Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[CH:7]=[C:8]([F:16])[CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:19]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][C:8]([F:16])=[CH:7][C:6]=2[C:4]2[C:3](=[O:17])[NH:30][C:28](=[O:29])[C:27]=2[C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][CH:19]=2)[CH:11]=[CH:12]1
Reactant: COC(=O)C(=O)c1cc(F)cc2ccn(C)c12
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)cc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a mixture of (1-methyl-5-fluoro-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.94 g, 4.0 mmol) and 2-(1H-indol-3-yl-acetamide (0.63 g, 3.64 mmol) in DMF (36 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 14.6 mL, 14.6 mmol) at room temperature. The reaction mixture was heated at 55° C. for 18 h, cooled to room temperature, and quenched with hydrochloric acid (conc.). After stirring at room temperature for 30 min, the mixture was extracted with ethyl acetate and the extract washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1-methyl-5-fluoro-1H-indol-7-yl)-4-(1H-indol-3-yl]-pyrrole-2,5-dione (0.72 mg, 55%). 1H NMR (d6-DMSO, 400 MHz) 3.67 (s, 3H), 6.34 (d, J=7.82 Hz, 1H), 6.48 (d, J=3.12 Hz, 1H), 6.54 (t, J=7.62 Hz, 1H), 6.77 (dd, J1=2.34 Hz, J2=9.77 Hz, 1H), 6.99 (t, J=7.42 Hz, 1H), 7.33˜7.42 (m, 3H), 7.97 (d, J=3.13 Hz, 1H), 11.20 (s, 1H), 11.93 (s, 1H); MS (ES, m/z): C21H14FN3O2: 360.15 (M++1), 358.23 (M+−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[O:29][CH3:30])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[O:29][CH3:30])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)ccc3OC)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cc(OC)ccc3OC)c2)=C(C)C1=O
Yield: 70.1 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-2,5-dimethoxyaniline (0.075 g, 0.147 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from a mixed solvent of ether and hexane (1:1) to obtain the titled compound (0.048 g, 0.103 mmol, 70%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[C:9]1([S:15]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of d/l-proline (2.0 g, 6.8 mmol) in aqueous sodium hydroxide (1M, 34.7 mL) chilled at 0° C., was added phenylsulfonyl chloride (2.21 mL, 17.0 mmol) slowly. The reaction was stirred overnight at room temperature. The reaction mixture was acidified with HCl (20 ml, aqueous, 1 N) and extracted with diethyl ether (2×20 mL). The combined organic extracts were then dried over magnesium sulfate and concentrated under reduced pressure to give the desired N-phenylsulfonyl proline (1.7 g) as a white solid used without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:17]([OH:19])=O)[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])[CH3:2].CC[N:22](CC)CC.ClC(OCC(C)C)=O>C1COCC1.N>[CH2:1]([O:3][C:4]([C:6]1([C:17](=[O:19])[NH2:22])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C1(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
Azetidine-1,3,3-tricarboxylic acid 1-tert-butyl ester 3-ethyl ester (Example 11b; 21.5 g; 78.9 mmol) and NEt3(17.6 ml; 126 mmol) are dissolved in THF (200 ml) and cooled to 0° C. Isobutyl chloroformate (15.5 ml; 118 mmol) is added dropwise. The thick suspension is stirred for another 10 minutes at 0° C., diluted with THF (200 ml) and NH3-gas introduced for 5 minutes, stirred for 15 minutes at 0° C. followed by a second NH3-gas treatment for 5 minutes. The reaction mixture is warmed to room temperature and stirred for 30 minutes, poured on water and extracted with TBME three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and purified via chromatography (SiO2; TBME ) to yield the title compound as colorless crystals (17.3 g; 80%).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:23]=[C:22]([F:32])[CH:21]=2)=[CH:14][C:13]=1[NH:34][C:35](=[O:50])[C:36]1[CH:41]=[C:40]([N:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)[CH:39]=[CH:38][C:37]=1[NH2:49].C(O)(=O)C>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[C:20]2[CH:25]=[C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:23]=[C:22]([F:32])[CH:21]=2)=[CH:14][C:13]=1[N:34]1[C:35](=[O:50])[C:36]2[C:37](=[CH:38][CH:39]=[C:40]([N:42]3[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]3)[CH:41]=2)[N:49]=[CH:1]1
Reactant: CN1CCN(c2ccc(N)c(C(=O)Nc3cc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)ccc3F)c2)CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCN(c2ccc3ncn(-c4cc(NC(=O)c5cc(F)cc(N6CCOCC6)c5)ccc4F)c(=O)c3c2)CC1

Procedure:
Triethyl orthoformate (0.123 ml) was added to a stirred mixture of N-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylpiperazin-1-yl)benzamide (0.31 g), glacial acetic acid (0.016 ml) and ethanol (4 ml) and the resultant mixture was heated to 76° C. for 18 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic solution was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.119 g); NMR Spectrum: (DMSOd6) 2.23 (s, 3H), 3.22 (m, 4H), 3.72 (m, 4H), 6.99 (d, 1H), 7.12 (d, 1H), 7.29 (s, 1H), 7.47 (m, 2H), 7.63 (s, 1H), 7.89 (m, 1H), 7.97 (m, 1H), 8.18 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M+H+561.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][CH2:16]2)=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(COc2ccc(N3CCNCC3)nc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(OCc3ccccc3)cn2)CC1
Reaction time: 3 h

Procedure:
A stirred solution of 1-[5-(benzyloxy)pyridin-2-yl]piperazine (104 g, 278 mmol) in CH2Cl2 (1.1L) at 0° C. was treated sequentially with triethylamine (94 mL, 672 mmol) and methanesulfonyl chloride (31 mL, 400 mmol). The reaction was brought to room temperature and stirred for 3 hour. The reaction was then diluted with DCM (3L) and washed with water (1L), HCl (0.5 M, 2×800 mL) and sat. NaHCO3 (800 mL), back-extracting with DCM (500 mL). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give 1-[5-(benzyloxy)pyridin-2-yl]-4-(methylsulfonyl)piperazine as a dark liquor (120 g, 278 mmol @ 81 wt %, 100%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[CH:23]=1>>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][O:19][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[O:30])[CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Product: CCOC(Cc1cccc(CCOC(=O)Nc2cccc(C(F)(F)F)c2)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and α,α,α-trifluoro-m-tolylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[C:9]1([C:6]2[N:7]=[CH:8][C:3]3[N:4]([C:15]([CH3:16])=[N:2][N:1]=3)[CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNc1cnc(-c2ccccc2)cn1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2cnc(-c3ccccc3)cn12

Procedure:
A solution of 0.5 g. (0.0027 mole) of 2-hydrazino-5-phenylpyrazine in 5.0 ml. of triethyl orthoacetate is heated under reflux for 5 hours. The crystalline product precipitates from the hot reaction solution, and at the end of the heating period the mixture is cooled and the product is collected. Recrystallization from ethanol gives 0.36 g. of the product of the example, m.p. 192°-195° C.
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25]([N:1]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:2]2[C:3]([O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:4])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)N2CCCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of 145 mg (0.37 mmol) of (S)-Benzyl pipecolate salt (134) (described in Example 1) in 8.0 mL of methylene chloride was added 102 mg (0.57 mmol) of 4-methoxycinnamic acid, 107 mg (0.55 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 130 μL (0.74 mmol) of diisopropylethylainine, The resulting solution was stirred at ambient temperature for 12 h and was then concentrated under reduced pressure. Flash chromatography (elution with 1:1 ethyl acetate-hexane) gave 91 mg (65%) of the amide (112) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.66 (d), 7.50 (d), 7.35 (m), 6.90 (d), 6.82 (d), 6.63 (d), 5.55 (d), 5.20 (br s), 4.86 (br s), 4.67 (br d) 4.03 (br d), 3.83 (s), 3.37 (dt), 2.78 (dt) 2.33 (br d), 1.74 (m), 1.43 (m). Rf 0.40 (1:1 ether-hexane).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>C1COCC1>[OH:41][C:37]1[CH:36]=[C:35]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:33])[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C(C)(C)C)n1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)cc2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 65, 100 mg, 0.225 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (27 mg, 0.25 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 31% (42 mg, 0.0954 mmol) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]4)[CH:16]=[N:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)(C)(C)C.[ClH:33].O1CCOCC1>CO>[ClH:33].[NH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]4)[CH:16]=[N:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4CCNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4CCN)ccc21
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of {2-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3,4-dihydro-2H-[1,7]naphthyridin-1-yl]-ethyl}-carbamic acid tert-butyl ester (example 11, 0.06 g, 0.137 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.137 mL, 0.550 mmol) and the reaction mixture was stirred at room temperature over night. Then, the reaction mixture was evaporated to dryness and the solid residue was triturated in diethyl ether, filtered off and further dried on the high vacuum to give the title compound (0.040 g, 70%) as an orange solid. MS: 337.3 (M+H+).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH2:7][CH2:8][CH:9]1[N:14]2[CH:15]=[C:16]([I:18])[CH:17]=[C:13]2[C:12](=[O:19])[NH:11][CH2:10]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:4][S:1]([O:6][CH2:7][CH2:8][CH:9]1[N:14]2[CH:15]=[C:16]([I:18])[CH:17]=[C:13]2[C:12](=[O:19])[NH:11][CH2:10]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCC(CCO)n2cc(I)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CNC(=O)c2cc(I)cn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mesyl chloride (0.172 g, 1.50 mmol) was added to an ice-cooled stirred solution of 4-(2-hydroxyethyl)-7-iodo-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (0.230 g, 0.75 mmol) and DIPEA (0.291 g, 2.25 mmol) in DCM (5 ml). The reaction mixture was stirred at room temperature under N2 for 1 h and then it was portioned between DCM and saturated NaHCO3 solution. The title compound was isolated by precipitation from the organic layer as a white solid (0.202 g, 0.52 mmol, 70%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](Cl)=[O:5])[CH3:2].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33]>>[CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33])=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Reactant: CCCCC(CC)C(=O)Cl
Product: CCCCC(CC)C(=O)Nc1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 76 %

Procedure:
Using a similar procedure to that described in Example 1, but starting from 2-ethylhexanoyl chloride and (A), there was obtained the title compound in 76% yield; partial NMR: 0.84(m,6H, 2×CH3), 1.24[m,6H, (CH2)3 ], 2.24(m,1H, CHCON), 10.78(d,1H, NH).
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32](#[N:35])[CH:33]=[CH2:34].C(N(CC)CC)C>CN(C=O)C.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>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:34]=[CH:33][C:32]#[N:35])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Oc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)C(F)(F)F
Reactant: C=CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Temperature: 100 °C
Yield: 45.8 %

Procedure:
To a solution of the triflate (5b) (560 mg, 1.25 mmol) in DMF (6 mL) was added acrylonitrile (2.10 g, 39.6 mmol), triethylamine (2.90 g, 28.6 mmol), and bis(triphenyl-phosphine)palladium(II) chloride (700 mg, 1.0 mmol). The mixture was placed in a pressure bottle and heated at 100° C. for 4 days. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 15% EtOAc/hexanes) to give the nitrile (5c) as a white solid (199 mg, 46%): 1H NMR (CDCl3) δ 7.30-7.13 (m, 11H), 6.94 (d, J=8.1 Hz, 2H), 6.82 (dd, J=7.3, 1.1 Hz, 1H), 5.75 (d, J=16.5 Hz, 1H), 2.81 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H), 2.19 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[CH:18][S:19][C:12]=12)C(OCC)=O)[CH3:2].O.[Cl-].[Li+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[CH:18][S:19][C:12]=12)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ccnc2ccsc12
Temperature: 110 °C
Yield: 53.9 %

Procedure:
Dissolve 2-(thieno[3,2-b]pyridin-7-yl)malonic acid diethyl ester (12.90 g, 44.0 mmol) in dimethyl sulfoxide (295 mL). Add water (0.79 mL) and lithium chloride (3.73 g, 87.9). Heat the solution to 110° C. for 3 hours. Quench the reaction with saturated brine (3 L) and extract with ethyl acetate (3×1 L). Rewash the organic layers with saturated brine (1 L). Treat the organic layers with magnesium sulfate, filter and concentrate. The residue was purified on silica using 25% ethyl acetate/hexanes to yield the desired compound (5.25 g, 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[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-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:8]([C:5]1[N:6]=[CH:7][C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)nc2)CC1
Temperature: 120 °C
Reaction time: 63 h
Yield: 74 %

Procedure:
To a solution of 5-bromopyridine-2-carbonitrile (551.3 mg, 3.012 mmol) in anhydrous dimethylformamide (6.0 ml) were added tert-butyl piperazine-1-carboxylate (670.6 mg, 3.601 mmol) and potassium carbonate (829.0 mg, 5.998 mmol). The mixture was stirred at 120° C. for 63 hrs and cooled to room temperature. Ethyl acetate (30 ml) was added, and the precipitate was collected by filtration. Water (30 ml) was added to the filtrate, and the precipitated solid was collected by filtration and dried under reduced pressure to give tert-butyl 4-(6-cyanopyridin-3-yl)piperazine-1-carboxylate (642.9 mg, yield 74.0%) as a slightly yellow solid.
Reaction SMILES: [H-].[Na+].I[CH3:4].[CH2:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].O>O1CCCC1>[CH2:5]([O:16][CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: CI
Reactant: C=CCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCCCCCOC
Temperature: 50 °C
Reaction time: 60 h
Yield: 81.6 %

Procedure:
Under an argon atmosphere a stirred mixture of 15.5 grams (0.375 mole) of sodium hydride (60% in mineral oil) in 180 ml of tetrahydrofuran was warmed to 50° C., and 28 ml (0.45 mole) of iodomethane was added portionwise. Upon completion of addition, 41.1 grams (0.24 mole) of 10-undecen-1-ol in 75 ml of tetrahydrofuran was added dropwise during a one hour period. Upon completion of addition, the reaction mixture was heated at 50° C. for an additional 90 minutes, and then it was allowed to cool to ambient temperature where it stirred for 60 hours. The reaction mixture was cooled in an ice water bath, and cold water was added dropwise until all of the solid material in the reaction mixture was dissolved. The aqueous layer was extracted with two portions of diethyl ether, and the ether extracts were combined with the organic layer from the reaction mixture. The organic layer extract combination was washed in turn with 50 ml of water and 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated at atmospheric pressure to a residue. The residue was distilled under reduced pressure, yielding 36.1 grams of methyl 10-undecenyl ether; b.p. 99°-100° C./5.5 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]2[CH2:14][C:15]3(OCC[O:17]3)[CH2:16][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]2[CH2:14][C:15](=[O:17])[CH2:16][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CC3(C[C@@H]2C1)OCCO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CC(=O)C[C@@H]2C1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
(cis)-tert-butyl-spiro[1,3-dioxolane-2,6′-3,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine]-2′-carboxylate 14g (620 mg, 2.20 mmol) was dissolved in 50 mL of acetone followed by the addition of p-toluenesulfonic acid (200 mg, 1.10 mmol). The resulting solution was heated to reflux for 30 minutes, then cooled down to room temperature, added dropwise with saturated sodium bicarbonate solution to adjust pH to 8 to 9, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (cis)-tert-butyl-6-oxo-3,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine-2-carboxylate 14h (450 mg, yield: 85.0%) as a colorless oil liquid.