Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[N:17]12.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCC.O1CCCC1>[O:26]=[C:22]1[N:17]2[C:18]3[C:14]([CH:15]=[C:16]2[CH2:25][CH2:24][CH:23]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:13][CH:21]=[CH:20][CH:19]=3
Reactant: O=C1CCCc2cc3ccccc3n21
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1CCc2cc3ccccc3n2C1=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
6.6 ml of a 1.6M solution of n-butyllithium in n-hexane were added to a stirred solution of 1.11 g of diisopropylamine in 150 ml of tetrahydrofuran at -78° C. under nitrogen. The mixture was allowed to warm to -20° C. for 5 minutes and was then again cooled to -78° C. Then, 1.85 g of 6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one in 10 ml of tetrahydrofuran were added dropwise. After stirring at -78° C. for 0.5 hour, 1.19 g of ethyl chloroformate were added and the mixture was allowed to warm to room temperature. The solvent was removed by evaporation and the residue was partitioned between diethyl ether and 2M hydrochloric acid. The ethereal extracts were washed with saturated sodium bicarbonate solution, dried and concentrated to give an oil. This oil was purified by chromatography on silica gel with dichloromethane. Crystallization of the product from methanol gave 1.35 g of ethyl 6,7,8,9-tetrahydro-6-oxopyrido[1,2-a]indole-7-carboxylate of melting point 82°-84° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[NH:28]C(=O)OCC[Si](C)(C)C)[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[C:24]([NH:23][C@@H:20]1[CH2:21][CH2:22][C@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:13]2=[O:38])[C@H:18]([NH:28][S:54]([CH3:53])(=[O:56])=[O:55])[CH2:19]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NS(C)(=O)=O)C1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A sample of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate and its 5S diastereomer (100 mg, 0.183 mmol; see Example 11, Step 4) was dissolved in dichloromethane (2 ml) prior to the addition of trifluoroacetic acid (2.54 ml, 32.9 mmol). After 30 min, the solution was concentrated in vacuo. The residue was dissolved in dichloromethane (3 ml) prior to the addition of triethylamine (0.100 ml, 0.720 mmol) and methanesulfonyl chloride (0.018 ml, 0.234 mmol). After 2 h, this was washed with sat NaHCO3 solution and the organic layer was dried (Na2SO4), filtered and concentrated to afford benzyl (S)-1-((1S,2R,4R)-4-(tert-butylamino)-2-(methylsulfonamido)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as a mixture with its 4S diastereomer (66 mg, 0.137 mmol, 76% yield). LC/MS found [M+H]+=481.22.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[CH:22]=[C:21]([C:23]#[C:24][Si](C)(C)C)[C:20](=[O:29])[N:19]([CH3:30])[CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CCO>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:17]1[CH:22]=[C:21]([C:23]#[CH:24])[C:20](=[O:29])[N:19]([CH3:30])[CH:18]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cc(C#C[Si](C)(C)C)c(=O)n(C)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C#Cc1cc(-c2cc(NS(=O)(=O)CC)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Temperature: 20 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
To a mixture of N-[4-(2,4-difluorophenoxy)-3-[1-methyl-6-oxo-5-(2-trimethylsilylethynyl)pyridin-3-yl]phenyl]ethanesulfonamide (100 mg, 0.19 mmol) in EtOH (10 mL) was added K2CO3 (157 mg, 1.14 mmol). The reaction was stirred at 20° C. for 12 h and poured into H2O (30 mL) and extracted with DCM (20 mL×3). The organic phase was washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (48 mg, 56%) as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ 7.90 (d, J=2.4 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.14-7.11 (m, 1H), 7.01-6.94 (m, 2H), 6.89-6.86 (m, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.55 (s, 1H), 3.67 (s, 3H), 3.34 (s, 1H), 3.14 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H). LCMS (M+H)+=445.
Reaction SMILES: CCN(CC)CC.I[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[SH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>CN(C=O)C>[O:12]1[CH2:13][CH2:14][CH:9]([S:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)Cc1ccc(S)cc1
Reactant: IC1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(SC2CCOCC2)cc1

Procedure:
NEt3 (1.3 mL, 9.0 mmol) and 4-iodotetrahydropyran (1.93 g, 9.0 mmol) were added to a stirred solution of ethyl (4-mercaptophenyl)acetate (1.21 g, 6.0 mmol) in anhydrous DMF (10 mL) at 0° C. The mixture was allowed to warm to room temperature over 3d, then the solvents were removed under reduced pressure. The residue was partitioned between Et2O (100 mL) and saturated aqueous NH4Cl (50 mL), the aqueous phase being extracted further with Et2O (45 mL). The combined ethereal extracts were washed with H2O (50 mL), H2O-saturated aqueous Na2CO3 (1:1, 50 mL), and brine (50 mL), before being dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (IH-Et2O, 10:1 to 2:1) afforded the title compound: RF (IH-Et2O, 2:1)=0.31.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=1.[N:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH:20]=1>>[NH:8]([C:3]1[CH:2]=[CH:1][C:6]([NH:7][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:19]3[CH:18]=[N:17][N:16]=[CH:20]3)=[CH:22][CH:23]=2)=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N:19]3[CH:20]=[N:16][N:17]=[CH:18]3)=[CH:29][CH:28]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(Nc2ccc(N)cc2)cc1
Reactant: O=C(O)c1ccc(-n2cnnc2)cc1
Product: O=C(Nc1ccc(Nc2ccc(NC(=O)c3ccc(-n4cnnc4)cc3)cc2)cc1)c1ccc(-n2cnnc2)cc1

Procedure:
Compound 747 was prepared according to the procedure described in Scheme IV from 4,4′-diaminodiphenylamine and 4-(4H-1,2,4-triazol-4-yl)benzoic acid. [M+H]+ calcd for C30H23N9O2: 542.20; found 541.99.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[CH:27][C:28](=[O:37])[N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=1>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:26]=[CH:27][C:28](=[O:37])[N:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(=O)n(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc(=O)n(-c5ccccc5)c4)ncnc3[nH]2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (75 mg, 0.22 mmol) and 5-amino-1-phenyl-1H-pyridin-2-one (50 mg, 0.27 mmol) in 1-butanol (3 mL) was heated at 120° C. overnight, LC-MS showed the desired product together with some de-Boc product. After the mixture was cooled to rt, it was diluted with methylene chloride (3 mL), then N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) and di-tert-butyldicarbonate (49 mg, 0.22 mmol) were added. The resulting mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc (30 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized with EtOAc/Hexane to give the title compound as a green solid. LC-MS (ES, Pos.): 485 [MH+], and 1H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.50 (m, 2H), 3.56 (m, 2H), 4.04 (m, 2H), 6.39 (s, 1H), 6.56 (d, J=9.7 Hz, 1H), 6.66 (s, 1H), 7.39-7.57 (m, 5H), 7.81 (dd, J=9.7, 2.7 Hz, 1H), 8.17 (s, 1H), 8.34 (d, J=2.7 Hz, 1H), 9.17 (s, 1H), 11.94 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1.[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].C[O-].[Na+].Cl>C(OC)(C)(C)C>[F:16][C:17]([F:24])([F:23])[C:18](=[O:19])[CH2:14][C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)=[C:2]([F:1])[CH:3]=1)=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2cscn2)c(F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)c(F)c1
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of 1-[3-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (666 mg, 3.01 mmol), ethyl trifluoroacetate (470 mg, 3.31 mmol) in t-butylmethylether (40 ml) was added sodium methoxide (28 wt.% solution in methanol; 0.8 ml, 3.6 mmol) over 5 minutes, and the mixture was stirred for 20 hours. The mixture was made neutral by addition of 2N HCl, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without further purification. (1.06 g, 99% yield).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].FC1C=[C:10]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH:11]=C(F)C=1F.[OH2:23]>C1COCC1>[CH2:2]([O:4][C:11]([CH:10]=[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:23])[CH3:1]
Reactant: O=C1CCC(c2cc(F)c(F)c(F)c2)CC1
Reactant: CC(C)(C)[O-]
Reactant: O
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCCCC1

Procedure:
A suspension of triethyl phosphonoacetate (21.8 g) in THF (50 ml) was stirred in a nitrogen gas stream, followed by adding potassium-t-butoxide (11.8 g) little by little at room temperature, stirring the reaction solution at room temperature for one hour, dropwise adding a solution of 4-(3',4',5'-trifluorophenyl)cyclohexanone (20 g) in THF (50 ml), stirring at room temperature for 2 hours, adding to water (100 ml), extracting with ethyl acetate (100 ml), washing the organic layer with water, drying over anhydrous MgSO4 and concentrating the solvent under reduced pressure, to obtain 4-(3',4',5'-trifluorophenyl))ethoxycarbonylmethylenecyclohexane (18.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=S)[NH:10][CH:11]2[CH:16]3[CH2:17][CH:13]4[CH:14]([CH2:15]3)[CH:12]24)=[CH:4][CH:3]=1.[NH3:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:19])[NH:10][CH:11]2[CH:16]3[CH2:17][CH:13]4[CH:14]([CH2:15]3)[CH:12]24)=[CH:4][CH:3]=1
Reactant: S=C(Nc1ccc(Cl)cc1)NC1C2CC3C(C2)C31
Reactant: N
Solvent: CCO
Product: N=C(Nc1ccc(Cl)cc1)NC1C2CC3C(C2)C31

Procedure:
To a solution of 3-[3-(p-chlorophenyl)thioureido]tricyclo[2,2,1,02,6 ]heptane (0.25 g.) in ethanol saturated with ammonia (10 ml.) was added 0.2 g. of yellow mercuric oxide, and the mixture stirred at room temperature for 16 hours. The solids were filtered off and the clear filtrate evaporated to dryness. The residual solid was recrystallised from toluene to give 3-[3-(p-chlorphenyl)guanidino]tricyclo[2,2,1,02,6 ]heptane, m.p. 204°-205°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=O)[CH3:12])=[CH:5][CH:4]=1.[C:16]1(=[O:23])[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1.C([O-])(=O)C.[NH4+:28]>C(O)C>[CH3:12][C:11]1[NH:28][C:18]2[CH2:19][CH2:20][CH2:21][C:16](=[O:23])[C:17]=2[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=2)[CH:10]=1
Reactant: CC(=O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: [NH4+]
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=CC(c2ccc(C(F)(F)F)cc2)C2=C(CCCC2=O)N1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
A mixture of 4-(4-trifluoromethyphenyl)-3-butene-2-one (4.9 g), 1,3-cyclohexanedione (2.68 g), ammonium acetate (2.65 g) and 75 mL of ethanol were heated at reflux for eight hours and then cooled to room temperature. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was dried, filtered, and evaporated to obtain a yellow oil. Chromatography, with hexane:ethyl acetate (1:1) as the eluent, and recrystallization from toluene:hexane provided the title compound as a yellow solid (4.0 g); mp 116°-118° C.; NMR: 1.73 (s,3, CH3), 1.87-1.98 (m,2, CH2), 2.14-2.16 (m,2, CH2), 2.45-2.49 (m,2, CH2), 4.49 (d,1, J=4.9, CH), 4.60 (d,1, J=4.9, CH), 7.35 (d,2, J=8.0, Ar), 7.57 (d,2, J=8.0, Ar), 8.54 (s,1, NH); (CI, CH4) MS: m/z=308(M+1); Analysis for C17H16F3NO: Calculated C, 66.44; H, 5.25; N, 4.56; Found: C, 66.72; H, 5.34; N, 4.41.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][CH2:22][CH3:23].S(=O)(=O)(O)[OH:25].OO>CO.C(O)(C)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH2:22][CH3:23])=[O:25]
Reactant: CCSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CO
Solvent: CC(C)O
Product: CCS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 302.9 %

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylthiopyrazole (22.25 g) in methanol was added a solution of sulfuric acid (1.5 g) in isopropanol. Hydrogen peroxide (6.95 g of 30% aqueous solution) was added and the temperature raised to 60° C. After two hours, the reaction was filtered and the solid washed with methanol. The filtrate was washed (water), dried and recrystallized (methanol) to give 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylsulfinylpyrazole (18.4 g), m.p. 173-174° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].C1C(=O)N([Br:22])C(=O)C1.COC(C)(C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:22])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(C)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 43.8 %

Procedure:
To a stirred solution of 4-methyl-2-nitro-benzoic acid methyl ester (108.5 g, 555.7 mmol) in acetonitrile (750 mL), was added NBS (97.9 g, 550.1 mmol). The mixture was heated to a gentle reflex with a 200 W light bulb on for 5.5 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate (1500 mL). The solution was washed with water (2×600 mL) and brine (300 mL), dried over magnesium sulfate, and concentrated to give a brown oil. To the oil, was added t-butyl methyl ether (300 mL). The mixture was heated at 70° C. for 15 minutes. The mixture was allowed to cool to about 53° C. over one hour, then to 45° C., and then at 20-25° C., while blowing nitrogen with a glass pipette overnight. The suspension was filtered via a medium pore-sized funnel. The solid was washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 4-bromomethyl-2-nitro-benzoic acid methyl ester as an off-white solid (66 g, 43% yield). The solid was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[C:27]([OH:46])(=[O:45])[CH2:28][CH2:29]CCCCC/C=C\CCCCCCCC.N[CH2:48][CH2:49]C(CN)O>>[OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:28]([C:27]([O:46][CH2:48][CH3:49])=[O:45])[CH3:29]
Reactant: NCCC(O)CN
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCC1=NCCN1CCO
Product: CCOC(=O)C(C)CCCCCCCC/C=C\CCCCCCCCC1=NCCN1CCO
Yield: 93.8 %

Procedure:
This example was carried out in the same manner as that in Example 1, except that 69.7 g (0.2 mol) of 1-(2-hydroxyethyl)-2-oleyl-2-imidazoline synthesized from oleic acid (AV 200, average molecular weight 280.5) and aminoethylethanolamine was used. 1-(2-hydroxyethyl)-2-(α-ethoxycarbonylethyl-oleyl)-2-imidazoline was obtained (yield 93.8%).
Reaction SMILES: C1(C(=O)CC(OC(C)(C)C)=O)CC1.[O-]CC.[Mg+2].[O-]CC.[CH3:21][C:22]1[C:30]([O:31][CH2:32][CH3:33])=[C:29]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C(Cl)(=O)C([Cl:41])=O>C(OCC)C>[CH3:21][C:22]1[C:30]([O:31][CH2:32][CH3:33])=[C:29]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:28]=[CH:27][C:23]=1[C:24]([Cl:41])=[O:25]
Reactant: CCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(C)(C)OC(=O)CC(=O)C1CC1
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 3-cyclopropyl-3-oxopropionate (9.2 g) in ethyl ether (200 mL) was added magnesium ethoxide (5.7 g). The reaction mixture was heated at reflux for 1 hour. After cooling back to room temperature, a solution of 2-methyl-3-ethoxy-4-methylsulfonylbenzoyl chloride (13.8 g), which was prepared from 2-methyl-3-ethoxy-4-methylsulfonylbenzoic acid (the preparation of which is described in U.S. Pat. No. 5,329,041 which is incorporated herein by reference) and oxalyl chloride, in ethyl ether (50 mL) was added over a period of 15 minutes. After stirring overnight at room temperature, the reaction mixture was poured over ice-water (100 mL), and the phases were separated. The ether layer was dried over magnesium sulfate and then concentrated in vacuo to afford 17 g of the crude product as an oil.
Reaction SMILES: Cl.[CH:2]12[NH:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][C:4](=O)[CH2:3]2.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C2C(=CC=CC=2)C=C1.O.C(O)(=O)C(O)=O.C(O)(=O)C(O)=O>C(Cl)Cl>[NH:10]1[CH:2]2[C:3]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:18][C:4]=3[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9]2
Reactant: O=C1CC2CCCC(C1)N2
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: ClCCl
Product: c1ccc2c3c([nH]c2c1)CC1CCCC3N1

Procedure:
This compound was prepared from 9-azabicyclo[3.3.1]nonan-3-one hydrochloride and phenylhydrazine by Fischer indole synthesis as described in Example 1, Method A, to give colorless crystals, mp 198°-203° C. (from methylene chloride; it was also converted to a hydrogen oxalate hemihydrate, mp 68°-72° C. (from ethanol-ether).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].CCN(CC)CC.[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[N:29]([CH2:30][CH2:31][O:32][C:33]4[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:34]=43)[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]>C(Cl)Cl>[CH:19]([N:22]1[C:26]([C:27]2[N:36]=[C:35]3[C:34]4[CH:37]=[C:38]([S:41]([N:9]5[CH2:8][CH2:7][N:6]([C:2]([CH3:1])([CH3:5])[CH2:3][OH:4])[CH2:11][CH2:10]5)(=[O:43])=[O:42])[CH:39]=[CH:40][C:33]=4[O:32][CH2:31][CH2:30][N:29]3[CH:28]=2)=[N:25][CH:24]=[N:23]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: CC(C)(CO)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN(C(C)(C)CO)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.9 %

Procedure:
To a solution of 2-methyl-2-piperazin-1-ylpropan-1-ol (71 mg, 0.45 mmol) and NEt3 (105 μL, 0.75 mmol) in DCM (10 mL) at 0° C. was added 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (97 mg, 0.15 mmol) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM then C18, gradient 10-40% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then freeze-dried from MeCN/H2O to afford 138 (20 mg, 26%) as a white solid. LCMS: RT 2.86 min [M+H]+ 516.4. 1H NMR (CDCl3, 400 MHz): δ 8.95 (1H, d, J=2.37 Hz), 7.88 (1H, s), 7.69 (1H, s), 7.64 (1H, dd, J=8.60, 2.40 Hz), 7.19 (1H, d, J=8.61 Hz), 5.86-5.84 (1H, m), 4.62-4.57 (2H, m), 4.54-4.50 (2H, m), 3.28-3.11 (6H, m), 2.69 (4H, brd s), 1.60 (6H, d, J=6.63 Hz), 1.03 (6H, brd s)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:33]3[CH:34]=[CH:35][C:30]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:31][CH:32]=3)=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O)cc2)COC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Oc3ccc(Oc4ccccc4)cc3)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.5 %

Procedure:
To a solution of (S)-4-(4-Hydroxy-benzyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.250 g, 0.846 mmol), 4-Phenoxyphenyl-boronic acid (0.181 g, 0.846 mmol), and triethylamine (0.59 mL, 4.232 mmol) in anhydrous dichloromethane (DCM) (20.8 mL) at room temperature under an atmosphere of nitrogen was added copper (II) acetate (0.154 g, 0.846 mmol), and the resulting mixture was stirred at room temperature for about 60 hours. The reaction mixture was washed with 20 mL of water and 20 mL of DCM and filtered. The DCM layer was then extracted. The aqueous layer was re-extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.030 g, 8%).