Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>[Pd].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[N:14][CH:15]=1
Reactant: COC(=O)c1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
A mixture of methyl 5-chloro-2-[(5-nitropyridin-2-yl)oxy]benzoate (step 1, 1.59 g, 5.2 mmol) and 5% palladium on activated carbon (149 mg) in ethyl acetate (25 mL) was stirred at room temperature for 1 h under hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and the filtrate was evaporated. The residue was purified by flush column chromatography on silica gel eluting with dichloromethane/methanol (50/1) to afford 301 mg (21%) of the title compound: 1H-NMR (CDCl3) δ 7.92 (1H, d, J=2.8 Hz), 7.56 (1H, d, J=2.6 Hz), 7.47 (1H, dd, J=8.7, 2.6 Hz), 7.11 (1H, dd, J=8.6, 2.8 Hz), 7.08 (1H, d, J=8.7 Hz), 6.82 (1H, d, J=8.6 Hz), 3.74 (3H, s), 3.49 (2H, br.s).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[C:4]2[CH:3]=[CH:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][S:15][C:13]1[O:14][C:10]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccnc3[nH]ccc23)o1
Reactant: Fc1cccc(CBr)c1
Product: Fc1cccc(CSc2nnc(-c3ccnc4[nH]ccc34)o2)c1
Yield: 64 %

Procedure:
In the same manner as in Example 1 and using 5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3,4-oxadiazole-2-thiol 5/6 triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 64%) was obtained as pale-yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[C:10]([F:26])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[F:26][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)cc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1COc1cc(F)c2c(CC(=O)O)csc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
A mixture of methyl(4-fluoro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (220 mg), 1N NaOH (2 mL), THF (2 mL) and MeOH (2 mL) was stirred at room temperature for 1.5 h. To the mixture were added 1N HCl (2 mL) and water. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residual solid was washed with hexane to give the title compound (180 mg). The crystals were crystallized from acetone-hexane.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH3:10][O:11][CH2:12][C:13]([O:15]C)=O.[Cl-].[NH4+]>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)([OH:15])[CH2:12][O:11][CH3:10])=[CH:4][CH:5]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COCC(=O)OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
4.9 g of magnesium, 5 cm3 of 4-bromofluorobenzene and 25 cm3 of tetrahydrofuran are heated to a temperature in the region of 60° C. 17 cm3 of 4-bromofluorobenzene in solution in 25 cm3 of tetrahydrofuran are added and the mixture is heated at a temperature in the region of 60° C. for 2 hours. 5 cm3 of methyl methoxyacetate in solution in 25 cm3 of tetrahydrofuran are added to the solution prepared above, cooled to a temperature in the region of 0° C. After stirring for 24 hours at a temperature in the region of 20° C., the reaction mixture is poured into 200 cm3 of saturated aqueous ammonium chloride solution and extracted with three times 75 cm3 of ethyl acetate, and the organic phases are washed with twice 100 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (35–70 μm), eluting with pure dichloromethane; 9.8 g of 1,1-bis(4-fluorophenyl)-2-methoxyethanol are thus obtained in the form of a yellow oil, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[C:9]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:18]([CH2:27]Cl)=[N:17][N:16]=2)=[CH:11][CH:10]=1>CN(C)C=O>[C:9]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:18]([CH2:27][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: C1COCCN1
Reactant: Fc1ccccc1-n1c(CCl)nnc1-c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1-n1c(CN2CCOCC2)nnc1-c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Morpholine (0.599 ml) was dissolved in N,N-dimethylformamide (6 ml), followed by addition of sodium hydride (60%, 275 mg) under ice cooling, and stirred at the same temperature for 30 minutes. Under ice cooling, 3-biphenyl-4-yl-5-chloromethyl-4-(2-fluorophenyl)-4H-1,2,4-triazole (599 mg) was added to the reaction solution, and stirred at ambient temperature for 17 hours. After the reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: toluene/acetone=3/2 to 1/1), and recrystallized from a mixture solution of n-hexane and ethyl acetate, to afford the entitled compound as white crystal (211 mg, 74%). The physico-chemical values are as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][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][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[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([O-])=O)[N:35]=[CH:34]2.[CH3:43][NH:44][CH3:45].O>CS(C)=O>[CH3:43][N:44]([CH3:45])[CH2:2][CH2:3][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][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[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)[NH:36][N:35]=[CH:34]2
Reactant: CNC
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCl
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN(C)C
Temperature: 85 °C

Procedure:
To an ice-cold solution of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.26 g, 0.55 mmol) in DMSO (3 mL) was bubbled dimethylamine for 3-4 minutes. The mixture was heated at 85° C. for 2 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1CC(NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, dissolved in DCM and cooled to 0 centigrade is added a corresponding benzaldehyde, then NaBH(OAc)3 and 5 drops of HOAc. The mixture is warmed to room temperature and stirred overnight. The mixture is diluted with DCM, washed with brine, and dried. After removal of solvent, the crude 4-(benzylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is obtained (33) and used for the next step without further purification.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1)(=O)C.Cl>[OH-].[Na+]>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([S:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])(=[O:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2ccc(S(=O)(=O)Nc3ccc(Cl)c(C(=O)O)c3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2ccc(S(=O)(=O)Nc3ccc(Cl)c(C(=O)O)c3)cc2c1
Temperature: 50 °C
Yield: 93.7 %

Procedure:
To 13.5 g (0.032 mol) of compound 132 was added 100 mL of 5N NaOH. This solution was heated at 50° C. for 8 hours. Then, the reaction was acidified-with 86 mL of 6N HCl and extracted with ethyl acetate. The ethyl acetate was washed with 1N HCl, water, and brine. The organic layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation to yield 11.3 g of compound 133.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.C([O-])(O)=O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:7]([O:6][C:4]([CH:3]1[CH2:9][CH2:10][CH2:11][N:1]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:2]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of 4.05 g (25.8 mmoles) of ethyl nipecotate and 4.33 g (51.5 mmoles) of NaHCO3 in water (26 mL) was added benzyl chloroformate (4.1 mL, 28.3 mmol). The reaction mixture was stirred at 23° C. under an atmosphere of N2 overnight. The crude products were diluted with water, extracted with Et2O, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→70:30 hexane:EtOAc) to yield the title compound as a clear colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[C:24]1([C@@H:30]2[CH2:34][O:33][C:32](=[O:35])[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:31]3[C@H:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:34][O:33][C:32]3=[O:35])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4c4ccccc4)cc3)CC2)c(C)c1
Yield: 9.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (841 mg) described in Preparation Example 8 and (R)-(−)-4-phenyloxazolidin-2-one (326 mg), the title compound (88 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1([CH2:32][OH:33])[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:11]3[C:17](=[O:18])[NH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[Br:34]N1C(=O)CCC1=O>>[Br:34][C:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][C:2]([OH:1])([CH2:32][OH:33])[CH2:3][CH2:4]3)[N:9]=[C:10]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:21]=3)[C:11]=2[C:17](=[O:18])[NH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Nc2nc(N3CCC(O)(CO)CC3)nc3cc[nH]c(=O)c23)cc1C(F)(F)F
Product: COc1ccc(Nc2nc(N3CCC(O)(CO)CC3)nc3c(Br)c[nH]c(=O)c23)cc1C(F)(F)F

Procedure:
The title compound was prepared as described in Example 183a by starting from 2-(4-hydroxy-4-(hydroxylmethyl)piperidin-1-yl)-4-(4-methoxy-3-(trifluoromethyl)phenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one and N-bromosuccinimide and continuing until the reaction yielded the title compound as pale brown solid. MS m/z: 544 and 546 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[CH2:7]2)[CH2:3][CH2:2]1.[CH2:16]=O>C(O)=O>[CH3:16][N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[CH2:7]2)[CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Solvent: O=CO
Product: CN1CCC2(CC1)CC(=O)c1ccccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To the product of Example 138A were added formic acid (88% sol, 0.64 g) and formaldehyde (36% sol, 0.45 g) and stirred at 120° C. overnight. The crude product was used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:19]([F:22])([F:21])[F:20])=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[NH4+:23].[OH-]>CS(C)=O>[NH2:23][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([C:19]([F:20])([F:21])[F:22])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:11]
Reactant: Cc1ccc(C(=O)/C=C(/c2ccc(Br)cc2)C(F)(F)F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)CC(N)(c2ccc(Br)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of Intermediate 3A (1.53 g, 4.14 mmol) in DMSO (23 mL) was added 15 N aq NH4OH (10 mL). The reaction vessel was sealed and the reaction was stirred at rt for 16 h. Additional DMSO (3 mL) and 15 N aq NH4OH (1 mL) were added and the reaction was stirred at rt for 16 h. Addition of DMSO (4 mL) was repeated and the reaction was stirred for another 16 h. The solution was concentrated in vacuo followed by lyophilization to provide Intermediate 3B (1.8 g, 100%) as a brown oil. LCMS Anal. Calc'd for C17H15BrF3NO 386.21, found [M+H] 388.1.
Reaction SMILES: [OH:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH:5]([NH:8]C(=O)OCC2C=CC=CC=2)[CH2:4][CH2:3]1>C(O)C.[C].[Pd]>[NH2:8][CH:5]1[CH2:6][CH2:7][C:2]([CH3:19])([OH:1])[CH2:3][CH2:4]1
Reactant: CC1(O)CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1(O)CCC(N)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The compound obtained in Step 1 of this Reference Example was dissolved in ethanol (12 mL). To the solution, 10% palladium-carbon catalyst (hydrated, 400 mg) was added, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere at normal pressure. After filtration through celite, the filtrate was concentrated under reduced pressure to obtain a crude product of 4-amino-1-methylcyclohexanol. This crude product and ethyl 3-(dimethylamino)-2-isocyanoacrylate (450 mg) were mixed and stirred at 75° C. for 8 hours. To the reaction solution, saturated aqueous ammonium chloride was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1-ethyl acetate) to obtain a diastereomeric mixture of the title compound (462 mg, trans:cis=1:3).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[O:24])[CH:17]=1.CS(C)=O.C(O)(=O)C.O.[NH2:41][C:42]([NH2:44])=[NH:43]>>[NH:43]([C:3](=[O:2])[CH2:4][N:5]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:17]=[C:18]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[O:24])[CH:19]=[CH:20][CH:21]=1)[C:42]([NH2:44])=[NH:41]
Reactant: N=C(N)N
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc1-c1cccc(NC(=O)c2cc(C)on2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)Nc2cccc(-c3ccc(-c4ccccc4)n3CC(=O)NC(=N)N)c2)no1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The residue from step 3 is dissolved in 300 μl guanidine in dimethylsulfoxide (500 μmoles) and agitated in a shaker at room temperature for 1-4 h. The reaction is quenched with excess acetic acid (ca. 1 mmole), DMSO (200 uL) and water (100 uL), and concentrated in vacuo. The residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL total) and purified by Gilson preparative HPLC system, Retention Time, 0.76 min., M+H 443.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:36])=[N:13][C:14]2[CH2:15][CH2:16][N:17]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:36])=[N:13][C:14]2[CH2:15][CH2:16][N:17]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(CCc1ccccc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c3c(nc(C)c2C(OC(C)(C)C)C(=O)O)CCN(CCc2ccccc2)C3)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(tert-butoxy)-2-(2-methyl-6-phenethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 19) (34.1 mg, 0.070 mmol) in dioxane (1 mL) was added 1N NaOH (0.700 mL) and the reaction was stirred at 75° C. After 1 h, the mixture was cooled to room temperature and neutralized with 0.7 ml 1M HCl then concentrated. The crude material was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column. Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 30-100% B over 12 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation 1H NMR (500 MHz, DMSO-d6) δ ppm 7.29-7.38 (m, 2H), 7.21-7.26 (m, 2H), 7.09-7.21 (m, 5H), 4.77 (s, 1H), 3.26 (s, 1H), 2.95 (d, J=14.95 Hz, 1H), 2.88 (br. s., 3H), 2.62-2.76 (m, 3H), 2.58 (d, J=7.02 Hz, 2H), 2.48 (s, 3H), 2.40 (s, 3H), 0.87 (s, 9H). LCMS (M+H) calcd for C30H37N2O3: 473.28. found: 473.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:16]=[C:15]([SH:17])[CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11]C)=[O:10])[CH2:2][CH2:3][CH3:4].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.P(Br)(Br)Br.FC(F)(F)C1C=CC(C2C=CC(CO)=CC=2)=CC=1>>[CH2:1]([C:5]1[CH:16]=[C:15]([S:17][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(S)ccc1OCC(=O)OC
Reactant: FC(F)(F)c1ccc(-c2ccc(CBr)cc2)cc1
Agent: BrP(Br)Br
Agent: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: CCCCc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 100F and 1-(bromomethyl)-4-[4-(trifluoromethyl)phenyl]benzene prepared from and phosphorous tribromide and (4′-trifluoromethyl-biphenyl-4-yl)-methanol in a manner analagous to Example 3B. 400 MHz 1H NMR (CDCl3) δ 7.68 (m, 4H), 7.51 (d, 2H), 7.29 (d, 2H), 7.15 (m, 2H), 6.60 (d, 1H), 4.62 (s, 2H), 4.04 (s, 2H), 3.79 (s, 3H), 2.60 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 0.88 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])=O)[O:5][C:6]=1[CH3:7].[NH3:17]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])=[N:17][C:6]=1[CH3:7]
Reactant: N
Reactant: Cc1ccncc1C(=O)c1cc(C)c(C)o1
Solvent: CO
Product: Cc1ccncc1-c1nc(C)c(C)cc1O
Temperature: 160 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanone (150 mg), methanol (2 ml), and a 28% aqueous ammonia solution (2 ml) were placed in a sealed tube and was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give 5,6,4′-trimethyl-[2,3′]bipyridin-3-ol (30 mg, yield 20%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1([CH3:24])[S:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[NH:11][C@H:10]1[C:21]([OH:23])=[O:22]>O>[C:1]([N:11]1[C@@H:10]([C:21]([OH:23])=[O:22])[C:9]([CH3:24])([CH3:8])[S:13][C@H:12]1[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C2N[C@@H](C(=O)O)C(C)(C)S2)cc1
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc(C)cc1
Temperature: 100 °C

Procedure:
5.6 ml of acetic anhydride are added to a hot suspension containing 2.51 g (10 mmoles) of 5,5-dimethyl-2-(4-methylphenyl)-thiazolidine-4(S)-carboxylic acid in 5.6 ml of water, then the mixture is heated at 100° C. for 5 minutes. On cooling, crystals are precipitated which are recrystallized from isopropanol to give the title compound in a yield of 2.15 g (73.3%), m.p.: 214°218° C., [α]D19 =-101° (c=0.71, methanol).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.CO>O1CCCC1.CCCCCC>[OH:3][CH2:4][C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Yield: 99.1 %

Procedure:
A suspension of 3.84 g (0.015 mole) of 5,6-dihydro-5-oxopyrazolo[1,5-c]quinazoline-2-carboxylic acid ethyl ester prepared as described in part A above is stirred in 150 ml of tetrahydrofuran under nitrogen at room temperature. There is added 24 ml (0.034 mole) of a 20% solution of diisobutyl aluminum hydride in hexane. The resultant solution is stirred for 1 hour at room temperature whereupon 50 ml of methanol is added and the reaction mixture refluxed for 1 hour. The precipitate of aluminum alkoxide is filtered, air dried and Soxhlet extracted for 48 hours with boiling methanol. The extract is combined with the above filtrate and stripped to give 3.2 g of a white solid (quantitative yield). Recrystallization from methanol gives 2.7 g of pure title compound, m.p. 285°-287°.