Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH3:33][C:34]([C:39]1[CH:40]=[CH:41][C:42](=[C:44]([CH3:46])[CH3:45])[CH:43]=1)([CH3:38])[CH2:35][CH2:36][CH3:37]>C1COCC1.CCOCC.O>[CH3:38][C:34]([C:39]1[CH:40]=[CH:41][CH:42]([C:44]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([CH3:45])[CH3:46])[CH:43]=1)([CH3:33])[CH2:35][CH2:36][CH3:37]
Reactant: CCCC(C)(C)C1=CC(=C(C)C)C=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(C)(C)C1=CC(C(C)(C)c2cc(C(C)(C)C)cc3c2Cc2ccc(C(C)(C)C)cc2-3)C=C1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of 1.70 g (6.1 mmol) of 3,6-di-tert-butylfluorene in 40 ml of THF, 3.9 ml (6.4 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 1.22 g (6.4 mmol) of 3-(1,1-dimethylbutyl)-6,6-dimethylfulvene in 35 ml of THF was dropwise, added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 1.73 g (3.69 mmol) of an oily liquid (yield: 61%). The analyzed values are given below.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:28]([NH:30][CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:29].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][OH:20])[CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:28]([NH:30][CH2:31][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A mixture of 6-Chloro-N-(cyclohexylmethyl)-2-[(3S)-3-[[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]amino]-1-pyrrolidinyl]-5-quinolinecarboxamide (Example 50(a)) (0.16 g) in 1,4-dioxane (1 mL) was treated with 4M HCl in 1,4-dioxane (1 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness. Purification (HPLC, Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) followed by conversion of the resultant product to its hydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane) afforded the title product (0.05 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(OCC)C>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (10.32 g, 59.92 mmol) in dimethylformamide (50 mL) was added imidazole (8.16 g, 119.8 mmol), followed by tert-butyldimethylsilyl chloride (9.94 g, 65.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. Diethyl ether was added (150 mL), and the mixture was washed with 1M HCl (150 mL). The aqueous layer was extracted with diethyl ether (150 mL). The combined organic layers were washed with 1M HCl (100 mL) and saturated sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated to afford a clear oil. MS (CI) m/z 287 (M+1)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>CN(C=O)C>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(S(=O)(=O)c2ccccc2Br)c2ccccc12
Reaction time: 0.5 h

Procedure:
A stirred solution of 1H-indole-3-carboxaldehyde (1 g, 6.89 mmol), in DMF (25 mL) was treated with sodium hydride (0.357 g, 60% in mineral oil, 8.95 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with 2-Bromobenzene sulfonyl chloride (1.8 mL, 8.25 mmol), stirred at room temperature for 3-5 hrs. After the completion of reaction (T. L. C.), the reaction mixture was quenched with 25 mL ice-cold water and diluted with 25 mL ethyl acetate. The organic phase was separated, washed sequentially with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel, EtOAc/Hexane, 2/8) to afford the title compound as an off-white foam, which was latter identified by IR, NMR and mass spectral data.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(CN(c2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-nitrobenzyl bromide
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:19]=1)[C:5](N[C@@H](C1C=CC=CC=1)CO)=[O:6])[CH3:2].C(=O)([O-])[OH:42].[Na+]>S(=O)(=O)(O)O.O1CCOCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:19]=1)[C:5]([OH:6])=[O:42])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCO[C@@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)N[C@H](CO)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 90 °C
Yield: 54 %

Procedure:
(2S)-2-Ethoxy-N-[(1S)-2-hydroxy-1-phenylethyl]-3-{4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl}propanamide (0.45 g, 0.84 mmol) was dissolved in a mixture of 1M sulphuric acid (17 ml) and dioxane/water (1:1.39 ml) and heated to 90° C. for 88 h. The pH of the mixture was adjusted to 3 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2×25 ml) and the organic phase was washed with water (50 ml), brine (25 ml), dried (Na2SO4) and evaporated. The residue was chromatographed over silica gel using a gradient of 50-75% ethyl acetate in petroleum ether to afford the title compound (0.19 g, 54%) as a white solid. mp: 89-90° C.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][CH:7]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][N:18]=3)[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[OH:30][CH:31](C1NC2C(C=1)=C(OC)C=CN=2)CN1C(=O)C2=CC=CC=C2C1=O.O1C=CCCC1>C(Cl)(Cl)Cl.Cl.C1C=CC=CC=1>[CH3:31][O:30][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[C:22]=1[CH:23]=[C:15]([CH:7]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH2:6][N:5]1[C:4](=[O:24])[C:3]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]3[C:1]1=[O:29])[NH:16]2
Reactant: O=C1c2ccccc2C(=O)N1CC(OC1CCCCO1)c1cc2cccnc2[nH]1
Reactant: COc1ccnc2[nH]c(C(O)CN3C(=O)c4ccccc4C3=O)cc12
Agent: C1=COCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccnc2[nH]c(C(CN3C(=O)c4ccccc4C3=O)OC3CCCCO3)cc12
Yield: 65 %

Procedure:
Following the same procedure as for 2-[2-Phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole . From 8b (3.8 g, 11 mmol) in CHCl3 (350 ml), 6N HCl in benzene (35 ml) and 2,3-dihydropyrane (10 ml, 110 mmol). 4Methoxy-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (3.07 g, 65%) as a diastereomeric mixture (1:1) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][C:25](=[O:27])[NH2:26])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>CC(C)=O.O>[C:25]([O:24][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:35](=[O:37])[CH3:36])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:27])[NH2:26]
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(N2CCN(CCC(OC(N)=O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 1-(4-fluoro-phenyl)-3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-propyl ester (0.6 mmol) prepared in Example 88 was dissolved in acetone (15 mL), and triethylamine (1.2 mmol) was added and acetylchloride (2.4 mmol) was added dropwise, and the resulting mixture was then stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH:9]=2)=[N:6][CH:7]=1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C>[Si:19]([O:14][CH:10]1[CH2:11][CH2:12][CH2:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:9]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: Nc1cnc(C2=CC(O)CCC2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1C=C(c2cnc(N)cn2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-(5-aminopyrazin-2-yl)cyclohex-2-enol (149 mg, 0.779 mmol) in DMF (5.5 mL) at 0° C. were added tert-butylchlorodimethylsilane (294 mg, 1.95 mmol)) and 1H-imidazole (212 mg, 3.12 mmol). The reaction mixture was stirred at room temperature overnight. After quenched with sat NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layers were dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was purified with flash chromatography eluting with 0-100% of EtOAc/heptane to provide 238 mg of crude product which was used as it was. LCMS (m/z): 306.9 (MH+), 1.04 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([NH:15][N:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>C1(C)C=CC=CC=1.CN(C)N>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([N:15]([CH3:25])[N:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Agent: CN(C)N
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
To a 50 mL volume three-necked flask, 1.0 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6), 3.5 ml of toluene and 629 mg of potassium carbonate were added and then, 9.1 mg of N,N-dimethylhydrazine solved in 2.3 ml of toluene and 577 mg of dimethyl sulfate were added thereto at 5° C. The mixture was stirred at 5° C. for 24 hours, 3 g of water was added thereto and the organic layer was removed. The aqueous layer was extracted with 3.5 ml of toluene two times. The organic layers were combined and concentrated under reduced pressure to give 1.037 g of a mixture (19:1 (GC area %)) of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5) and methyl 2-(2,6-diethyl-4-methylphenyl)-2-oxo-N-(phenylmethylidene)ethanehydrazonate (x-1)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCN1CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)OCCCN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6.38 g (14.06 mmol) of the crude product from Example 26A are dissolved in 108 ml of dry THF, and 4.04 g (15.47 mmol) of tetra-n-butylammonium fluoride are added. The reaction mixture is stirred at RT for 48 h. After removal of the solvent the residue is directly purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 20:1→1:1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5](/[CH:6]=[N:7]\[S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[C:4]([Cl:16])[CH:3]=1.[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C@H:6]([NH:7][S@@:8]([C:10]([CH3:12])([CH3:13])[CH3:11])=[O:9])[C:18]([F:20])([F:19])[F:17])=[C:4]([Cl:16])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(Br)cc1Cl)C(F)(F)F
Temperature: 35 °C
Reaction time: 18 h

Procedure:
To a stirring solution of (R,Z)—N-(4-bromo-2-chlorobenzylidene)-2-methylpropane-2-sulfinamide (1370 mg, 4246 μmol) and (trifluoromethyl)trimethylsilane (943 μl, 6369 μmol) in DMF (5 mL) was added 1,3-bis(1-adamantyl)imidazol-2-ylidene (143 mg, 425 μmol). Reaction stirred at 35° C. for 18 h then quenched with sat NH4Cl (10 mL). Reaction partitioned between EtOAc (40 mL) and 5% NaHCO3 (10 mL). Organic dried over MgSO4, concentrated to and oil from toluene, then purified on silica (80 g) eluting with 20>30% EtOAc/Hex. Product isolated as a white solid.
Reaction SMILES: C[C@:2]12[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C@H:10](N1)C[C:8]1[CH:7]=[CH:6]C=C[C:3]2=1.[Cl-].C1(N2C=[NH+]N(C3C=CC=CC=3)N2C2C=CC=CC=2)C=CC=CC=1.[OH2:42].[Cl-].[Na+].[OH2:45]>>[CH2:3]([CH:2]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:45])[O:42]1)[CH2:8][CH2:7][CH3:6]
Reactant: C[C@]12N[C@H](Cc3ccccc31)c1ccccc12
Reactant: O
Agent: C1=[NH+]N(c2ccccc2)N(c2ccccc2)N1c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: CCCCC1OC(=O)c2ccccc21

Procedure:
l-, d-, and dl-NBP were all provided by department of synthetic pharmaceutical chemistry of our institute, both optical and chemical purity of which are >99%, and the optical activity of which is −66.49°, +66.88° and 0°, respectively. They were formulated with vegetable oil. MK801 is the product of Sigma, and was formulated with physiological brine. Triphenyltetrazolium chloride (TTC), which was manufactured by Beijing Chemical Plant, was formulated with distilled water into 4% solution for use.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[Br:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[C:29](N)[C:28]=1[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[C:28]2[C:27]([Br:26])=[C:32]([F:33])[CH:31]=[CH:30][C:29]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)c(Br)c1Nc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.0 g, 5.4 mmol) in DCM (10 mL) was added triethyloxonium tetrafluoroborate (1.1 g, 5.78 mmol) and the reaction mixture stirred at RT for 2 h, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (10 mL). 3-Bromo-4-fluoro-N2-pyridin-2-yl-benzene-1,2-diamine (0.96 g, 3.4 mmol) was added and the reaction heated at 75° C. for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (832 mg, 56%). LCMS (Method C): RT=3.39 min, [M+H]+=435+437.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([O:15]C)=[C:9]([O:17]C)[N:8]=2)[CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9](=[O:17])[C:10]([OH:15])=[CH:11][C:12]=2[C:13]#[N:14])[CH:2]=1
Reactant: COc1cc(C#N)c(-c2cccc(-c3ccccc3)c2)nc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(O)c(=O)[nH]c1-c1cccc(-c2ccccc2)c1
Temperature: 45 °C
Reaction time: 19 h
Yield: 12.8 %

Procedure:
To a solution of 2-(biphenyl-3-yl)-5,6-dimethoxypyridine-3-carbonitrile (17 mg, 0.054 mmol) in CH2Cl2 (1 mL) was added BBr3 solution (1 M in CH2Cl2, 0.537 mL) and stirred at 45° C. for 19 h. The reaction mixture was concentrated and the residue was stirred in 3 N aqueous HCl for 30 min. The precipitated white solid was collected by filtration and purified by preparative HPLC (5-50% CH3CN/H2O over 20 min, 0.05% added TFA) to give 2 mg (13%) of 2-(biphenyl-3-yl)-5-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile as a white solid. 1H NMR (500 MHz, CD3OD): δ 7.89 (s, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.70 (d, J=7.6 Hz, 2H), 7.65-7.58 (m, 2H), 7.47 (t, J=7.6 Hz, 2H), 7.38 (t, J=7.4 Hz, 1H) 1 6.96 (s, 1H). High resolution mass spec (FT/ICR) calc (M+H)+=289.0972 found 289.0969.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]([F:28])([F:27])[CH2:18]OS(C(F)(F)F)(=O)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:18][C:17]([F:28])([F:27])[F:16]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To 2-chloro-4-fluorophenol (52, 1.58 g, 0.0108 mol) in N-methylpyrrolidinone (25.0 mL), cesium carbonate (7.02 g, 0.0215 mol) and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (2.50 g, 0.0108 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 90 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% to 100% ethyl acetate in hexane to give a colorless oil (124, 2.10 g, 85.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[NH2:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1>>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]2[CH:7]=[C:2]([NH:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)[CH:3]=[C:4]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[Si:27]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:35])[CH3:36])[CH:28]([CH3:29])[CH3:30])[CH:5]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(COc2cc(Br)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Product: COc1ccc(COc2cc(Nc3ccc(C#N)cc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1

Procedure:
4-[3-Bromo-5-(4-methoxy-benzyloxy)-phenyl]-1-triisopropylsilanyl-1H-indole was coupled with 4-amino-benzonitrile to give 4-[3-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenylamino]-benzonitrile using the conditions of Example 80. This compound was deprotected to give 4-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-benzonitrile as described in Example 35. 1H NMR (400 MHz, CD3OD): δ 7.46 (d, J=2.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.25 (d, J=3.1 Hz, 1H), 7.15-7.11 (m, 3H), 7.06 (dd, J=7.2, 1.0 Hz, 1H), 6.96 (t, J=1.7 Hz, 1H), 6.84 (dd, J=2.1, 1.4 Hz, 1H), 6.66 (t, J=2.1 Hz, 1H), 6.62 (q, J=1.4 Hz, 1H).
Reaction SMILES: Cl[Si:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[CH2:3][CH3:4].C(=O)=O.Br[C:13]([F:16])([F:15])[F:14].C(N(CC)P(N(CC)CC)N(CC)CC)C>CC(C)=O.ClCCl>[CH2:3]([Si:2]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:13]([F:16])([F:15])[F:14])[CH3:4]
Reactant: CC[Si](Cl)(CC)CC
Reactant: FC(F)(F)Br
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC[Si](CC)(CC)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
A flask equipped with a dry ice condenser was flame dried under a nitrogen stream, and charged with 25 g (0.17 mol) of chlorotriethylsilane and 40 mL of dichloromethane. After cooling the resulting solution to -78° C. and charging the condenser with dry ice and acetone, 40 mL (0.43 mol) of bromotrifluoromethane (Freon 13Bl) that had been condensed into a graduated tube was warmed to room temperature and allowed to distill into the flask. The cold solution was treated dropwise with 66 mL (0.24 mol) of hexaethylphosphorous triamide, allowed to stir at -78° C. for two hours, and allowed to stir at room temperature overnight. Low boiling components were then short path distilled into a cold (-78° C.) receiving flask at >1 torr with the pot temperature kept at <50° C. The distillate was further fractionated by removal of the dichloromethane (40°-45° C. at atmospheric pressure) and short path distillation to give 22.0 g of 98% pure (69% yield) triethyltrifluoromethylsilane: bp 52°-54° C. at 10 torr; 1H NMR (CDCl3) δ0.59-1.16 (m); 19F NMR (CDCl3, relative to CFCl3)-61.3 ppm (s); IR (neat) 2960, 2915, 2882, 1458, 1413, 1206, 1055, 1020, 734, 693 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 115 (66, M--CF3), 105 (46), 87 (85), 77 (100), 59 (56), 49 (41), 47 (37), 41 (38). Anal. Calcd. for C7H15F3Si:C, 45.62; H, 8.20. Found: C, 47.53: H, 8.56.