Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)([CH3:5])[CH:3]=[CH2:4].C(O)(=[O:21])C.O>[O-2].[Cr+6].[O-2].[O-2].C(Cl)Cl>[CH3:5][C:2]1([CH3:1])[C:6]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[O:18][C:4](=[O:21])[CH2:3]1
Reactant: CC(=O)O
Reactant: C=CC(C)(C)C1(O)CCN(C(=O)OC(C)(C)C)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)OC(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a soultion of borane-dimethyl sulfide complex (0.409 mL, 0.00460 mol) in methylene chloride (6.00 mL, 0.0936 mol) was slowly added a solution of tert-butyl 3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate (3.20 g, 0.0125 mol) in methylene chloride (6.00 mL, 0.0936 mol) with stirring at rt. After 2 h, the reaction mixture was slowly added to a solution of chromium(VI) oxide (7.52 g, 0.0752 mol) in acetic acid (45.00 mL, 0.7915 mol), and water (5.00 mL, 0.278 mol) at 5° C. After stirring the reaction mixture at rt for 12 h, water (60 mL) and methylene chloride (30 mL) were added. The organic layer was seperated and the aqueous layer was further extracted with methylene chloride (2×30 mL). The organic layers were combined, washed with brine (2×30 mL), dried and concentrated. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the product. LCMS (M+Na) 292.2.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[C:5]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(O)(=[O:20])C.C([O-])(=O)C.[K+].Cl>O>[CH:2]([C:3]1[CH:4]=[C:5]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:20]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C)(C)c1cccc(C(Br)Br)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(C)(C)c1cccc(C=O)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixed liquid of 2.95 g of ethyl 2-[3-(dibromomethyl)phenyl]-2-methylpropionate and 30 ml of acetic acid was added 4.77 g of potassium acetate, followed by stirring at 100° C. for 6 hours. After cooling the reaction solution, 10 ml of 6 M hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, followed by extraction with hexane, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 1.74 g of ethyl 2-(3-formylphenyl)-2-methylpropionate as a colorless oily substance.
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:14]([CH:18](O)C([O-])=O)[CH2:15]CC>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:15][CH2:14][CH3:18])=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Reactant: CCCCC(O)C(=O)[O-]
Product: CCCCOC(=O)COS(=O)(=O)C(F)(F)F

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with butylglycolate.
Reaction SMILES: [NH2:1][C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N([C:54]([O:56][CH2:57][CH:58]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:64]2[C:59]1=[CH:60][CH:61]=[CH:62][CH:63]=2)=[O:55])[C@H](C(O)=O)CSC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S(=O)(=O)(O)O>CO>[NH:1]([C:54]([O:56][CH2:57][CH:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:65]2[C:70]1=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:55])[C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
and H2N-Cys(Trt)-OMe 26. 7.2 g (12.3 mmol) of Fmoc-Cys(Trt)-OH was dissolved in 70 ml of MeOH and added 1.5 ml of conc. sulfuric acid. The reaction mixture was refluxed for 4 hr, the solvent was removed. The mixture was then mixed with ethyl acetate, and washed with water, saturated NaHCO3, and brine. Removing the solvent under vacuum gave 25 as a white foamy solid. The crude product was dissolved in 20 ml of 20% piperidine solution in DMF. After 2 hr, the solvent was removed. Silicagel chromatography (CH2Cl2: MeOH=10:1) gave 4.0 g (86% two step yield) of 26 as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([NH:16][CH:17]1[C:23](=[O:24])[N:22]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:18]1=[O:37])=O)C>>[CH:1]1([CH2:6][C:7]([NH:16][C@H:17]([C:23]([C:17]2([NH2:16])[C:23](=[O:24])[N:22]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:18]2=[O:37])=[O:24])[CH3:18])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white foam. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.50 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH:21]=C)[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:29].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH:21]=[O:29])[N:12]2[CH:17]([CH3:18])[CH2:16][N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1c(C(=O)OCC)c(OCc2ccccc2)c2n1C(C)CN(C)C2=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C=O)C(C)CN(C)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 8-(benzyloxy)-2,4-dimethyl-1-oxo-6-vinyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.11 g, 0.29 mmol), osmium tetroxide (2.5% in t-butanol, 0.59 mL, 0.058 mmol), sodium periodate (0.19 g, 0.87 mmol) in aqueous THF (6 mL, 1:2 v/v) was stirred at room temperature for 4 hours. The reaction mixture was treated with 10% aqueous sodium sulfite and diluted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with a hexanes and ethyl acetate gradient to provide the titled product.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:6]=2[CH:21]=1.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>CN1CCCC1=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:22]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:6]=2[CH:21]=1)=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(NCCc1csc2ccc(I)cc12)C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1

Procedure:
15 mmol of the product obtained in Step C, 16 mmol of vinyl tributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladium, are heated at 110° C., with stirring, for 3 hours in 30 ml of N-methylpyrrolidinone. After removal of the solvent by evaporation, the residue is taken up in 20 ml of dichloromethane and treated with an aqueous 10% potassium fluoride solution. Extraction, concentration under reduced pressure and chromatography over silica gel yield the pure title product.
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@@](CCn1ccc(/C=C/c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 4 h
Yield: 100.6 %

Procedure:
A solution of hydrochloric acid (2.5 mL, 4.0 M in 1,4-dioxane) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-{2-oxo-4-[(E)-2-phenylvinyl]pyridin-1(2H)-yl}-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (40 mg, 0.084 mmol) in 5:1 dichloromethane-methanol (2.5 mL) at 0° C. After 4 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 1:1 pentane-diethyl ether, filtered, washed with pentane and dried under reduced pressure to provide a light yellow solid (33 mg, 76%). MS (LCMS) m/z 391.4 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3 H) 2.30-2.42 (m, 1 H) 2.56-2.69 (m, 1 H) 3.08 (s, 3 H) 3.93-4.06 (m, 1 H) 4.32 (td, J=11.76, 4.98 Hz, 1 H) 6.75 (s, 1 H) 7.00 (d, J=6.24 Hz, 1 H) 7.11 (d, J=16.39 Hz, 1 H) 7.30-7.42 (m, 3 H) 7.47 (d, J=16.39 Hz, 1 H) 7.62 (d, J=7.02 Hz, 2 H) 7.75 (s, 1 H)
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH3:7][C:6]1[N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]([C:8](=[O:9])[NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(C(=O)Nc2ccccc2)n1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: Cc1ccc(C(=O)Nc2ccccc2)n1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 73.1 %

Procedure:
The title compound was prepared following the experimental procedure described in preparation 20a from 380 mg (1.77 mmol) of 1-amino-5-methyl-N-phenyl-1H-pyrrole-2-carboxamide and 334 mg (1.77 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich). The crude product was purified by flash chromatography in hexane/ethyl acetate to afford 500 mg (59% yield) of the title compound.
Reaction SMILES: [ClH:1].Cl.OC1([C:10]2(O)[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[O:16]C(F)(F)F)CCCCC1.Cl.Cl.OC1(C([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([O:55][C:56]([F:59])([F:58])[F:57])[CH:49]=2)CN2CCNCC2)CCCCC1>>[ClH:1].[ClH:1].[OH:16][C:11]1([CH:21]([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([O:55][C:56]([F:57])([F:59])[F:58])[CH:49]=2)[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH2:10][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN1CCN(CCC2(OC(F)(F)F)C=CC=CC2(O)C2(O)CCCCC2)CC1
Reactant: Oc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1OC(F)(F)F
Agent: Cl
Product: CN1CCN(CC(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 4-[1-(1-hydroxycyclohexyl)-2-(4-methylpiperazin-1-ylethyl]-2-(trifluoromethoxy)phenol dihydrochloride was prepared from 4-[1-(1-hydroxycyclohexyl)-2-piperazin-1-ylethyl]-2-(trifluoromethoxy)phenol dihydrochloride (see Example 400). MS (ESI) m/z 403; HRMS: calcd for C20H29F3N2O3+H+, 403.22030; found (ESI, [M+H]+), 403.2201.
Reaction SMILES: [CH2:1]([C:7]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:19]2[CH:18]=[C:17]3[C:20](=[O:24])[CH:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[BH4-].[Na+]>C1COCC1>[CH2:25]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]3[CH:20]([OH:24])[CH:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(O)C(C)C3
Reaction time: 12 h
Yield: 96 %

Procedure:
In a 1000 mL round flask, 9,9-dihexyl-2-methyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (85 g, 211.1 mmol) was dissolved in 400 mL of THF and 400 mL of ethanol and then stirred. Sodium borohydride (NaBH4) (10 g, 265.0 mmol) was added to the reactant in five lots, and then stirred for 12 hours. After removal of the solvent, the resultant material was dissolved in ethylacetate, and then washed with water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, thereby obtaining 82.0 g of 9,9-dihexyl-2-methyl-1,2,3,9-tetrahydrocyclopenta[b]fluoren-1-ol (yield: 96.0%) (two isomers) as highly viscous oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:34]([O:38]C1C=CC(C(O)=O)=CC=1)[CH2:35][CH2:36][CH3:37]>>[C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([O:38][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)OCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(F)cc3)cc2)cc1
Product: C=CC(=O)OCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCC)cc3)cc2)cc1

Procedure:
3c was prepared by the same procedure as 3b except that 4-butoxybenzoic acid was used instead of 4-fluorobenzoic acid.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[NH:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=3)[CH2:30][CH2:29]2)[CH2:5][CH2:6]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: BrCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)(F)c1cccc(N2CCN(CC[C@H]3CC[C@H](Nc4ncccn4)CC3)CC2)c1

Procedure:
A mixture of trans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine (0.26 g, 0.91 mmol), 1-(3-trifluoromethyl-phenyl)-piperazine (0.21 g, 0.91 mmol), and potassium carbonate (0.21 g, 1.5 mmol) was heated in 10 mL refluxing acetonitrile for 18 hours. The reaction was diluted with methylene chloride, filtered, and the solvents were removed under reduced pressure. The residue was partitioned between chloroform and aqueous 2N sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated. The resulting residue was recrystallized from acetonitrile to give the title compound; mp 167° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38]>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][N:14]([CH2:38][CH2:37][CH2:36][CH:35]=[CH2:34])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCN(C[C@@H](C(=O)OC)C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
To a mixture of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitrophenylsulfonamido)-propanoate iii (150 mg, 0.37 mmol) in 3 mL of DMF was added potassium carbonate (102 mg, 0.74 mmoL). This mixture was stirred at rt for 20 min followed by the addition of 5-bromo-1-pentene (65 μL, 0.55 mmoL). The reaction mixture was stirred at rt for 2 days. It was then filtered, concentrated and purified by silica gel chromatography (eluting with 25% ethyl acetate in hexane) to give 75 mg (43%) of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoate iv as a yellow solid. 1H NMR (CD3OD, 300 MHz) δ 1.42 (s, 9H), 1.54–1.64 (m, 2H), 1.97 (q, J=7.20 Hz, 2H), 3.37 (m, 2H), 3.57–3.80 (m, 2H), 3.72 (s, 3H), 4.42 (dd, J=8.60, 5.31 Hz, 1H), 4.91–5.01 (m, 2H), 5.69–5.79 (m, 1H), 7.75–7.85 (m, 3H), 8.04 (m, 1H). LC-MS (Method D, retention time: 2.68 min), MS m/z 372 (M++1-Boc).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:11][N:12]=[C:13]=[O:14]>C1(C)C=CC=CC=1>[CH3:11][NH:12][C:13]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])=[O:14]
Reactant: CC1Cc2ccccc2N1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)N1c2ccccc2CC1C
Reaction time: 24 h

Procedure:
1 mole of 2-methylindoline is dissolved in 300 ml of toluene and 1 mole of methyl isocyanate is added, the temperature not rising above 25° C. The mixture is left to stand for 1 day and the resulting precipitate is then filtered off. N-Methylaminocarbonyl-2-methylindoline with a melting point of 158°-160° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1c[nH]c2ncc(Br)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Yield: 21.2 %

Procedure:
To a 10 ml round bottom flask, 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.450 g, 0.00199 mol) and NaH (0.143 g, 0.00597 mol) were taken in DMF (5 ml) and stirred in cooling for 15 min. SEM-Cl (0.497 g, 0.00298 mol) was added dropwise and stirred at room temperature for 2 hr. After completion of the reaction, the reaction mixture was poured in to water and extracted with ethyl acetate. The combined organics were washed with brine solution. The organic layer was separated and dried over sodium sulphate, concentrated to give the crude product which was purified using column purification by eluting the compound with 10% ethyl acetate in hexanes to yield 150 mg of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH:44]([OH:46])[CH3:45])=[CH:40][C:39]=3[F:47])=[CH:35][C:34]=2[CH:48]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:23]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]3[CH:43]=[CH:42][C:41]([C:44](=[O:46])[CH3:45])=[CH:40][C:39]=3[F:47])=[CH:35][C:34]=2[CH:48]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(O)c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin reagent (0.411 g, 0.970 mmol) was added to a solution of 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)ethanol (0.280 g, 0.808 mmol) in DCM (25 mL) and stirred at room temperature for 1 h. The mixture was treated with saturated aqueous NaHCO3, stirred for 5 min, and extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Purification by flash chromatography using EtOAc/hexanes gave 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)ethanone. 1H NMR (300 MHz, CDCl3) δ ppm 8.11 (t, J=7.7 Hz, 1H), 7.68-7.88 (m, 2H), 7.41-7.48 (m, 2H), 7.12-7.35 (m, 7H), 4.09 (s, 2H), 2.63 (s, 3H). MS (ESI) m/z: Calculated; 344.4 Observed: 345.0 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12.I[CH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH2:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: ICC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(nn(CC3CCOCC3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 140 °C

Procedure:
A mixture of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (50 mg, 0.155 mmol), 4-(iodomethyl)-tetrahydro-2H-pyran (70 mg, 0.310 mmol), and Cs2CO3 (101 mg, 0.310 mmol) in DMF (1 mL) is heated in microwave at 140° C. for 30 min. After cooling, the mixture is filtered through a 0.45 μM microfilter, and the filtrate is purified by a semi-preparative HPLC to give pure product as white powder. MS (ESI) m/z 421.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20](OCC)=[O:21])#[N:18].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:19]([C:17]#[N:18])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: O=C(C=NNc1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1c(C(F)(F)F)cnn(-c2ccc(Cl)cc2)c1=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
After 0.281 g of 3, 3, 3-trifluoro-2-oxopropanal 1-(4-chlorophenylhydrazone) was dissolved in 5 mL of pyridine, 0.304 g of ethyl cyanoacetate was added to the pyridine solution, which was followed by stirring for 5 hours at 110° C. After cooling to room temperature, the reaction mixture was poured into 3N-hydrochloric acid and extracted with diethyl ether. After the organic layer was washed with aqueous saturated sodium bicarbonate and concentrated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane =1/9), and furthermore recrystallized from a solvent mixture (toluene/hexane =1/3) to afford 0.234 g of 2-(4-chlorophenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-15). 1H-NMR (300 MHz, CDCl3)δ(ppm): 7.49(2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz), 8.19 (1H,s)