Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[S:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:48]([CH2:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:42]=2[CH:41]=1)C1C=CC=CC=1.C(S)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C@@H:10]1([C:40]2[S:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:48]([CH2:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:42]=3[CH:41]=2)[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8]
Reactant: c1ccc(CCc2cccc3sc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCS
Product: OC[C@H]1O[C@@H](c2cc3c(CCc4ccccc4)cccc3s2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 30.8 %

Procedure:
To a solution of 2-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-(2-phenylethyl)benzo[b]thiophene (0.58 g) and ethanethiol (1.13 mL) in dichloromethane (10 mL) was added boron trifluoride diethyl ether complex (1.43 mL) at room temperature, and the mixture was stirred for 3 hours. A saturated potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (94 mg).
Reaction SMILES: [CH:1]1([N:4]([CH3:22])[C:5]2[C:6]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:7]=3[N:8]=[C:9]([CH2:11][C:12](O)=[O:13])[N:10]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C[CH2:34][N:35]=[C:36]=NCCCN(C)C.Cl>C1COCC1.O>[CH:1]1([N:4]([CH3:22])[C:5]2[C:6]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([N:35]([CH3:36])[CH3:34])=[O:13])[N:10]=2)[CH2:2][CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetic acid (100 mg, 0.000315 mol) in anhydrous THF (10 ml) 2M dimethyl amine in THF (0.017 g, 0.000378 mol) and HOBt (0.051 g, 0.000378 mol) were added. This mixture was cooled to 0° C. and then treated with EDC HCl (0.120 g, 0.00063 mol). The reaction mixture was allowed to warm to room temperature and kept stirred for 16 h. After completion, the reaction was diluted with water (50 ml) and extracted with ethyl acetate (25 ml×3). Combined organic extracts were washed with water (50 ml), dried over anhydrous Na2SO4 and concentrated under vacuum to get crude compound. It was then purified by column chromatography by using 100-200 mesh silica gel. Pure compound was eluted in 1-2% MeOH: DCM to afford 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-N,N-dimethylacetamide as a pale yellow oil. Yield—50 mg, (46.29%); 1H-NMR: (400 MHz, CDCl3); δ=3.97 (s, 2H), 3.04 (s, 3H), 3.01 (s, 3H), 2.97 (s, 3H), 2.89-2.80 (m, 5H), 1.92-1.86 (m, 2H), 1.77-1.71 (m, 2H), 0.72-0.67 (m, 2H), 0.45-0.41 (m, 2H); LC-MS [M+H]=345.3; HPLC purity=98.78%.
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.O1CCOCC1.C(N(C(C)C)CC)(C)C.CC1(C)C(C)(C)[O:37][BH:36][O:35]1>ClCCl.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[O:7][C:6]3[C:2]([B:36]([OH:37])[OH:35])=[CH:3][S:4][C:5]=3[C:10](=[O:11])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(N2CCOCC2)oc2c(B(O)O)csc12
Temperature: 160 °C
Yield: 109.2 %

Procedure:
A 20 mL microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (1.20 g, 3.80 mmol), 1,3-bis(diphenylphosphino)propane (156 mg, 0.38 mmol), 1,3-bis(diphenylphosphino)propane nickel(II) chloride (205 mg, 0.38 mmol), dioxane (8 mL), diisopropylethylamine (1.98 mL, 11.39 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 mL, 7.59 mmol). The reaction mixture magnetically stirred and heated via microwave irradiation for 15 minutes at 160° C. Upon cooling to room temperature, the reaction was transferred to a separatory funnel, diluted with dichloromethane (100 mL), and washed three times with saturated aqueous ammonium chloride solution (100 mL). The dichloromethane layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown foam was stirred in aqueous hydrochloric acid (1.0M, 100 mL) for 30 minutes, frozen, and lyophilized to give 5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-ylboronic acid (69) (1.51 g, 4.15 mmol) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCC1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CCC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a mixture of 2-chloro-4-(3-hydroxy-5-oxo-2-propyl-2,5-dihydro-1H-pyrrol-1-yl)benzonitrile (800 mg) and acetic acid (1.82 mL) in acetonitrile (25 mL) was added sodium borohydride (273 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 578 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: O=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl

Procedure:
A solution of 31.8 g of 2,3-dichloro-4-hydroxy-2'-fluoro-benzophenone and 15.3 g of hydroxylamine hydrochloride in 150 ml of pyridine is refluxed for 64 hours. Thereafter, the pyridine is evaporated under vacuum and a 5% aqueous hydrochloric acid solution is added. The acidified solution is extracted with ethyl acetate and the combined extracts are dried before being concentrated to dryness. The resulting solid is recrystallized from an aqueous ethanol solution to yield the product 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime with a melting point of 168° to 175° C.
Reaction SMILES: C(O)(=O)C.[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[N+:20](/[CH:23]=[CH:15]/[C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:13]=1)([O-:22])=[O:21]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])/C=C/c1cccc(Oc2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To an acetic acid (20.0 mL) solution of 3-phenoxybenzaldehyde (3.00 g, 15.1 mmol) were added nitromethane (4.61 g, 75.5 mmol) and ammonium acetate (2.33 g, 30.2 mmol) under nitrogen atmosphere at room temperature, which was stirred for 3 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.60 g) as a crude product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:21]=[C:20](O)[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[C:20]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:21]=[C:12]([C:11]([O:10][CH3:9])=[O:23])[CH:13]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: OCCCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCCCCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 22 h
Yield: 54.6 %

Procedure:
13.02 g (95.3 mmol) of 6-chlorohexanol were added to a solution of 20.04 g (95.3 mmol) of 5-hydroxyisophthalic acid dimethyl ester and 47.4 g (180.5 mmol) of triphenylphosphine in 300 ml of tetrahydrofuran. The colourless solution was cooled to 0° C. and then 79 ml (180.5 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise over a period of 2 hours and 45 minutes. The mixture was allowed to react for another 30 minutes at 0° C. and then for 22 hours at room temperature. The reaction mixture was concentrated by evaporation under vacuum. The residue was filtered through silica gel using dichloromethane:diethylether (85:15) as eluent. The filtrate was concentrated in vacuum and further purified by column chromatography on silica gel with hexane:ethyl acetate (9:1) to give 17.12 g (55%) of 5-[(6-chlorohexyl)oxy]isophthalic acid dimethyl ester as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][CH:1]([C:4]2[CH:17]=[CH:16][C:7]3[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=3[CH:5]=2)[CH3:2])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cc2ccc(C(C)=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1cc2ccc(C(C)NCc3ccc(OC)cc3)cc2s1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Ethyl 6-acetyl-1-benzothiophene-2-carboxylate (0.3 g, 1.21 mmol) was dissolved in DCE (3.0 mL). 4-methoxybenzyl amine was then added to the reaction followed by acetic acid (0.1 mL, 1.69 mmol) and NaBH(OAc)3 (0.41 g, 1.93 mmol). The reaction was allowed to stir for 5 d at room temperature before it was quenched with saturated sodium bicarbonate solution. The reaction mixture was then extracted with ethyl acetate (3×) and the combined organic layers was dried over Na2SO4. After concentrating in vacuo, the crude reaction mixture was purified by flash column chromatography to provide the amine. 1H (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 3.93 (q, J=6.5 Hz, 1H), 3.79 (s, 3H), 3.57 (dd, J=21.0, 12.9 Hz, 2H), 1.42-1.26 (m, 6H). MS: cal'd (MH+) 370, exp (MH+): 370.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.Cl.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]3[C:36]([O:38][CH3:39])=[O:37])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.Cl>O1CCOCC1>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:32][CH:31]3[C:36]([O:38][CH3:39])=[O:37])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: COC(=O)C1CNCCC1NCc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CN(CCn2c(=O)ccc3ccc(OC)cc32)CCC1NCc1ccc2c(c1)OCCO2

Procedure:
As similarly to Example 1, to 0.10 g of methyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidine-3-carboxylate obtained from (7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde and methyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-3-carboxylate hydrochloride, 1.0 mL of 6 mol/L hydrochloric acid and 1.0 mL of dioxane were added. The reaction mixture was stirred under reflux with heating for 3 hours. The solvent was removed, acetonitrile was added, and resulting solid was filtered to afford 54 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidine-3-carboxylic acid hydrochloride as a brown solid.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:7][CH2:8][CH2:9][OH:10])[CH3:6])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O.[F:40][C:41]([F:62])([F:61])[C:42]([C:51]1[CH:56]=[CH:55][C:54](O)=[C:53]([CH2:58][CH2:59][CH3:60])[CH:52]=1)([O:47][CH2:48][O:49][CH3:50])[C:43]([F:46])([F:45])[F:44]>O1CCCC1>[C:1]([O:4][CH:5]([CH2:7][CH2:8][CH2:9][O:10][C:54]1[CH:55]=[CH:56][C:51]([C:42]([O:47][CH2:48][O:49][CH3:50])([C:43]([F:46])([F:45])[F:44])[C:41]([F:40])([F:61])[F:62])=[CH:52][C:53]=1[CH2:58][CH2:59][CH3:60])[CH3:6])(=[O:3])[CH3:2]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: CC(=O)OC(C)CCCO
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCC(C)OC(C)=O
Yield: 84.7 %

Procedure:
5-Hydroxypent-2-yl acetate (58.5 mg), triphenylphosphine (131 mg) and ethyl azodicarboxylate (2.2 mol/L, 200 μL) were added to a mixed solution of 4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenol (69.3 mg, 200 μmol) in tetrahydrofuran (2 mL) at room temperature. After completion of the reaction, the solvent was evaporated, and the residue was purified by silica gel preparative thin-layer chromatography (hexane:ethyl acetate=5:1) to obtain 80.4 mg of the title compound (yield: 85%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1C
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Into a suspension of 75 g (499 mmol) 2,5-dimethylbenzoic acid, 103 g (748 mmol) potassium carbonate in 500 mL of DMF was added dropwise 77.9 g (549 mmol) of iodomethane with stirring at ambient temperature. After addition, the suspension was stirred for additional 5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. All solids were removed by filtration and the filtrate was concentrated to 80 g of colorless oil as product in 97.6% yield. 1H NMR (CDCl3) (300 MHz) δ 2.7 (s, 3H), 2.8 (s, 3H), 3.95 (s, 3H), 7.45 (s 1H), 7.51 (d, 3JHCCH=7.9 Hz, 1H), 7.42 (d, 3JHCCH=7.9 Hz, 1H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](OS(C)(=O)=O)[CH:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:24]>CO>[NH2:24][CH:11]1[CH:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C(OS(C)(=O)=O)C1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C(OCC(F)(F)F)C1
Temperature: 140 °C
Reaction time: 10 h

Procedure:
A mixture of 3.95 g (0.011 mole) of 1-t-butoxycarbonyl-3-(2,2,2-trifluoroethoxy)-4-methylsulfonyloxypyrrolidine [prepared as described in step (a) above] and 100 ml of methanol containing 20% w/v ammonia was transferred to an autoclave and then stirred at 140° C. for 10 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 1:9 by volume mixture of ethanol and ethyl acetate as the eluent, to give 1.61 g of 3-amino-1-t-butoxycarbonyl-4-(2,2,2-trifluoroethoxy)pyrrolidine as a colorless oil. Mass Spectrum (CI): m/e 285 (M+ +1), 229 (M+ +1--CH2 =C(CH3)2).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@:11]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH2:15][O:14][C@@H](C(C)(C)C)[N:12]1C=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>O>[CH2:1]([O:8][C:9](=[O:10])[C@:11]([NH2:12])([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:15][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@@H]1OC[C@](Cc2cccc(C#N)c2)(C(=O)OCc2ccccc2)N1C=O
Agent: Cl
Solvent: O
Solvent: CO
Product: N#Cc1cccc(C[C@](N)(CO)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
A 1L round bottom flask equipped with a reflux condenser and a Teflon-coated magnetic stirring bar was charged with compound 2 (30 g, 73.8 mmol) and MeOH (1 L). 6N HCl (45 mL) was added and the slightly cloudy reaction mixture was heated to a gentle reflux with stirring for 48 hours. The reaction mixture was cooled to ambient temperature and concentrated to dryness to give a white colorless solid, which was dissolved in H2O (300 mL) and extracted with CH2Cl2 (50 mL). The aqueous phase was concentrated to give the title compound as a white colorless solid (22.7 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:43])[CH:33]([C:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1)[CH3:34]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:41][C:38]3[CH:37]=[CH:36][C:35]([CH:33]([CH3:34])[C:32]([OH:43])=[O:31])=[CH:40][CH:39]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(C)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CC(C(=O)O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-(4-formyl-phenyl)-propionic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 555.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>O1CCCC1>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([B:15]([OH:20])[OH:16])=[CH:3][C:4]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 4-bromo-1-(methylthio)-2-(trifluoromethoxy)benzene (6.63 g, 23.1 mmol) and triisopropyl borate (6.92 mL, 30.0 mmol) in tetrahydrofuran (50 mL) was added dropwise 1.6 M n-butyllithium-hexane solution (25.0 mL, 40.0 mmol) at −78° C., and the resulting mixture was stirred for 30 min. The reaction mixture was warmed to 0° C., 2 M hydrochloric acid (150 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (5/1) and recrystallized from hexane/tetrahydrofuran to give the title compound (4.13 g, yield 71%) as colorless crystals.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[N:11]1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].Cl>C(Cl)(Cl)Cl>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC(=O)c1ccccc1N
Reactant: c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cccc(N)c1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
2-Amino-benzamide (1 g, 7.3 mmol) was dissolved in chloroform (25 ml) in a 50 ml round bottomed flask and cooled to 0° C. Pyridine (0.6 ml, 7.3 mmol) was added followed by 2-fluoro-benzoyl chloride (1 ml, 8 mmol) and the mixture was magnetically stirred for 1 hr at this temperature. 10% Hydrochloric acid (50 ml) was added and the precipitated solid was filtered, washed with water and dried to yield pure title compound (1.56 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C:12](=[O:28])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]3[C:22]([CH3:27])=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2.[C:29]([O:32][CH2:33]Br)(=[O:31])[CH3:30].[B-](C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+]>C(#N)C>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C:12](=[O:28])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]3[C:22]([CH3:27])=[N+:23]([CH2:33][O:32][C:29](=[O:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2
Reactant: CC(=O)OCBr
Reactant: Cc1ncccc1Oc1ccc(NC(=O)N2CCc3cc(Cl)c(Cl)cc32)cn1
Agent: [Na+]
Agent: c1ccc([B-](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=O)OC[n+]1cccc(Oc2ccc(NC(=O)N3CCc4cc(Cl)c(Cl)cc43)cn2)c1C
Product: [Cl-]
Yield: 80 %

Procedure:
5,6-Dichloro-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline (0.25 g, 0.6 mmol) was treated with bromomethyl acetate and sodium tetraphenylboron at reflux in acetonitrile (15 ml) for 10 h according to the procedure described in Example 1 to give the title compound (E3) (0.26 g, 80%) m.p. 125-135° C. which contained approximately 15% starting material as an off-white solid.
Reaction SMILES: C(S(N1CCC(C2C3C(=C(C(N)=O)C=C([C:21]4[S:22][C:23]([CH2:26][NH:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH3:31])=[CH:24][CH:25]=4)C=3)NC=2)CC1)(=O)=O)C.C(C1SC([B:43]([OH:45])[OH:44])=CC=1)=O.C[C@@H](CC)CN.[BH3-]C#N.[Na+]>>[CH3:32][C@@H:29]([CH2:30][CH3:31])[CH2:28][NH:27][CH2:26][C:23]1[S:22][C:21]([B:43]([OH:45])[OH:44])=[CH:25][CH:24]=1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CC[C@H](C)CN
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@H](C)CNCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(2S)-2-methylbutyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude [5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 37.6 mg of the title compound (39%).