Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20]N)[O:17][C:16]3=[O:22])=[CH:11][C:10]=2[F:23])[CH2:5][CH:4]1[F:24].[N:27]1C=CC=[CH:29][CH:28]=1.C(OC(=O)C)(=[O:35])C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:29][C:28]([NH2:27])=[O:35])[O:17][C:16]3=[O:22])=[CH:11][C:10]=2[F:23])[CH2:5][CH:4]1[F:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1F
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2F)CC1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
The mixture of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (6.73 mmol), pyridine (26.9 mmol), acetic anhydride (9.43 mmol) in ethyl acetate (25 ml) was stirred for 5 hours at room temperature. The reaction mixture was extracted with the ethyl acetate water mixture and combined organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel to give title compound in 58% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Br[C:15]1[C:16]([NH2:33])=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:33][C:16]1[C:15]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[N:20][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][N:17]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(N3CCC(NC(=O)OC(C)(C)C)C3)n2)cc1
Temperature: 100 °C
Yield: 47.3 %

Procedure:
tert-Butyl N-pyrrolidin-3-ylcarbamate (43.14 mg, 0.2316 mmol) was added to a stirred solution of 3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine (75 mg, 0.2105 mmol) and DIPEA (29.93 mg, 40.34 μL, 0.2316 mmol) in NMP (1 mL) and the reaction mixture heated to 100° C. under microwave conditions for 90 minutes. The reaction mixture was partitioned between EtOAc/water and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether). The fractions were collected concentrated in vacuo and freeze-dried to give the title compound as a yellow solid (46 mg, 48% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 1.40 (s, 9H), 1.79-1.82 (m, 1H), 2.08-2.17 (m, 1H), 3.30-3.38 (m, 1H), 3.42-3.44 (m, 2H), 3.60-3.71 (m, 2H), 4.06-4.12 (m, 1H), 6.22 (s, 2H), 7.16 (d, 1H), 7.83 (d, 2H), 8.18 (d, 2H) and 8.20 (s, 1H) ppm; (ES+) 462.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([OH:35])[CH2:12]1)[C:8](=[O:36])[NH:7]2)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.[CH2:46]([O:48][CH2:49]Cl)[CH3:47]>ClCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][CH2:49][O:48][CH2:46][CH3:47])[CH2:12]1)[C:8](=[O:36])[NH:7]2)=[O:5])[CH3:2]
Reactant: CCOCCl
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O)CC1C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCOC1CC2C(=O)NC3(C(=O)OCC)CC3C=CCCCCCN(Cc3ccc(OC)cc3)C(=O)N2C1
Temperature: 25 °C

Procedure:
To a stirred solution of the alcohol 21f (1.35 g, 2.70 mmol, 75% purity) and N-ethyldiisopropylamine (1.42 ml, 8.1 mmol) in dichloromethane (15 ml) at 0° C. was added chloromethyl ethyl ether (0.5 ml, 5.4 mmol). After stirring at rt on the reaction mixture was cooled to 0° C. and more N-ethyldiisopropylamine (1 ml, 5.7 mmol) and chloromethyl ethyl ether (0.3 ml, 3.2 mmol) was added, then stirred additional 16 h at rt. The reaction mixture was then directly applied on a silicagel column and eluted using stepwise gradient elution (ethyl acetate in hexane 50-80%). Concentration of the appropriate fractions gave the title compound as a slight brown syrup which crystallized upon standing (0.8 g, 53%). LR-MS: Calcd for C30H44N3O7: 558. Found: 558 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.O[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.[C:39]([O-])([O-])=[O:40].[Na+].[Na+].C(Cl)Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([CH2:39][OH:40])[CH:31]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CO)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.5 g, 3.4 mmol), 3-hydroxyphenyl boronic acid (0.614 g, 4.07 mmol) and Pd(PPh3)4 (0.391 g, 0.33 mmol) in 1,4-dioxane (20 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (1.29 g, 12.21 mmol) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 80° C. for 2 h. After completion of the reaction, water was added to it and extraction carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-6-(3-(hydroxymethyl)phenyl)-1H-indazole-4-carboxamide (1.2 g, 75.4%). LCMS: 471.20 (M+1)+; HPLC: 97.18% (@ 254 nm) (Rt; 6.614); 1H NMR (DMSO-d6, 400 MHz) δ 11.51 (s, 1H), 8.63 (t, 1H, J=4.8 Hz), 8.35 (s, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.71 (d, 1H, J=7.6 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.36 (d, 1H, J=7.2 Hz), 5.88 (s, 1H), 5.35-5.26 (m, 1H), 5.25 (t, 1H, J=4.4 Hz), 4.60 (d, 2H, J=6 Hz), 4.39 (d, 2H, J=4.4 Hz), 2.21 (s, 3H), 2.18-2.12 (m, 2H), 2.11 (s, 3H), 2.05-1.97 (m, 2H), 1.92-1.86 (m, 2H), 1.74-1.68 (m, 2H).
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>CCOCC>[CH3:5][C:2]([N:10]1[CH2:9][CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]1)([CH3:6])[CH:3]=[O:4]
Reactant: CC(C)(Br)C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 2-bromo-2-methylpropanal (5 g, 33.11 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (18.6 g, 99.87 mmol, 3.02 equiv) in ether (80 mL). The resulting solution was stirred overnight at 25° C. The solids were filtered out. The organic filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum to give 6 g of tert-butyl 4-(2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate as a white solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:37])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CCc1ccccc1-n1nc(C(C)(C)C)cc1NC(=O)Cc1ccc(-n2cnc3cccnc32)cc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2-ethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 479.10 [M+H]+; tR=3.3 min (System 3).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[C:35]#[CH:36].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH:36]=[CH:35][C:34]([O:38][CH2:39][CH3:40])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OCC
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25.0 g (53.2 mmol) of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester and 10.8 mL (106 mmol, 2 equivalents) of ethyl propiolate in 200 mL of dry tetrahydrofuran at 1° C. was treated with 53.2 mL (53.2 mmol, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M) over 45 minutes. The resulting solution was allowed to warm slowly to ambient temperature and stirred overnight. The tetrahydrofuran was displaced with toluene at reduced pressure, and the toluene solution was washed with water and brine, diluted to 600 mL with toluene, stirred with 90 g of silica gel for three hours, filtered, and concentrated to 25.14 g (83%) of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid benzyl ester as an orange oil. 1H NMR (CDCl3) indicated a 1.5:1 trans/cis ratio.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:17])=[C:13]([CH:14]=1)[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1CO
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(OCc2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of (5-(benzyloxy)-2-methylphenyl)methanol (280 mg) in DMSO (5.0 ml) was added 2-iodoxybenzoic acid (343 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (250 mg) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13](#[N:15])[CH3:14].[CH:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>CCCCCC.O1CCCC1>[OH:22][CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][C:13]#[N:15]
Reactant: CC#N
Reactant: CCCCCC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCC(O)CC#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.1 %

Procedure:
A 1.9 M solution (21 ml., 40 millimole) of n-butyl lithium in hexane is added cautiously to a stirred solution of freshly distilled diisopropylamine (4.04 g., 40 millimole) in anhydrous tetrahydrofuran (60 ml.) maintained at 0° C. under a nitrogen atmosphere. The resulting solution is stirred at ambient temperature for 15 minutes, cooled to -78° C. and treated with a solution of anhydrous acetonitrile (1.64 g., 40 millimole) in anhydrous tetrahydrofuran (5 ml.). The resulting turbid suspension is stirred and maintained at -78° C. for 30 minutes and then treated with a solution of 1-hexanal (4.0 g., 40 millimole) in anhydrous tetrahydrofuran (5 ml.). After attaining a clear, yellow, reaction solution, cooling at -78° C. is maintained for an additional 15 minutes. The cold reaction solution is treated with 2 N hydrochloric acid (50 ml.) and extracted with ether (100 ml.). The organic extract is washed with water (50 ml.) and 5% aqueous sodium bicarbonate (50 ml.), dried over magnesium sulfate, filtered, and evaporated in vacuo, leaving the title compound as a pale yellow oil (5.2 g., 92%) pmr (CDCl 3) δ 0.97 (3H, t), 2.55 (2H, d), 3.10 (H, s) and 3.93 (H, bs).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](=O)[CH2:3][CH2:2]1.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1Br)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-:27].[K+].[K+].CN1C(=O)CCC1>[Cl-].[Na+].O.C(OC(=O)C)C>[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:12]1[C:13]2[C:1](=[O:27])[CH2:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1CCCc2[nH]c3ccccc3c21
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccccc1Br
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1-n1c2c(c3ccccc31)C=CCC2=O
Temperature: 25 °C
Yield: 38.2 %

Procedure:
In a 500 ml two-neck flask, 1,2,3,4-tetrahydro-9H-carbazole-4-one (Compound E, 20 g), t-butyl bromobenzene (60 g), potassium carbonate (43 g), Cu powder (2.1 g), and NMP (70 ml) were mixed and stirred. The reaction mixture was refluxed and stirred for 24 to 30 hours in a state in which the temperature was raised. When the reaction was completed, the reactant was cooled at room temperature, and then the reactant was mixed with ethylacetate (500 ml) and brine (500 ml) and strongly stirred. Floating materials was filtered and removed using celite, and the organic layer was separated. The water layer was extracted using ethylacetate, and the organic layer was collected and dried over magnesium sulfate. The organic layer was concentrated, and the residual was purified using a column chromatography, thereby obtaining 13 g of N-(t-butylphenyl) carbazolone (Compound F).
Reaction SMILES: C([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([NH:18][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])[CH:29]=[CH:30][CH:31]=4)[C:22]([F:37])=[CH:21][N:20]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.[C:38](OC(=O)C)(=O)C.N1C=CC=CC=1>C(Cl)Cl>[C:6]([N:8]1[C:13]2[CH:14]=[C:15]([NH:18][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])[CH:29]=[CH:30][CH:31]=4)[C:22]([F:37])=[CH:21][N:20]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)(=[O:5])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc4c(c3)N(C(=O)OC(C)(C)C)CCO4)ncc2F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc4c(c3)N(C(C)=O)CCO4)ncc2F)c1

Procedure:
The title compound was prepared by treating the product of Example 85 with acetic anhydride and pyridine in CH2Cl2 at rt for 1 hr, followed by washing with 1N HCl, then with aqueous NaHCO3, drying over Na2SO4 and removal of solvents in vacuo. MS m/z: 449.1 (M+H+).
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.CC([O-])=O.[Na+].Cl.[NH2:26][OH:27]>CCO.O>[OH:27][N:26]=[C:16]1[C:10]2[N:11]([CH3:15])[C:12]3[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=3[C:9]=2[CH2:18][CH2:17]1
Reactant: NO
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NO

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (8.0 g) was suspended in EtOH (200 ml) and a solution of NaOAc (15.6 g) in water (25 ml) and a solution of hydroxylamine hydrochloride (8.0 g) in water (25 ml) were added and the mixture was refluxed for 3 hours. The mixture was concentrated in vacuo and the residue was recrystallized from 95% EtOH to provide 3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol as an off-white solid. The oxime was dissolved in tetrahydrofuran (100 ml), and thereafter acetic anhydride (8.1 g) and 4-dimethylaminopyridine (400 mg) were added and the mixture was stirred under nitrogen at ambient temperature overnight. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added and the solution was washed successively with water (50 ml), 5% NaHCO3 (50 ml) and water (50 ml). After drying (Na2SO4), the solvent was removed in vacuo and the product recrystallized from EtOH to provide 3-acetyloximino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl acetate (1.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:6]=2[CH:18]=1.[C:20](Cl)(Cl)=[S:21].C(=O)(O)[O-].[Na+]>ClCCl>[F:19][C:3]1[C:2]([N:1]=[C:20]=[S:21])=[CH:18][C:6]2[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)c(N)cc32)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(Cn2c(=O)sc3cc(F)c(N=C=S)cc32)no1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
A mixture of 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (1.33 g), dichloromethane (10 ml) and ice (10 g) was prepared. To this mixture was added thiophosgene (0.7 g), and then portionwise added sodium bicarbonate at a temperature of 5° to 10° C. so as to make the mixture slightly alkaline. The mixture was stirred for 20 minutes, and tested to confirm whether the mixture was alkaline (if the mixture was acidic, then a further amount of sodium bicarbonate was added). The dichloromethane layer was separated, and the aqueous layer was extracted with fresh dichloromethane (10 ml×2). The dichloromethane layers were gathered together, washed with water, and distilled to remove the dichloromethane solvent therefrom. The resulting solid residue was recrystallized from a toluene-hexane solvent mixture, so that the aimed compound, i.e. 6-fluoro-5-isothiocyanato-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (1.49 g) was obtained. m.p. 168°-170° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([C:2]2[C:3]([NH:12][C@H:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1

Procedure:
A suspension of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (2.44 g, 5.73 mmol), cyclopropylboronic acid (2.46 g, 28.6 mmol), potassium carbonate (3.17 g, 22.9 mmol) and tetrakis(triphenylphosphine)palladium (0.662 g, 0.57 mmol) in 1,4-dioxane (15 ml) and water (4 ml) was subjected to microwave irradiation at 140° C. for 2 hours. The reaction was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37]O)([CH3:34])[CH3:33].C1(C(N)=O)CC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:37][CH2:36][N:35]([CH:39]([CH3:41])[CH3:40])[CH:32]([CH3:34])[CH3:33])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)N(CCO)C(C)C
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: NC(=O)C1CC1
Product: COc1ccccc1C(OCCN(C(C)C)C(C)C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(diisopropylamino)ethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(diisopropylamino)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][NH:7][N:6]=1)=[O:4]>[Pd].C(O)C.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)c1n[nH]cc1N
Reaction time: 8 h

Procedure:
A mixture of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (10 g, 58 mmol) and 10% palladium on carbon (500 mg) in ethanol (150 ml) and DMF (30 ml) stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered through celite reduced in vacuo and dried through azeotrope with toluene and methanol to afford 4-amino-1H-pyrazole-3-carboxylic acid methyl ester as a dark amber tar (9.35 g). (LC/MS (acidic): Rt 0.39 min, [M+H]+ 142).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 22.4 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and isopropylamine (44 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (48 mg, 0.13 mmol, yield 22%).