Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:23][CH:22]([N:24]([CH3:26])[CH3:25])[CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:21][CH:22]([N:24]([CH3:25])[CH3:26])[CH2:23]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4F)ccn3)CC2)C1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
To a solution of 4-(3-dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (258 mg) in tetrahydrofuran (50 ml) was added 20% palladium hydroxide carbon (198 mg), followed by stirring under a hydrogen atmosphere at room temperature for 12 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with tetrahydrofuran:methanol=1:1. The filtrate was concentrated to provide the titled compound (236 mg, 97.8%) as a yellow amorphous substance.
Reaction SMILES: [C:1]1(=[O:13])[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([N-]C(C)C)(C)C.[Li+].C(OC(=O)C)(=O)C>C1COCC1>[C:15]1([CH2:14][N:21]2[CH2:26][CH2:25][CH:24]([CH:27]=[C:2]3[CH2:3][C:4]4[NH:5][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:12]=4[C:1]3=[O:13])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCc2[nH]c3ccccc3c21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2[nH]c3ccccc3c21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1,2,3,4-tetrahydrocyclopent[b]-indol-1-one (440 mg, 2.6 mmol) and 1-benzylpiperidine-4-carboxaldehyde (581 mg, 2.86 mmol) in 90 ml dry THF was added 5.4 mmol of lithium diisopropylamide at -78° C. The mixture was stirred at -78° C. for 30 minutes, then warmed up to 0° C. for 1.5 hours, and then to r.t. for 15 minutes. Acetic anhydride (0.265 g, 2.6 mmol) was added, the mixture was stirred at r.t. for 1.5 hours and quenched ammonium chloride, water and extracted with chloroform. The organic layer was dried, concentrated, and purified through silica gel to give the title compound. 1HNMR (CDCl3)δ 1.45-1.7 (m, 3H), 1.8-2.3 (m, 4H), 2.8-3.0 (m, 2H), 3.46 (s, 2H), 3.55 (s, 2H), 6.5 (m, 1H), 7.1-7.4 (m, 8H), 7.9 (m, 1H), 9.2 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:13][C:14]=1[N:15]([CH:25]([CH3:27])[CH3:26])[C:16]([CH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])=[O:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:13][C:14]=1[N:15]([CH:25]([CH3:26])[CH3:27])[C:16]([CH:18]1[CH2:23][CH2:22][C:21](=[CH2:1])[CH2:20][CH2:19]1)=[O:17])=[O:9]
Reactant: [Li]CCCC
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(=O)CC1)C(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)OC)C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Butyllithium (2.5 M, 0.9 mL, 2.280 mmol) was added to a cold solution (−78° C.) of methyltriphenylphosphonium bromide (939 mg, 2.630 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 1 h and then 3-[Isopropyl-(4-oxo-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. (700 mg, 1.754) in THF (5 mL) was added at −78° C. The reaction mixture was allowed to stir at room temperature for 12 h. The reaction was quenched by adding saturated solution of NH4Cl and diluted with ethyl acetate. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate:hexane (1:4) to obtain 3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (300 mg, 43%) as a solid. 1H NMR (CDCl3, 400 MHz): δ7.63 (d, 2H), 7.50-7.38 (m, 3H), 7.12 (s, 1H), 4.99 (m, 1H), 4.55 (d, 2H), 3.85 (s, 3H), 2.25 (m, 3H), 1.83-1.63 (m, 5H), 1.50 (m, 1H), 1.25 (d, 3H), 0.99 (d, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:10]1
Reactant: BrCCCCCCCCBr
Reactant: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 54.3 %

Procedure:
A mixture of 4,5-diphenyltriazole (11 g), 1,8-dibromooctane (67.6 g), and potassium carbonate (10.31 g) in dry butanone (300 ml) was heated at reflux temperature for 24 hours. The mixture was filtered and the solvent evaporated to give an oily residue. Distillation to remove 1,8-dibromooctane and column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 2-(8-bromooctyl)-4,5-diphenyl-triazole (11.13 g, 54%) as an oil. NMR d (CDCl3) 1.2-1.5 (8H, m, 4×CH2), 1.84 (2H, m, CH2), 2.05 (2H, m, CH2), 3.37 (2H, t, Br--CH2), 4.47 (2H, t, N--CH2), 7.3-7.6 (10H, m, 2×Ph) ppm
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:15](=O)[C@@H:14]3[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:15][C@@H:14]3[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(N2C[C@@H]3[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 4 h
Yield: 6.2 %

Procedure:
To a solution of compound 23G (150 mg, 0.5 mmol) in anhydrous THF (12 mL) cooled to −78° C. was added dropwise 1.0 M LiEt3BH solution in THF (0.5 mL, 0.5 mmol). After addition, the reaction was stirred at −78° C. for 4 h, then quenched by addition of saturated aqueous Na2CO3 (5 mL). The reaction was warmed to 0° C., 30% H2O2 (˜0.5 mL) was added, and the reaction was stirred at 0° C. for 30 min, then extracted with CH2Cl2 (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure overnight. The residue (˜120 mg) was dissolved in anhydrous CH2Cl2, and to the resulting solution cooled to −78° C. was added dropwise triethylsilane (0.5 mL, 3.1 mmol), followed by boron trifluoride diethyl etherate (0.5 mL, 3.9 mmol). The reaction mixture was stirred at −78° C. for 2 h, then additional triethylsilane (0.3 mL, 1.88 mmol) and boron trifluoride diethyl etherate (0.3 mL, 2.35 mmol) were added, and the reaction was stirred at 0° C. overnight. The reaction was then quenched with saturated aqueous Na2CO3 (10 mL), then extracted with CH2Cl2 (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give a crude product (˜100 mg). The crude product was purified using preparative HPLC to give 30 mg, which was further purified using chiral preparative HPLC to afford the title compound (9 mg). HPLC: 98% at 4.39 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). Chiral HPLC: retention time=10.59 min (99%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in hexane for 30 min at 1 mL/min; MS (ES) m/z 292 [M+1]+.
Reaction SMILES: C([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=1[CH2:11][OH:12])O.[N+:13]([O-])([OH:15])=[O:14]>O>[N+:13]([C:6]1[CH:7]=[C:8]([CH3:9])[CH:3]=[C:4]([CH2:11][OH:12])[C:5]=1[OH:10])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c(CO)c1CO
Solvent: O
Product: Cc1cc(CO)c(O)c([N+](=O)[O-])c1
Yield: 80 %

Procedure:
The 6-nitro-2-methylol p-cresol was prepared by charging 134.3 grams of bis-methylol para cresol (BMPC) (assay: 97.9%, melting point: 124.5 to 126.5° C.), and 3000 grams of deionized water into a 5 liter, wide mouth beaker and stirring to achieve a colloidal suspension of the BMPC before 200 grams of concentrated nitric acid was added in 30 minutes as the temperature was maintained between 20 and 30° C. The mixture was mixed an additional 24 hours at room temperature before a Buchner funnel filtration. The wetcake was washed with deionized water until the effluent achieved a pH of 6. The wetcake was then vacuum oven dried (30-35° C.,<10 torr) until the residual water assay was less than 1 percent. Yield: 80 to 85%.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:13][CH:14](C(OCC)=O)[C:15](OCC)=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:25]([OH:29])([CH3:28])([CH3:27])[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>CO>[C:3]1([CH2:13][CH2:14][C:15]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
18.7 g (0.333 mmole) of potassium hydroxide were added to a solution of 20 g (66.6 mmole) of diethyl (1-naphthyl)methylmalonate dissolved in 200 ml of 80% v/v aqueous methanol, The mixture was then stirred at room temperature for 1 hour, after which it was concentrated by evaporation under reduced pressure. The residue was dissolved in water, and the resulting solution was washed with ethyl acetate. The aqueous solution was acidified with concentrated hydrochloric acid and then extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was decarboxylated by heating at 200° C. for 30 minutes, and was then suspended in 200 ml of diethyl ether. 19 ml of t-butanol, 16.5 g (80 mmole) of dicyclohexylcarbodiimide and 0.8 g of N,N-dimethylaminopyridine were added to the suspension. The mixture was allowed to stand for 24 hours. The precipitated insoluble materials were removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: methylene chloride), to afford 12.18 g (71.4%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]([CH3:38])([CH3:37])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[CH:17][C:16]=2[N+:33]([O-])=O)=[C:8]([CH3:36])[CH:7]=1>P(OCC)(OCC)OCC>[CH3:1][O:2][C:3](=[O:39])[C:4]([CH3:38])([CH3:37])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:33][C:16]3[C:15]([CH:14]=2)=[CH:20][CH:19]=[C:18]([C:21]2[O:22][C:23]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)=[N:24][N:25]=2)[CH:17]=3)=[C:8]([CH3:36])[CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(/C=C/c2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[N+](=O)[O-])c(C)c1
Agent: CCOP(OCC)OCC
Product: COC(=O)C(C)(C)Cc1cc(C)c(-c2cc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(C)c1

Procedure:
Slurry 3-[4-((E)-2-{4-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-nitro-phenyl}-vinyl)-3,5-dimethyl-phenyl]-2,2-dimethyl-propionic acid methyl ester (245 mg, 0.449 mmol) in triethyl phosphite (6 mL) and heat to 160° C. for 2 h under N2. Concentrate the reaction under reduced pressure. Purify the concentrate by silica gel chromatography (5-35% EtOAc/HEP) to afford 3-(4-{6-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-indol-2-yl}-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester as a yellow solid: (M+H)+ 514.3.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of naphthalene-1-carboxylic acid (300 mg, 1.74 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (357 mg, 1.74 mmol), HATU (992 mg, 2.61 mmol) in anhydrous DMF (8 mL) is added DIPEA (431 μL, 2.61 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (41) as white solid (383 mg, 61%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15].ClCCl.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(N(CC)CC)C>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCOS(C)(=O)=O
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirred solution of 18.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane are added 11.9 parts of N,N-diethylethanamine. Then there are added dropwise (slowly) 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 4-methyl-2-pentanone, yielding 15 parts (58%) of 3-(2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate; mp 125° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=O)CC([C:32]3[CH:37]=[CH:36][C:35](F)=[CH:34][C:33]=3[C:39]3[CH:40]=[N:41]C=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]4[C:33]=3[CH:39]=[CH:40][NH:41]4)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccccc1Br)CC2=O
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1cccc3[nH]ccc13)CC2=O

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/h stage 2), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one using 4-boronic acid-1H-indole instead of 3-pyridyl boronic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]#[N:27])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(O)=[O:29].[Na+]>S(=O)(=O)(O)O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([NH2:27])=[O:29])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: N#CC[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trans-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)cyclohexyl)acetonitrile hydrochloride (0.056 g, 0.14 mmol) was suspended in sulfuric acid (2 mL) at 0° C. The reaction was warmed to rt and stirred for 16 h. After this time, the mixture was added dropwise to a saturated NaHCO3 solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol), followed by formation of the hydrochloride salt to afford the title compound (0.048 g, 82%) as a white solid. MW=420.38. 1H NMR (DMSO-d6, 500 MHz) δ 13.50 (s, 1H), 7.99-7.96 (m, 1H), 7.86-7.82 (m, 1H), 7.71-7.67 (m, 1H), 7.62-7.58 (m, 2H), 7.27 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 3.89-3.79 (m, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H), 1.96 (d, J=7.0 Hz, 2H), 1.92-1.85 (m, 2H), 1.78-1.71 (m, 2H), 1.70-1.60 (m, 1H), 1.50-1.38 (m, 2H), 1.21-1.09 (m, 1H); APCI MS m/z 384 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][CH:17]=3)=[CH:14][CH2:13][CH:12]2[C:30]2[CH:35]=[CH:34][C:33]([N:36]3C(C)=CC=C3C)=[CH:32][CH:31]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:36][C:33]1[CH:34]=[CH:35][C:30]([CH:12]2[CH:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=3)[C:15]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:21]=3)=[CH:14][CH2:13]2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(C)n1-c1ccc(C2CC=C(c3ccc(NC(=O)OC(C)(C)C)cc3)C2c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(C2=CCC(c3ccc(N)cc3)C2c2ccc(C(C)(C)C)cc2)cc1

Procedure:
A mixture of Example 7K (475 mg, 0.847 mmol), hydroxylamine hydrochloride (353 mg, 5.08 mmol) and KOH (143 mg, 2.54 mmol) in ethanol (6 mL) and water (2 mL) was stirred at 65° C. for 48 hours. The mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL) and washed with brine (6 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was used directly in the next step without further purification. LC/MS (ESI) m/z 483 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:16])=[C:11]([CH:15]=2)[C:12]([NH2:14])=[O:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:17]1([CH:27]=O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:15]=[C:11]3[C:10](=[CH:9][CH:8]=2)[N:16]=[C:27]([C:17]2[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=2)[NH:14][C:12]3=[O:13])[CH2:2][CH2:3]1
Reactant: O=Cc1cccc2ccccc12
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Product: O=c1[nH]c(-c2cccc3ccccc23)nc2ccc(N3CCOCC3)cc12

Procedure:
Compound 29 was synthesized from 5-morpholinyl-2-aminobenzamide (13) (1.6 g, 7.3 mmol) and 1-naphthaldehyde (14) (1.1 g, 7.3 mmol): yield 1.7 g (64%); yellow crystals; mp 291 to 293° C.; 1H NMR (DMSO-d6) δ 3.22 (4H, t, J=4.7 Hz, CH2NCH2), 3.77 (4H, t, J=4.7 Hz, CH2OCH2), 7.51-7.66 (6H, m, 6×ArH), 7.73-7.76 (1H, m, 1×ArH), 8.00-8.11 (3H, m, 3×ArH), 12.48 (1H, br s, NH) ppm; MS (ESI) m/z 357; Anal. (C22H19N3O2): C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:15])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Yield: 97.3 %

Procedure:
4-Chloro-5-methyl-2-nitroanisole was prepared by the same procedure as described for Step 2 of Preparation 2a except using 4-chloro-5-methyl-2-nitrophenol (50 g), methyl iodide (75.8 g), and potassium carbonate (44 g). Workup gave crude 4-chloro-5-methyl-2-nitroanisole (52.3 g, 97%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ7.85 (s, 1 H), 6.95 (s, 1 H), 3.94 (s, 3 H), 2.45 (s, 3 H).
Reaction SMILES: [CH2:1]([C:5]1NC2C(N=1)=NC=CC=2)[CH2:2][CH2:3][CH3:4].[Br:14][C:15]1[C:16]([CH3:23])=[C:17]([NH2:22])[C:18]([NH2:21])=[N:19][CH:20]=1>>[Br:14][C:15]1[C:16]([CH3:23])=[C:17]2[NH:22][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:21][C:18]2=[N:19][CH:20]=1
Reactant: Cc1c(Br)cnc(N)c1N
Reactant: CCCCc1nc2ncccc2[nH]1
Product: CCCCc1nc2ncc(Br)c(C)c2[nH]1

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-butylimidazo[4,5-b]pyridine starting with 5-bromo-2,3-diamino-4-picoline. Yield: 2.54 g (95%) of an amorphous solid: 1H NMR (250 MHz, CDCl3) δ 8.45 (s 1H), 3.05 (t, 2H, J=7 Hz), 2.73 (s, 3H), 2.02-1.87 (m, 2H), 1.61-1.45 (m, 2H), 1.02 (t, 3H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B(O)O)=[C:28]([CH3:33])[O:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[C:25]([CH3:24])=[N:26][O:27][C:28]=3[CH3:33])=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc(C(=C2CCCCCCC2)c2ccc(O)cc2)cc1
Yield: 76.7 %

Procedure:
The procedure described for 202 was used. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (9) (0.150 g, 0.404 mmol), PdCl2(PPh3)2, (0.028 g, 0.40 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.113 g, 0.80 mmol), Na2CO3 (0.086 g, 0.808 mmol), and THF/H2O (4:1, 5 mL). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 0.120 g (77%) of the title compound 205 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 9.27 (s, 1H), 7.30 (d, J=6.00 Hz, 2H), 7.21 (d, J=6.30 Hz, 2H), 6.96 (d, J=6.0 Hz, 2H), 6.69 (d, J=6.0 Hz, 2H), 2.37 (br s, 3H), 2.19 (s, 7H), 2.60 (br s, 2H), 1.50 (br s, 8H). LCMS (ESI): m/z 386 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1I.N#N.[CH3:17][N:18](C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=1[F:1])#[N:18]
Reactant: CN(C)C=O
Reactant: COC(=O)C(C)c1ccc(I)c(F)c1
Agent: [Pd]
Agent: N#N
Agent: [C-]#N
Product: COC(=O)C(C)c1ccc(C#N)c(F)c1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
Methyl 2-(3-fluoro-4-iodophenyl)propanoate, tetrakis(triphenylphosphine) palladium(0) and zinc cyanide are placed in dimethylformamide and charged with N2. The reaction mixture was stirred at 120° C. for 15 h and cooled to room temperature. The reaction mixture is filtered by celite packed filter, washed with ethyl acetate. After concentrate solvent, residue is purified on a silica gel column using ethylacetate-hexane as solvent system to give methyl 2-(4-cyano-3-fluorophenyl)propanoate.