Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[CH3:50][C:51]([O:54][C:55]([C:57]1[N:58]2[CH:61]([S:62][CH2:63][C:64]=1[CH2:65][O:66][C:67](=[O:69])[CH3:68])[CH:60]([NH2:70])[C:59]2=[O:71])=[O:56])([CH3:53])[CH3:52]>ClCCl>[CH3:53][C:51]([O:54][C:55]([C:57]1[N:58]2[CH:61]([S:62][CH2:63][C:64]=1[CH2:65][O:66][C:67](=[O:69])[CH3:68])[CH:60]([NH:70][C:27](=[O:28])[C:26](=[N:30][O:31][CH3:32])[C:24]1[N:25]=[C:21]([NH:20][C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=1)[C:59]2=[O:71])=[O:56])([CH3:50])[CH3:52]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 76 %

Procedure:
To a stirred suspension of 48 g (0.1 mole) of 2-[2-(tritylamino)thiazole-4-yl]-2-methoxyiminoacetic acid in 750 mL of anhydrous dichloromethane was added 13.94 mL (0.1 mole) of triethylamine and the mixture was mechanically stirred until a clear solution formed (approx. 45 min). After complete dissolution 20.6 g (0.1 mole) of N,N-dicyclohexylcarbodiimide and 13.5 g (0.1 mole) of 1-hydroxybenzotriazole were added and the mixture stirred at ambient temperature for 2 hours. A solution of 32.8 g (0.1 mole) of [6R-[6 alpha,7 beta(z)]]-3-(acetoxymethyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 carboxylic acid 1,1-dimethylethyl ester (from Example 1) in 250 mL of anhydrous dichloromethane was added and the resulting solution was stirred overnigh (16 hours) at ambient temperature. The precipitate was removed by filtration and the filtrate was washed successively with 2×250 mL=500 mL of saturated aqueous sodium bicarbonate and 2×250 mL=500 mL of saturated aqueous sodium chloride and dried over sodium sulphate. Removal of the dichloromethane afforded the crude product as a gummy-oil which was purified by preparative liquid chromatography (0-10% EtoAc in CH2Cl2), to give 57.2 g (76%) of pale yellow solid. NMR (CDCl3): 1.54 (s) 9H (t-bu) 2.09 (s) 3H (OAc); 3.35, 3.56 (d of d, J=18 Hz) 2H (CH2S); 4.08 (s) 3H (OCH3); 4.86 5.04 (d of d, J=14 Hz) 2H (CH2O); 5.04 (d, J=6 Hz) 1H (C6); 5.93 (d of d, J=6 Hz J=10 Hz), 1H (C7); 6.71 (s) 1H (thiazole); 6.91 (d, J=10 Hz) 1H (NH); 7.08 (s) 1H (NH); 7.30 (s) 15H (CPh3).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)[CH2:2][CH3:3].[C:12]1([CH3:24])[CH:17]=[CH:16][C:15]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([CH:4]1[CH2:5][C:6](=[O:11])[CH:7]([C:22](=[O:23])[NH:21][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:24])=[CH:13][CH:14]=2)(=[O:19])=[O:20])[C:8](=[O:10])[CH2:9]1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCCC1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CCCC1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-propyl-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-PROPYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 132.5°-133.5° C. (corr.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5](F)=[CH:4][N:3]=1.Cl[C:11]1N=C(Cl)C(F)=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1nc(Cl)ncc1F
Product: Cc1cnc(Cl)nc1C

Procedure:
The title compound was prepared in a manner analogous to Intermediate 55, substituting 2,4-dichloro-5-methylpyrimidine for 2,4-dichloro-5-fluoropyrimidine. MS (ESI): mass calculated for C6H7ClN2, 142.03, m/z found 143.1 [M+1]+. 1H NMR (500 MHz, CDCl3): 8.32-8.25 (m, 1H), 2.52-2.46 (m, 3H), 2.28-2.22 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Oc1ccc(F)cc1F
Reactant: NS(=O)(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzenesulfonamide (400 mg, 1.6 mmol) and 2,4-difluorophenol (228 mg, 1.76 mmol) in DMSO (16 ml) was treated with cesium carbonate (1 g, 3.2 mmol). The resulting mixture was heated to 120° C. for 20 min by microwave irridation (normal). The mixture was treated with water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan solid. The solid was purified by silica gel chromatography (12 g ISCO, 30% EtOAc in hexanes 30 ml/min) to give the title compound (340 mg, 58%) as a tan solid LCMS (M−H)−=362.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.Br.[Br:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[BrH:13].[N:1]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: BrCCNCCBr
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Cc2cc(N3CCNCC3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A mixture of 5-aminooxindol (14 g), 29 g of bis(β-bromoethyl)amine.hydrobromide in 250 ml of ethanol was stirred under reflux for 8 hours and allowed to stand overnight at room temperature. To the mixture was added sodium carbonate (10.1 g) and the mixture was stirred further for 8 hours under reflux. After cooling to room temperature, crystals which precipitated were collected by filtration and recrystallized from a mixture of water and ethanol to give 16 g of 5-(1-piperazinyl)oxindol.hydrobromide.
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=[CH:17][CH:16]=2)[C:9]2[CH:14]=CC=C[CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Li])[CH2:23]CC.C1C2CC3C(=CC=CC=3)C=2C=CC=1C=O>C1COCC1.CCCCCC>[CH:22]([C:17]1[CH:16]=[CH:15][C:8]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][C:9]=2[CH:10]=1)=[CH2:23]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc2c(c1)Cc1ccccc1-2
Reaction time: 2 h

Procedure:
Triphenylmethyl phosphonium bromide (36 gms/0.1 mole) in 500 milliliters of dry THF is treated under nitrogen with 90 milliliters of a 1.1 molar solution of n-butyl lithium in hexane and stirred for 2 hours. A solution of 19.4 gms. (0.1 mole) of fluorene-2-carboxaldehyde in 100 milliliters of THF is added dropwise and the final mixture refluxed for 1 1/2 hours. One liter of hexane is added to the cold solution and the precipitate filtered off. The filtrate is evaporated and the residue chromatographed on alumina (Woehlm neutral) using hexane to give 15 gms. (75% theory) of product. Recrystallization from hexane yields 2-vinylfluorene as colorless plates. The structure of the product is confirmed by nuclear magnetic resonance and elemental analysis.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:29][C:28]4[C:23](=[N:24][CH:25]=[CH:26][C:27]=4Cl)[CH:22]=3)=[CH:17][CH:16]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[C:36]([N+:38]([O-:40])=[O:39])[CH:35]=[CH:34][C:33]=1[OH:41].C(=O)([O-])[O-].[K+].[K+].CO.CCOC(C)=O>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:29][C:28]4[C:23](=[N:24][CH:25]=[CH:26][C:27]=4[O:41][C:33]4[CH:34]=[CH:35][C:36]([N+:38]([O-:40])=[O:39])=[CH:37][C:32]=4[F:31])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(-c3cc4nccc(Cl)c4s3)cc2)C1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)C1
Temperature: 195 °C
Yield: 30 %

Procedure:
To a solution of 100 (250.0 mg, 0.54 mmol) in Ph2O (4 ml) was added 2-fluoro-4-nitrophenol (171 mg, 1.1 mmol) and potassium carbonate (304 mg, 2.2 mmol). The the reaction mixture was heated to 195° C. for 3 hrs, cooled to room temperature, diluted with DCM, filtered and concentrated. The residue was purified by column chromatography, eluents EtOAc, then MeOH/EtOAc (20-80), to afford title compound 101 (94 mg, 30% yield) as a white solid. MS (m/z): 580.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:13](=[O:14])[NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
Methyl-3,4-diaminobenzoate (1.251 g, 7.5 mmol, Lancaster) was reacted with 1,1′-carbonyldiimidazole (2.128 g, 13.1 mmol, Aldrich) under the conditions of Example 1b to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 193 (M#1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:8])=[N:4][S:5][C:6]=1[Cl:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](I)[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:8][CH2:15][CH3:16])=[N:4][S:5][C:6]=1[Cl:7]
Reactant: CCI
Reactant: Oc1nsc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nsc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
To a mixture of 4,5-dichloro-3-hydroxyisothiazole (17.00 g, 0.100 mol) and potassium carbonate (13.82 g, 0.100 mol) in dry DMF (80 ml) was added dropwise a solution of ethyl iodide (8.84 ml, 0.110 mol) in dry DMF (20 ml). The mixture was stirred 18 hours at ambient temperature. Water (500 ml) was added and the mixture was extracted with ether (3×400 ml). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product (18.35 g). The crude product was distilled to give 4,5-dichloro-3-ethoxyisothiazole (14.63 g, 74%, b.p. 64°-66°/0.1 mm). TLC (2% methanol/chloroform, silica): Rf=0.72.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+]>C=O>[F:13][C:4]1[C:3]([NH:2][CH3:19])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc(N)c1F
Agent: C=O
Agent: Cl
Agent: O=S(=O)(O)O
Product: CNc1cccc(C(=O)OC)c1F
Temperature: 40 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
Methyl 3-amino-2-fluorobenzoate hydrochloride (18.65 g, 0.09 mol) was dissolved in a 37% formalin solution. While maintaining the temperature at 40° C. or lower, 98% sulfuric acid (680.81 g, 6.80 mol) was added dropwise thereto. Thereafter, the mixture was naturally cooled, and agitated for 2 hours at room temperature. The reaction mixture was poured into ice water, and was neutralized with sodium bicarbonate. The neutralized liquid was filtered, and washed with ethyl acetate. Then, the filtrate was extracted, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and then the concentration residue was purified by silica gel column chromatography (developer solvent: ethyl acetate/n-hexane=1/4), as a result of which 6.27 g (yield: 38%) of the indicated compound was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([CH2:12][OH:13])=[C:8]2[CH3:14])[CH3:2]>ClCCl.[O-2].[Mn+4].[O-2]>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([CH:12]=[O:13])=[C:8]2[CH3:14])[CH3:2]
Reactant: CCc1cccc2c(C)c(CO)[nH]c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1cccc2c(C)c(C=O)[nH]c12
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A mixture of (7-ethyl-3-methyl-1H-indol-2-yl)methanol (1.6 g, 9.1 mmol) and manganese (IV) oxide (3.97 g, 45.7 mmol) in dichloromethane (15 mL) was stirred overnight. The mixture was filtered through celite and evaporated to afford the title compound (1.1 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.90 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 2.83 (q, J=7.5 Hz, 2H), 2.62 (s, 3H), 1.31 (t, J=7.5 Hz, 3H)
Reaction SMILES: [ClH:1].Cl.C([O:7][CH:8](OCCCC)[C@H:9]([CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41])[NH:10][C:11](=[O:35])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:34])[C@H:18]1[CH2:22][CH2:21][C:20](=[O:23])[N:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])CCC.[OH-].[Na+]>C(#N)C>[ClH:1].[CH2:27]([O:26][C:24]([N:19]1[C:20](=[O:23])[CH2:21][CH2:22][C@@H:18]1[C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:11]([NH:10][C@H:9]([CH:8]=[O:7])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42])=[O:35])=[O:34])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1
Yield: 100 %

Procedure:
After 1N hydrochloric acid aqueous solution (30 ml) was added to a solution of N-benzyloxycarbonyl-D-pyroglutamyl-L-prolyl-L-argininal dibutylacetal hydrochloride (0.40 g, 0.60 mmol) in acetonitrile (60 ml), the mixture was reacted at 36° C. for 1.5 hour with stirring. After completion of the reaction, pH of the reaction mixture was adjusted to 4.8 with 1N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and chloroform was added to the residue. Insoluble matters were removed by filtration. After the filtrate was concentrated, the residue was recrystallized from chloroform-hexane to give 0.33 g (100%) of N-benzyloxycarbonyl-D-pyroglutamyl-L-prolyl-L-argininal hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[Cl:26])[C@H:12]([CH3:18])[CH:13]([OH:17])[CH2:14][CH:15]=[CH2:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1>CCO.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[Cl:26])[C@H:12]([CH3:18])[CH:13]([OH:17])[CH2:14][CH2:15][CH3:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=CCC(O)[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Pt]
Solvent: CCO
Product: CCCC(O)[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 80 %

Procedure:
A suspension of 4-chloro-N-(2,5-dichlorophenyl)-N-(1R)(2-hydroxy-1-methylpent-4-enyl)benzenesulfonamide (150 mg, 0.3 mmol) and sulfided platinum (5 wt. % on carbon, 50 mg) in EtOH (50 mL) was hydrogenated at 45 psi for 3 h. The suspension was filtered through celite and concentrated in vacuo. Silica gel chromatography (10% EtOAc/hexanes) of the concentrate afforded the title compound as a clear wax (120 mg, 80% yield): MS (ESI): (M−H)−436.34; [α]D=−15.3° (c 1.00, MeOH), 1H NMR (DMSO-d6) δ 7.81 (d, 2H, J=7.0 Hz), 7.60 (d, 2H,) J=7.0 Hz), 7.50 (s, br, 1H), 7.41 (d, 2H, J=8.0 Hz), 7.32 (m, 2H), 7.24 (m, 1H), 7.18 (s, br, 1H), 4.76 (dd, 2H, J=50 Hz, 15 Hz), 4.36 (t, 1H, J=7.0 Hz), 3.33 (s, 3H), 1.20–1.34 (m, 3H), 0.79 (d, 3H, J=6.0 Hz), 0.46 (d, 3H, J=6.0 Hz).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([C:18]1([C@@H:21]2[CH2:25][N:24]([C@H:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[C:23](=[O:34])[C@H:22]2[F:35])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:13]([O:15][C:16]([C:18]1([C@H:21]2[CH2:25][N:24]([C@H:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[C:23](=[O:34])[C@H:22]2[F:35])[CH2:20][CH2:1][CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CC1
Reactant: CC(C)NC(C)C
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
Under a nitrogen atmosphere, diisopropylamine (2.97 ml, 21.19 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml) to which, after cooling to −78° C., was subsequently added dropwise an n-hexane solution of 1.63 M n-butyl lithium (10.8 ml, 17.60 mmol) over a period of 5 minutes. After 15 minutes of stirring at 0° C., the reaction solution was cooled to −78° C. and trans 4-(1-ethoxycarbonylcyclopropyl)-3-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (optical isomer B; 4.71 g, 14.13 mmol) dissolved in anhydrous tetrahydrofuran (30 ml) was added dropwise thereto over a period of 5 minutes. The reaction solution was stirred at −78° C. for 3 minutes, and 2,6-di-tert-butylphenol (4.37 g, 21.18 mmol) dissolved in anhydrous tetrahydrofuran (40 ml) was added dropwise thereto over a period of 5 minutes. The reaction solution was stirred at −78° C. for 10 minutes, mixed with saturated ammonium chloride aqueous solution (200 ml) and then warmed to room temperature. The organic layer was separated and then the aqueous layer was extracted with chloroform (100 ml×2). The organic layers were combined, washed with water (100 ml×2) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and eluted with an eluant of n-hexane:ethyl acetate=2:1 to recover 1.96 g (42%) of the starting material and then with n-hexane:ethyl acetate=3:2 to obtain 1.79 g (38%) of the title compound in an oily form.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:14]#[N:15])([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8]1>CCOCC>[NH2:13][CH2:12][C:7]1([CH2:14][NH2:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CC1(C#N)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC1(CN)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of LiAlH4 (4.74 g) in dry Et2O (100 mL) was cooled in an ice bath, and a solution of cyclopentane-1,1-dicarbonitrile (5.0 g) in Et2O (50 mL) was added dropwise at such a rate that the temperature was kept below 20° C. The mixture was stirred overnight at room temperature, cooled in an ice bath, and quenched by adding H2O (5 mL), 2M aqueous NaOH (10 mL) and again H2O (5 mL). The suspension was filtered, the filter cake was washed with Et2O, and the combined filtrates were evaporated to dryness under reduced pressure to give 4.95 g of a clear, colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.24 (br s, 4H), 1.22-1.40 (m, 4H), 1.55-1.64 (m, 4H), 2.62 (s, 4H).
Reaction SMILES: FC(F)(F)C1N=C(N2CCNCC2)C=CC=1.BrCC[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>>[C:21]1(=[O:30])[C:22]2[C:23](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:25])[NH:20]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: FC(F)(F)c1cccc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1NC(=O)c2ccccc21
Yield: 33 %

Procedure:
A mixture of 69.3 g of 1-[6-(trifluoromethyl) -2-pyridinyl]piperazine, and 129.6 g of N-(2-bromo-ethyl)phthalimide and 57.2 g of sodium carbonate is heated at reflux for 23 hours. The resulting precipitate is filtered off and the ethanol evaporated. The concentrate is dissolved in dichloromethane, washed with water, dried over magnesium sulfate, and evaporated. The resulting precipitate is recrystallized from isopropanol to give 39.5 g of 2-μ-[4-[6-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl]ethyl]-1H-isoindole-1,3-dione (yield 33%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][C:14]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16][C:15]=3[CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[CH3:32][Zn+]>O1CCCC1.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:12]([CH3:32])=[CH:13][C:14]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16][C:15]=3[CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN1CCc2cc(OS(=O)(=O)C(F)(F)F)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CCN(C)CC2
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of D7 (100 mg, 0.21 mmol) in dry tetrahydrofuran (2 mL) was degassed with argon for 10 minutes. To the solution Pd(PPh3)4 (30 mg) was added followed by methylzinc chloride (0.22 mL, 0.43 mmol) then heated at reflux for 30 minutes. The mixture was cooled to room temperature and quenched with water. Extraction with dichloromethane followed by purification by SCX and chromatography on silica gave the title compound D8 as a gum (56 mg). MH+ 334. 1H NMR δ (CDCl3) 2.36 (3H, s), 2.38 (3H, s), 2.47-2.66 (4H, m), 2.90-3.05 (4H, m), 6.96 (1H, s), 7.10-7.20 (2H, t), 7.83-7.92 (3H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1)=[O:16])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[CH2:12]([O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH:19]([O:22][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCC(O)C1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(Oc2ccc(Cl)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of 1,4-dichloro-2-nitro-benzene (190 mg, 1.1 mmol), 3-hydroxy-cyclopentanecarboxylic acid ethyl ester (180 mg, 1.14 mmol), triphenylphosphine (448 mg) and DIAD (345 mg) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was then evaporated under reduced pressure and the crude residue was purified by flash chromatography to afford 280 mg of 3-(4-chloro-2-nitro-phenoxy)-cyclopentanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cc1OC
Temperature: 110 °C
Yield: 35.8 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 3,4-dimethoxyphenylboronic acid (41 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (45-45% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (27.8 mg, 36%). ESI-MS: m/z 447.2 (M+H)+.