Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[O:8]=[C:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[S:22][C:21]([CH2:23][CH2:24][C@@H:25]([NH:37]C(=O)OC(C)(C)C)[CH2:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)=[N:20][N:19]=3)[CH:15]=2)[NH:10]1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:37][C@@H:25]([CH2:26][C:27]1[CH:28]=[N:29][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:31][CH:32]=1)[CH2:24][CH2:23][C:21]1[S:22][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:8])[CH2:17]3)=[N:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl (R)-4-(5-(2-oxoindolin-5-yl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (185 mg, 347 μmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting yellow oil was purified by reversed phase HPLC (Shimadsu Valiant, Phenomenex Gemini C18 5 μm 100×30 mm, 10% to 70% H2O/MeCN, 0.1% TFA) to provide 5-(5-((R)-3-amino-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)indolin-2-one trifluoroacetate as a white solid (38 mg, 88%). LCMS (API-ES) m/z: 434.0 (M+H+); 1H NMR (300 MHz, CD3OD) δ ppm 2.24 (q, J=7.4 Hz, 2 H), 3.12 (dd, J=14.3, 7.4 Hz, 1 H), 3.24 (dd, J=14.3, 6.7 Hz, 1 H), 3.33-3.40 (m, 2 H), 3.61 (s, 2 H), 3.78 (quin, J=6.7 Hz, 1 H), 7.01 (d, J=8.0 Hz, 1 H), 7.76-7.83 (m, 2 H), 8.01 (dd, J=8.0, 1.1 Hz, 1 H), 8.68 (d, J=1.1 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:1][C:2]1[CH:11]=[C:10]([SH:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(O)c2ccccc2n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(S)c2ccccc2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 60.6 %

Procedure:
A stirred suspension of 2-methylquinolin-4-ol (5.10 g, 32.0 mmol, 1.0 eq.) in tetrahydrofuran (51 mL) was heated to 50° C., and 6.5 g of Lawesson's Reagent (6.5 g, 16.0 mmol, 0.5 eq.) was added in one portion. The reaction was heated to 80° C. and stirred at that temperature for 6 hours. The reaction was poured into a hot biphasic solution of ethyl acetate (200 mL) and water (200 mL) and was vigorously stirred. A viscous orange gel precipitated from the solution. The water/ethyl acetate solution was decanted into a separating funnel and the organic layer isolated. The aqueous layer was extracted with ethyl acetate (4×200 ml), and the combined extracts were dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. The resulting orange gel was purified by flash chromatography (50% EtOAc:50% petroleum ether→100% EtOAc) to yield 5a as a yellow solid (1.70 g, 30%).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([O:24]C(=O)C2C=CC=CC=2)=[CH:19][C:18]=1[Cl:33])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>CO.O>[C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[C:18]([Cl:33])=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[Cl:23])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(COCCCCCOc1c(Cl)cc(OC(=O)c2ccccc2)cc1Cl)=NOC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(COCCCCCOc1c(Cl)cc(O)cc1Cl)=NOC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.99 g of 5-(2,6-dichloro-4-(benzoyloxy)phenoxy)-pentyloxyacetone O-tert-butyloxime dissolved in 7.5 ml of methanol is added a solution of 0.15 g of potassium hydroxide dissolved in 1.5 ml of water. After stirring at room temperature for 1 hour, the reaction mixture is acidified by the addition of diluted hydrochloric acid, and concentrated. Water is added to the residue, and the mixture is extracted twice with ethyl acetate. The ethyl acetate layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-di-chloro-4-hydroxyphenoxy)pentyloxyacetone O-tert-butyloxime.
Reaction SMILES: [C:1]([N:9]1[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C1C=CC=CC=1.CO>O(CC)CC>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:25])[CH2:20][CH2:21][N:22]([CH2:10][CH2:11][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:23][CH2:24]2)=[CH:15][CH:14]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(c1ccccc1)N1CC1
Solvent: CO
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1

Procedure:
A mixture of 0.74 parts of 1-(benzoyl)aziridine, 1.06 parts of 4-(4- chlorophenyl)-4-piperidinol, 5.4 parts of benzene and 0.4 parts of methanol is stirred and refluxed for 2 hours. The reaction mixture is cooled. Upon the addition of 1,1'-oxybisethane, the product is precipitated. After stirring for 15 minutes, the product is filtered off and dried, yielding 1.1 parts of N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl] ethyl} benzamide; mp. 169° C.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:14]=1[CH:15]=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].N[C@H](C(O)=O)CCSC>CS(O)(=O)=O.C(OCC)(=O)C>[CH2:1]([O:12][C:13]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:14]=1[CH:15]=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOc1ccc(OC)cc1C=O
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCOc1ccc(O)cc1C=O
Yield: 49.8 %

Procedure:
The 2-undecyloxy-5-methoxybenzaldehyde (16.2 g, 52.9 mmoles) in 100 ml of methanesulfonic acid was treated with L-methionine (16 g, 0.1057 mole) at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with ice-cold water and saturated sodium chloride solution. The organic extract was dried with anhydrous magnesium sulfate, treated with charcoal and the solvent was removed in vacuo. The resulting solid was recrystallized twice from hexane to give 7.7 g (50%) of the product as a white solid, mp 66°-67° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11](Br)[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]=1Br)[CH3:2].[Li].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].C(Br)CCC>O.CO>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([Si:17]([CH3:19])([CH3:18])[CH3:16])[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]=1[Si:17]([CH3:19])([CH3:18])[CH3:16])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCOc1cc(Br)c(OCC)cc1Br
Agent: [Li]
Solvent: O
Solvent: CO
Solvent: CCCCBr
Product: CCOc1cc([Si](C)(C)C)c(OCC)cc1[Si](C)(C)C
Temperature: 35 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To 32.4 g (0.1 mol) of 2,5-dibromohydroquinone diethyl ether were successively added 160 ml of diether ether, 2.8 g (0.4 gram-atom) of metallic lithium and 21.7 g (0.2 mol) of trimethylsilyl chloride, and the mixture was stirred under a nitrogen stream at 20° to 23° C. 27.4 g (0.2 mol) of butyl bromide was added dropwise to the mixture over a period of 1 hour, and the stirring was continued for an additional one hour while heating at 35° C. After cooling with ice, 50 ml of methanol was added thereto, followed by stirring. The reaction mixture was poured into water, and was extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed with 200 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness and crystallized from acetonitrile. Recrystallization from acetonitrile gave 15.5 g (yield: 50%) of 2,5-bis(trimethylsilyl)hydroquinone diethyl ether having a melting point of 129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:12][C:13]([N:15]2[CH2:24][C:23]([F:26])([F:25])[C:22]3[CH:21]=[N:20][C:19]([NH:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[CH2:9]OC)=[CH:4][C:3]=1F.[Cl:35]C1C=CC([C@H](N)COC)=CC=1F.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.FC1(F)C2C=NC(NC3CCOCC3)=NC=2CNC1>O.C(Cl)Cl>[Cl:35][C:3]1[CH:4]=[C:5]([C@H:8]([NH:12][C:13]([N:15]2[CH2:24][C:23]([F:25])([F:26])[C:22]3[CH:21]=[N:20][C:19]([NH:27][CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[CH3:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC[C@@H](NC(=O)N1Cc2nc(NC3CCOCC3)ncc2C(F)(F)C1)c1ccc(Cl)c(F)c1
Reactant: COC[C@@H](N)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: FC1(F)CNCc2nc(NC3CCOCC3)ncc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](NC(=O)N1Cc2nc(NC3CCOCC3)ncc2C(F)(F)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)—N-(1-(4-chloro-3-fluorophenyl)-2-methoxyethyl)-5,5-difluoro-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (I-51) To a solution of 197 (0.0854 g, 0.293 mmol) and DCM (5 mL) was added sequentially TEA (0.123 mL, 0.880 mmol) and CDI (0.0476 g, 0.293 mmol) and the solution was stirred at RT for 30 min. To the solution was added dropwise a solution of TEA (0.123 mL, 0.880 mmol), 208 (0.090 g, 0.293 mmol) and DCM (5 mL). The reaction was stirred for 18 h then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 2% MeOH/DCM to afford 0.060 g (40.9%) of I-51: MS m/z (APCI-pos) M+1=499.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].C([O-])(=O)C.[K+]>O.C1(C)C=CC=CC=1>[C:20]([O:5][CH:4]=[CH:3][C:2]([CH3:12])([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])(=[O:22])[CH3:21]
Reactant: CC(C)=CCCC(C)(C)CC=O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OC=CC(C)(C)CCC=C(C)C
Temperature: 25 °C

Procedure:
The general method for the preparation of the starting enol esters is illustrated by the following example: 0.063M of 3,3,7-trimethyl-oct-6-ene-1-al were added under stirring to a mixture consisting of 0.06M of triethylamine, 0.126M of acetic anhydride and 1.1 g of potassium acetate pre-heated to 80°. The reactive mixture was refluxed for approximately 7 h. After cooling to room temperature, toluene and water were added and the two phases separated. 3,3,7-Trimethyl-1,6-octadienyl acetate was then obtained as a toluene solution and finally isolated by evaporation at reduced pressure.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([NH:27][C:28]1[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:29]=1[C:30]([O:32]C)=[O:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C(=O)C>[C:19]([NH:27][C:28]1[CH:37]=[C:36]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH:35]=[CH:34][C:29]=1[C:30]([OH:32])=[O:31])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: OB(O)c1cc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(-c2cc3ccccc3s2)ccc1C(=O)O)c1ccccc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 3.2 %

Procedure:
56 mg of benzothiophene-2-boronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 12 hours. After cooled to room temperature 37 mg of benzothiophene-2-boronic acid and 22 mg of sodium carbonate were added and stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated, and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1.0 mL of 2.0 mol/L aqueous sodium hydroxide and 2.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid was added to the reaction mixture and a solid substance was separated by filtration to obtain 2.5 mg of 2-(benzamido)-4-(benzothiophen-2-yl)benzoic acid as white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([OH:14])[CH2:6]2)[CH2:2]1.Cl[CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:1]2[CH2:5][CH2:4][C:3]3([C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH:7]([OH:14])[CH2:6]3)[CH2:2]2)=[CH:26][CH:25]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: OC1CC2(CCNC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC2(CC(O)c3ccccc32)C1)c1ccc(F)cc1
Reaction time: 20 h

Procedure:
8.5 g of spiro[indan-1,3'-pyrrolidin]-3-ol, 12.0 g of 4-chloro-p-fluorobutyrophenone and 11.5 g of sodium carbonate are heated at reflux in 100 cc of dimethyl formamide while stirring for 20 hours. After cooling, filtration is effected, the filtrate is evaporated to dryness, taken up in 300 cc of chloroform and extracted thrice with 50 cc amounts of 2 N hydrochloric acid. The acid extract is rendered alkaline with 2 N caustic soda solution while cooling and extraction is effected with chloroform. The crude title compound, obtained as oil after concentrating the chloroform phase by evaporation, is converted into the hydrogen fumarate with fumaric acid. The hydrogen fumarate of the title compound has a M.P. of 174°-176° (from ethanol/ether).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:24][C:25]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[O:26])[C:9](=[O:23])[NH:10][C@H:11]2[CH2:17][CH2:16][C@@H:15]([CH3:18])[N:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C@@H:12]2[OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O.O>[CH:1]1([CH2:7][C@H:8]([NH:24][C:25]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[O:26])[C:9](=[O:23])[NH:10][C@H:11]2[CH2:17][CH2:16][C@@H:15]([CH3:18])[N:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCN1C[C@H](O)[C@@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)c2ccco2)CC[C@H]1C
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCN1CC(=O)[C@@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)c2ccco2)CC[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Sulfur trioxide-pyridine complex (0.0.35 g, 2.2 mmol) was added to a solution of Furan-2-carboxylic acid [(S)-2-cyclohexyl-1-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-ylcarbamoyl)-ethyl]-amide (0.19 g, 0.44 mmol) in DMSO (4.0 ml) and triethylamine (0.61 ml, 4.4 mmol) was stirred at RT for 1 h. The reaction mixture was diluted with water, then was extracted with EtOAc. Then, the organic layer was was extracted with brine. The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (3% methanol/methylene chloride) gave the title compound (0.15 mg, 79%): 1H NMR: 7.44(s, 1H), 7.11(d, 1H), 7.04(d, 1H), 6.92(d, 1H), 6.49(d, 1H), 5.29(m, 1H), 4.69(m, 1H), 3.40(d, 1H), 3.08(m, 2H), 2.51(m, 2H), 1.88-0.81(m, 29H); Electrospray mass spec: M+H+=432.2.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2[CH3:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].[Sn](Cl)(Cl)(Cl)Cl>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([C:10]1[N:6]([N:5]2[C:4](=[O:12])[C:3]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]3[C:1]2=[O:17])[C:7]([CH3:11])=[CH:8][CH:9]=1)=[O:22]
Reactant: Cc1cccn1N1C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccccc2Cl)n1N1C(=O)c2ccccc2C1=O
Yield: 75.1 %

Procedure:
To a suspension of 1-phthalimido-2-methylpyrrole (105 g, 0.46 mol) and o-chlorobenzoyl chloride (162.5 g, 0.93 mol) in 1.5 liters of dichloromethane at 0° was added tin(IV) chloride (243 g, 0.94 mol) over 15 minutes. The resultant mixture was warmed to room temperatue over 30 minutes and then quenched with 2 liters of H2O. The organic layer was washed with H2O and brine, dried (MgSO4), charcoaled and filtered. Evaporation of the volatiles left an oil which was purified by flash chromatography (silica, dichloromethane) to give 126 g of powder. This powder was recrystallized from ether-petroleum ether to give 82 g (48%) of powder, m.p. 260°-262°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[K].Br[CH2:44][C:45]1[C:46]([C:53]2[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][C:54]=2[Cl:60])=[N:47][O:48][C:49]=1[CH:50]1[CH2:52][CH2:51]1>O1CCCC1.C(O)(C)(C)C>[CH:50]1([C:49]2[O:48][N:47]=[C:46]([C:53]3[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][C:54]=3[Cl:60])[C:45]=2[CH2:44][O:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=4)=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)[CH2:52][CH2:51]1
Reactant: COc1ccc(COc2ccc(C3CCC(O)CC3)cc2)cc1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc([C@H]3CC[C@H](OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
4-[4-(4-Methoxy-benzyloxy)-phenyl]-cyclohexanol (2.24 mmol, 700.00 mg) and 18-crown-6 (2.69 mmol, 710.70 mg) in tetrahydrofuran (10 mL) is treated with tert-butyl alcohol, potassium derivative (2.69 mmol, 2.69 mL; 1M in THF). The mixture is stirred for 30 minutes and 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (3.36 mmol, 1.17 g) is added. The mixture is stirred at room temperature for 5 minutes and heated to 40° C. for 1.5 h. Silica gel is added and the reaction mixture is concentrated under reduced pressure. The crude mixture is purified by silica gel flash chromatography eluting with a gradient of 10-60% EtOAc in hexanes. A second chromatography is performed on silica gel eluting with 0.5% EtOAc in DCM to yield the title compound (960 mg, 74%). MS m/z 577.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])C(OCC)=O)[CH3:2].[Cl-].[Li+].O.CS(C)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 68.2 %

Procedure:
To a 100 ml RB flask was added 1.5 g (5.3 mmol) of 3-nitro4-pyridinyl-propanedioic acid diethyl ester, 0.450 g (10.6 mmol) of lithium chloride, 0.095 g (5.3 mmol) of water and 35 mL of DMSO. The solution was heated at 100° C. for 4 h. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was chromatographed on silica gel eluting with a hexane-10% EtOAc/hexane gradient to give 0.76 g of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 1.14 (t, J=7.1 Hz, 3H), 4.06 (q, J=7.1 Hz, 2H), 4.12 (s, 2H), 7.63 (d, J=4.9 Hz, 1H), 8.82 (d, J=4.9 Hz, 1H), 9.21 (s, 1H); C9H10N2O4: APES+MS m/z 211 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Li]CCCC.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>C1COCC1.CCCCCC>[Br:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]([OH:21])[C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccc(Br)c2)cc1
Reaction time: 0.5 h
Yield: 1756.7 %

Procedure:
To a stirred −78° solution of m-dibromobenzene (70.9 g, 0.3 mol) in 200 mL of dry THF under Ar was added 117 mL of 2.56 M n-BuLi (0.3 mol) in hexane over 10 min. After 30 min, p-methoxybenzaldehyde (27.2 g, 0.02 mol) in 50 mL of THF was added over 20 min. The solution was stirred for 1 hr at −78° (complete by tlc) prior to quenching with saturated aq. NH4Cl. After warming to 20°, the reaction was diluted 2 fold with EtOAc prior to washing with H2O followed by brine. After drying over Na2SO4 and concentration using a rotary evaporator, 103 g of 3-bromo-4′-methoxybenzhydrol was obtained as a yellow oil that was carried forward without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:19])[C:16]=3[F:18])[C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[CH:33]2[CH2:35][CH2:34]2)[CH:6]=[N:5]1.CCN(CC)CC.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:55]=[C:56]=[O:57].N>C1COCC1.O>[Cl:19][C:15]1[C:16]([F:18])=[C:17]2[C:12]([C:11]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]([CH:33]3[CH2:35][CH2:34]3)[N:9]2[C:7]2[CH:6]=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:56]([NH2:55])=[O:57])[CH:8]=2)=[CH:13][CH:14]=1
Reactant: [N-]=C=O
Reactant: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCN)c3)c3c(F)c(Cl)ccc23)c1F
Agent: N
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CCNC(N)=O)c3)c3c(F)c(Cl)ccc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirred solution of indole 1 (Example 14, Step 2; 80 mg, 0.15 mmol) in THF (5 mL) under inert atmosphere were added Et3N (0.04 mL, 0.31 mmol) and triphosgene (18.3 mg, 0.06 mmol) at 0° C., stirred for 1 h, warmed to RT and stirred for 2 h. To this solution of crude isocyanate was passed ammonia gas at −78° C. for 10 min; warmed to 0° C. and stirred for 1 hr. The mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified by triturating with Et2O (2×5 mL) and dried under reduced pressure to afford 2 (30 mg, 34%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.82 (s, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.22-7.11 (m, 3H), 6.84 (t, J=7.2 Hz, 1H), 6.04-6.03 (m, 1H), 5.53 (br s, 2H), 4.33 (q, 2H), 4.21 (t, J=6.0 Hz, 2H), 3.43 (t, J=6.0 Hz, 2H), 1.84-1.78 (m, 1H), 1.32 (t, J=7.2 Hz, 3H), 0.92-0.91 (m, 2H), 0.87-0.85 (m, 2H); MS: m/z 560.6 (M+H+).
Reaction SMILES: C([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([NH:14][NH2:15])=O)C.[C:16](Cl)(Cl)=[O:17].C(=S)=[S:21]>>[O:17]=[C:16]1[NH:15][N:14]=[C:12]([C:4]2[CH2:3][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[S:21]1
Reactant: S=C=S
Reactant: O=C(Cl)Cl
Reactant: CCC1C(C(=O)NN)=Cc2ccccc21
Product: O=c1[nH]nc(C2=Cc3ccccc3C2)s1

Procedure:
Ethyl indene-2-carboxylic acid hydrazide, (17.4 g., 0.1 mol) in 200 ml. of carbon disulfide was treated with 22 g. (0.1 mol) of phosphorous pentasulfide, and the mixture stirred at reflux for 24 hours. The mixture was extracted with 3 portions of 10% sodium hydroxide solution and the organic phase was dried and concentrated to a solid. The thiohydrazide thus prepared was reacted with phosgene as described in EXAMPLE 4 to give the title product.