Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)[N:3]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C.CO>[CH:17](=[N:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1cccc(N2CCC(N)=N2)c1
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)c1cccc(N2CCC(N=Cc3ccccc3)=N2)c1
Reaction time: 4 h

Procedure:
3-Amino-1-(3-t-butylphenyl)-2-pyrazoline (500 mg) was reacted with benzaldehyde (500 mg) in boiling methanol (5 ml) in the presence of glacial acetic acid (1 drop). After some 4 hours, the mixture was cooled and 3-benzylideneamino-1-(3-t-butylphenyl)-2-pyrazoline separated in crystals m.p. 140°-141°, (yield 500 mg).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](C(O)=O)([C:14]([OH:16])=[O:15])[CH2:9]2)[CH3:3].Cl>CN1C(=O)CCC1>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH3:1]
Reactant: CC(C)Oc1cccc2c1CC(C(=O)O)(C(=O)O)C2
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(C)Oc1cccc2c1CC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
A solution of 4-(2-propyl)oxyindan-2,2-dicarboxylic acid (11.5 g) in NMP (20 ml) was heated to 150° C. After a further 15 minutes, the solution was allowed to cool to room temperature, and was poured into aqueous hydrochloric acid (1500 ml, 1 M). This mixture was extracted with ethyl acetate (2×500 ml) and a standard workup gave 4-(2-propyl)oxyindan-2-carboxylic acid (3.98 g) as a dark brown solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[C:14](Cl)(Cl)=[S:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[C:14]=[S:15])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: S=C(Cl)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(N=C=S)cc(OC)c1OC

Procedure:
A mixture of 3,4,5-trimethoxyaniline (440 mg; 2.4 mmol) in toluene (20 ml), thiophosgene (300 mg; 2.5 mmol) and triethylamine (500 mg; 5 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4,5-trimethoxyphenylisothiocyanate. To the crude product was added 3-[4-(4-chlorophenyl)-1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (40 ml) and refluxed for 16 h. The solvent was evaporated and the residue resuspended in ethyl acetate filtered and evaporated to dryness. The residue was submitted to flash chromatography on silica gel 60 eluting with toluene/ethyl acetate (1:1). The product was taken up in ethanol, which was treated with hydrogen chloride in ether to give 200 mg of the title compound. M.p. 172°-173° C. MS (70 eV): m/z 479 (M+, 0.1%), 254 (55), 225 (100), 209 (80), 182 (32).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:36][CH2:37][NH2:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH2:37][CH2:36][C:30]1[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[CH:29]=1)=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: COc1ccc(CCN)cc1OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C2=C(C(=O)Nc3cc(OC4CCCC4)c(Cl)cc3F)CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-(3,4-dimethoxyphenyl)ethylamine (0.600 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (20. ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{2-(3,4-dimethoxyphenyl)ethyl}-3,4,5,6-tetrahydrophthalamide as white crystals (1.16 g, 77.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][OH:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][O:13][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CCO)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCOS(C)(=O)=O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 4-[ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester, methanesulfonyl chloride and triethylamine in methylene chloride was stirred at rt until all starting material were consumed. The mixture was quenched with water, brine and extracted with methylene chloride. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR(CDCl3) d 6.83(s,2H), 6.25(s,1H), 4.34(t,2H), 3.86(s,3H), 3.6(t,2H), 3.38(t,2H), 3.09s,3H), 2.25(s,3H), 2.20(s,3H), 2.04(s,6H), 1.18(t,3H) ppm.
Reaction SMILES: ClC1C2O[CH:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=O)OC=2C(Cl)=C(Cl)C=1Cl.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:11](=[N:28][NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:8]=[N:28][NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(c1cccs1)C1Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2O1
Reactant: NNc1ccccc1
Solvent: CCO
Product: C(=NNc1ccccc1)C(=NNc1ccccc1)c1cccs1

Procedure:
A mixture of (4,5,6,7-tetrachlorobenzo[d][1,3]dioxol-2-yl)(thiophen-2-yl)methanone (1 g, 2.70 mmol) and phenyl hydrazine (880 mg, 8.13 mmol) in ethanol (14 mL) was heated under reflux for 30 minutes. The reaction mixture was then cooled in an ice bath. A solid precipitated, and the precipitate was collected by filtration and washed with hexane. Crude 2,2′-(1-(thiophen-2-yl)ethane-1,2-diylidene)bis(1-phenylhydrazine) was obtained as a brown solid (500 mg, 57.8% yield) and used in the next step without further purification.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=[CH:6]1)(C)C.F[C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOCCOC.CCOCC>[NH:5]1[C:9]2=[N:10][CH:11]=[C:12]([O:14][C:22]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=3[C:24]([O:26][CH3:27])=[O:25])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(O)cnc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(F)cc1Oc1cnc2[nH]ccc2c1

Procedure:
A mixture of EXAMPLE 277G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and K3PO4 (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24 hours. The reaction was cooled, diluted with ether (600 mL), and washed twice with water, and brine, and concentrated. The crude product was chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Reaction SMILES: [CH2:1]1[N:12](CC(O)=O)[CH2:11][CH2:10][N:9]([CH2:17][C:18]([OH:20])=[O:19])[CH2:8][CH2:7][N:6]([CH2:21][C:22]([OH:24])=[O:23])[CH2:5][CH2:4][N:3]([CH2:25][C:26]([OH:28])=[O:27])[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:11]1[NH:12][CH2:1][CH2:2][N:3]([CH2:25][C:26]([OH:28])=[O:27])[CH2:4][CH2:5][N:6]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:8][N:9]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10]1
Reactant: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8.0 equivalents of DOTA mono acid was dissolved in NMP and treated with 8.0 equivalents of HBTU and 16.0 equivalents of DIEA. This solution was stirred for 15 min at RT and then transferred to the amine on the resin and the coupling was continued for 24 h at RT. The resin was then drained, washed and then the peptide was cleaved and purified.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: COc1cccc(B(O)O)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(OC)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 13 mg, 12%; LC/MS tr 1.48 min; MS(ES+) m/z 366 (M+H)
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1>>[CH3:1][NH:2][CH2:10][C:7]1[CH:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: CN
Product: CNCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 16.6 g of 40% aqueous MeNH2 solution and 52 ml of CH2CN was cooled with ice and 6.08 g (0.043 mole in terms of pure product) of crude (6-methyl-3-pyridyl)methyl chloride was added dropwise with constant stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 1.5 hours, at the end of which time the solvent was distilled off. The solid residue was extracted with CH2Cl2 and the CH2Cl2 layer was dried over MgSO4. The CH2Cl2 was distilled off and the residue was diluted with 70 ml of Et2O and filtered to remove the insoluble matter. Finally the filtrate was concentrated to recover 4.60 g of the title compound as a crude oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Yield: 93.5 %

Procedure:
Stir (2R,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.1 g, 0.14 mmol) and 20% palladium hydroxide on carbon (0.1 g, 0.06 mmol, 60% moisture) in ethyl acetate (5 mL) under 1 atmosphere of hydrogen gas at room temperature overnight. Filter the suspension through a pad of filtering agent, wash with ethyl acetate and concentrate to give the title compound (0.06 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[C:11](=[O:17])[CH2:12][CH2:13][C:14]=2[O:15][CH3:16])=[C:4]([Cl:18])[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:29](Br)[C:30]#[CH:31]>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[C:11](=[O:17])[CH:12]([CH2:31][C:30]#[CH:29])[CH2:13][C:14]=2[O:15][CH3:16])=[C:4]([Cl:18])[CH:3]=1
Reactant: C#CCBr
Reactant: COC1=C(c2c(Cl)cc(Br)cc2OC)C(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCC1CC(OC)=C(c2c(Cl)cc(Br)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 45.5 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chloro-6-methoxy-phenyl)-3-methoxy-cyclopent-2-en-1-one (0.500 g, 1.51 mmol) in anhydrous tetrahydrofuran (10 mL) under an nitrogen atmosphere at −78°C. was added KHMDS (potassium hexamethyldisilazide) (1.81 mL of a 1.0M solution in tetrahydrofuran, 1.81 mmol) dropwise and the reaction was allowed to stir at this temperature for 55 minutes. Propargyl bromide (80 wt % in toluene, 0.202 mL, 1.81 mmol) was diluted in anhydrous tetrahydrofuran (2.5 mL) under an nitrogen atmosphere and then added dropwise to the reaction mixture. The reaction was stirred at −78°C. for 30 minutes and then allowed to warm to room temperature over 18 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (10 mL) followed by EtOAc (10 mL). Water (1 mL) was added and then the phases were separated and aqueous was extracted with further EtOAc (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give an orange gum. The crude product was dissolved in dichloromethane, adsorbed onto silica and purified by flash chromatography over silica using a dichloromethane/MeOH gradient to give the desired product (254 mg, 46%) as a yellow gum. 1H NMR (400 MHz, CDCl3) δ ppm 7.23 (s, 1H), 6.95 (s, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 3.14-3.10 (m, 1H), 2.79-2.51 (m, 4H), 2.00 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13]([F:16])([F:15])[F:14])[C:11]=1F)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:11]=1[N:27]1[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]1)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: CC1CNCCN1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C(F)(F)F)c21
Solvent: c1ccncc1
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C)c3c2C(F)(F)F)CCN1
Temperature: 105 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
In 30 ml of pyridine were dissolved 1.5 g (0.0049 mole) of 6,7-difluoro-8-trifluoromethyl-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 1.5 g (0.015 mole) of 2-methylpiperazine, the mixture was stirred at 105° C. for 3 hours, and then the solvent was removed by evaporation under reduced pressure. Ethanol was added to the residue, precipitated crystals were collected by filtration, the crystals obtained were washed with ethanol and dried, and then 1.49 g of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-(3-methylpiperazin-1-yl)quinoline-3-carboxylic acid was obtained as yellow powder.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)C>CS(C)=O>[CH:27]1([C:26]2[N:15]3[CH2:14][C@@H:13]([CH2:12][O:11][C:10]4[CH:19]=[CH:20][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:8][CH:9]=4)[O:17][C:16]3=[N:18][C:24](=[O:23])[CH:25]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CC1CCCCC1
Solvent: CS(C)=O
Product: O=c1cc(C2CCCCC2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and cyclohexyl-propynoic acid ethyl ester (see Example 103) employing the procedure described in Example 100. [α]D25 +17.80 (c 0.5, DMSO)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:14]([CH2:18][CH2:19][NH2:20])[N+:15]([O-:17])=[O:16].C(OC(C)C)(C)C>>[O:14]([CH2:18][CH2:19][NH:20][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[N+:15]([O-:17])=[O:16]
Reactant: Cc1ccsc1C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: Cc1ccsc1C(=O)NCCO[N+](=O)[O-]
Yield: 42.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.60 g of 3-methyl-2-thiophenecarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.35 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(Nc2cccc3nc(NC(=O)c4ccccc4)nn23)CC1

Procedure:
The title compound was prepared following procedure and work up described for example 71 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 100 mg; 0.37 mmol; 1.0 eq.) and 4-amino-1-methyl-piperidine (ABCR, 0.50 mL) as a white powder (59 mg, 46%). 1H NMR (DMSO-d6) δ 10.91 (brs, 1H), 8.00 (d, J=7.2 Hz, 2H), 7.57 (m, 4H), 6.87 (d, J=8.3 Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 6.29 (d, J=7.9 Hz, 1H), 3.84 (m, 1H), 2.74 (m, 2H), 2.16 (s, 3H), 2.03 (m, 2H), 1.92 (m, 2H), 1.66 (m, 2H). HPLC, Rt: 1.70 min. (purity 99.4%). LC/MS, M+(ESI): 351.4, M−(ESI). 349.4.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH2:28][C:29]([OH:31])=[O:30])=[CH:18][CH:17]=1>>[CH2:1]([O:31][C:29](=[O:30])[CH2:28][C:23]1[C:24]([CH3:27])=[N:25][O:26][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl bromide (0.491 mL, 4.13 mmol) and cesium carbonate (1.68 g, 5.16 mmol) were added to [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid (1.02 g, 3.44 mmol) and the reaction stirred at room temperature. After two hours, a second aliquot of benzyl bromide (0.100 mL) was added. When the reaction was complete by analytical LCMS it was submitted to standard aqueous workup to obtain the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([N:25]=C=O)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(#N)C>[C:16]1([CH3:28])[CH:17]=[CH:18][C:19]([S:22]([N:25]=[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]2)(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: COC(=O)c1cc(O)c2ccccc2n1
Solvent: CC#N
Product: COC(=O)c1cc(=NS(=O)(=O)c2ccc(C)cc2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
According to the procedure of Wright, Synthesis, 1984, 1058, methyl 4-hydroxy-2-quinolinecarboxylate (2.03 g, 0.01 m) and p-toluenesulfonyl isocyanate (1.97 g, 0.01 m) were mixed in reagent grade acetonitrile at RT. The heterogeneous mixture was heated at reflux until the evolution of COz had ceased (ca 2-3 hours). During this time a yellow solid formed. After cooling to RT, the yellow solid was collected by filtration, washed with acetonitrile, and dried to give methyl 4-(p-toluenesulfonylimino)-1,4-dihydroquinoline-2-carboxylate (2.93 g, 82%), melting point of 264°-265° C. (dec.), as a yellow solid.
Reaction SMILES: [BH4-].[Li+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)/[C:9](=[CH:13]\[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)/[C:8]([CH3:26])=[C:7]2[CH2:27][C:28](Cl)=[O:29]>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)/[C:9](=[CH:13]\[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)/[C:8]([CH3:26])=[C:7]2[CH2:27][CH2:28][OH:29]
Reactant: COc1cc(/C=C2/C(C)=C(CC(=O)Cl)c3cc(F)ccc32)cc(OC)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(/C=C2/C(C)=C(CCO)c3cc(F)ccc32)cc(OC)c1OC

Procedure:
Lithium borohydride (1.38 mmol) in THF (2 ml) is added to a suspension of (Z)-5-Fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetyl chloride (2.78 mmol) in THF (20 ml) at 0° C. The reaction is quenched after 5 minutes with HCl (10%, aqueous, 30 ml). Ethyl acetate (50 ml) is added in order to extract the product. The organic layer is washed with water (2×50 ml), is dried over Na2SO4 and is evaporated to give the title compound, which is purified with flash chromatography (ethylacetate:hexane 8:2). (R1 =F, R2 =CH3, R3 =H, R4 =H, Y=3,4,5-trimethoxyphenyl, n=1, R5 and R6 form a double bond, R7 =H, m=1, p=1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])C)[C:3]=1[O:20][CH2:21][CH3:22].C([N-][CH:27]([CH3:29])[CH3:28])(C)C.[Li+].CI>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH:27]([CH3:28])[CH3:29])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOc1c(C(=O)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-109, 512 mg, 1.4 mmol) in THF (10 mL) at −78° C. was added lithium diisopropylamide (1.5 M in cyclohexane, 2.0 mL, 3.0 mmol). The cold bath was removed and the mixture was stirred for 3 h. The mixture was cooled to −78° C. again and methyl iodide (0.52 mL, 8.34 mmol) was added. The mixture was stirred at room temperature for 16 h then quenched with ammonium chloride (sat), extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexanes) followed by HPLC (Waters-Nova Pak column, 2% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2Cl)CC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
Tert-Butyl piperazine-1-carboxylate (0.931 g, 5 mmol) and 3-chloro-4-fluorobenzonitrile (0.785 g, 5.00 mmol) were combined, K2CO3 (0.898 g, 6.50 mmol) was added and the reaction mixture was stirred at 90° C. for 1 d. The mixture was triturated with ethyl acetate (3×5 mL) and the combined organic extracts were filtered. This was concentrated down to about 5-10 mL and subjected to flash column chromatograhy on silica gel (120 g SiO2, hexanes:ethyl acetate 1:0 to 4:1) to afford tert-butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (1.264 g, 3.93 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9 H) 3.00-3.09 (m, 4 H) 3.42-3.53 (m, 4 H) 7.25 (d, J=8.59 Hz, 1 H) 7.77 (dd, J=8.34, 2.02 Hz, 1 H) 7.97 (d, J=2.02 Hz, 1 H); [M+H] calc'd for C16H20ClN3O2, 322; found, 322.