Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH:3](O)[CH2:4][N+:5]([O-:7])=[O:6].S(Cl)(C)(=O)=O.C(N(CC)CC)C.O>ClCCl>[CH3:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CCCC(C)C(O)C[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C)C=C[N+](=O)[O-]
Yield: 67.5 %

Procedure:
After dissolving 15.0 g of 3-methyl-1-nitro-2-hexanol in 100 ml of dichloromethane, 11.7 g of mesyl chloride and 18.8 g of triethylamine were gradually dropped thereto at 4° C., respectively. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for an hour. Water was added to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 9.0 g of 3-methyl-1-nitrohex-1-ene (yield: 81.4%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:16][CH3:17])[C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7][C:6]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[S:30][CH:31]=[CH:32][N:33]=1>CN(C=O)C>[CH2:16]([N:4]1[C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7][C:6]=2[N:15]=[C:3]1[CH2:2][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[CH3:17]
Reactant: CCn1c(CCl)nc2cnc(C(F)(F)F)cc21
Reactant: c1c[nH]c(-c2nccs2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
A solution of 2-Chloromethyl-1-ethyl-6-trifluoromethyl-1H imidazo[4,5-c]pyridine (1 g, 3.8 mmol) in anhydrous DMF (15 mL) were added K2CO3 (2.68 g, 19 mmol), and 2-(1H-imidazol-2-yl)-thiazole (555 mg, 3.8 mmol) and stirred at room temperature for 48 h. The crude residue after usual work up was purified eluting with 5% MeOH—CH2Cl2 containing few drops of NH4OH to afford 1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (800 mg, 80%); 1H NMR (CD3OD): δ 8.83 (s, 1H), 8.14 (s, 1H), 7.71 (d, J=2.7 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.19 (d, J=0.9 Hz, 1H), 6.30 (s, 2H), 4.54 (q, J=5.4 Hz, 2H), 1.46 (t, J=5.4 Hz, 3H); m/z 379 [M+1]
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:21][CH2:22][C:23]([NH:13][C@@H:9]1[CH2:8][O:7][C:6]2=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]2[CH2:10]1)=[O:24]
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
Under argon protection, I-7-(S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (134 mg, 0.73 mmol) was dissolved in anhydrous DMF (2 mL), added triethylamine (0.3 mL, 2.18 mmol), added dropwise chloroacetyl chloride (0.082 mL, 1.09 mmol) at 0° C., stirred for 2 h at room temperature, added saturated sodium bicarbonate solution, extracted by ethyl acetate, followed by anhydrous sodium sulphate drying and suction filtration, spun dry solvents, separated by column chromatography to give 92 mg yellow viscous liquid, yield was 50%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>N1C=CC=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[O:13][C:17](=[O:18])[N:16]([CH3:20])[CH3:15]
Reactant: CC1(C)CN(c2ccccc2)NC1=O
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)OC1=NN(c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of 4,4-dimethyl-1-phenyl-3-pyrazolidinone (1.90 g) in a mixture of 25 mL pyridine and 4 mL triethylamine at 0° C. is added N,N-dimethylcarbamoyl chloride (1.37 mL). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with methylene chloride (100 mL) and washed with 10% aqueous hydrochloric acid (200 mL). The organic layer is dried (MgSO4), filtered and evaporated. Chromatography on silica gel gave a light yellow solid. Recrystallization from ethanol gave 1.80 g (73%) of pale yellow crystals. (MP-99°-100° C.;
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]#[N:20])=[N:11]1>C(O)C.CO>[CH:15]1[CH:14]=[C:13]2[C:12]([NH:11][NH:10][C:18]2=[CH:17][CH:16]=1)=[C:19]([N:2]=[O:3])[NH2:20]
Reactant: NO
Reactant: N#Cc1n[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: NC(N=O)=C1NNc2ccccc21
Temperature: 25 °C
Yield: 36.6 %

Procedure:
Hydroxylamine hydrochloride (1.5 g) and potassium carbonate (3.83 g) were stirred together in absolute ethanol (100 ml) for 15 minutes. Indazole-3-carbonitrile (2 g) was added and the solution heated at reflux for 4 hours, cooled to room temperature and diluted with methanol (5 ml). The solution was filtered and the solvent evaporated. The residue was extracted with anhydrous ether, the extracts were dried over MgSO4, filtered and the solvent removed to afford a white solid, which was recrystallised from acetone/dichloromethane to afford the title compound (900 mg), m.p. 155°-158° C. δH (360 MHz, CDCl3) 6.46 (1H, brm, N-OH), 7.17 (1H, t, J=1 Hz, H-6), 7.41 (1H, t, J=2 Hz, H-5), 7.55 (1H, d, J=2 Hz, H-4), 8.03 (1H, t, J=2 Hz, H-7); m/z (M+ , 100%), 176 (100), 144 (80), 119 (25), 92 (15).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][NH:22][C:23](=[O:26])[CH2:24][NH2:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CC[O:36][CH2:35]C1)C.C(Cl)(Cl)=O>ClCCl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][N:22]1[C:23](=[O:26])[CH2:24][NH:25][C:35]1=[O:36])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN1CCOCC1
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)CN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.83 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-glycinyl-4-methylvalerohydrazide in 50 ml of dichloromethane was cooled to 0° C. under nitrogen and treated with 0.76 ml of N-ethylmorpholine and 1.34 ml of a 1.93M solution of phosgene in toluene. The mixture was left to warm to room temperature and was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with 2M aqueous hydrogen chloride and saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulphate and evaporated. Trituration of the residue with diethyl ether gave 0.783 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,5-dioxo 1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH2:14]1C2C(=CC=CC=2)C[CH:15]1C(O)=O.S(=O)(=O)(O)O.C([N-]C1CCCCC1)(C)C.C(Br)C>>[CH2:14]([C:5]1([C:3]([OH:2])=[O:4])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH3:15]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: COC(=O)C1Cc2ccccc2C1
Agent: CC(C)[N-]C1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CCBr
Product: CCC1(C(=O)O)Cc2ccccc2C1

Procedure:
Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole with 10% palladium on carbon.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Temperature: 0 °C
Yield: 85.9 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) in THF (8 ml) was added at room temperature triethylamine (0.59 ml, 4.21 mmol), the mixture was cooled (ice-water) and a solution of commercially available 1-BOC-piperazine (2.14 g, 11.5 mmol) in THF (8 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and subsequent crystallization from dichloromethane/hexane to yield the title compound (1.35 g, 86%) as a white solid. MS (ISP) 413.2 [(M+H)+], mp 127° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.OP(O)(O)=O>O.CS(C)=O>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
A solution of 1-fluoro-4-(methylsulfonyl)benzene (2.2 kg), KOH (906.3 g), 4-(trifluoromethoxy)phenol (2.364 kg) and DMSO (4.4 L) was heated to 90° C. and stirred until HPLC showed <0.5% starting material remained (about 10 hours). HPLC conditions: Zorbax SB-C8 4.6 mm×25 cm; mobile phase was a gradient of 70% water with 0.1% H3PO4/30% acetonitrile to 10% water with 0.1% H3PO4/90% acetonitrile over 15 minutes at a flow rate of 1.5 mL/min, followed by a five minute hold at 10/90; UV detection at 220 nM. Retention times: starting sulfone, 4.5 min; desired product, 7.8 min.
Reaction SMILES: [C:1]([CH:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][N:15]=2)[CH:12]=[CH:11][C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9]3)[C:6]1=O)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:25].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[C:14]([Cl:25])[N:15]=2)[CH:12]=[CH:11][C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9]3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc2cnc3c(c2c1)C(=O)C(C(C)(C)C)C=C3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc2nc(Cl)c3ccc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
The above 2,9-di-t-butylphenanthridinone (3.0 g, 9.7 mmole) was added to a reaction flask containing phosphorus pentachloride (3.0 g, 14.6 mmole) and 50 mL of phosphoryl chloride. The reaction mixture was refluxed overnight, cooled to room temperature and diluted with toluene. The excess phosphoryl chloride and toluene were removed by a rotary evaporator. The residue was dissolved into ethyl acetate and washed with distilled water followed by brine. The solvent layer was dried over magnesium sulfate, filtered and concentrated to give the desired 2,9-di-tert-butyl-6-chlorophenanthridine (3.0 grams, 98%) as an off white solid. The product was confirmed by GC Mass Spec and not purified further but used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)[CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:28]4([CH3:33])[O:32][CH2:31][CH2:30][O:29]4)[CH:27]=3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20]
Reactant: CC1(c2cncc(Br)c2)OCCO1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2cc(-c3cncc(C4(C)OCCO4)c3)ccc21
Temperature: 105 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (109 mg, 0.4 mmol), prepared as described in Example 3a, was added 3-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (CAS#59936-01-5, 107 mg, 0.44 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (182 mg, 0.02 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 105° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-5-[5-(2-methyl-[1,3]-dioxolan-2-yl)-pyridin-3-yl]-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 311.1395 (M+H)+; 1H NMR (400 MHz, CDCl3) δppm 1.73 (s, 3H), 3.28 (s, 3H), 3.62 (s, 2H), 3.82-3.88 (m, 2H), 4.08-4.16 (m, 2H), 6.94 (d, J=7.8 Hz, 1H), 7.49-7.58 (m, 2H), 7.97 (s, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:21])[CH:19]=1)[N:16]([CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])[CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCc2cc(CC(C)N(CCOc3ccccc3OCC)C(=O)OC(C)(C)C)cc(C#N)c21
Yield: 34.9 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (300 mg) and cis-dicyclohexano-18-crown-6 (24 mg) in dry tetrahydrofuran (4 ml) were added potassium carbonate (107 mg) and ethyl bromoacetate (129 mg), and the mixture was reacted in a sealed tube at 100° C. for 24 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (1/2) as eluent to give 124 mg of ethyl [5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-7-cyanoindolin-1-yl]acetate as an oil.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.Cl>O.CO>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:23]3[N:22]=[CH:21][C:25]([C:26]#[N:27])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol) were dissolved in the mixture of water (35 cm3) and methanol (20 cm3). Concentrated (37%) hydrochloride acid (1.0 cm3, 0.012 mol) was then added and the mixture was stirred at room temperature for about 2 hours. The reaction mixture was then cooled to about 5° C. and the crystalline product that formed was collected, washed with water and dried at about 60° C. to yield zaleplon (2.80 g, 91.8%) in 98.69% purity as determined by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: C1CCNCC1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCCCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and piperidine in tetrahydrofuran are reacted to give 8-chloro-1-(piperidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.C(O)(=O)C>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=NNc1ccc(Br)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
4-Bromophenylhydrazine hydrochloride (15 g), ethyl pyruvate (11 ml) and acetic acid (1 ml) were dissolved in ethanol and heated to reflux for 2 hours, then cooled to room temperature, resulting in precipitation of a yellow solid, which was filtered off and dried in vacuo to give the ethyl pyruvate 4-bromophenylhydrazone (16.3 g, 71%), mp 153-154°; NMR δ (CD3SOCD3) 1.23 (t, 3H), 2.03 (s, 3H), 4.18 (q, 2H), 7.19 (d, 2H), 7.40 (d, 2H), 9.88 (brs, 1H); M/z (−) 285 (M+), 283, 171, 169, 113.
Reaction SMILES: S(=O)(=O)(O)O.O[C:7]([CH3:20])([CH3:19])[CH2:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1.[Cl:21][CH2:22][C:23]#[N:24].[OH2:25]>C(O)(=O)C>[Cl:21][CH2:22][C:23]([NH:24][C:7]([CH3:20])([CH3:19])[CH2:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)=[O:25]
Reactant: CC(C)(O)Cc1cccc(CC(=O)O)c1
Reactant: N#CCCl
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(Cc1cccc(CC(=O)O)c1)NC(=O)CCl
Temperature: 25 °C

Procedure:
Concentrated sulphuric acid (21 ml) was added dropwise to a solution of [3-(2-hydroxy-2-methylpropyl)-phenyl]-acetic acid (Preparation 49) (10.6 g, 51.0 mmol) and chloroacetonitrile (4.8 ml, 76.0 mmol) in glacial acetic acid (16 ml) at 0° C. The reaction was allowed to warm to room temperature and after 2 hours was poured onto iced water (500 ml). The aqueous was extracted with ethyl acetate (2×250 ml) and the combined organics washed with brine (50 ml), dried (sodium sulfate), and the solvent removed in vacuo to furnish the title compound as a golden oil (14.0 g). 1H NMR (400 MHz, CDCl3): δ=7.31-7.06 (4H, m), 6.19 (1H, bs), 3.95 (2H, s), 3.62 (2H, s), 3.02 (2H, s), 1.36 (6H, s) ppm. LRMS (electrospray): m/z [M−H]− 282/284.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C@H:10]([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12].C(OCC)(=O)C>C1COCC1.C(O)(C)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C@H:10]([CH3:19])[C:11]([NH:13][CH2:14][C:15]([F:16])([F:17])[F:18])=[O:12])[N:7]=1
Reactant: C[C@@H](N)C(=O)NCC(F)(F)F
Reactant: Clc1ncnc(Cl)n1
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1ncnc(Cl)n1)C(=O)NCC(F)(F)F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (298 mg, 2.0 mmol) in 4 mL THF and isopropanol(1:1 v:v) at −20° C. was added (R)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (412 mg, 2.0 mmol, 1.0 equiv.), followed by the addition of N,N-isopropyl ethyl amine (516 mg, 4.0 mmol, 2.0 equiv.). The reaction was stirred at −20° C. for 20 minutes then was allowed to warm to room temperature. After 30 minutes, the reaction was poured into ethyl acetate and washed with water. The organic layer was concentrated. The oily residue was purified by chromatography (2:1 hexane/ethyl acetate) to produce 186 mg of (R)-2-(4-chloro-1,3,5-triazin-2-ylamino)-N-(2,2,2-trifluoroethyl)propanamide (compound 1034) (LC/MS: MS+1=284.1, MS−1=282.3, R.T.=1.5 min).
Reaction SMILES: [Li:1][CH2:2][CH2:3][CH2:4][CH3:5].Br[C:7]1[CH:14]=CC=C[C:8]=1[CH:9]=C.C1COCC1>C(OCC)C>[Li:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:14][C:3]=1[CH:4]=[CH2:5]
Reactant: C=Cc1ccccc1Br
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: [Li]c1ccccc1C=C

Procedure:
A 0.35M solution of 2-lithiostyrene was prepared dropwise addition of nBuLi to a -78° C. solution of 2-bromostyrene in 5:1 THF:diethyl ether.