Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]([NH:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=O)[CH2:36][CH3:37]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[N:14]=[N:15][CH:34]=[C:35]([CH2:36][CH3:37])[C:11]=2[C:10](=[O:26])[CH2:9]1
Reactant: CCC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccccc3Cl)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (1.56 g), anhydrous potassium carbonate (0.72 g), 1-bromobutan-2-one (0.785 g) and methanol (30 ml) was stirred at room temperature for 2.5 hours. To the mixture was added anhydrous potassium carbonate (0.72 g), and the mixture was stirred at room temperature 1.5 hours and refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography to give 7-(2-chlorophenyl)-4-ethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.492 g) as oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([C:31]#[N:32])[N:28]=[CH:27]2)=[C:22]([O:33][CH3:34])[CH:21]=1.CC(O)=O.[OH-].[Na+]>O1CCOCC1>[CH3:34][O:33][C:22]1[CH:21]=[C:20]([NH:19][C:2]2[N:3]=[C:4]([NH:17][CH3:18])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([C:31]#[N:32])[N:28]=[CH:27]1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-n3cnc(C#N)c3)c(OC)c2)nc2c1CCC2c1ccccc1
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a solution of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Ga) (150 mg, 0.578 mmol) in Dioxane (Ratio: 1, Volume: 1013 μl) was added 1-(4-amino-2-methoxyphenyl)-1H-imidazole-4-carbonitrile (Preparation AA) (124 mg, 0.578 mmol), and AcOH (Ratio: 1.000, Volume: 1013 μl). The resulting mixture was brought to 100° C. in a sealed vial and stirred overnight. The mixture was brought to pH 8 by the addition of 1 N aqueous sodium Hydroxide. The resulting mixture was extracted with EtOAc (3×1 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by prep HPLC (Waters Sunfire C18, 50×250 mm, acetonitrile/H2O/ammonium acetate) gave 1-(2-methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)-1H-imidazole-4-carbonitrile (57 mg, 0.130 mmol, 22.56% yield). LC-MS (M+H)+=438.2. 1H NMR (500 MHz, MeOD) δ ppm 8.02-8.08 (2H, m), 7.90-7.94 (1H, m), 7.31 (2H, t, J=7.63 Hz), 7.16-7.24 (4H, m), 6.99 (1H, dd, J=8.55, 2.14 Hz), 4.18 (1H, t, J=8.09 Hz), 3.56 (3H, s), 3.07 (3H, s), 2.76-2.84 (1H, m), 2.59-2.74 (2H, m), 1.98-2.05 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([NH:13][C:14](=[O:24])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([NH:13][C:14](=[O:24])[CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: COCCOCCOCC(=O)Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOCC(=O)Nc1cc(N)cc(C(=O)O)c1

Procedure:
3-Amino-5-(3,6,9-trioxadecanamido)benzoic Acid [H; T is CH3OCH2CH2OCH2CH2OCH2, Z is OH] was prepared by hydrogenation of 80 g. of 3-nitro-5-(3,6,9-trioxadecanamido)benzoic acid in absolute ethanol in the presence of palladium-on-charcoal catalyst. There was thus obtained 54.7 g. of 3-amino-5-(3,6,9-trioxadecanamido)benzoic acid, m.p. 130.5°-131° C. when recrystallized from isopropyl alcohol.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[C:15]([CH3:16])[C:10]3=[CH:9][N:8]=2)[CH2:4][C:3]1=[O:17].CN(C)C=O.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:9]1[N:8]=[C:7]([CH:5]2[CH2:6][N:2]([CH3:1])[C:3](=[O:17])[CH2:4]2)[N:11]2[CH:12]=[CH:13][N:14]=[C:15]([CH3:16])[C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn2c(C3CC(=O)N(C)C3)ncc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn2c(C3CC(=O)N(C)C3)nc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
1-Methyl-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-2-one (293 mg, 1.27 mmol) was dissolved N,N-dimethylformamide (12 ml) and N-bromosuccinimide (227 mg, 1.27 mmol) was added and reation mixture was stirred at room temperature overnight. Then water was added to the reaction mixture and extracted with chloroform/iso-propanol (9/1) three times. The combined organic layers were dried (Na2SO4) and concentrated in vacuo and a brown oil was obtained. The residue was purified by column chromatography (silica gel; dichloromethane/methanol/heptane=9/1/4) to give 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)-1-methylpyrrolidin-2-one (200 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2>>[F:22][C:23]1[C:31]([O:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2
Reactant: COCCOCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Product: COCCOCCOc1cc2nncc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Yield: 18.4 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)cinnoline (100 mg, 0.32 mmol) was reacted with 4-fluoro-5-hydroxy-2-methylindole (64 mg, 0.38 mmol), (prepared as described for the starting material in Example 1), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)cinnoline (26 mg, 19%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Cl[C:15]1[CH:27]=[C:19]2[N:20]([CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:28])[N:16]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])[CH2:12][O:13][C:15]1[CH:27]=[C:19]2[N:20]([CH:24]([CH3:25])[CH3:26])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:28])[N:16]=1
Reactant: CC(C)N1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(C(F)(F)F)c(F)c1
Product: CC(C)N1CCCn2c1cc(OCc1ccc(C(F)(F)F)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(trifluoromethyl)phenyl)methanol and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][C:27]#[C:28][C:29]4[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>C1COCC1.[Pt]=O>[CH3:1][C:2]1([CH3:39])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]4[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCC#Cc4cccc(S(N)(=O)=O)c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(N)(=O)=O)c4)C(=O)O3)ccc2O1
Yield: 98 %

Procedure:
3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide (2.35 g) was stirred with platinum oxide (0.3 g) in THF (30 ml) under hydrogen for 2 h. The catalyst was removed by filtration using a filter aid and the filter cake was leached with ethyl acetate. The combined filtrates were passed through silica gel (200 g) in ethyl acetate and the eluate was evaporated to give the title compound (2.32 g), LCMS RT=3.49 min.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30]([C:33]1[CH:34]=[C:35]([CH:39]([CH3:43])[CH2:40][CH:41]=O)[CH:36]=[CH:37][CH:38]=1)([CH3:32])[CH3:31].CC(O)=O>C1COCC1>[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH2:40][CH:41]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)[CH3:43])[CH:34]=1)([CH3:32])[CH3:31]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C=CCC(C)c2cccc(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Potassium t-butylat (17.1 mL, 17.1 mmol, 1.0 equiv., 1M in THF) was added to a solution of (4-methoxyphenyl)methyltriphenylphosphonium bromide (7.90 g, 17.1 mmol, 1.0 equiv.) in THF (17 mL) at 25° C. After the dark red suspension was stirred at 25° C. for 10 min, 3-(3-isopropylphenyl)butanal (3.24 g, 17.1 mmol, 1.0 equiv.) in THF (8.5 mL) was added, and the mixture was stirred at 25° C. 12 h. After addition of 20% aq. AcOH-solution at 25° C., the aqueous layer was extracted with hexane. The combined organic phases were washed with MeOH/H2O (4:1; 2-3x), dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5→99:1) to yield 4.03 g (80%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:25])[CH:3]=1.C(Cl)(=[O:33])C1C=CC=CC=1>N1C=CC=CC=1>[C:15]([OH:24])(=[O:33])[C:13]1[CH:14]=[CH:9][CH:10]=[CH:11][CH:12]=1.[CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:15]([OH:24])([C:16]([F:19])([F:18])[F:17])[C:20]([F:21])([F:22])[F:23])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:25])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)OCC2
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1
Temperature: 0 °C

Procedure:
To a suspension of 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-5H-pyrido[1,2,3-de]-1,4-benzoxazin-5-one in pyridine is added benzoyl chloride. The suspension is stirred and heated at reflux until homogenous. The solution is added to ice cold 2 N hydrochloric acid. The resultant mixture is extracted with ether; the etheral solution is dried with anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to give 2,3-dihydro-7-methyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-5H-pyrido[1,2,3-de]-1,4-benzoxazin-5-one benzoate.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([NH:10][C:11](=[O:21])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[N:8][CH:9]=1)=O.[OH-].[NH4+:23]>>[CH2:14]([O:13][CH2:12][C:11]([NH:10][N:6]1[C:5]([C:3]([NH2:23])=[O:2])=[CH:9][N:8]=[CH:7]1)=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cncn1NC(=O)COCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cncn1NC(=O)COCc1ccccc1
Temperature: 70 °C
Yield: 88 %

Procedure:
Compound 2 (8.7 g, 30.1 mmol) and ammonium hydroxide (15 ml) were combined in a sealed tube and heated to 70° C. under microwave irradiation for 2 hours. The mixture was concentrated in vacuo to afford compound 3 (7.3 g, 88% yield) as a white solid. LC-MS: m/z 275.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12].O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:11]([NH2:12])=[N:16][NH:17][C:13]=1[NH2:14]
Reactant: NN
Reactant: N#CC(C#N)Cc1cccc(Cl)c1Cl
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Yield: 46.8 %

Procedure:
To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 mL) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH (20 mL) was added and the mixture was stirred at rt for 20 min and cooled to 0° C. in an ice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%). To a solution of [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 34.9 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.57 mL, 52.4 mmol). The mixture is heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (4.2 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.77 (s, 2H) 7.09 (m, 1H) 7.19 (t, J=7.96 Hz, 1H) 7.38 (m, 1H); LC/MS: MS (ES+) m/e 257.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17](Br)[C:16]([OH:20])=[C:15](Br)[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6](Br)[C:7]=1[OH:8].CC1C=C(C(C2C=C(C)C(O)=C(C)C=2)(C)C)C=C(C)C=1O.OC1C=CC(C2(C3C=CC(O)=CC=3)CCCCC2)=CC=1.CC1C=C(C2(C3C=C(C)C(O)=C(C)C=3)CCCCC2)C=C(C)C=1O.OC1C=CC(C(C2C=CC(O)=CC=2)CCCCCCCCC)=CC=1.OC1C=CC(C2(C3C=CC(O)=CC=3)CCCCCCCCCCC2)=CC=1.CC1C=C(C2(C3C=C(C)C(O)=C(C)C=3)CCCCCCCCCCC2)C=C(C)C=1O.S(C1C=CC(O)=CC=1)C1C=CC(O)=CC=1.OC1C=CC(OC2C=CC(O)=CC=2)=CC=1>>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([C:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=2)([CH3:12])[CH3:11])=[CH:5][CH:6]=1
Reactant: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Agent: CCCCCCCCCC(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cc1cc(C(C)(C)c2cc(C)c(O)c(C)c2)cc(C)c1O
Agent: Cc1cc(C2(c3cc(C)c(O)c(C)c3)CCCCC2)cc(C)c1O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane; 2,2-bis(3,5-dimethyl-4-hydroxyphenyl)propane; 1,1-bis(4-hydroxyphenyl)cyclohexane; 1,1-bis(3,5-dimethyl-4-hydroxyphenyl)cyclohexane; 1,1-bis(4-hydroxyphenyl)decane; 1,4-bis(4-hdroxyphenyl)propane; 1,1-bis(4-hydroxyphenyl)cyclododecane; 1,1-bis(3,5-dimethyl-4-hydroxyphenyl)cyclododecane; 4,4'-thiodiphenol; and bis(4-hydroxyphenyl)ether.
Reaction SMILES: C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C.[CH3:15][C:16]1([CH3:40])[O:20][CH:19]([CH2:21][N:22]2[C:34]3[C:33]4[CH:32]=[CH:31][C:30]([OH:35])=[CH:29][C:28]=4[N:27]=[CH:26][C:25]=3[N:24]=[C:23]2[CH2:36][O:37][CH2:38][CH3:39])[CH2:18][O:17]1.O[CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:15][C:16]1([CH3:40])[O:20][CH:19]([CH2:21][N:22]2[C:34]3[C:33]4[CH:32]=[CH:31][C:30]([O:35][CH:42]5[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]5)=[CH:29][C:28]=4[N:27]=[CH:26][C:25]=3[N:24]=[C:23]2[CH2:36][O:37][CH2:38][CH3:39])[CH2:18][O:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOCc1nc2cnc3cc(O)ccc3c2n1CC1COC(C)(C)O1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC1COC(C)(C)O1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of diisopropyldiazodicarboxylate (0.710 g, 3.50 mmol) in tetrahydrofuran (6 mL) was added dropwise to a mixture of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol (prepared as described in Parts A-D of Example 372, 1.00 g, 2.80 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.70 g, 3.50 mmol), and triphenylphosphine (0.920 g, 3.50 mmol) in tetrahydrofuran (35 mL) at 0° C. The resulting solution was allowed to warm to room temperature over 16 hours. The solution was concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, gradient elution with 0-50% CMA in chloroform) to provide 1.16 g of tert-butyl 4-{[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a white foam.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:7]=O)[C:3]([O:5][CH3:6])=[O:4].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:9])[CH2:7][N:13]1[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: COC(=O)C(C)(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Stir a solution of methyl 2,2-dimethyl-3-oxo-propanoate (30.88 g, 237.31 mmoles) and tert-butyl piperazine-1-carboxylate (34.00 g, 182.55 mmoles) in DCM (500 mL) at room temperature for 20 minutes. Add acetic acid (2 equiv); 20.92 mL, 365.09 mmoles) followed by sodium triacetoxyborohydride (1.4 equiv; 54.17 g, 255.56 mmoles) over 0.5 h and stir the resulting mixture stirred at room temperature overnight. Carefully quench with water (250 mL) and transfer the mixture to a separating funnel with DCM (300 mL). Wash the resulting organic layer with brine. Dry over MgSO4, filter and evaporate to give tert-butyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)piperazine-1-carboxylate. (58 g, 100%). MS (m/z): 301.2 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C@@:7]12[CH2:18][CH2:17][CH2:16][C:14]3[C:15]1=[C:10]([CH:11]=[CH:12][CH:13]=3)[NH:9][C:8]2=[O:19])([OH:3])=[O:2].Cl.[CH:21](OC(C)C)(C)C>CO>[CH3:21][O:2][C:1]([CH2:4][CH2:5][CH2:6][C@@:7]12[CH2:18][CH2:17][CH2:16][C:14]3[C:15]1=[C:10]([CH:11]=[CH:12][CH:13]=3)[NH:9][C:8]2=[O:19])=[O:3]
Reactant: O=C(O)CCC[C@@]12CCCc3cccc(c31)NC2=O
Reactant: CC(C)OC(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)CCC[C@@]12CCCc3cccc(c31)NC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
(S)-2a-(3-carboxypropyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (7.00 g, 27 mmol) was dissolved in methanol (200 ml). Then, 36% hydrochloric acid 0.1 ml was added thereto and stirred at room temperature for two days. The solvent was evaporated from the reaction mixture, and ethyl acetate and water were added to the resulting residue. A reaction product was extracted with ethyl acetate, and the extracted product was washed with saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent. The resulting product was crystallized from diisopropyl ether, whereby 6.89 g (yield 93%) of the above-described object compound could be obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][C:10]2=[O:12]
Reactant: O=C(O)CCc1ccccc1Cl
Solvent: O
Product: O=C1CCc2c(Cl)cccc21
Yield: 36.6 %

Procedure:
A mixture of 200 ml of polyphosphoric acid and 23.6 g (128 mmol) of 3-(2-chlorophenyl)-propanoic acid was heated on the steam bath for six hours. The mixture was allowed to cool, diluted with 500 ml of water, and the resulting solid collected. The solid was partitioned between ether and saturated sodium bicarbonate, the ether layer was separated, dried (MgSO4), and concentrated to a solid. The solid was crystallized from ether/hexane to give 7.8 g (37%) of 4-chloro-2,3-dihydro-1H-inden-1-one; mp 89°-92°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]([C:36]1[CH:40]=[C:39]([NH2:41])[O:38][N:37]=1)([CH3:35])[CH3:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:41][C:39]2[O:38][N:37]=[C:36]([C:33]([CH3:35])([CH3:34])[C:32]([F:31])([F:42])[F:43])[CH:40]=2)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Reactant: CC(C)(c1cc(N)on1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (1.060 g, 2.58 mmol) and 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (0.5 g, 2.58 mmol) in pyridine (20 mL) was added T3P® (50% in EA, 5 mL, 2.58 mmol) dropwise and stirred at 25° C. for 1 h. The mixture was poured into stirring cold water (100 mL). The mixture was stirred for 0.5 h and left standing for 10 h. The resulting solid was filtered, washed with H2O (200 mL×3) and TBME (200 mL×2) and dried in vacuo to give an off white solid 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (1.5 g, 2.298 mmol, 89% yield): 1H NMR (400 MHz, CD3OD): δ 7.96 (s, 1H), 7.40-7.32 (m, 3H), 7.28 (d, J=9.6 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.45 (s, 1H), 6.38 (s, 1H), 5.27 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.83 (s, 2H), 3.79 (s, 3H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 588 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][C:12]=2[CH:26]=[O:27])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(-c2coc(-c3ccccc3)n2)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-phenyloxazole (14.43 g), phosphorus oxychloride (12.97 g), N,N-dimethylformamide (100 mL) was stirred at 90° C. for 1.5 hrs. The reaction mixture was poured into iced water, and the precipitated solid was collected by filtration, washed successively with aqueous sodium hydrogen carbonate solution and water and dried. The obtained crystals were recrystallized from acetone-hexane to give 4-(4-chlorophenyl)-2-phenyl-5-oxazolecarbaldehyde (7.90 g, 49%) as yellow prism crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH:7]=[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1ccccc1

Procedure:
To a stirred suspension of 10% palladium on carbon (15 mg) in ethanol (2 mL) was added a solution of 3-phenyl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acid tert-butyl ester 29-7a (62 mg) in ethanol (3 mL) and the mixture was subjected to an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through Celite and concentrated at reduced pressure to give 29-8a as an oil.