Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1>C(O)C>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:12][CH2:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[CH:18][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: SCCc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc(CSCCc2ccc3c(c2)OCO3)ccn1
Temperature: 70 °C
Yield: 59.8 %

Procedure:
3.30 g of 2-(1,3-benzodioxol-5-yl)ethanethiol was dissolved in 30 ml of ethanol. 1.65 g of sodium hydroxide and then 2.70 g of 4-picolyl chloride hydrochloride were added to the solution and the mixture was heated under reflux at 70° C. for 30 min. The solvent was distilled off and water was added to the residue. After extraction with ethyl acetate, 1N hydrochloric acid was added to the extract. The aqueous layer was acidified, taken up and washed with ethylacetate. The pH of the aqueous layer was adjusted to 8 with potassium carbonate. After extraction with ethyl acetate, the extract was washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified according to silica gel column chromatography (ethyl acetate/hexane=1:4) to obtain 2.69 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [C:1]1([C:7](=[N+]=[N-])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>CC(C(C)C)C.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@H](C(O)=O)CCC2)(=O)=O)=CC=1.[Rh].[Rh]>[CH3:11][O:10][C:8]([C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@@H:22]1[NH:21][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccccc1
Agent: [Rh]
Agent: CC(C)C(C)C
Agent: CCCCCCCCCCCCc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](c1ccccc1)[C@H]1CCCCN1
Yield: 49 %

Procedure:
As shown above in Scheme V and Table III, Rh2(S-DOSP)4 7 catalyzed decomposition of methyl phenyldiazoacetate 9a in the presence of N-BOC-piperidine (15, 4 equiv) in 2,3-dimethylbutane at room temperature followed by treatment with trifluoroacetic acid resulted in the formation of a mixture of threo and erythro methyphenidate, 16 and 17, in 49% yield. However, the threo isomer 16 was the minor diastereomer and was formed in only 34% ee. The combined yield of 16 and 17 was improved to 86% by using the N-BOC-peperidine as the limiting reactant. This result is different to what was observed with N-BOC-pyrrolidine, which gave bis C—H insertion when an excess of phenyldiazoacetate was used. A major improvement in enantioselectivity and diastereoselectivity was achieved by carrying out the reaction with the Rh2[bridged(S-TBSP)2]2 8 catalyst. The ratio of 16:17 (73% yield) was improved to 2.5:1 and (2R, 2′R)-threo isomer 16 was formed in 86% ee and 52% isolated yield. As shown in Table III, Rh2[bridged(S-TBSP)2]2 8 results in opposite asymmetric induction to Rh2(S-DOSP)4 7, and, in the reaction of 9a and 15 catalyzed by 8, the biologically active enantiomer of threo-methylphenidate is formed.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[C:15]([F:23])[CH:16]=[CH:17][CH:18]=3)[C:13]([F:25])([F:24])[C:12]([F:27])([F:26])[C:11]=2[C:10]=1[F:28])[CH3:7].B(OC)(OC)[O:30]C.C(O)(=O)C.O.OO>C1COCC1>[CH2:6]([O:8][C:9]1[C:10]([F:28])=[C:11]2[C:20]([C:19]3[CH:18]=[CH:17][C:16]([OH:30])=[C:15]([F:23])[C:14]=3[C:13]([F:24])([F:25])[C:12]2([F:27])[F:26])=[CH:21][CH:22]=1)[CH3:7]
Reactant: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c(F)cccc1-2
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c-2ccc(O)c1F
Temperature: -60 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Under a nitrogen atmosphere, n-butyllithium (1.63 M, 8.71 mL, 14.20 mmol) was slowly added dropwise, at −60° C. or lower, to a THF (40 mL) solution of compound (87) (4.29 g, 12.91 mmol) prepared in Example 11. The reaction mixture was agitated at −60° C. or lower for 1 hour, and then trimethyl borate (1.61 g, 15.49 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then acetic acid (1.16 g, 19.37 mmol) and hydrogen peroxide water (2.93 g, 25.80 mmol) were added thereto, and the resultant mixture was agitated for 3 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and extracted with 50 mL of toluene three times. Combined organic layers were washed with a sodium thiosulfate aqueous solution, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 7-ethoxy-1,8,9,9,10,10-hexafluoro-9,10-dihydrophenanthrene-2-ol (91) (3.76 g, yield 84.0%) was obtained.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]Br)=[CH:13][CH:12]=1.[NH4+].[Cl-]>C(OCC)C.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:8])=[CH:13][CH:12]=1
Reactant: O=Cc1cccnc1
Reactant: Fc1ccc(CCBr)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: OC(CCc1ccc(F)cc1)c1cccnc1

Procedure:
A solution of 10.7 g (0.10 mole) of nicotinaldehyde in 100 ml of diethyl ether is added dropwise, while stirring, to a solution prepared from 2.92 g (0.12 mole) of magnesium and 24.4 g (0.12 mole) of 2-(4-fluorophenyl)-ethyl bromide in 250 ml of diethyl ether, and the mixture is then refluxed for 2 hours. Cooling is followed by hydrolysis with water, and the pH is brought to 8 with saturated aqueous NH4Cl solution. The phases are separated, the aqueous phase is extracted twice more with ether, and the combined organic phases are washed with water and dried over NgSO4. The solvent is evaporated off and the residue is distilled under reduced pressure to give 10.2 g (44% of theory) of compound No. 4 of boiling point 190° C. (2 mbar).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[NH3:14].[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:11][CH3:12])=[C:6]([CH:8]([NH2:14])[CH3:9])[CH:7]=1
Reactant: COc1c(C)cc(F)cc1C(C)=O
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1c(C)cc(F)cc1C(C)N
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of 1-(5-fluoro-2-methoxy-3-methylphenyl)ethanone (1.2 g, 6.59 mmol), titanium(IV) isopropoxide (3.89 mL, 13.17 mmol) and ammonia in ethanol (16.5 mL) was stirred under nitrogen in a capped flask at ambient temperature for 6 h. Sodium borohydride (0.37 g, 9.88 mmol) was added and resulting mixture was stirred at room temperature for 3 h. The reaction was then quenched by pouring into ammonium hydroxide (30 mL), the resulting inorganic precipitate was filtered off, and washed with ethyl acetate (2×25 mL). the organic layer was separated and aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to afford 1-(5-Fluoro-2-methoxy-3-methylphenyl)ethanamine (1.0 g, 82%): 1H NMR (400 MHz, CDCl3): δ 6.98 (dd, 1H), 6.78 (dd, 1H), 4.15 (m, 1H), 3.82 (s, 3H), 2.31 (s, 3H), 1.45 (d, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:4]1=[O:19])[CH3:2].CS([C:24]1[N:25](COCC[Si](C)(C)C)[C:26]2[C:27]([N:32]=1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O.[H-].[Na+]>CN(C=O)C.CO>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:24]3[NH:32][C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[N:25]=3)=[CH:16][CH:17]=2)[C:4]1=[O:19])[CH3:2]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Temperature: 200 °C
Yield: 14.7 %

Procedure:
The mixture of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (281 mg), 2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-b]pyridine (240 mg) and NaH (35.2 mg) in DMF (dry) (3 ml) was heated at 200° C. for 3 h under microwave irradiation. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was diluted with 6N HCl. The mixture was neutralized with aq. NaHCO2 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as white crystals.
Reaction SMILES: [H-].[Na+].I.[N:4]1[C:8]2[C:9]3[C:14]([CH2:15][CH2:16][C:7]=2[S:6][C:5]=1[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>O1CCCC1>[N:4]1[C:8]2[C:9]3[C:14]([CH2:15][CH2:16][C:7]=2[S:6][C:5]=1[NH:17][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: Nc1nc2c(s1)CCc1ccccc1-2
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(Nc1nc2c(s1)CCc1ccccc1-2)c1ccncc1
Reaction time: 0.25 h

Procedure:
Added sodium hydride (26 mg; 1.1 mmol) to a stirred suspension of 4,5-Dihydro-naphtho[1,2-d]thiazol-2-ylamine hydroiodide 15 in dry tetrahydrofuran under nitrogen at room temperature. After 15 minutes, isonicotinoyl chloride hydrochloride (107 mg; 0.60 mmol) was added and the mixture allowed to stir for 2 hr. at room temperature and then concentrated in vacuo. The residue was diluted with water the solid material was filtered off. Purification using reverse phase HPLC (eluent: acetonitrile/water/0.1% trifluoroacetic acid) provided 20 mg of N-(4,5-Dihydro-naphtho[1,2-d]thiazol-2-yl)-isonicotinamide 16 as the trifluoroacetate salt. ES-HRMS m/e calcd for C17H13N3OS (M+H) 308.0852, found 308.0851.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[NH:17](C(OC(C)(C)C)=O)[C@H:18]([C:23](O)=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[NH2:17][C@@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:23]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([Br:1])=[C:6]3[N:7]=2)[CH2:12][CH2:13]1)=[O:24]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 213.8 %

Procedure:
3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (200 mg, 0.71 mmol), Boc-L-Leu (196 mg, 0.85 mmol), HATU (245 mg, 1.06 mmol), and triethylamine (394 uL, 2.83 mmol) taken up in DMF and stirred at room temperature overnight. Reaction was diluted with DCM and washed with water. The organic layer was dried over magnesium sulfate, filtered and reduced in vacuo. The residue was taken up in 20 mL of a 40% TFA in DCM solution and stirred at 35° C. overnight. The mixture was concentrated in vacuo and passed through a silica plug with 10% MeOH in DCM. Solvent was removed and the residue was dried to give 600 mg crude product as TFA salt for further reactions.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14]C)=[C:9]([O:12]C)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Oc1cc2nccc(Cl)c2cc1O
Temperature: 200 °C
Reaction time: 1 h

Procedure:
In a tube with a stirring bar was introduced 4-chloro-6,7-dimethoxyquinoline (1.5 g, 6.71 mmol) and 15 g of pyridinium hydrochloride. The tube was sealed and the mixture stirred at 200° C. for 1 h. The reaction was cooled to RT and a saturated solution of NaHCO3 was added followed by EtOAc. The EtOAc layer was washed with a saturated solution of NaHCO3, and the aqueous solution was back extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The crude mixture was used in the next step.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:39][C:40]1[O:41][C:42]2[C:48]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:1]([N:8]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:39][C:40]2[O:41][C:42]3[C:48]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:46]=[CH:45][C:43]=3[N:44]=2)[CH2:20][CH2:19]1)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: FC(F)(F)c1cccc2nc(S)oc12
Reactant: CCCCCCCN(CCN1CCN(CCO)CC1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCN(CCN1CCN(CCSc2nc3cccc(C(F)(F)F)c3o2)CC1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
To a solution of this alcohol (500 mg, 1.35 mmol) in THF (10 ml) were added triethylamine (180 mg, 1.78 mmol) and 4-(dimethylamino) pyridine (16 mg, 0.13 mmol), and then methanesulfonyl chloride (190 mg, 1.66 mmol) was dropped there into with ice-cooling and stirred for 20 minutes. Further, to the same solution were added triethylamine (45 mg, 0.44 mmol) and methanesulfonyl chloride (45 mg, 0.39 mmol) was dropped thereinto with ice-cooling and stirred for 1 hour. The reaction solution was filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in DMF (3 ml), and the resulting solution was dropped into a solution of 2-mercapto-7-trifluoromethylbenzoxazole (310 mg, 1.41 mmol) and potassium carbonate (280 mg, 2.03 mmol) in DMF (7 ml) and stirred at 80° C. for 90 minutes. The reaction solution was concentrated in vacuo and the resulting residue was filtered off with ether. The filtrate was concentrated in vacuo and the resulting residue was purified by a silica gel column chromatography (silica gel 35 g, developing solvent; hexane:acetone=10:1) to provide 283 mg (yield 37%) of tert-butyl N-heptyl-N-[2-[4-[2-(7-trifluoromethylbenzoxazol-2-ylthio)ethyl]piperazin-1-yl]ethyl]carbamate as pale yellow oil.
Reaction SMILES: C1(S([O-])(=O)=O)C=CC=CC=1.[CH3:11][CH:12]1[CH2:15][NH2+:14][CH2:13]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)Cl.CO.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:11][CH:12]1[CH2:15][N:14]([C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[N:20][CH:21]=2)[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC1C[NH2+]C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC1CN(c2ccc([N+](=O)[O-])nc2)C1
Temperature: 25 °C
Yield: 69 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 3-methylazetidinium benzenesulfonate (4.02 g, 17.5 mmol), 2-nitro-5-bromo pyridine (3.56 g, 17.5 mmol), cesium carbonate (28.5 g, 87.7 mmol) and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (862 mg, 1.50 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (800 mg, 0.900 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at reflux for 3 h. After this time, the mixture was cooled to room temperature and diluted with 90:10 methylene chloride/methanol (100 mL) and water (75 mL), and the layers were separated. The aqueous layer was extracted with 90:10 methylene chloride/methanol (2×50 mL), and the combined organic extracts were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 0% to 80% ethyl acetate/hexanes) to afford 236a in 69% yield (2.35 g) as an amorphous yellow solid: mp 141-143° C.; 1H NMR (500 MHz, CDCl3) d 8.12 (d, 1H, J=9.0 Hz), 7.60 (d, 1H, J=2.5 Hz), 6.66 (dd, 1H, J=9.0, 2.5 Hz), 4.23 (t, 2H, J=8.5 Hz), 3.68 (m, 2H), 2.99 (m, 1H), 1.36 (d, 3H, J=7.0 Hz; MS (ESI+) m/z 194.0 (M+H)
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].C([OH:18])C#CC.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1>[Cl:13][C:8]1[CH:7]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:11]=[CH:10][C:9]=1[OH:18]
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: CC#CCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1ccc(O)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The product from example 4 step (i) (1.0 g) in dry NMP (20 ml) was treated with 2-butyn-1-ol (0.63 ml) and sodium tert-butoxide (0.864 g) and the mixture stirred at 80° C. for 2 h. The mixture was partitioned between water/ethyl acetate, the organics separated, dried and evaporated under reduced pressure, yield 1.06 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 3-chlorobenzyl bromide (0.15 g, 0.7 mmol)(Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.18 g, 75.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:8])([O-:3])=[O:2]
Reactant: CCCCCCCCCCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: CCCCCCCCCCNC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Using this procedure 3-nitrobenzoyl chloride was treated with decylamine to give 3-nitro-N-decylbenzamide, mp 86°-88°, which was hydrogenated to give 3-amino-N-decylbenzamide, mp 56°-58°, which gave nmr and mass spectra consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[NH2:37][C:38]([CH2:43][OH:44])([CH2:41][OH:42])[CH2:39][OH:40].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:40][CH2:39][C:38]([NH:37][C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:34])([F:35])[F:36])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25])([CH2:43][OH:44])[CH2:41][OH:42]
Reactant: NC(CO)(CO)CO
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NC(CO)(CO)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (0.50 g, 1.02 mmol) and 2-amino-2-hydroxymethyl-1,3-propanediol (0.15 g, 1.24 mmol) in N,N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.15 g, 1.11 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.22 g, 1.15 mmol) followed by N,N-diisopropylethyl amine (0.27 mL, 1.55 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography using a solvent system of 5% methanol in chloroform provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.19 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH2:30]([NH:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH2:1]([O:3][C:4](=[O:29])[C:5]([N:7]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:42]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:43])=[O:25])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=1)=[O:6])[CH3:2]
Reactant: CCCCCCCCCCCCNC
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCCN(C)C(=O)c1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Yield: 56 %

Procedure:
The same procedure as employed in the preparation of Example 5, step d, but using 4-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)benzoic acid and dodecyl-methyl-amine gave the title compound as a colorless oil (56%). HPLC (Condition A), Rt: 7.41 min (HPLC purity: 82%).