Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1.[N:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:21]=[O:22].CCN(C(C)C)C(C)C>C1COCC1>[CH2:23]([NH:20][C:21]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1)=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1CCCNC1
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc2[nH]ccc2c1NC1CCCN(C(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a solution of 4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (62 mg, 0.24 mmol, 1.0 eq) and (isocyanatomethyl)benzene (35 mg, 0.26 mmol, 1.1 eq) in THF (2 mL) were added DIPEA (93 mg, 0.72 mmol, 3.0 eq). The mixture was stirred at rt for 3 h and the solvent was removed in vacuo to afford a residue which was purified by prep-HPLC (MeOH/H2O with 0.05% NH3.H2O) to give the title compound as a light brown solid (23 mg, yield: 11%). 1H NMR (400 MHz, CD3OD) δ: 8.32 (s, 1H), 7.15-7.09 (m, 6H), 6.91 (d, J=3.6 Hz, 1H), 4.23-4.20 (m, 3H), 3.87-3.83 (m, 1H), 3.46-3.34 (m, 3H), 2.09-2.05 (m, 1H), 1.81-1.80 (m, 2H), 1.62-1.59 (m, 1H). ESI-MS (M+H)+: 393.20.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C.O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCSc1nnc(N)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
In 185 ml of ethanol and 185 ml of water, 68.0 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 22.4 g of sodium hydroxide were added. To this mixture, 84.6 g of 1-bromoheptane was added, and the resulting mixture was warmed to 60° C. and stirred for 2 hours. After cooling, water was added and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/hexane mixture. Thus 90.2 g of 2-amino-5-heptylthio-1,3,4-thiadiazole was obtained.
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].[CH3:5][C:6]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[Cl-].[NH4+]>O1CCCC1>[CH:1]([C:8]1([OH:13])[CH2:9][CH:10]([CH3:12])[CH2:11][C:6]([CH3:14])([CH3:5])[CH2:7]1)=[CH2:2]
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: C=CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC1(O)CC(C)CC(C)(C)C1
Yield: 74.1 %

Procedure:
A Grignard compound is prepared from 80 g of vinyl bromide and 20 g of magnesium in 1 litre of tetrahydrofuran. To this Grignard compound there are added dropwise at room temperature 100 g of 3,3,5-trimethylcyclohexanone (dihydroisophorone) in 100 ml of tetrahydrofuran. The mixture is held at reflux temperature for 12 hours. The mixture is then cooled, treated with saturated ammonium chloride solution and extracted with ether. The organic phase is washed neutral with saturated sodium chloride solution, dried and evaporated. The crude product is distilled in a high vacuum (55° C./0.1 mm Hg). There are obtained 88.9 g of 1-vinyl-1-hydroxy-3,3,5-trimethyl-cyclohexane.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Br)[CH:34]=1>CS(C)=O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:39][C:35]4[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=4)[C:32]([O:31][CH3:30])=[O:41])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product from step (ii) (0.7 g) in DMSO (5 ml) was added cesium carbonate (0.75 g). After 5 minutes a solution of 3-bromomethylbenzoic acid methyl ester (0.53 g) in DMSO (5 ml) was added. The mixture was stirred at room temperature for 20 minutes and partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried (MgSO4) and evaporated. Purified by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.34 g.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:26][CH:27]1[CH2:29][CH2:28]1)C.[OH-].[Na+].CO>O1CCCC1>[C:21]([O:20][C:18]([NH:17][CH:14]1[CH2:15][CH2:16][N:12]([C:8]2[C:9]([Cl:11])=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([NH:26][CH:27]3[CH2:28][CH2:29]3)[C:7]=2[F:25])[CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc(Cl)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2c(Cl)cc(C(=O)O)c(NC3CC3)c2F)C1
Yield: 91.3 %

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoic acid ethyl ester (Example 3k, 2.00 g, 4.50 mmol) and aqueous sodium hydroxide (2.0N, 20 mL) in tetrahydrofuran (20 mL), and methanol (20 mL) is refluxed for 1 hour. The solution is partially concentrated in vacuo, acidified to pH 6, and extracted with chloroform. The combined organic extracts are dried over Na2SO4, filtered, and concentrated to give the title compound (1.70 g). 1H NMR (CDCl3): δ 7.71 (d, 1H), 4.91-4.82 (bd, 1H), 4.40-4.25 (m, 1H), 3.77-3.69 (m, 2H), 3.53-3.34 (m, 2H), 3.00-2.88 (m, 1H), 2.24-2.15 (m, 1H), 1.90-1.80 (m, 1H), 1.46 (s, 9H), 0.72-0.54 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:23]3[CH2:24][CH2:25][CH:21]([OH:20])[CH2:22]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: OC1CCNC1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCC(O)C3)s2)c(C)[nH]c1=O
Yield: 48.8 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3-hydroxypyrrolidine as described in Step 5, Example 24 to give the title compound as a solid (48.8% yield). LC/MS: RT 2.42 min; m/e 369 (M+H); 1H NMR (δ, ppm): 11.8 (1H, s), 7.6 (1H, d); 7.38 (1H, d); 7.2 (1H, d), 4.92 (1H, br s), 4.2 (1H, s), 3.38 (4H, m), 3.07 (1H, d), 2.4 (2H, q), 2.32 (3H, s), 1.8 (2H, m), 1.08 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([C:22]([NH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1ccc2sc3ccccc3c2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1
Yield: 65.3 %

Procedure:
2-Aminodibenzthiophene (Bull. Soc. Chim. Fr. (1996), 133 (6), 597-610; 2.0 g, 10 mmol) and triethylamine (1.11 g, 11 mmol) were dissolved in DCM (50 ml) and cooled in an ice bath. A solution of pivaloyl chloride (1.21 g, 10 mmol) in DCM (10 ml) was added slowly and the resultant solution was stirred at ambient temperature for 16 hours then evaporated in vacuo. The residue was triturated with methanol to leave the product as a colourless solid (1.85 g). NMR: 9.40 (s, 1H), 8.59 (s, 1H), 8.17 (m, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7.73 (dd, 1H), 7.46 (m, 2H), 1.15 (s, 9H); m/z 284.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([N:25]2[CH2:39][C:28]3=[C:29]4[N:34]([N:35]=[C:27]3[CH2:26]2)[C:33]([CH3:36])=[C:32]([Cl:37])[C:31]([CH3:38])=[N:30]4)=[O:24])[CH2:10]1)=O)(C)(C)C.O>O1CCOCC1>[Cl:37][C:32]1[C:31]([CH3:38])=[N:30][C:29]2[N:34]([N:35]=[C:27]3[CH2:26][N:25]([C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH:11]4[O:12][CH2:13][CH2:14][NH:9][CH2:10]4)=[O:24])[CH2:39][C:28]3=2)[C:33]=1[CH3:36]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CN(C(=O)OC(C)(C)C)CCO1)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CNCCO1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 112.4 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (0.6 mL; 2.39 mmol; 4 eq.) was added to a suspension of 2-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (366 mg; 0.6 mmol; 1 eq.) in 1,4-dioxane (3 mL) followed by water (304) and the resulting mixture was stirred at room temperature for 16 hours. A 4M solution of HCl in 1,4-dioxane (0.3 mL; 1.2 mmol; 2 eq.) was added and the resulting mixture was stirred at room temperature for 3 hours. Concentration in vacuo afforded the title compound (298 mg, quantitative) as an orange solid. 1H NMR (DMSO-d6) δ 7.46 (t, J=7.9 Hz, 1H), 7.38-7.28 (m, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 4.95-4.77 (m, 2H), 4.69-4.39 (m, 2H), 4.27-4.06 (m, 2H), 4.06-3.87 (m, 1H), 3.77-3.53 (m, 2H), 3.30-3.17 (m, 1H), 3.12-2.94 (m, 1H), 2.92-2.74 (m, 4H), 2.72-2.53 (m, 4H). HPLC (max plot) 99.5%, Rt 2.70 min. UPLC/MS: (MS+) 442.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20]([NH:24][NH2:25])(=O)[CH2:21][CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:20]([CH2:21][CH3:22])=[N:24][N:25]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CCC(=O)NN
Solvent: CCO
Product: CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione was heated in ethanol with propionic acid hydrazide and the resulting product heated to 250° C. to give 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine of melting point 231.5°-232.5° C. The ultraviolet spectrum (ethanol) had end absorption λ max. 224 (ε = 39,250) and inflections 248 (ε = 15,000), 266 (ε = 6,900) and 290 mμ(ε = 3,250).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([OH:22])=O)=[CH:4][CH:3]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:27][CH2:24][CH2:25][N:26]2[C:20](=[O:22])[C:11]2[N:10]([CH:14]=[C:13]([C:15]([N:16]([CH3:17])[CH3:18])=[O:19])[CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)c1cc(C(=O)O)n(CC(=O)c2ccc(Cl)cc2)c1
Reactant: NCCN
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc2n(c1)CC1(c3ccc(Cl)cc3)NCCN1C2=O
Yield: 26.8 %

Procedure:
To a suspension of 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylic acid (90 mg, 0.27 mmol) in 1,4-dioxane (10 mL) was added ethane-1,2-diamine (0.1 mL, 1.5 mmol). The reaction mixture was heated at reflux 4 h (monitored by LCMS). The reaction mixture was then concentrated in vacuo to give an oil that was purified using flash chromatography (Biotage SP4, 12 g cartridge, 0-20% MeOH gradient in CH2Cl2) to give 10a-(4-chlorophenyl)-N,N-dimethyl-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carboxamide as a light brown solid (26 mg, yield 27%) 1H NMR (400 MHz, d6-acetone): δ 2.75-2.84 (m, 1H), 2.95-3.21 (m, 6H), 3.33 (ddd, 1H, J 11.2, 7.7, 3.3 Hz), 3.49 (ddd, 1H, J 11.0, 7.7, 3.2 Hz), 3.72 (dt, 1H, J 11.0, 8.0 Hz), 4.41 (d, 1H, J 12.6 Hz), 4.75 (d, 1H, J 12.6 Hz), 7.01 (d, 1H, J 1.6 Hz), 7.13 (d, 1H, J 1.6 Hz), 7.26-7.35 (m, 4H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][C@H:31]([OH:34])[CH:30]4[C:35](OC)=[O:36])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][C@H:31]([OH:34])[C@@H:30]4[C:35]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:36])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)C1[C@@H](O)CCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)[C@H]1[C@@H](O)CCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.3 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (292 mg, 2.61 mmol) in dry THF (12 mL) was added 2M solution of isopropylmagnesium chloride in THF (1.3 mL, 2.60 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of (3S)-methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3-hydroxypyrrolidine-2-carboxylate (250 mg, 0.65 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL). The product was extracted with EtOAc (2×40 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded an oily residue that was purified by reverse phase HPLC to afford (2R,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide (10 mg). Compound No. 11a: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.82-0.96 (m, 2H), 1.77 (brs, 1H), 2.00-2.18 (m, 3H), 2.19-2.30 (m, 1H), 2.70-2.83 (m, 4H), 3.78-3.98 (m, 2H), 4.58-4.77 (m, 2H), 6.28 (brs, 1H), 6.98 (d, 1H), 8.02 (brs, 1H), 8.23 (s, 1H). Compound No. 11b: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.82-0.96 (m, 2H), 1.77 (brs, 1H), 2.00-2.18 (m, 3H), 2.19-2.30 (m, 1H), 2.70-2.83 (m, 4H), 3.78-3.98 (m, 2H), 4.58-4.77 (m, 2H), 6.28 (brs, 1H), 6.98 (d, 1H), 8.02 (brs, 1H), 8.23 (s, 1H). Separation by chiral HPLC provided additional diastereomers 11c and 11d.
Reaction SMILES: CO.[CH:3]1([NH:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][C:15]=2[NH2:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.Cl.[C:31](=N)(OC)[CH3:32]>O>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[C:18]1[CH:19]=[CH:20][C:14]2[N:13]([CH:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][CH2:5][CH2:4]3)[C:31]([CH3:32])=[N:16][C:15]=2[CH:17]=1
Reactant: COC(C)=N
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCCc2ccccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCCc2ccccc21
Yield: 49.4 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(1,2,3,4-tetrahydronaphthalen-1-yl)aminoanilin-5-yl)benzoxazole (see Working Example 87-1) (0.30 g, 0.8 mmol) was added methyl acetimidate hydrochloride (0.10 g, 0.9 mmol), and this was heated to reflux for 3 hours. After the reaction solution was cooled, water was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.15 g, 47% yield) as a colorless amorphous mass.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[O:12][C:13]3[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][C:14]=3[C:15]=2[Br:16])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:23]([C:25]1[NH:26][C:27]2[C:28]([N:35]=1)=[N:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[O:12][C:13]3[CH:20]=[CH:19][C:18]([CH2:21][N:35]4[C:28]5=[N:29][C:30]([CH3:34])=[CH:31][C:32]([CH3:33])=[C:27]5[N:26]=[C:25]4[CH2:23][CH3:24])=[CH:17][C:14]=3[C:15]=2[Br:16])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2oc3ccc(CBr)cc3c2Br)CCCC1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Product: CCOC(=O)C1(c2oc3ccc(Cn4c(CC)nc5c(C)cc(C)nc54)cc3c2Br)CCCC1

Procedure:
The product of Step 6, above (60), was alkylated as described in Example 12, Step 3 using 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (7) to obtain the title compound (61).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH:7]1[CH2:12][CH2:11][C:10]2([CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13]2)[CH2:9][CH2:8]1.O.[OH-].[Na+]>N1C=CC=CC=1>[CH:1]1([C:4]([N:7]2[CH2:12][CH2:11][C:10]3([CH2:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[O:13]3)[CH2:9][CH2:8]2)=[O:5])[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: O=C(C1CC1)N1CCC2(CC1)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1.8 g of cyclopropylcarbonyl chloride are added dropwise to a stirred solution at 0° C. of 3.2 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine] in 50 ml of pyridine. After total addition the reaction is stirred for 60 hours at ambient temperature and then heated at reflux for 3 hours. Thereafter, the reaction mixture is successively permitted to cool to ambient temperature, poured into 500 ml of water, basified with 20% sodium hydroxide and the solvent is removed under reduced pressure. The residue is triturated with 500 ml of water, extracted twice with ethyl acetate and the combined extracts are dried and the solvent is removed under reduced pressure, leaving a solid. The solid is recrystallized thrice from water to provide white flakes, 2,3-dihydro-1'-cyclopropylcarbonylspiro[benzofuran-2,4'-piperidine], mp 111°-113° C.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([I:26])[C:14]([O:16][CH2:17][C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O>O>[I:26][C:13]1[C:14]2[O:16][CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]=2[C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH2:10][C:9]=2[CH:12]=1
Reactant: O=C(COc1cc2c(cc1I)CCN(C(=O)C(F)(F)F)CC2)c1ccccc1
Solvent: O
Product: Ic1cc2c(c3c(-c4ccccc4)coc13)CCNCC2
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Poly phosphoric acid (˜1 ml) was added to a vial containing the product from step (b) (0.255 g, 0.50 mmol) and heated to 90° C. for 20 minutes. Water was added to the reaction mixture and extracted with dichloromethane (3×). The organic layers were washed with saturated sodium bicarbonate, and brine. To the crude material was added 8 ml of methanol, 5 ml of water, and potassium carbonate (˜100 mg). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated and to this was added 2N HCl, and extracted with dichloromethane (3×). Purification by silica-gel chromatography (gradient elution: 0-20% methanol in dichloromethane) gave the sub-title compound as an off white solid (0.034 mg). MS: ESI (positive): 390 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:11])[CH3:2].[N:24]1([CH2:33][C:34](O)=[O:35])[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:11])[C:34](=[O:35])[CH2:33][N:24]1[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-])C(=O)Cn1cc(C)c(=O)[nH]c1=O
Yield: 92.5 %

Procedure:
The title compound (2.46 g, 92%) was synthesized by the reaction of N-[2-(4-chloro-2-nitro-benzenesulfonylamino)-ethyl]-glycine ethyl ester (1.84 g, 5 mmol) and (thymin-1-yl)-acetic acid (0.92 g, 5 mmol) as per the procedure of example 46. 1H-NMR (500 MHz; DMSO-d6) δ 11.31 (s, 0.6H), 11.28 (s, 0.4H), 8.31˜7.95 (m, 4H), 7.31 (s, 0.6H), 7.23 (s, 0.4H), 4.64 (s, 1.2H), 4.46 (s, 0.8H), 4.28 (s, 0.8H), 4.16 (q. 0.8H), 4.07 (q. 1.2H), 4.00 (s, 1.2H), 3.49 (t, 1.2H), 3.22 (q, 1.2H), 3.12˜3.01 (m, 1.6H), 1.74 (s, 3H), 1.22 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:11][C:9]1([CH3:10])[O:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:12])[CH2:8]1
Reactant: CC(C)=CC(=O)c1sccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2sccc2O1

Procedure:
A solution of 3-hydroxy-2-(3-methyl-1-oxo-2-buten-1-yl) thiophene (39.0 g, 0.214 mol) and p-toluenesulfonic acid (3.5 g, 18 mmol) in toluene (400 mL) was heated to reflux for 3.5 d. The resultant solution was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo to give a brown oil, 38.62 g (99%). A portion of the resultant oil was purified for analysis by distillation in a Kugelrohr oven at 145° to 155° C. at 0.35 mm Hg to give the product as an amber oil: IR (neat): 2979, 1664, 1530 and 1442 cm-1 ; MS: m/z 183 (MH+); 1H NMR (CDCl3): δ1.51 (s, 6H); 2.67 (s, 2H); 6.67 (d, J=5.4 Hz, 1H) and 7.60 (d, J=5.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 79.9 %

Procedure:
A mixture of 3,5-dichlorophenylboronic acid (3.8 g, 20.0 mmol), 2-bromo-3,3,3-trifluoro-prop-1-ene (4.9 g, 28 mmol), Cs2CO3 (20 mL, 2 M, 40 mmol) and Pd(PPh3)2Cl2 (421 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to give 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.85 g; yield 80%). 1H NMR (500 MHz, CDCl3): δ 7.41 (s, 1H), 7.35 (s, 2H), 6.06 (s, 1 H), 5.83 (s, 1 H) ppm.