-phenyl-1H-tetrazole (9.90 g) in DMF (40 ml) was added dropwise to the solution with stirring. The solution was stirred for two hours longer and then at 45° C. for another 0.5 hour. The solution was chilled and poured into 900 ml of ice and H2O. The solution was extracted with 2× 250 ml of ether. The combined ethyl layers were washed with 300 ml of water. The ether solution was dried and reduced to about 125 ml. The solid was filtered off, m.p. 140°-142° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:22][C:23]1([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:24]1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]([CH:24]1[C:25]([CH3:27])([CH3:26])[C:23]1([CH3:31])[CH3:22])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(OCc4ccccc4)cc23)C1(C)C
Yield: 26.8 %

Procedure:
A mixture of 5-benzyloxyindole (1.2 g, 5.6 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.1 mL, 6.1 mmol), zinc chloride (1.0 M solution in Et2O, 6.1 mL, 6.1 mmol) and the product of Example 1A (5.6 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.53 g, 1.5 mmol, 27% yield). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:11]([N:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])=[O:12])[CH2:7]1)(=[O:4])=[O:3].[CH2:19](N(CC)CC)C.CI>CO.O1CCCC1>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([CH3:19])[C@H:8]([C:11]([N:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])=[O:12])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)O[C@H]1CN[C@H](C(=O)N2CCNC2=O)C1
Solvent: CO
Solvent: CI
Solvent: C1CCOC1
Product: CN1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCNC1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (14.9 g) in a mixture of methanol (150 ml) and tetrahydrofuran (150 ml) were added triethylamine (32.5 ml) and methyl iodide (11.4 ml) and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (600 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give a residue. The residue was washed with dichloromethane (100 ml). The resulting precipitates were collected and dried in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-methyl-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (2.30 g).