Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[C:22]1[CH:23]=[C:24]2[CH:30]=[CH:29][N:28]([CH:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])[C:25]2=[CH:26][N:27]=1)[CH3:13]>C(Cl)Cl>[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[C:22]1[CH:23]=[C:24]2[CH:30]=[CH:29][N:28]([CH:31]([CH2:32][CH2:33][CH3:34])[CH2:35][CH2:36][CH3:37])[C:25]2=[CH:26][N+:27]=1[O-:9])[CH3:13]
Reactant: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)ncc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)[n+]([O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Chloro-benzenecarboperoxoic acid (c.a. 60%, 198 mg, 0.69 mmol) is added to a solution of 5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.057 mmol) in DCM (4 mL), and the mixture is stirred for 30 min at room temperature. The mixture is washed with a saturated aqueous Na2CO3 solution, brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the residue on silica gel (EtOAc) gives 5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridine 6-oxide as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[O:26][CH3:27])=[CH:14][C:13]1=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=3[O:26][CH3:27])=[CH:14][C:13]2=[O:28])[C:3]([OH:29])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2OC)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1OC
Temperature: 23 °C
Reaction time: 2 h
Yield: 128.4 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (600 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (187 mg, 0.008 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (500 mg, 86%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=CC=1)([O-])=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:14]2[CH2:15][N:16]([C:37]([NH:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CNCC2
Reactant: O=C(Nc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1cc2c(s1)CN(C(=O)Nc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (1.0 eq) in DMF was added Et3N (3.0 eq.) followed by pyridin-3-yl-carbamic acid 4-nitro-phenyl ester (1.0 eq) and reaction was stirred at room temperature overnight. Reaction mixture was then quenched with water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[OH-].[K+].[CH2:13]1[CH:15]([CH:16]([OH:19])C#N)[CH2:14]1>CN(C=O)C>[CH:15]1([CH:16]([OH:19])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:13][CH2:14]1
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: N#CC(O)C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1CC(O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To 4.9 g (35.7 mmol) of 2-nitrotoluene in 30 ml of DMF are added, within one hour, 0.168 g (2.55 mmol; 85% purity) of KOH and simultaneously 5 g (71.34 mmol) of cyclopropylcarboxaldehyde. The mixture is stirred at room temperature (RT) for 0.5 h, then 0.5 equivalent of cyclopropylcarboxaldehyde is added and the mixture is stirred at RT for a further hour. Subsequently, a majority of the DMF is distilled off under reduced pressure, and the residue is admixed with water and extracted with ethyl acetate. After the evaporation of the solvent and chromatography using silica gel (elution with toluene/ethyl acetate mixtures), 4.2 g (yield 55% of theory, purity (GC-MS 95.9%) of 1-cyclopropyl-2-(2-nitrophenyl)ethanol were obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:20]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSc2cccs2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSc4cccs4)CC3)c2c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]-piperidine-4-carboxylate in 5 cm3 of aqueous 5N hydrochloric acid and 3 cm3 of dioxane was maintained at a temperature in the region of 100° C. with stirring and under an inert atmosphere for 20 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The mixture was filtered and then chromatographed, under atmospheric pressure, on a column of silica gel (particle size 40-63μ; diameter 1.5 cm; mass 55 g), eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and collecting 15-cm3 fractions. Fractions 5 to 12 were combined and then concentrated to dryness under the above conditions. 0.26 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-4-carboxylic acid was obtained in the form of a white crystalline solid melting at 180° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21](OCC)=[O:22])[CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][NH2:27]>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:20][C:21]([NH:26][NH2:27])=[O:22])[CH:9]1[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CN(C(=O)OC(C)(C)C)C1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N(CC(=O)NN)C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 17 h
Yield: 92.9 %

Procedure:
A mixture of tert-butyl 3-(tert-butoxycarbonyl(2-ethoxy-2-oxoethyl)amino)azetidine-1-carboxylate (7.2 g, 20 mmol), hydrazine (5.0 g, 100 mmol) and ethanol (50 mL) was stirred at 80° C. for 17 hrs. The reaction mixture was then concentrated to afford the crude tert-butyl 3-(tert-butoxycarbonyl(2-hydrazinyl-2-oxoethyl)amino)azetidine-1-carboxylate (6.4 g, 94%) as a white solid, which was used directly in the next step. ESI-MS (EI+, m/z): 345.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=3)[CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccccc3F)c2)nc1
Temperature: 120 °C
Yield: 28.8 %

Procedure:
A mixture of 1-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-1,2,3-triazole (268 mg, 1.1 mmol), methyl 6-chloronicotinate (190 mg, 1.1 mmol) and potassium carbonate (305 mg, 2.2 mmol) in DMF (6.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 2 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 100% ethyl acetate in heptane) afforded the title compound (120 mg, 29%) as an off white solid. MS: m/e=379.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[O:4][N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:37]([C:36]4[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:26]5[CH:25]=[C:24]6[C:29](=[CH:28][CH:27]=5)[NH:21][CH:22]=[CH:23]6)=[O:32])=[CH:40][CH:39]=4)[NH:18][C:11]=3[CH:10]=2)[O:4][N:3]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3[nH]ccc3c2)cc1
Reactant: Cc1noc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)n1
Product: Cc1noc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc6[nH]ccc6c5)cc4)[nH]c3c2)n1

Procedure:
Compound 659 was prepared according to the procedure similar to that described in Scheme III from 1-(3-methyl-1,2,4-oxadiazol-5-yl)methoxy-3,4-dinitrobenzene and 4-(5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C26H20N6O3: 465.16; found: 464.98.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[NH2:8][C:9]1[C:10]([Cl:26])=[N:11][C:12]([CH3:25])=[C:13]([CH3:24])[C:14]=1[NH:15][CH2:16][C:17]1([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>ClCCl>[Cl:26][C:10]1[C:9]([NH:8][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:14]([NH:15][CH2:16][C:17]2([OH:23])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([CH3:24])=[C:12]([CH3:25])[N:11]=1
Reactant: Cc1nc(Cl)c(N)c(NCC2(O)CCOCC2)c1C
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Cl)nc(C)c(C)c1NCC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere ethoxyacetyl chloride (2.26 g, 16.6 mmol) was added dropwise to a chilled (0° C.) suspension of 4-{[(3-amino-2-chloro-5,6-dimethylpyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (3.96 g) in dichloromethane (140 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was cooled to 0° C., more ethoxyacetyl chloride (0.3 mL) was added, and the reaction mixture was stirred at ambient temperature for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to provide crude N-(2-chloro-4-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-5,6-dimethylpyridin-3-yl)-2-ethoxyacetamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:27]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:3])[C:7]=2[OH:27])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2cccc(OC)c2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Cn2cc(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)c1

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(3-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 415 (M+H)+.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:12])[CH3:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:13]([Cl:17])(=O)(=[O:15])[OH:14]>>[C:10]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:13]([Cl:17])(=[O:15])=[O:14])=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)NCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
N-Phenethylacetamide (4.50 g, 27.6 mmol) was added to sulfurochloridic acid (30 mL) slowly at 0-5° C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice-water and stirred for 10 min. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a brown solid (3.30 g, 12.64 mmol, 45% yield). MS (ESI) m/z 262.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C@H:10]([CH3:11])[O:9]1.[N:18]1([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[CH:32][NH:31][C:30]3=[O:34])=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[N:19]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:9])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C@H:10]([N:31]1[CH:32]=[CH:33][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[CH:21][N:20]=[N:19]3)=[CH:28][CH:27]=2)[C:30]1=[O:34])[CH3:11]
Reactant: O=c1[nH]ccn1-c1ccc(-n2ccnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Product: C[C@@H](n1ccn(-c2ccc(-n3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F

Procedure:
(2R,3S)-2-(2-Fluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 32).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][C:4]=1[S:13]([NH2:16])(=[O:15])=[O:14].[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[NH:23][C:24]([NH2:26])=[S:25].II>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:25][C:24]([NH:23][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][N:17]=3)=[N:26][C:10]=2[CH3:11])=[CH:5][C:4]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: COc1ccc(CC(C)=O)cc1S(N)(=O)=O
Reactant: NC(=S)Nc1cnccn1
Agent: II
Solvent: c1ccncc1
Product: COc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1S(N)(=O)=O
Yield: 22.2 %

Procedure:
2-Methoxy-5-(2-oxo-propyl)-benzenesulfonamide (S. Sakurai et al. Chem. Pharm. Bull. 40(6) 1443-1451 (1992)) (0.3 g, 1.23 mmol), pyrazin-2-yl-thiourea (0.19 g, 1.23 mmol), iodine (0.31 g, 1.23 mmol) in pyridine (2.5 ml) is stirred at 60° C. for 20 hours. The mixture is concentrated. To the residue is added water, the precipitate is collected and recrystallised from ethanol to give the titled compound (0.103 g). m.p. 378.2° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:13])[CH3:12]
Reactant: Cc1ccc(C#N)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(C)ccc1C#N
Yield: 97.2 %

Procedure:
To a solution of 2-Hydroxy-4-methylbenzonitrile (0.563 g, 4.23 mmol) in CH2Cl2 (21 mL) was added acetic anhydride (0.60 mL, 6.36 mmol) followed by triethylamine (1.20 mL, 8.61 mmol) and the resultant solution was stirred at room temperature for 30 minutes. The mixture was diluted with CH2Cl2 (60 mL), washed with saturated aqueous NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried (Na2SO4) and concentrated and provided 0.72 g (97%) of (2-cyano-5-methyl-phenyl) acetate as a white solid. 1H NMR (CDCl3) δ 2.38 (s, 3H), 2.43 (s, 3H), 7.08 (s, 1H), 7.13 (d, 1H, J=9 Hz), 7.54 (d, 1H, J=9 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH2:10][CH:9]2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C-:21]#[N:22].[K+]>O1CCCC1.O>[OH:13][CH:12]([CH:9]1[CH2:10][CH2:11][N:8]1[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:21]#[N:22]
Reactant: O=CC1CCN1C(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)C1CCN1C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a solution of 1.4 g (5.57 mmoles) of 1-diphenylmethyl-2-formylazetidine in a mixture of 7.5 ml of tetrahydrofuran and 7.5 ml of water is added 0.91 ml (11.14 mmoles) of concentrated hydrochloric acid under cooling and then 0.724 g (11.14 mmoles) of potassium cyanide is added thereto. The mixture is stirred for 2 hours and extracted with 30 ml of ether. The aqueous layer is reextracted with 30 ml of ether. The extract and the above organic layer are combined, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 1.6 g of crude syrupy 2-hydroxy-2-(1-diphenylmethylazetidin-2-yl)acetonitrile in quantitative yield.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1.Cl>O.CO>[C:17]1([C:15]2[N:16]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:23])=[O:4])[O:13][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCCCCCc1nc(-c2ccccc2)co1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCc1nc(-c2ccccc2)co1
Temperature: 40 °C
Yield: 91.6 %

Procedure:
Add solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (30 mL) to a solution of 7-(4-phenyloxazol-2-yl)heptanoic acid methyl ester (5.75 g, 20.0 mmol) in methanol (40 mL) at room temperature and heat the mixture at 40° C. for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (600 mL). Wash the organic extract with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by filtration to provide 7-(4-phenyloxazol-2-yl)heptanoic acid (5.01 g, 91%): APCI mass spectrum m/z 272 [C16H19NO3—H]−.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([C@@H:36]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[N:37]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:33]([OH:35])=O)=[C:28]([F:50])[CH:27]=1.Cl.Cl.[CH3:53][C@H:54]1[C:62]2[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)=[N:60][CH:59]=[N:58][C:57]=2[C@H:56]([OH:69])[CH2:55]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([C@H:36]2[N:37]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]([CH3:41])([CH3:42])[CH2:39][CH2:40]2)[C:33]([N:66]2[CH2:67][CH2:68][N:63]([C:61]3[C:62]4[C@H:54]([CH3:53])[CH2:55][C@@H:56]([OH:69])[C:57]=4[N:58]=[CH:59][N:60]=3)[CH2:64][CH2:65]2)=[O:35])=[C:28]([F:50])[CH:27]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@H](C(=O)O)c2ccc(Br)cc2F)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
HATU (0.149 g, 0.391 mmol) was added to a solution of (R)-2-(4-bromo-2-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.168 g, 0.391 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.1 g, 0.326 mmol; see Example 3, Step 12), and N-ethyl-N-isopropylpropan-2-amine (0.171 mL, 0.977 mmol) in DCM (8 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was then quenched with H2O. The reaction was washed with H2O (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography yielded (S)-tert-butyl 5-((S)-1-(4-bromo-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.0334 g, 0.0517 mmol, 15.9% yield). LCMS (APCI+) 646.4, 648.5 m/z [M+H]+; Retention time=4.25 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 2,5-dimethyl-4-nitrobenzoic acid (480 mg, 2.4 mmol) in dry methanol (8.2 mL) at 0° C. under dry nitrogen was added thionyl chloride (0.538 mL, 7.38 mmol). The resulting mixture as allowed to warm to room temperature and stirred for about 7 hours. Additional thionyl chloride (0.300 mL) was added and stirring was continued at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide methyl 2,5-dimethyl-4-nitrobenzoate (578 mg) as a pale yellow solid. HPLC (10-70) Rt=4.61; NMR (300 MHz, CDCl3) δ 2.57 (s, 3H), 2.61 (s, 3H), 3.94 (s, 3H), 7.82 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[N:15]=[CH:14]3)=[N:8][CH:9]=1
Reactant: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1ncc2cc(Oc3ccc(N)cn3)ccc21
Reaction time: 3 h
Yield: 131.7 %

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1-methyl-1H-indazole (0.79 mmol) in 10 mL of methanol was added 10 mL of ethyl acetate and 30 mg of platinum (IV) oxide. After shaking under 50 psi of H2 for 3 h, the mixture was filtered through a pad of Celite and concentrated in vacuo, affording 0.25 g of 5-(5-Amino-pyridin-2-yloxy)-1-methyl-1H-indazole.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Clc1cccc(CBr)c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4cccc(Cl)c4)CC3)cccc2n1
Yield: 67 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3-Chlorobenzyl bromide (76 mg; 0.37 mmol) to obtain 49.5 mg. (67% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 1H), 10.0 (s, 1H), 9.0 (s, 1H), 7.72 (m, 2H), 7.34 (m, 4H), 7.22 (d, J=8.0 Hz, 1H), 3.59 (s, 2H), 3.03 (br d, J=10.8 Hz, 2H), 2.90 (m, 4H), 2.31 (m, 2H). ESIMS+369.2 m/z