Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(OC(NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C>>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)c(F)c2)ccn1
Agent: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)c(F)c2)ccn1
Yield: 87.5 %

Procedure:
The reaction was carried out in the same manner as in Example 37-2) except for using 3.00 g (6.12 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-(3,4-difluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 40-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-phenyl-1-([1,2,4]triazolo[4,3-b]-pyridazin-6-yl)-1H-pyrazole to obtain 2.09 g of the title compound as a white powder. (Yield: 88%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](=S)=[S:13].[OH-].[K+]>O.C(O)C>[SH:13][C:12]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: S=C=S
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2[nH]c(S)nc2c1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A mixture of 3,4-diaminobenzoic acid (1.52 g, 10 mmol), carbon disulfide (0.837 g, 11 mmol), and potassium hydroxide (0.617 g, 11 mmol) in water (30 mL) and ethanol (8 mL) was heated under reflux for 16 h and then cooled to rt. The reaction mixture was evaporated in vacuo and then taken up in water (25 mL). The resulting mixture was neutralized by the addition of 1 N HCl and the resulting brown solid isolated by vacuum filtration, washed with water and air dried to provide the title compound (1.15 g, 59% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.20 (d, J=8.09 Hz, 1H) 7.66 (s, 1H) 7.76 (dd, J=8.46, 1.47 Hz, 1H) 12.76 (s, 1H) 12.82 (s, 1H). MS (ESI−) m/z 193.0 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:14](O)[CH:15]=[CH2:16]>>[CH2:16]([O:8][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=1)[CH:15]=[CH2:14]
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Reactant: C=CCO
Product: C=CCOC(=O)COc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.4 %

Procedure:
To a solution of commercially available (3,4-dichloro-phenoxy)-acetic acid (2.65 g, 12.0 mmol) in allyl alcohol (12.0 cm3, 180 mmol) at ambient temperature under an atmosphere of dry nitrogen was added 4 drops concentrated sulfuric as a catalyst. The solution was stirred at ambient temperature for 20 hours and the volatile fractions removed in vacuo. The residue was dissolved in ethyl ether (50 cm3), washed with water (25 cm3), washed with saturated sodium bicarbonate (25 cm3), washed with brine (25 cm3), dried over magnesium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to afford the title compound as a colorless viscous oil (3.02 g, 96.8%) with positive ion ESI (M+H)+261.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[C:22]3[C:21]([NH:23][C@H:24]([C:26]4[N:31]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:30](=[O:38])[C:29]5=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]5[N:27]=4)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=3[N:16](COCC[Si](C)(C)C)[CH:15]=2)[CH:5]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:3]=[C:4]([C:14]2[C:22]3[C:21]([NH:23][C@H:24]([C:26]4[N:31]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:30](=[O:38])[C:29]5=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]5[N:27]=4)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:7]=1
Reactant: Cc1nnc(-c2cc(O)cc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)o1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(-c2cc(O)cc(-c3c[nH]c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)o1
Yield: 25.5 %

Procedure:
(S)-2-(1-((5-(3-Hydroxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.07 mmol) was treated with trifluoroacetic acid (2 ml, 25 mmol) and a solution of ammonia (7N in methanol, 3 ml, 135 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (DCM to DCM-Isopropyl alcohol 15%) to give 10 mg (67% yield) of the title compound. Purity 98%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]([NH2:19])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:20][O:21][CH:22]([O:33][CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25](F)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[CH3:34][O:33][CH:22]([O:21][CH3:20])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH:1][C:2]2[S:3][C:4]([C:17]([NH2:19])=[O:18])=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=3)[N:6]=2)[CH:24]=1
Reactant: NC(=O)c1sc(N)nc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccc(C(F)(F)F)cc3)c(C(N)=O)s2)c1
Yield: 91.8 %

Procedure:
A mixture of 0.1171 g (0.40 mmole) of 2-amino-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.47), 0.0892 g (0.414 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene, 6 mL of dimethylformamide and 0.6741 g (2.069 mmole) of cesium carbonate was heated at 60 degrees for 5 hours. The cooled mixture was added to dilute aqueous ammonium chloride. The precipitate was collected by filtration to give 0.1771 g of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.47a).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH:8]=[N:7]1>CO.[Ni]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[N:7]1
Reactant: COCCCn1ncc2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Solvent: CO
Product: COCCCn1ncc2ccc(N)cc21
Reaction time: 2 h
Yield: 94 %

Procedure:
1-(3-Methoxypropyl)-6-nitro-1H-indazole (33 g, 0.14 mol) was dissolved in methanol (400 mL) and Raney Ni (7 g) was added. The reaction mixture was hydrogenated under an atmosphere of hydrogen at rt for about 2 h. When the starting material has been consumed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 1-(3-methoxypropyl)-1H-indazol-6-amine (27 g, 94% yield) which was used in the next step without purification. 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.73 (s, 1H), 6.67-6.65 (dd, J=6.8, 2.0 Hz, 1H), 4.36-4.33 (t, J=6.4 Hz, 2H), 4.30-3.80 (brs, 2H), 3.30 (s, 3H), 3.30-3.28 (m, 2H), 2.16-2.10 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][C@@:10]3([NH:14][C:13](=[O:15])[O:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br-].[C:29]([O:33][C:34](=[O:37])[CH2:35][Zn+])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2]>[O:15]=[C:13]1[O:12][CH2:11][C@:10]2([CH2:16][CH2:17][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:37])=[CH:3][CH:4]=3)[CH2:9]2)[NH:14]1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: O=C1N[C@@]2(CC[C@@H](c3ccc(Br)cc3)C2)CO1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of (5R,7R)-7-(4-bromophenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (Int. 4, 2.1 g, 7.09 mmol) in THF (25.3 ml) at room temperature was added LiHMDS (7.80 ml, 7.80 mmol). The solution was stirred for 15 min. Next, Pd2(dba)3 (0.195 g, 0.213 mmol), 1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino)ferrocene (0.151 g, 0.213 mmol), and (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide, tetrahydrofuran (7.07 g, 21.27 mmol) were sequentially added. The slurry was stirred at 24° C. for 2 h. LCMS analysis showed complete consumption of the starting material. The reaction mixture was diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (40 g) using hexane:acetone 100:0 to 0:100 over 25 CV. tert-Butyl 2-(4-((5R,7R)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetate (2.35 g, 7.09 mmol) was isolated. HPLC retention time=0.95 min (Condition I): LC/MS M+1=332: 1H NMR (400 MHz, chloroform-d) δ 7.27-7.21 (m, 2H), 7.21-7.15 (m, 2H), 5.11 (br. s., 1H), 4.40-4.26 (m, 2H), 3.53 (s, 2H), 3.22-3.01 (m, 1H), 2.36 (dd, J=13.2, 7.3 Hz, 1H), 2.25-2.10 (m, 2H), 2.04-1.92 (m, 2H), 1.91-1.76 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].O>ClCCl>[CH2:11]([O:10][C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([O:1][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of ethyl 4-hydroxycyclohexane carboxylate (5.0 g, 29.03 mmol) in dichloromethane (200 mL) was added imidazole (4.97 g, 73 mmols) and tert-butylchlorodiphenylsilane (15.96 g, 15.2 mL, 58.0 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 mL) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
[1,4]Diazepane-1-carboxylic acid tert-butyl ester was reacted with 1-Fluoro-4-nitro-benzene at 60° C. by method D. The product with the molecular weight of 321.38 (C16H23N3O4) was obtained in this way; MS (ESI): 322 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=O)=[CH:8][CH:7]=[CH:6]2.C(Cl)(=O)C(Cl)=O.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:44])[CH:31]([NH2:43])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([OH:44])[CH:31]([NH:43][C:13]([C:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH:6]=[CH:7][CH:8]=2)=[O:15])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc2c(C(=O)O)cccc2c1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(C(=O)NC(Cc3ccc(C(F)(F)F)cc3)C(O)c3ccc(F)cc3)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of 6-methoxy-1-naphthalenecarboxylic acid (129 mg, 0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.28 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give the title compound (148 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:19])=[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ncnc2c1CCC2
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cnc(Cl)c2c1CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.69 g, 36.8 mmol) in chloroform (200 mL) was added MCPBA (19 g, 84.8 mmol) in chloroform (50 mL) dropwise. The mixture was stirred at room temperature for 16 hour. After cooling with ice-water, the mixture was quenched with Na2S2O3 (27.5 g) in water (110 mL) dropwise and followed by Na2CO3 (14 g) in water (52 mL) dropwise. The organic phase was separated and the aqueous phase was extracted with chloroform (3×200 mL). The organic phase was dried and concentrated at low temperature (<25° C.). The residue was subject to chromatography on silica gel, eluting by ethyl acetate to afford 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (2.93 g, 47%). MS (APCI+) [M+H] +171.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([Sn:15]([CH3:17])([CH3:16])[CH3:14])=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccc(F)cc1
Yield: 28.8 %

Procedure:
3.0 g (13 mmol) of 4-fluorobromobenzene, 100 ml of anhydrous diethyl ether, 12 ml (19 mmol) of 1.6 M n-butyllithium (hexane solution) and 3.8 g (19 mmol) of trimethyltin chloride were subjected to reaction, treatment and purification in the same manner as in Example 13 (a) to give 970 mg of 4-flurophenyltrimethyltin as a colorless oil (yield 22%).
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([NH2:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([NH:31][C:14](=[O:15])[CH2:13][CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[C:17]([OH:16])=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reactant: CCCCCCCCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(=O)CC(NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 12 h
Yield: 97 %

Procedure:
N-Carbobenzyloxy-L-aspartic anhydride (1 mmol) was dissolved in 50 mL methylene chloride, followed by the addition of 1.05 eq of dodecylamine and 1.1 eq of triethylamine. The reaction was capped to prevent evaporation, and stirred for 12 hours. When no trace of starting material could be detected by thin layer chromatography (TLC) (CH2Cl2, 5% MeOH), the reaction was quenched with 20 mL 1N hydrochloric acid followed by extraction with chloroform (5×). The organic layer was dried over magnesium sulfate, and 7 was obtained as a white solid (yield 97%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)cc1N
Solvent: c1ccncc1
Product: CCOC(=O)Cn1nc(-c2ccccc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
Acetic anhydride (12.7 mL, 134.8 mmol) was added dropwise to a solution of ethyl 2-(5-amino-3-phenyl-pyrazol-1-yl)acetate (31.5 g, 128.4 mmol) in pyridine (200 mL) at 0° C. under an atmosphere of nitrogen. Upon complete addition, the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted in CH2Cl2 (250 mL). The organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from diethyl ether, filtered and dried to provide the title compound as a white solid (34.81 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]=1[N:10]([C:35]([C@H:32]1[CH2:33][CH2:34][C@H:29]([CH3:28])[CH2:30][CH2:31]1)=[O:36])[CH:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2ccnn2)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2ccnn2)CC1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-(4-[1,2,3]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (0.20 g, 0.50 mmol) in toluene (1 ml) is added a solution of trans-4-methylcyclohexyl carboxylic acid chloride 1 M (1.0 ml, 1.0 mmol) and pyridine (0.046 ml, 0.58 mmol). The mixture is stirred overnight at 105° C. and diluted with ethyl acetate. The organic layer is washed with NaHCO3 sat (2×) and brine. The organic layer is dried with sodium sulfate, filtered and concentrated under reduce pressure. The residue is purified by silica gel column chromatography (20% ethyl acetate/hexane to 100% ethyl acetate followed by 10% MeOH/ethyl acetate) to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,3]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.C(N(CC)CC)C.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1.CN(C)C1C=CN=CC=1>[O:7]([CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C=CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (191 g, 1.95 mol, prepared in example 1) and triethylamine (430 mL, 3.09 mol) in anhydrous tetrahydrofuran (1L) is treated with 4-dimethylaminopyridine (4.90 g, 40.0 mmol). The solution is cooled to 0° C. and treated portionwise, over 10 minutes, with tert-butyldimethylsilyl chloride (278 g, 1.84 mol) maintaining the temperature at or below 10° C. The reaction is then allowed to stir overnight at room temperature. It is then poured into aqueous HCl (0.5N, 1L). The phases are separated and the aqueous phase is extracted with heptane (2×1L). The organic phase and organic extracts are combined, washed with aqueous HCl (0.5N, 2×500 mL), then 5% sodium bicarbonate (500 mL), then brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40° C., 20 mmHg) to provide the title compound (325 g). This is purified by Kugelrohr distillation (70°-80° C., 1 mmHg) to provide the title compound (282 g, 72% yield) as a light yellow oil, Rf =0.55, 20% ethyl acetate/hexane, GC retention time is 14.97 minutes; 1H NMR (CDCl3) δ7.48 (dd, J=5.7, 2.4 Hz, 1H), 6.20 (d, J=5.7 Hz, 1H), 4.95-4.99 (m, 1H), 2.72 (dd, J=18.2, 6.0 Hz, 1H), 2.25 (dd, J=18.2, 2.3 Hz, 1H), 0.88 (s, 9H), 0.11 (s, 6H); 13C NMR (CDCl3) δ 206.4, 163.8, 134.4, 70.8, 44.9, 25.7, 25.6, 18.0; IR (neat) νmax 2957, 2931, 2887, 2858, 1725 cm-1 ; MS (EI) m/e (% relative intensity) 212 (M+, 5), 155 (M+ -57,100).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[CH:3]=1.[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.CNC1CCCCC1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([N:19]3[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15][C:14]3=[O:13])=[CH:3]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Brc1ccc2ccc(Br)cc2c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ccc(Br)cc3c2)C(=O)C1
Temperature: 150 °C

Procedure:
To a 20 mL microwave vial charged with 2,7-dibromonaphthalene (1.1 g, 3.8 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (0.50 g, 2.5 mmol), and a stir bar was added copper (I) iodide (95 mg, 0.50 mmol), N,N′-dimethylcyclohexane-1,2-diamine (142 mg, 1.0 mmol), K3PO4 (1100 mg, 5.0 mmol), and dioxane (15 mL). The mixture was purged three times with nitrogen, and heated to 150° C. in a microwave reactor. The crude solution was diluted with EtOAc, adsorbed onto silica gel, and purified by silica gel chromatography (Hex:EtOAc). The solvent was removed to provide the title compound. LC-MS (IE, m/z): 405 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:12]=[C:13]([NH:17]N)[CH:14]=[CH:15][CH:16]=1.C1(C)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:16]=[CH:15][C:14]2[C:7]3[C:2]([OH:1])=[N:3][CH:4]=[CH:5][C:6]=3[NH:17][C:13]=2[CH:12]=1
Reactant: Oc1ccnc(O)c1
Reactant: NNc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1nccc2[nH]c3cc(C(F)(F)F)ccc3c12
Temperature: 25 °C

Procedure:
A mixture 2,4-dihydroxypyridine and 3-trifluoromethylphenylhydrazine (2.6 equiv) in diphenyl ether was heated at reflux with a Dean Stark apparatus for 2 h as described by C. H. Nguyen in Tetrahedron 1987, 43, 527. The reaction was cooled to room temperature followed by the addition of toluene. The solid was collected and washed with toluene. The solid was then dissolved in EtOAc and purified by flash chromatography (EtOAc to 5% MeOH in EtOAc) to provide the title compound.