Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])([CH3:21])C)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)CCC[CH2:27]1>CCO.CCO.CCO.CCO.[Ti].[F-].[K+]>[I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:22][CH2:27][CH2:26][CH2:21]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2
Reactant: OC1CCCC1
Agent: [Ti]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: O=C(OC1CCCC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2

Procedure:
3.5 g (7.7 mmol) of tert.butyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 10 g (116 mmol) of cyclopentanol and 0.8 g (3 mmol) of tetraethyl orthotitanate are stirred at 125° overnight, the solution obtained is evaporated and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered over siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By a rapid filtration through about 200 g of silica gel while eluting with ethyl acetate and subsequent crystallization from ethyl acetate there is obtained cyclopentyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 184°-185°.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:4][S:5]([CH3:8])(=[O:7])=[O:6].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:24]([OH:40])[CH:25]([NH:28][C:29](=[O:39])[CH:30]([NH2:38])[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:24]([OH:40])[CH:25]([NH:28][C:29](=[O:39])[CH:30]([NH:38][C:3](=[N:4][S:5]([CH3:8])(=[O:6])=[O:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:26][CH3:27]
Reactant: CCC(NC(=O)C(N)CC1CCCCC1)C(O)c1nc2ccccc2o1
Reactant: COC(=NS(C)(=O)=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCC(NC(=O)C(CC1CCCCC1)NC(=NS(C)(=O)=O)c1ccccc1)C(O)c1nc2ccccc2o1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a mixture of N-(methoxy-phenyl-methylene)methansulfonamide (250 mg, 0.616 mmol) and 2-amino-3-cyclohexylpropionic acid [1-(benzoxazol-2-ylhydroxymethyl)-propyl]amide (255 mg, 0.616 mmol) in dry acetonitile (4 mL) at room temperature was added DBU (0.37 mL, 2.46 mmol), and the mixture was stirred at the same temperature overnight. After a removal of the solvent, the reaction mixture was partitioned between ethyl acetate and 1N-HCl solution, washed brine and then water. The organic extracts were dried, concentrated in vacuo, and purified by flash chromatography on silica gel (eluted with EtOAc/hexanes=3/1) to yield 250 mg of N-[1-(benzoxazol-2-yl-hydroxymethyl)propyl]-3-cyclohexyl-2-[(methanesulfonyliminophenylmethyl)amino]-propionamide.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@H:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([N:27]([CH3:32])[NH:28][C:29](=[O:31])[CH3:30])=[O:26])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:29]([NH:28][N:27]([C:25](=[O:26])[C@H:24]([N:22]([CH3:23])[C:21](=[O:40])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)NN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)NC(C)=O
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
To a solution of N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (0.14 g, 0.25 mmol) in methylene chloride (2 ml) at 0° C. was added trifluoroacetic acid (2 ml) and the mixture was stirred for 90 min. Then methylene chloride (50 ml) and saturated sodium bicarbonate (5 ml) was added and the mixture was titrated with solid sodium bicarbonate until pH=7. The water layer was separated and extracted with methylene chloride (20 ml) and the combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.10 g (87%) of (2R)-N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide as an oil.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:12][C:13](=O)[CH2:14][CH:15]([C:20](=[O:23])[NH:21][CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18].[CH2:25]([O:32][C:33](=[O:40])[CH2:34][NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:32][C:33](=[O:40])[CH2:34][N:35]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:13](=[O:12])[CH2:14][CH:15]([C:20](=[O:23])[NH:21][CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)CNCC(=O)OCc1ccccc1
Reactant: CNC(=O)C(CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)CC(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C(CC(=O)N(CC(=O)OCc1ccccc1)CC(C)C)CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To an ice-cooled solution of 5-methyl-3-methylcarbamoyl-hexanoic acid 2,3,4,5,6-pentafluorophenyl ester (350 mg, 0.99 mmol) in DMF (5 ml) was added isobutylamino-acetic acid benzyl ester (110 mg, 0.49 mmol) with stirring. The reaction mixture was allowed to warm to room temperature and stirred for 2 days then for 3 h at 50° C. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed successively with 1M HCl, 1M Na2CO3 and brine. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel, 50→100% ethyl acetate in hexane) to give the title compound as a colourless oil (130 mg, 70%). 1H-NMR; δ(CDCl3, rotamers), 7.33 (5H, m), 6.17 (1H, m), 5.15 (1H, m), 4.21 (1H, m), 3.91 (1H, m), 3.41-2.95 (2H, br m), 2.81 (2H, m), 2.75 (3H, m), 2.32 (1H, m), 1.91-1.40 (3H, br m), 1.28-1.05 (1H, m) and 0.85 (12H, m).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH:19]=O)=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:19][C:18]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[N:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:17]=1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 98681 %

Procedure:
A solution of carbon tetrabromide (2.866 gm, 8.64 mmol) in CH2 Cl2 (8 ml) was added over a 10 minute period to a cold (-10° C.) solution of 2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.840 gm, 5.76 mmol) (the preparation of which is described in Example 3) and triphenylphosphine (4.590 gm, 17.5 mmol) in CH2Cl2 (30 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 2× with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and concentrated. The concentrate was chromatographed (flash, Merck, SiO2, 1:1 CH2Cl2 : hexane) to give 3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine as a white solid (2,701 gm, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[CH2:32]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[CH3:33]>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:35]2[C@H:34]([CH2:32][CH3:33])[CH2:38][O:37][C:36]2=[O:39])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CC[C@@H]1COC(=O)N1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CC)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 84.8 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 180 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (459 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[N:3]=[C-:2]1.[H-].[Na+].[CH3:9][O:10][C:11](=[O:29])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[CH2:27]Br)[CH:14]=1.Cl.[O:31]1CCOCC1>CCOC(C)=O>[CH3:9][O:10][C:11](=[O:29])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[CH2:27][N:3]2[CH2:4][CH2:5][O:1][C:2]2=[O:31])[CH:14]=1
Reactant: C1COCCO1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: O=C1CO[C-]=N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reaction time: 0.25 h

Procedure:
To 2-oxazolidone (0.69 g, 8.0 mmol) in 1,4-dioxane (30 mL) under N2 was added sodium hydride (60% in mineral oil; 0.38 g, 9.4 mmol). After stirring for 15 minutes, [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester (3 g, 7.2 mmol) was added, and the reaction was stirred for 24 hours at room temperature. Once no starting material was seen by analytical LCMS, the mixture was worked-up with 10% aqueous HCl and EtOAc, and the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (2 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[CH:28]5)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc5[nH]ccc5c4)ncnc32)CC1
Yield: 37.1 %

Procedure:
4-[4-(1H-Indol-5-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (29 mg, 38%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 5-hydroxyindole (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 24 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol). Mass spectrum MH+=435.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.[NH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([NH:12][C@H:4]2[CH:5]3[CH2:10][N:1]4[CH2:8][CH:7]([CH2:9][CH:3]2[CH2:2]4)[CH2:6]3)=[CH:18][CH:17]=1
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: Nc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc(NC2C3CC4CC2CN(C4)C3)cn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 1-azatricyclo[3.3.1.13,7]decan-4-one (1.51 g, 10 mmol; see Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080) in HOAc (50 mL) was treated with 3-amino-6-chloropyridine (1.90 g, 15 mmol; Aldrich), anhydrous Na2SO4 (18.5 g, 0.13 mol; Aldrich), and NaBH(OAc)3 (4.22 g, 20 mmol; Aldrich) and was stirred at ambient temperature for 10 hours. After the reaction was complete, the solid was filtered off, and the filtrate was concentrated. The residue was carefully basified with saturated aqueous Na2CO3 (pH 10), extracted with CHCl3 (3×100 mL), and the combined extracts were purified by flash chromatography [silica gel, ammonium hydroxide-methanol-chloroform (2:10:90)] to afford the title compounds:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[CH3:22][O:23][CH:24]([O:28][CH3:29])[C:25](=[O:27])[CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:25]([OH:27])([CH3:26])[CH:24]([O:28][CH3:29])[O:23][CH3:22])=[CH:9][N:10]=1
Reactant: COC(OC)C(C)=O
Reactant: c1csc(C2OCCO2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)C(C)(O)c1cnc(C2OCCO2)s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (1.00 g) in tetrahydrofuran (20 mL) was slowly added a 1.6M n-butyllithium hexane solution (4.5 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min, and 1,1-dimethoxypropan-2-one (1.50 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.58 g, yield 90%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 276 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][Cl:26])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][Cl:26])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C#CCCCCl)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)cc(C#CCCCCl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
The ester (Step 1) (0.500 g, 1.23 mmol) was dissolved in THF-ethanol-water (7:2:1; 10 mL). It was treated with sodium hydroxide (0.49 mL, 1.23 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 mL). Diethyl ether (10 mL) was added and the mixture acidified with concentrated HCl. The organic layer was separated, and the aqueous phase was extracted with diethyl ether (2×10 mL). The combined extracts were dried over MgSO4, filtered, and evaporated to yield a yellow solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a yellow solid (0.371 g, 80%): mp 154.4–156.4° C. 1H NMR (acetone-d6/300 MHz) 7.88 (s, 1H), 7.53 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=2.4 Hz), 5.94 (q, 1H, J=7.1 Hz), 3.83 (t, 2H, J=6.5 Hz), 2.68 (t, 2H, J=6.8 Hz), 2.12–2.04 (m, 2H). ESLRMS m/z 377 (M−H). ESHRMS m/z 376.9930 (M−H, Calc'd. 376.9959). Anal. Calc'd. for C16H11Cl2F3O3+1.18% H2O: C, 5.0.08; H, 3.02; Cl, 18.48. Found: C, 50.11; H, 2.73; Cl, 18.28.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C[O-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1C(=O)[C@H](NC(=O)OC(C)(C)C)Cc2ccccc21
Yield: 72.4 %

Procedure:
(R)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril (26 mg), as prepared in Example 5, was dissolved in tetrahydrofuran (5 mL) at room temperature under argon. To the stirring solution was added methyl bromoacetate (31 mg), followed by sodium methoxide (26 mg). The resulting suspension was stirred for 30 min before dilution with ethyl acetate (25 mL) and water (25 mL). The organic phase was separated, washed with water (25 mL), and dried over anhydrous sodium sulfate. After solvent evaporation under vacuum, the crude product was purified by reverse phase preparative HPLC to provide (R)-3-t-butyloxycarbonylamino-1-carbomethoxymethyl-3,4-dihydrocarbostyril (24 mg).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([N:11]1[C:20](=[O:21])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:22])[CH2:8][CH:9]=[CH2:10].BrC1C=CC(S(O[C@@H:34]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:36]([C:46]([O:48][CH3:49])=[O:47])[CH2:35]2)(=O)=O)=CC=1.CCOC(C)=O>CN1C(=O)CCC1.O>[CH2:7]([N:11]1[C:20]([O:21][C@H:34]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:36]([C:46]([O:48][CH3:49])=[O:47])[CH2:35]2)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:22])[CH2:8][CH:9]=[CH2:10]
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: C=CCCN1C(=O)Cc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CCCn1c(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)cc2ccccc2c1=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Cs2CO3 (1.1 g, 3.39 mmol) was added to a solution of 2-but-3-en-1-ylisoquinoline-1,3(2H,4H)-dione (0.49 g, 2.26 mmol) and 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.05 g, 2.26 mmol) in NMP (10 mL), and the reaction mixture was stirred for 16 hours at 40° C. An additional portion of 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.0 g, 2.16 mmol) was added, and the reaction mixture was stirred at 40° C. for 16 hours. The reaction mixture was cooled and poured onto a mixture of EtOAc and H2O, and the layers were separated. The organic layer was washed with H2O (2×), 1N HCl (1×) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient elution, 10-40% EtOAc/Hexane) to afford the title compound (0.83 g, 83%) as an oil. LCMS (ES+) m/z 443.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2Br)=[N:15][NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(O)C.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:23][CH:24]=[CH:25][C:26]=3[N:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NNCC(F)(F)F)c2sccc2Br)CC1
Agent: [Cu]I
Agent: COC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nn(CC(F)(F)F)c3ccsc23)CC1
Temperature: 75 °C
Yield: 104.7 %

Procedure:
4-{(3-Bromo-thiophen-2-yl)-[(2,2,2-trifluoro-ethyl)-hydrazono]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (2.34 g, 4.98 mmol) was mixed with CuI (50 mg). CsCO3 (1.9 g, 1.2 eq) in methoxyethanol (25 mL). The mixture was heated to 75° C. for 1 hour. The mixture was then diluted with EtOAc and filtered. The filtrate was evaporated and the residue was purified via chromatography (eluted with 0-10% MeOH in DCM) yielding 2.03 g (>95%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[NH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([N:25]4[CH2:26][CH2:27][CH:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH2:29][CH2:30]4)=[C:18]([CH3:17])[CH:19]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(Cl)cc3)c2C)ccc1N1CCC(N2CCOCC2)CC1
Yield: 52.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.0 g) and 3-methyl-4-(4-morpholinopiperidin-1-yl)aniline (1.07 g), the title compound (1.0 g) was obtained, melting point: 235–245° C.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[Br:11]Br>C(OCC)(=O)C>[Br:11][C:4]1[C:3]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=2[S:1][N:5]=1
Reactant: Cc1cccc(S)c1C#N
Reactant: BrBr
Solvent: CCOC(C)=O
Product: Cc1cccc2snc(Br)c12
Temperature: 0 °C
Reaction time: 3 h
Yield: 179.3 %

Procedure:
To a solution of 2-mercapto-6-methylbenzonitrile (1.00 g, 6.71 mmol) in ethyl acetate (10 mL), bromine (1.05 g, 6.60 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 3 h. The reaction mixture was then allowed to warm to room temperature, followed by heating at reflux for 3 h. The reaction mixture was concentrated under reduced pressure. Crystallization of the crude mixture with hexanes gave 3-bromo-4-methylbenzo[d]isothiazole (2.7 g), which was carried forward without further purification. MW=228 confirmed by LC-MS, tr=6.82 min (Method E) MH+=229.
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5].B([O-])[O-].N1C=CC=CC=1.Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][Cl:48])=[O:42]>C1COCC1.CN(C1C=CN=CC=1)C>[C:41](=[O:42])([O:28][C@@H:19]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)/[CH:18]=[CH:17]/[C@H:16]1[C@H:15]([OH:29])[CH2:14][C@H:13]([OH:30])[C@@H:12]1[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:4]([NH:3][CH2:2][CH3:1])=[O:5])[O:43][CH2:44][CH2:45][CH2:46][CH2:47][Cl:48]
Reactant: O=C(Cl)OCCCCCl
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: [O-]B[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC(=O)OCCCCCl)[C@H](O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 48 h
Yield: 133.5 %

Procedure:
To a solution of bimatoprost boronate b-1 (529 mg, 1.10 mmol) in THF was added DMAP (6.9 mg, 0.055 mmol). The solution was cooled to 0° C. and successively slowly added pyridine (0.22 mL, 2.75 mmol) and 4-chlorobutyl chloroformate (0.375 mL, 2.75 mmol). Allowed to stir at ambient temperature over 2 days. Added more pyridine (89 uL, 1.11 mmol) and 4-chlorobutyl chloroformate (150 uL, 1.10 mmol) and stirred for another 24 h. The resultant mixture was concentrated under reduced pressure, residue partitioned with ethyl acetate and water. Washed organic layer with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 808 mg (134%) of a crude oil, which was used without further purification.