Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[CH3:24][O:25][C:26]([CH:28]([NH2:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:27].Cl.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:24][O:25][C:26](=[O:27])[CH:28]([NH:37][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]3[C:5]([CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=3[N:8]=2)=[CH:19][CH:18]=1)[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1
Reactant: COC(=O)C(N)Cc1ccc(Cl)cc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Cl)cc1)NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
At room temperature, a 2-dram vial, equipped with a magnetic stirrer was charged with 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (153 mg, 0.5 mmol, INTERMEDIATE 2), DL-4-chlorophenylalanine methyl ester hydrochloride (125 mg, 0.5 mmol), bromotrispyrrolidinophosphonium hexafluorophosphate (233 mg, 0.5 mmol) and 5 ml of dimethylformamide. To this was added diisopropylethylamine (524 μl, 3 mmol) dropwise, during which addition the reaction turned a reddish-orange. After a few minutes the reaction mixture faded to a pale yellow clear solution. The reaction mixture was allowed to stir at room temperature for 3 d. The residue was purified by chromatography using a Biotage SP1, 40M silica cartridge, eluting with a linear gradient of hexanes in ethyl acetate from 20% to 100% over 15 column volumes to provide the title compound as a white solid (150 mg). Mass spectrum (ESI) 502.2 (M+1). 1H NMR (600 MHz, CDCl3): δ 8.31 (d, J=8.2 Hz, 2H), 7.93 (d, J=1.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.5 (s, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.1 (d, J=8.3 Hz, 2H), 6.66 (d, J=7.3 Hz, 1H), 3.79 (s, 1H), 3.46 (m, 1H), 3.3 (dd, J=5.9, 5.9 Hz, 1H), 3.21 (dd, J=5.2, 5.0 Hz, 1H), 1.44 (J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[N:5][N:4]=[N:3]1>[OH-].[OH-].[Pd+2].CO.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1ccc(N)cc1
Yield: 95.4 %

Procedure:
1-Methyl-5-(4-nitro-phenyl)-1H-tetrazole (470 mg), 20% Pd(OH)2 (94 mg), and 1:1 MeOH/EtOAc (25 ml), were hydrogenated at 50 PSI for 1 hour. The reaction was filtered through fiberglass filter paper under nitrogen. The filtrate was stripped to yield 383 mg of yellow solids as product. Mass Spec detects 176 (M+H). NMR (300 MHz, CDCl3) δ 7.57 (d, 2H, J=7 Hz), 6.80 (d, 2H, J=7 Hz), 4.14 (s, 3H), 4.03 (M, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([OH:16])=O)[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][C:23]=1[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:17][C:18]4[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:21]=[CH:22][C:23]=4[CH3:24])=[O:16])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxylic acid (5.3 g, 22.49 mmol) obtained in Step 3 of Preparation Example 4 was dissolved in DMF (60 mL). t-Butyl 3-amino-4-methylphenylcarbamate (6 g, 26.99 mmol) obtained in Step 2 of Preparation Example 9, EDCI (6.5 g, 33.74 mmol), HOBT (6.1 g, 44.98 mmol) and TEA (4.7 mL, 33.74 mmol) were sequentially added to the reaction mixture, which was stirred at room temperature for 24 hours. After the reaction was completed water (120 mL) was added thereto, and the resulting yellow solid was filtered and dried to obtain the title compound without further purification.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH:8]([OH:11])([CH3:10])[CH3:9]>>[CH:8]([O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7])([CH3:10])[CH3:9]
Reactant: CC(C)O
Reactant: C1CCC2OC2C1
Product: CC(C)OC1CCCCC1O
Yield: 84.1 %

Procedure:
Cyclohexene oxide (9.8 g, 0.1 mole) was added dropwise to a refluxing mixture of isopropanol (2 moles) in which was suspended acidified Fullers' earth (Fulcat 22B) (1% w/w) as catalyst. Immediately thereafter the catalyst was removed by filtration and the product was stripped of isopropanol by distillation. The residue was fractionated to yield 13.3 g of 2-isopropoxy cyclohexanol (yield 90% based upon cyclohexene oxide).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15]N1CCCC1=O.C[Mg]Cl.[Cl-].[NH4+]>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[N:11]=[C:10]([CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CN1CCCC1=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc2nc(Cl)nc(C)c2c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a mixed solution of 2,4-dichloro-6-methoxyquinazoline (CAS.105763-77-7) (0.15 g), iron(III) acetyl acetonate (0.023 g), N-methyl-2-pyrrolidinone (0.4 mL), and THF (8 mL) was added a solution (0.22 mL) of 3 M methyl magnesium chloride in THF at room temperature, and the mixture was stirred for 12 h. The reaction mixture was added dropwise to a mixture of ice (30 g) and ammonium chloride (0.3 g), and then the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform) and crystallized with diisopropyl ether to obtain 2-chloro-6-methoxy-4-methylquinazoline (0.08 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][N:14]=[CH:15]2)=[CH:10][CH:9]=1.Br[CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C>[CH:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: Oc1ccc2ccncc2c1
Reactant: CCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCC(Oc1ccc2ccncc2c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.70 g (20.6 mmol) of caesium carbonate are added to a solution of 3.00 g (20.7 mmol) of 7-hydroxyisoquinoline and 4.33 g (20.7 mmol) of ethyl 2-bromopentanoate in 30 ml of acetonitrile, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving ethyl 2-(isoquinolin-7-yloxy)-pentanoate as a colourless solid; ESI 274.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10].[OH-].[Na+].[Na]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10]
Reactant: Brc1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1cc(Br)ccc1Br
Temperature: 150 °C
Yield: 86 %

Procedure:
A modification of the published procedures of H. Borns, Annalen der Chemie 1877, 187, 350 was used. A 300 mL round-bottom flask equipped with a reflux condenser, stirring bar, and gas inlet was charged with 1,4-dibromobenzene (118 g, 0.50 moles) and 30% fuming sulfuric acid (76 mL). The mixture was heated to 150° C. for 3 hours under nitrogen to give a clear solution. The solution was cooled to room temperature to give a solidified mass and transferred into a beaker with water to give a slurry. The slurry was treated with 50% sodium hydroxide solution (130 g) and diluted to 900 mL with water with heating to disperse the precipitated solids. The mixture was cooled to room temperature and the solids collected by vacuum filtration under a rubber dam. The solids were washed with two times with isopropanol (200 mL) and air dried on the filter then dried under vacuum at 100° C. to give 159 g (93% crude yield). The product was recrystallized from ethanol/water (4:1) and dried under vacuum at 150° C. to give 146 g (86% yield) of 2,5-dibromobenzenesulfonic acid, sodium salt. 1H NMR (DMSO-d6): 7.42 (dd, 8.4, 2.6 Hz, 1H), 7.53 (d, 8.4 Hz, 1H), 8.01 (d, 2.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1>NC(C)(C)C>[CH3:11][C:10]([NH:9][C:4]1[N:5]=[C:6]([Cl:8])[CH:7]=[C:2]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(C)Nc1nc(Cl)cc(Cl)n1
Solvent: CC(C)(C)N
Product: CC(C)(C)Nc1cc(Cl)nc(NC(C)(C)C)n1

Procedure:
A solution of 5.0 g 4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine in 25 ml of 1-amino-1,1-dimethylethane is heated in a closed tube at 130° C. for 15 hours. Then, the reaction mixture is evaporated and the residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. After recrystallization from hexane the title compound is obtained in a yield of 5.45 g (93.4%), m.p.:128°-130° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C=O.[C:8](O)(=O)[CH2:9][C:10]([OH:12])=[O:11].N1CCCCC1>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:9](=[CH2:8])[C:10]([OH:12])=[O:11]
Reactant: O=Cc1cccs1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(C(=O)O)c1cccs1

Procedure:
2-thienyl acrylic acid was prepared by reaction of 2-thiophene carboxaldehyde with malonic acid. A solution of 2-thiophene carboxaldehyde (25.7 g.), malonic acid (41.6 g.), pyridine (100 ml.), and piperidine (2 ml.) was refluxed for 31/2 hours. 2-thienyl acrylic acid was recovered from the reaction mixture in a manner parallel to that described in Example 41.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:6](I)[N:5]=[C:4]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:2].[N:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34][CH:33]=1>>[CH2:1]([N:3]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:6]([C:36]2[CH:37]=[N:32][CH:33]=[N:34][CH:35]=2)[N:5]=[C:4]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:2]
Reactant: CCn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: CCn1c(-c2cccc(C(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [3-ethyl-5-iodo-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 69) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as light yellow solid. MS: 499.2 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1C=CC=CC=1>[CH2:32]([O:31][C:29]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CCC3(CC2)OC(c2ccccc2)c2ccccc23)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC2(CC1)OC(c1ccccc1)c1ccccc12

Procedure:
A solution of 7.7 g. of 1'-benzyl-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine] (Example 4), 40 ml. of benzene and 2.5 ml. of ethyl chloroformate is heated under reflux for 18 hours and concentrated to a solid. Recrystallization from cyclohexane provides colorless crystals, m.p. 115°-119°.
Reaction SMILES: P.Cl[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:10]1([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 500 mL of round-bottomed flask equipped with magnetic stir bar was charged with 1.00 g (6.06 mm) of (Me3C)2PH(O), 670 mg (2.98 mm) of Pd(OAc)2 and 100 mL of 1,4-dioxane. The resulting mixture was then heated to a gentle reflux under open-to-air condition for 2 h. The phosphorus-31 NMR spectrum of the reaction mixture showed only the δ123.0 (singlet) resonance, and no unchanged (Me3C)2PH(O). Next, 112.659 g (100.0 mm) of 4-chlorotoluene, 113.41 g (110.0 mm) of PhB(OH)2 and 22.785 g (150 mm) of CsF were added into the flask. The resulting mixture was refluxed for 18 h. The reaction mixture was then cooled to room temperature, quenched with 200 mL of H2O, and extracted with diethyl ether (2×300 mL). The organic extracts were washed with H2O (2×250 mL), brine (250 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 4-phenyltoluene.
Reaction SMILES: NC(N)=O.[CH2:5]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[CH2:6][CH3:7].[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([S:9]([NH:8][CH2:5][CH2:6][CH3:7])(=[O:11])=[O:10])[C:13]=1[OH:20])=[O:30]
Reactant: O=C=Nc1ccccc1Br
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 45.4 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-propyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (186 mg, 0.71 mmol) and 2-bromophenylisocyanate (140 mg, 0.71 mmol) were coupled to form the desired urea (149 mg, 46%). LC-MS (m/z) 464.0 (M+).
Reaction SMILES: [NH:1]([C:5]1[CH:15]=[CH:14][C:8]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:16])C(C)=O.O.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:5]1[CH:15]=[CH:14][C:8]([N:9]([CH2:10][CH3:11])[CH2:12][CH3:13])=[CH:7][C:6]=1[CH3:16]
Reactant: CCN(CC)c1ccc(NC(C)=O)c(C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)c1ccc(N)c(C)c1

Procedure:
22g of 4-acetamino-3-methyl-(N,N-diethyl)aniline were dissolved in 30g of 50% sulfuric acid and stirred and reacted for 5 hours at 80° to 100° C. Then, after 50g of water had been added thereto, the reaction mixture was neutralized with 30% sodium hydroxide and extracted with 150ml of benzole. The benzole used was distilled off from the extract to obtain 14.4g of 4-amino-3-methyl-(N,N-diethyl)aniline. The product was distilled for purification under a reduced pressure of 130° C/2mmHg to obtain 13.5g of 4-amino-3-methyl-(N,N-diethyl) aniline. The free amine was dissolved in 100ml of diethyl ether and was converted to the hydrogen chloride salt thereof by introducing dry hydrogen chloride gas into the system. Then, the salt was filtered out and dried to obtain 17.7g of 4-amino-3-metnyl-(N,N-diethyl)aniline hydrochloride.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([OH:26])(=O)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][C:17]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16])=[O:26])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCCCC(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 100.3 %

Procedure:
Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzyl ester hydrochloride and 300 mg (2.1 mmol) adipic acid afforded, after flash chromatography (EtOAc), 1.07 g (100%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH:3]1[CH2:8][O:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[CH2:16][C:17]([C:19]1[CH2:23][CH:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[O:21][N:20]=1)=O>CO>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[CH:22]1[O:21][N:20]=[C:19]([C:17]2[N:1]=[C:2]([CH:3]3[CH2:8][O:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]3)[S:14][CH:16]=2)[CH2:23]1
Reactant: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Reactant: CCOC(=O)N1CCC(C(N)=S)CO1
Solvent: CO
Product: CCOC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CO1

Procedure:
A solution of ethyl 5-(aminothioxomethyl)tetrahydro-2H-1,2-oxazine-2-carboxylate (i.e. the product of Step I) (0.19 g, 0.87 mmol) and 2-bromo-1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (the product of Example 1, Step C) (0.264 g, 0.87 mmol) in methanol (2 mL) was heated at 50° C. for 1 h. Methanol was removed under reduced pressure and the resulting material was partitioned between sodium acetate (10%, 5 mL) and diethyl ether (5 mL). The layers were separated and the aqueous phase was extracted with diethyl ether (2×). The organic fractions were concentrated under reduced pressure to provide the title compound as a pale-tan oil (0.383 g).
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[C:10]1([N:20]=[C:21]=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:20][CH:21]=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: O=C=Nc1ccccc1
Product: O=CNc1cccc2ccccc12
Reaction time: 0.75 h
Yield: 94 %

Procedure:
The catalytic hydrogenation procedure of Example 1 was repeated except that the phenyl isocyanate used therein was replaced by 1.7 g. (0.01 mole) of 1-naphthylisocyanate. Reduction was complete in 45 minutes. The catalyst was removed by filtration and the colorless filtrate then evaporated to dryness giving 1.71 g. of tan-white crude product, m.p. 134° - 135° C. The solid was recrystallized from ethanol-water to give 1.62 g. (94% yield) of dried title product, m.p. 137.5° - 138.5° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH:13]([OH:14])[CH2:12][C:11]([CH3:16])([CH3:15])[NH:10][C:9]1([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]=O.[OH-].[Na+]>O1CCOCC1>[CH2:1]([CH:8]1[CH:13]([OH:14])[CH2:12][C:11]([CH3:16])([CH3:15])[N:10]([CH3:19])[C:9]1([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)C(Cc2ccccc2)C(C)(C)N1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1C(C)(C)CC(O)C(Cc2ccccc2)C1(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
Into a 100 ml-flask equipped with a thermometer, a cooling tube, a dropping funnel and a magnetic stirrer were added 3.7 g of 3-benzyl-2,2,6,6-tetramethyl-4-piperidinol prepared in Example A1 above, 30 ml of dioxane and 0.78 g of fumic acid, and the content in the flask was heated to 80° C. When the temperature of the content was at a constant level, 2.44 g of 37% aqueous formaldehyde in which 10 ml of dioxane had been dissolved was introduced gradually through the dropping funnel, and the content of the flask was heated at the same temperature under agitation for 8 hours. The temperature was then lowered to room temperature, 10% aqueous NaOH was added so that the pH became to 7, and the solution was subjected to extraction with 150 ml of diethylether. The extract obtained was washed three times with 30 ml of water, 10 g of magnesium sulfate and the solution was kept standing for 2 hours, and the solution was filtered and concentrated to give 3.3 g (yield: 83%) of the title compound as a white solid product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C.Cl[C:30]([O:32][CH3:33])=[O:31].Cl>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:30]([O:32][CH3:33])=[O:31])[CH2:17]1
Reactant: Cn1c(OC2CCCNC2)nc(-c2ccncn2)cc1=O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCCC(Oc2nc(-c3ccncn3)cc(=O)n2C)C1
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of 1-methyl-2-(piperidine-3-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (0.10 g, 0.35 mmol) and triethylamine (70 μl, 0.5 mmol) in dichloromethane (5 ml) was added methyl chloroformate (40 μl, 0.5 mmol) at 0° C. The resulting mixture was stirred for 2 hours and poured into 1N aqueous hydrochloric acid. The partitioned organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent; chloroform/methanol=100/0 to 90/10) to afford methyl 3-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidine-1-carboxylate as a white solid (52 mg, 0.15 mmol, 43%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([F:43])([F:42])[F:31])[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccccc4C(F)(F)F)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-trifluoromethylphenylboronic acid in step C. MS (ESI): mass calcd. for C19H11F3N4O3, 400.1; m/z found, 401.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 2H), 8.99 (s, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.31-8.25 (m, 2H), 8.13 (d, J=7.6 Hz, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.77 (dt, J=15.3, 7.8 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][C:8]12[O:16][CH2:15][CH2:14][O:13]1.[CH2:17]([Li])CCC.CI>O1CCCC1>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:17])[CH2:10][CH2:9][C:8]12[O:16][CH2:15][CH2:14][O:13]1
Reactant: OCc1cccc2c1NCCC21OCCO1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CN1CCC2(OCCO2)c2cccc(CO)c21
Reaction time: 0.5 h

Procedure:
To a solution of 8-hydroxymethyl-4,4-ethylenedioxy1,2,3,4-tetrahydroquinoline (2.5 g) in tetrahydrofuran (30 ml) was added n-butyllithium (14.5 to 17% solution in n-hexane) (10 ml) at --40° C. and stirred for 30 minutes. Then methyl iodide (1.9 g) was added to the reaction mixture and the mixture was stirred for 3 hours at -30° C. to -10° C. and for 30 minutes at -5° C. After distilling off the solvent, n-hexane-ethyl acetate was added to the resulting residue and the insoluble matter was filtered off. The filtrate was concentrated to give 8-hydroxymethyl-4,4-ethylenedioxy-1-methyl-1,2,3,4-tetrahydroquinoline (1.9 g).