Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCC>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1F
Temperature: 140 °C
Yield: 78 %

Procedure:
Potassium fluoride (water content 0.2%) (69.6 g; 1.2 mole) and tetradecyltrimethylammonium bromide (18 g; 0.055 mole) were added to molten 2-chloronitrobenzene (157.5 g; 1 mole) with stirring. The mixture was heated to 140° C. for 28 hours. The reaction mixture was then allowed to cool to c. 100° C. and was filtered with the assistance of added toluene. The toluene was distilled and the residue was finally distilled in high vacuum to give 2-fluoronitrobenzene in 78% yield together with 5% recovered 2-chloronitrobenzene.
Reaction SMILES: [Br-:1].[CH2:2]([N+:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(OC(=O)C)(=O)C>[Br-:1].[CH3:19][N:20]([CH3:29])[C:21]1[CH:28]=[CH:27][C:24](/[CH:25]=[CH:18]/[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:9]=2[CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:23][CH:22]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1sc2ccccc2[n+]1Cc1ccccc1
Agent: [Br-]
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(/C=C/c2sc3ccccc3[n+]2Cc2ccccc2)cc1

Procedure:
A mixture of 3-benzyl-2-methylbenzothiazol-3-ium bromide (0.30 g, 0.94 mmol) and 4-dimethylaminobenzaldehyde (0.21 g, 1.41 mmol) in 5 mL of acetic anhydride was heated under nitrogen. Upon refluxing, the mixture turned red and all solids appeared to be in solution. The solution was refluxed for 15 minutes, cooled, and filtered. The solid was washed with ethyl acetate to give (E)-2-[2-(4-dimethylaminophenyl)vinyl]-3-benzylbenzothiazol-3-ium bromide as a purple solid, mp 247-248° C., decomposed (dec).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: OC1CCN(Cc2ccc(Br)cc2)CC1
Yield: 62.5 %

Procedure:
4-Bromobenzylbromide (3 g) was stirred with 4-hydroxypiperidine (1.21 g) and potassium carbonate (1.99 g) in dimethylacetamide (15 ml) at 50° C. for 3 h. The reaction mixture was then allowed to cool, poured into water (80 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography, eluting with a gradient of 0–3% methanol in dichloromethane, to afford the product as a viscous, colourless oil (2.02 g).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[CH2:15]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCCCCCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCN(c1ccccc1)c1ccccc1
Temperature: 120 °C

Procedure:
253.8 Grams of diphenylamine, 297.0 g of 1-bromohexane and 1,500 ml of toluene were mixed, and 150 g of sodiumamide was added little by little with stirring. After completion of the addition, the mixture was refluxed under heat on an oil bath at 120° C. with stirring for 10 hours. Then, the reaction mixture was poured into 2,000 ml of water little by little, and the mixture was stirred at room temperature for 1.0 hours. During the stirring, heat generation was observed. The mixture was transferred into a separation funnel, and an organic layer was recovered. The recovered liquid was washed consecutively with water and saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The resultant oily substance was distilled under reduced pressure, to give 337 g of N-hexyldiphenylamine (117) having a boiling point of 173-175° C. (0.4 Torr). The yield thereof was 88.6%.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[C:12]([O:11][C:9]([N:1]([CH2:19][C:20]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])[C:2]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:3])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1cc(F)ccc1CBr
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)ccc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
In a dry flask under nitrogen, di-tert-butyl iminodicarboxylate (Aldrich, 3.86 g, 17.8 mmol) was dissolved in dry DMF (5 mL) and treated with NaH (60% dispersion in oil, 0.71 g, 17.8 mmol). After the evolution of gas had ceased, Methyl 2-(bromomethyl)-5-fluorobenzoate (4 g, 16.2 mmole) dissolved in DMF (5 mL) was added. An additional 5 mL of DMF was added to aid stirring. The reaction was stirred for 2 hrs, then partitioned between water and EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated and the residue was purified on silica eluting first with toluene, then with a gradient of 0-5% MeOH(CHCl3. The impure product thus obtained was re-chromatographed on silica eluting with a gradient of 0-30% EtOAc/Hexanes. The product was obtained as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27](=[CH2:31])C(O)=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCC[N:45]([CH3:47])C)C.[NH4+].[OH:49]N1C2C=CC=CC=2N=N1.O>CN(C)C=O>[NH2:45][C:47](=[O:49])/[CH:31]=[CH:27]/[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:19]2[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: C=C(C(=O)O)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C=C/C(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a solution of (2E)-3-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]acrylic acid (0.30 g, 0.63 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2 mmol) and 1-hydroxy-1H-benzotriazole ammonium salt (0.18 g, 1.2 mmol) and the mixture was stirred at room temperature for 12 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl {[6-[(1E)-3-amino-3-oxoprop-1-en-1-yl]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.25 g, yield 83%) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=1)#[N:2].C([O-])([O-])=[O:32].[K+].[K+].OO.O>CS(C)=O.CCOC(C)=O>[NH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:32])=[C:4]([NH:24][C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)ccc2C#N)cn1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)ccc2C(N)=O)cn1
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(4-cyano-3-(1-methyl-1H-pyrazol-4-ylamino)phenylamino)cyclohexylcarbamate (50 mg, 0.12 mmol) in DMSO (1 mL), K2CO3 (100 mg, 0.724 mmol) and H2O2 (50% aq., 0.800 mL) were added. The mixture was stirred at 100 C for 10 min. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in TFA (1 mL). After 10 min of standing, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (31 mg). MS 329.4 (M+H); UV 205.3, 258.4, 280.5, 327.9 nm
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.NO.Cl.CCN=C=NCCCN(C)C.C1C=CC2[N:63]([OH:64])N=NC=2C=1.CCN(CC)CC>CN(C)C=O>[OH:64][NH:63][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:32][CH:33]=1)=[O:36]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)NO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 44.3 %

Procedure:
To a solution of rac 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid prepared in Example 232 (50 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) was added. NH2OH.HCl (18 mg, 0.26 mmol), EDCI (33 mg, 0.17 mmol), HOBT (21 mg, 0.15 mmol) and NEt3 (0.036 mL, 0.26 mmol). The reaction mixture was heated at 80° C. for 48 h. The mixture was cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by prep-HPLC to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydroxycarbamoyl-phenyl)-amide as a white solid (24 mg, 47%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccccc1CBr
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccccc4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 1-bromomethyl-2-chloro-benzene. MS (ESI) m/z 503.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:29][NH:30][CH3:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([N:30]([CH3:31])[CH3:29])=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Reactant: CNC
Product: CN(C)C(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and dimethylamine were coupled to give 111bp. 1H NMR (400 MHz, CDCl3) δ 7.15-7.31 (m, 3H), 6.82-7.00 (m, 4H), 5.13 (s, 2H), 3.33 (m, 3H), 2.94-3.13 (m, 6H). LCMS (ESI) m/z: 429.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:21])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: OCc1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)methanol (0.45 g, 1.9 mmol) in acetone (10 mL) was added Jones' reagent (3 mL) dropwise at 0° C. The reaction mixture was stirred at rt for 1 hr and concentrated under reduced pressure. Water was added to the residue and the solid that separates out was filtered, washed with water and dried to give 1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.43 g, 1.7 mmol, 89% yield) as a yellow solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C@@H:13]2[C@H:18]3[CH2:19][O:20][C@H:16]([O:17]3)[C@@H:15]([O:21]C(=O)C3C=CC=CC=3)[C@H:14]2[O:30][CH3:31])=[CH:8][CH:7]=1>ClCCl.CO.ClCCl>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C@@H:13]2[C@H:18]3[CH2:19][O:20][C@H:16]([O:17]3)[C@@H:15]([OH:21])[C@H:14]2[O:30][CH3:31])=[CH:10][CH:11]=1
Reactant: COc1ccc(O[C@H]2[C@H](OC)[C@H](OC(=O)c3ccccc3)[C@@H]3OC[C@H]2O3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(O[C@H]2[C@H](OC)[C@H](O)[C@@H]3OC[C@H]2O3)cc1
Reaction time: 1 h
Yield: 59 %

Procedure:
Sodium methoxide (13.5 g, 250 mmol) is added to a solution of the above crude residue 90 in dichloromethane/methanol (540 ml, 1/1). After stirring for 1 h, the reaction medium is diluted with dichloromethane (500 ml) and then washed with aqueous 3% hydrochloric acid solution and water. After drying, filtration and concentration, the residue is purified on silica to give compound 91 (10.5 g, 59% over two steps).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:52])[CH2:5][CH2:6][NH:7][C:8]([C@:10]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:45])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:9].[C:53]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])(=[O:60])[CH2:54][CH2:55][C:56](OC)=[O:57].C(Cl)CCl>ClCCl>[C:56]([O:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH:7][C:8]([C@:10]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:45])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[CH:43][CH:44]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:9])[CH3:52])(=[O:57])[CH2:55][CH2:54][C:53]([O:61][C:62]([CH3:64])([CH3:63])[CH3:65])=[O:60]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)CCC(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)CCOC(=O)CCC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A mixture of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2-hydroxyethyl)(methyl)amino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.056 mmol), tert-butyl methyl succinate (21.06 mg, 0.112 mmol), Hunig'sBase (0.049 mL, 0.280 mmol) and EDC (21.45 mg, 0.112 mmol) in dichloromethane (1 mL) was stirred at 20° C. for 12 hours. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×4 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude including the title compound as a white solid (40 mg, 82%). LCMS: m/e 871.43 (M+H)+, 3.93 min (method 1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[C:24]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]([C:4]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:2]([NH:35][CH2:34][CH2:33][CH2:32][NH:31][C:24](=[O:25])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:3]=1)=[O:6]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Yield: 96 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (1.6 g, 1 eq), N-Boc-1,3-diaminopropane (0.9 g, 1.2 eq) and potassium carbonate (1.35 g, 2 eq) in acetonitrile (80 ml) is heated under reflux for 5 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (100 ml) and water (40 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 6:4) produces the expected compound in the form of a yellow oil (2.2 g; 96% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH:24]1[CH2:27][C:26](F)(F)[C:25]1([F:31])[F:30]>CN(C)C=O.O.C(OCC)C>[F:30][C:25]1([F:31])[C:26]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])=[CH:27][C:24]1=[CH2:23]
Reactant: FC1(F)CC(CCl)C1(F)F
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C=C1C=C(Oc2cc(C(=O)OC)ccc2OC)C1(F)F
Reaction time: 6 h

Procedure:
A stirred solution of methyl 3-hydroxy-4-methoxybenzoate (1.72 g), potassium iodide (0.1 g), and potassium carbonate (1.55 g) in dimethylformamide (50 mL) is treated with 1-chloromethyl-2,2,3,3-tetrafluorocyclobutane (2.0 g), and the solution is stirred at 70°-80° C. for 6 hours. After cooling, the reaction mixture is diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts are combined, dried over magnesium sulfate and concentrated, to give a golden oil. The oil is subjected to flash chromatography, using diethyl ether as eluent, to give methyl 3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoate, m.p. 60°-62° C. [Elemental analysis: C,59.5; H,4.3%; calculated: C,52.2; H,4.4%].
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:22])=O>>[Cl:22][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)c1ccc(C2CCCCC2)cc1
Product: CCOC(=O)C(Cl)c1ccc(C2CCCCC2)cc1
Yield: 89 %

Procedure:
To ethyl 2-hydroxy-2-(4-cyclohexylphenyl)acetate (52 g) was added thionyl chloride (100 ml) and the mixture was refluxed for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residual oil was diluted with water and extracted with ether. The ether layer was washed with water, dried (MgSO4) and subjected to vacuum distillation to give ethyl 2-chloro-2-(4-cyclohexylphenyl)acetate (50 g, yield 89%).
Reaction SMILES: [CH:1]1[CH:2]=CC([C@H]2[O:9][C@@H:8]2C2C=CC=CC=2)=C[CH:6]=1.N[CH2:17][CH:18]([C:20]1C=CC=CC=1)[OH:19]>>[CH3:8][OH:9].[CH:1]([O:19][CH:18]([CH3:17])[CH3:20])([CH3:2])[CH3:6]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: NCC(O)c1ccccc1
Product: CC(C)OC(C)C
Product: CO
Reaction time: 16 h

Procedure:
A mixture of trans-stilbene oxide (2.44 g, 0.0125 mol) and 2-amino-1-phenylethanol (5.12 g, 0.0374 mol) was heated on a steam bath for 3 hours and allowed to stand at ambient temperature for 16 hours. Trituration with methanol-isopropyl ether gave a white solid (1.12 g, 77% yield). The solid was recrystallized from methanol-water to obtain 0.8 g of the product, mp 162°-163° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C1(=O)O[CH2:10][CH2:9][O:8]1.C(N(CC)CC)C>>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:10][CH2:9][OH:8]
Reactant: OCC(F)(F)F
Reactant: O=C1OCCO1
Solvent: CCN(CC)CC
Product: OCCOCC(F)(F)F

Procedure:
A mixture of 36 ml (0.50 mol) of 2,2,2-trifluoroethanol, 66 g (0.75 mol) of ethylene carbonate and 70 ml (0.50 mol) of triethylamine was heated to reflux for 16 h. Distillation of the reaction mixture through a Vigreux column at normal pressure yielded the title compound as a colorless liquid.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:16]=[CH:15][C:8]2[C:9]([CH3:14])=[CH:10][C:11](=[O:13])[O:12][C:7]=2[CH:6]=1.C[O-].[Na+].C(OCC)(=O)C.C1(C)C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CO>[SH:4][C:5]1[CH:16]=[CH:15][C:8]2[C:9]([CH3:14])=[CH:10][C:11](=[O:13])[O:12][C:7]=2[CH:6]=1
Reactant: Cc1cc(=O)oc2cc(SC(=O)N(C)C)ccc12
Agent: C[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(=O)oc2cc(S)ccc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
26.3 g (0.1 mol) of S-(4-methyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate are suspended in 300 ml of methanol under a nitrogen atmosphere. 0.2 mol of sodium methylate (8% solution of Na (w/v) in methanol) is added at room temperature and the mixture is heated at 45° C. for 4 hours. The disappearance of the starting material is monitored by thin layer chromatography using an ethyl acetate/toluene mixture (1/4 v/v) as the eluent. After cooling, the reaction medium is hydrolyzed on an ice/concentrated hydrochloric acid mixture and, after stirring for 30 minutes, the precipitate obtained is filtered off and then washed with water. After drying over P2O5, 19.2 g (yield≈100%) of the expected product are obtained.