Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:17].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][C:3]=2[OH:17])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccccc3)cc2O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.8 %

Procedure:
To a solution of 2-amino-5-benzenesulfonyl-phenol (1.00 g., 4.016 mmol) in 20 mL dichlormethane was added 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.880 g, 4.418 mmol) followed by sodium triacetoxyborohydride (1.78 g, 8.43 mmol) and the resulting suspension was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was washed twice with 50 mL water, once with 50 mL brine, then dried over sodium sulfate and concentrated in vacuo. The resulting crude solid was purified by flash chromatography (20-30% ethyl acetate in hexanes) to give 1.823 g (4.53 mmol, 94%) of 4-(4-benzenesulfonyl-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a foam. MS: 333 (M−CO2tBu+H)+, 377 (M−tBu+H)+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]1([C:20]2[C:29]([CH3:30])=[CH:28][C:27]3[C:22](=[C:23]([C@H:31]([OH:34])[CH2:32][OH:33])[CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[C:14]1([C:20]2[C:29]([CH3:30])=[CH:28][C:27]3[C:22](=[C:23]([C@H:31]([OH:34])[CH2:32][O:33][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc2cccc([C@H](O)CO)c2nc1-c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2cccc([C@H](O)CO[Si](C)(C)C(C)(C)C)c2nc1-c1ccccc1
Reaction time: 16 h
Yield: 92 %

Procedure:
3.7 g (24.3 mmol) of tert-butyldimethylsilyl chloride and 3.4 g of (50 mmol) of imidazole are added at ambient temperature to a solution of 6.5 g (23.2 mmol) of 2-phenyl-3-methyl-8-(1-(S),2-dihydroxyethyl)-quinoline in 200 ml of dimethylformamide. The reaction medium is stirred for 16 hours. After addition of 200 ml of distilled water, the reaction mixture is extracted with 3×200 ml of ethyl acetate. The organic phases are combined, washed with 300 ml of distilled water, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography (eluent: ethyl acetate/cyclohexane to provide 8.4 g of 2-phenyl-3-methyl-8-(1-(S)-hydroxy-2-[tert-butyldimethylsilyloxy]ethyl)quinoline in the form of a colorless oil. (Yield: 85%)
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:19]3[N:27]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]=3)=[CH:14][N:15]2[CH3:18])=[CH:11][C:10]=1[O:38][CH3:39])C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:19]3[N:27]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]=3)=[CH:14][N:15]2[CH3:18])=[CH:11][C:10]=1[O:38][CH3:39]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A solution of 2-(6-benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [1.24 g, Reference Example 13(p)] in acetonitrile (100 mL) was treated with iodotrimethylsilane (820 μl). The reaction mixture was stirred at 50° C. for 2 hours and then concentrated in vacuo. The residue was treated with water (40 mL) and the mixture was extracted three times with dichloromethane (100 mL). The combined organic phases were washed with brine (40 mL), then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (1:1, v/v) to give the title compound (686 mg) as a white foam. TLC: RF=0.27 (cyclohexane/ethyl acetate: 1/1). MS: EI (70 eV); m/z=447 M+. (45%); 292 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]2.[S:24](Cl)([Cl:26])=[O:25]>CCCCCCC>[Cl:26][S:24]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:25]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2n1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCCC
Product: CCOC(=O)c1c(S(=O)Cl)c2cc(OC)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A suspension of 7.0 g (0.023 mole) of 5-methoxy-1-phenylmethyl-1H-indole-2-carboxylic acid, ethyl ester (Y. Murakami, et al, Synthesis, 738 (1984)) in 75 ml of n-heptane under an argon atmosphere was cooled in ice and treated with 15.0 ml (24.5 g; 0.21 mole) of thionyl chloride. The mixture was stirred for 30 minutes, and the precipitated sulfinyl chloride intermediate was filtered and washed several times with hexane to yield 7.3 g (76% yield) of 3-(chlorosulfinyl)-5-methoxy-1-phenylmethyl-1H-indole-2-carboxylic acid, ethyl ester.
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]([OH:13])([C:11]#[CH:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:14][CH2:15][C:16]3[C@@H:22]([C@H:5]1[CH2:4][CH2:3]2)[CH2:21][CH2:20][C:18](=O)[CH:17]=3.Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[CH3:1][C@@:2]12[C@:10]([OH:13])([C:11]#[CH:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:14][CH2:15][C:16]3[C@@H:22]([C@H:5]1[CH2:4][CH2:3]2)[CH2:21][CH2:20]/[C:18](=[N:24]\[OH:25])/[CH:17]=3
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C/C(=N/O)CC[C@@H]4[C@H]3CC[C@@]21C
Temperature: 98 °C
Yield: 95 %

Procedure:
A solution of norethindrone, 6.5 m moles, and hydroxylamine hydrochloride, 16.4 m moles, in 10 ml of dried pyridine was stirred at room temperature for 48 hours. The progress of the reaction was followed by tlc (thin layer chromatography). The reaction mixture was then heated at 98°C. (bath temperature) for 15 minutes, allowed to cool to 55°C and the pyridine was evaporated in vacuo. The residue was extracted with ether. Drying and removal of the ether gave a residue which was recrystallized from methanol-water and methanol to yield 1.93 g (95%) of norethindrone oxime, mp 121.5°-123°C. Tlc with ethyl acetate: petroleum ether; acetone 1:1:0.2 indicated the product to be a mixture of the syn and anti isomers of the oxime.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1(C)C=CC=CC=1>[CH:20]1([N:25]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1C1CCCC1
Reaction time: 10 h
Yield: 46 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 3.0 ml (0.0305 mol) of cyclopentylamine were added thereto and the mixture was boiled for 40 hours on a water separator. After concentration the residue was hydrogenated with 1.2 g of Raney-nickel in 500 ml of ethanol at 120° and 140 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ether 1:1. There were obtained 2.0 g (46%) of rac-cis-3-cyclopentyl-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one as white crystals with m.p. 84°-88°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:24][C@:25]12[CH2:42][CH2:41][C@H:40]3[C@@H:30]([CH2:31][CH2:32][C@@H:33]4[C@:38]3([CH3:39])[CH2:37][CH:36]=[CH:35][CH2:34]4)[C@@H:29]1[CH2:28][CH2:27][C:26]2=O>C(O)C>[CH3:24][C@:25]12[CH2:42][CH2:41][C@H:40]3[C@@H:30]([CH2:31][CH2:32][C@@H:33]4[C@:38]3([CH3:39])[CH2:37][CH:36]=[CH:35][CH2:34]4)[C@@H:29]1[CH2:28][CH2:27][C:26]2=[N:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4CC[C@]23C)cc1

Procedure:
4-Methylbenzenesulphonic acid hydrazide (525 g) and 4-methylbenzenesulphonic acid (5.25 g) were added to a hot, stirred solution of (5α)-androst-2-en-17-one (700 g) in ethanol (5.6 l) and the solution was heated under reflux for 8 h. The stirred mixture was cooled and further ethanol (1 l) was added to give 4-methylbenzenesulphonic acid [(5α)-androst-2-en-17-ylidene]hydrazide as a crystalline solid.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]O)[CH2:4][CH3:5].P(Br)(Br)[Br:15]>C(Cl)Cl>[CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][Br:15])[CH2:4][CH3:5]
Reactant: BrP(Br)Br
Reactant: CCC(CC)c1cccc(CO)c1
Solvent: ClCCl
Product: CCC(CC)c1cccc(CBr)c1
Yield: 90 %

Procedure:
According to example 17, 1.84 g of 3-(3-pentyl)benzyl alcohol was treated with 0.34 mL of PBr3 in 25 miL of anhydrous CH2Cl2 to afford 2.23 g (90%) of 3-(3-Pentyl)benzyl bromide as a clear liquid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35](=[O:37])[CH3:36].CC(C)=O>C(Cl)Cl>[CH3:26][C:6]1[C:5]2[C:10](=[C:11]([CH3:12])[C:2]([O:1][CH2:34][C:35](=[O:37])[CH3:36])=[CH:3][CH:4]=2)[O:9][C:8](=[O:13])[C:7]=1[CH2:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20]
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)COc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A slurry of 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin (4.00 g, 11.5 mmol), potassium carbonate (4.5 g, 36.9 mmol), chloroacetone (1 mL, 11.5 mmol) and acetone (200 mL) were refluxed overnight. After the solution was allowed to cool to room temperature, CH2Cl2 (200 mL) was added and the resulting solid was filtered off. The remaining solution was cold decolorized with charcoal and the solvent evaporated. The resulting solid was stirred with water, vacuum filtered, and washed with water. After air drying, 4,8-dimethyl-7-(2-oxo)propyloxy-3-(phthalimidomethyl)coumarin (4.06 g, 87.1% ) was obtained as an off-white solid. 1H NMR (CDCl3): δ7.66-7.83 (m, 4H), 7.48 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.91 (s, 2H), 4.62 (s, 2H), 2.59 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[NH2:7].[N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18])=[C:10]=[O:11]>[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:8])[NH:7][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:9]=[C:10]=[O:11]
Reactant: COCCOC(N)=O
Reactant: O=C=NCCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: COCCOC(=O)NC(=O)CCCCCN=C=O
Temperature: 60 °C
Reaction time: 26 h
Yield: 85.2 %

Procedure:
6.65 g (0.05 mol) of carbamic acid-β-methoxyethyl ester and 0.15 g of zinc chloride were heated to 50° C. 8.8 g (0.05 mol) of 6-isocyanato-caproyl chloride were added dropwise to the resulting melt. Nitrogen was passed through the mixture while it was heated to 60° C. for 3 hours and then to 100° C. for 26 hours. The reaction was then terminated (IR control). The mixture was cooled, taken up in 100 ml of toluene and decanted to remove insoluble constituents; the toluene was removed under vacuum. 11 g of a colorless oil was obtained, which solidified to a waxy solid. Yield: 11 g=85%
Reaction SMILES: C(O[C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[O:5])C.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:7]2[CH2:6][C:4](=[O:5])[N:26]([CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reactant: NCCN1CCOCC1
Product: COC(=O)C1CN(CCN2CCOCC2)C(=O)CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
A title compound was prepared by the same method as in Example 4, except that the compound of Example 3 and N-(2-aminoethyl)morpholine were used to prepare a yellow oil (yield 74%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[CH3:10].Cl>CCOCC>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]([OH:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CCOc1cccc(C=O)c1
Agent: Cl
Solvent: CCOCC
Product: CCOc1cccc(C(O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 242.5 %

Procedure:
To an ether solution of phenylmagnesium bromide [prepared from bromobenzene (3.69 ml, 35 m mol), magnesium (0.95 g, 39 m mol) and ether (50 ml)], an ether solution (30 ml) of 3-ethoxybenzaldehyde (3.0 g, 20 m mol) was added dropwise thereto with stirring and under cooling with ice. After 30 minutes, 1 N hydrochloric acid (20 ml) was added thereto. The ether layer was separated and the aqueous layer was extracted with ether (20 ml). After the combined ether layer was washed with a saturated aqueous solution of sodium chloride (15 ml) and dried, the solvent was distilled off under reduced pressure. The resulting residue was subjected to chromatography on silica gel (100 g) using hexane, and eluted with hexane and then with hexane-ethyl acetate (5:1). The resulting yellow oily material containing the desired compound was distilled to obtain the desired compound (2.9 g, 60%) as a colorless oily material (150-153° C./1-2 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1([CH2:18][CH2:17][CH2:16]1)[CH2:5][CH2:6][N:7]2[CH2:12][C:13]([NH2:15])=O.CSC.B>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1([CH2:16][CH2:17][CH2:18]1)[CH2:5][CH2:6][N:7]2[CH2:12][CH2:13][NH2:15]
Reactant: NC(=O)CN1CCC2(CCC2)c2c(F)cccc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NCCN1CCC2(CCC2)c2c(F)cccc21
Temperature: 70 °C
Yield: 26.7 %

Procedure:
A solution of 40 mg (0.16 mmol) of 2-(5′-fluoro-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-quinolin]-1′-yl)-acetamide obtained in step 31.4 in 1 ml of tetrahydrofurane was treated with 38 μl (0.40 mmol) of borane dimethylsulfide and heated to 70° C. for two hours. The mixture was quenched with water and hydrochloric acid, diluted with dichloromethane and extracted twice with water. The combined aqueous phases were set to pH 10 with sodium hydroxide solution and extracted 3× with dichloromethane. The combined organic phases were dried and evaporated to yield 10 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[NH:18][CH3:19].C([Li])CCC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N:18]([S:26]([CH3:25])(=[O:28])=[O:27])[CH3:19]
Reactant: CCOC(=O)c1cc(NC)c(C)nc1C(=O)OCC
Reactant: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N(C)S(C)(=O)=O)c(C)nc1C(=O)OCC
Temperature: -65 °C

Procedure:
A solution of 1.33 g of 6-methyl-5-(N-methylamino)pyridine-2,3-dicarboxylic acid, diethyl ester, in 30 mL dry tetrahydrofuran is cooled under nitrogen with stirring to -65° C., and treated dropwise with 2.6 mL of 2.3M n-butyllithium (hexane solution). When the addition is complete, 0.4 mL of methanesulfonyl chloride is added, and the reaction is allowed to warm to room temperature over a 30 minute period. The reaction is quenched with 10 mL of water and concentrated in vacuo. The residue is partitioned between methylene chloride and water, and the organic layer is dried and concentrated in vacuo. This residue is chromatographed on silica gel using ether to afford the desired product, mp 90°-93° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.Cl.ClC[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:6][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:18]=1
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(CN2CCNCC2)c1
Yield: 86.7 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (930 mg), 3-chloromethyl-pyridine hydrochloride (902 mg) and cesium carbonate (3.6 g) were reacted in DMF (5 ml), followed by further treatment with TFA, to obtain 1-pyridin-3-ylmethyl-piperazine (767 mg, 87%) as a pale brown oil.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.O[N:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45]>CN(C=O)C>[O:45]=[C:40]1[CH2:41][CH2:42][C:43](=[O:44])[N:39]1[O:3][C:2](=[O:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[CH:11]([NH:12][C:13](=[O:14])[NH:15]2)[CH2:10][S:9]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
The method for synthesis of 2 was modified from that of Bayer and Wilchek. In brief, biotin (1; 0.31 g, 1.26 mmol) was completely dissolved in DMF (9 mL) with gentle warming. After cooling the 1 solution to room temperature without reprecipitation, it was added to N,N′-dicyclohexylcarbodiimide (DCC; 0.26 g, 1.28 mmol) and pyridine (0.10 mL, 1.26 mmol) while stirring for 5 min at room temperature, followed by the addition of N-hydroxysuccinimide (NHS; 0.19 g, 1.65 mmol) with continuous stirring for 24 h. The reaction product was filtered and concentrated under reduced pressure. The obtained solid was redissolved in 2-propanol (50 mL) with gentle heating, cooled down to room temperature, and reprecipitated at 4° C. overnight. The product was scraped out of the glassware, washed with cold 2-propanol, and air dried to give 2 as white solid (0.36 g; 82.4%). 1H NMR (400 MHz) (DMSO) δ: 6.46 (s, 1H, CONH), 6.39 (s, 1H, CONH), 4.31 (t, 1H, CHN), 4.16 (t, 1H, CHN), 3.12 (dd, 1H, CHS), 2.83 (s, 4H, CH2 of NHS), 2.71 (d, 1H, CHHS), 2.69 (t, 2H, CH2CO), 2.59 (d, 1H, CHHS), 1.43-1.68 (m, 6H). 13C NMR (100.67 MHz) (DMSO) δ: 170.42, 162.85, 61.01, 59.28, 55.33, 30.08, 27.91, 27.68, 25.51. HRMS (ESI) calculated for C14H19N3O5S, [M+Na]+ 364.0943 (calcd.), 364.0940 (found).
Reaction SMILES: O1CCOCC1.C(=O)(O)[O-].[Na+].[NH2:12][C:13]1[N:17]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23]([CH3:25])=[N:24][C:20]=3[CH:19]=2)[N:16]=[CH:15][C:14]=1[C:28]([C:30]1[N:31]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=[C:33](Br)[CH:34]=1)=[O:29].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O>[NH2:12][C:13]1[N:17]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23]([CH3:25])=[N:24][C:20]=3[CH:19]=2)[N:16]=[CH:15][C:14]=1[C:28]([C:30]1[N:31]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=[C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:34]=1)=[O:29]
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)cc2C(=O)c2cnn(-c3ccc4[nH]c(C)nc4c3)c2N)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3)cc2C(=O)c2cnn(-c3ccc4[nH]c(C)nc4c3)c2N)cc1

Procedure:
Dioxane (1.5 ml) and an aqueous solution (1.5 ml) of 1 M sodium bicarbonate were added to [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4-bromo-1-(toluene-4-sulfonyl)-1H-pyrrol-2-yl]-methanone (57 mg), palladium chloride bis-triphenylphosphine complex (10 mg), and phenylboronic acid (37 mg). The mixture was reacted at 140° C. in a microwave reactor for ten minutes. The reaction mixture was diluted with water (5 ml), and then extracted with ethyl acetate. The organic layers were combined, and concentrated under reduced pressure. After HPLC purification, the eluate was desalted using PLHCO3 cartridge (PolymerLabs), and then concentrated under reduced pressure. Thus, [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrrol-2-yl]-methanone was obtained as a yellow powder (15 mg, 26%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[NH2:42][C:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[C:43]([C:45]1[CH:50]=[C:49]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])[CH:48]=[CH:47][CH:46]=1)(=[O:44])[NH2:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3cccc(C(N)=O)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 47.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (5.6 mL), and the solution was added with (3-aminocarbonylphenyl)boronic acid (89 mg, 0.54 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (17.6 mg, 0.0216 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.049 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(3-carbamoylphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.1 mg, yield 47%).