Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
To a solution of 2-benzylacrylic acid (1.02 g, 6.3 mmol) in dimethylformamide (10 ml) was added potassium carbonate (1.04 g, 7.6 mmol) and water (0.25 ml) with stirring. After 10 minutes, benzyl bromide (0.9 ml, 7.6 mmol) was added. After 3 hours, water was added and the resulting mixture was extracted with ether. The ether layer was washed 3 times with water, dried over magnesium sulfate, filtered over silica gel, and concentrated under reduced pressure. The resulting oil was distilled (70° C., 0.2 torr) to remove any unreacted starting material, then distilled (125° C., 0.2 torr) to yield 1.38 g (87%) of clear oil. 1H NMR (CDCl3): δ 3.7 (s, 2H), 5.2 (s, 2H), 5.5 (s, 1H), 6.3 (s, 1H), 7.2-7.6 (m, 10H).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.C(OC([NH:19][C@H:20]([CH2:28][N:29]([CH3:39])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[C@@H:21]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[OH:22])=O)(C)(C)C>CCO.CCOCC>[NH2:19][C@H:20]([CH2:28][N:29]([CH3:39])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[C@@H:21]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[OH:22]
Reactant: CN(C[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1CCCC1)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CN(C[C@@H](N)[C@H](O)C1CCCC1)C(=O)OCC[Si](C)(C)C

Procedure:
A solution of TsOH (36.8 mg, 0.194 mg) in 1.0 mL EtOH (1 mL) was added to (1R,2R)-2-(t-butoxycarbonylamino)-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-1-ol (68.2 mg, 0.164 mmol) in 3.0 mL Et2O (3 mL). The solvent was removed under reduced pressure at 60° C. and the residue maintained at this temperature for 1 h. The residue was taken up into CH2Cl2 (50 mL), washed with 1 N aq NaOH and brine, and dried over Na2SO4. Removal of the solvent left (1R,2R)-2-amino-1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol which was used without purification.
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COc1c(F)cccc1CO
Solvent: ClCCl
Product: COc1c(F)cccc1CCl

Procedure:
A solution of 3-fluoro-2-methoxy-benzenemethanol (WO 20000419) (0.50 g) and thionyl chloride (0.47 ml) in dichloromethane (30 ml) was stirred for 2 hours then concentrated in-vacuo to give the subtitled compound, which was used directly in the next step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[C:8]=1[C:46]([NH:48][CH3:49])=[O:47])(=O)=O.C(O)=O.C(N(CCCC)CCCC)CCC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:45][C:17]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:46]([NH:48][CH3:49])=[O:47])=[CH:7][CH:16]=[CH:15]2)([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CNC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O=CO
Product: CNC(=O)c1cccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc12
Temperature: 80 °C
Yield: 121.1 %

Procedure:
A mixture of 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-1-(methylaminocarbonyl)-2-naphthyl trifluoromethanesulfonate (700 mg), formic acid (0.1 mL), tributylamine (1.0 mL), dichlorobis(triphenylphosphine)palladium (70 mg), and 1,3-bis-(diphenylphosphino)propane (103 mg) in anhydrous DMF (5 mL) was heated at 80° C. for 4 h. After dilution with water, the yellow precipitate was filtered and washed with water. The precipitate was purified by flash column chromatography on silica gel (hexane:AcOEt=3:2→1:1) to give the title compound (384 mg) as a colorless amorphous powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][CH:3]=1.[CH:12]1([CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:19]=[C:17]([NH:16][CH2:15][CH:12]3[CH2:14][CH2:13]3)[S:18][CH:7]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)NCC1CC1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2csc(NCC3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Slurry 4-bromophenacyl bromide (11.2 g, 50 mmol) in absolute ethanol (50 mL). Add N-cyclopropylmethyl-thiourea (6.5 g, 50 mmol) and sodium bicarbonate (4.2 g, 50 mmol), heat to reflux for 2 h, then stir at room temperature overnight. Concentrate to ¼ volume and partition between water/EtOAc (4:1, 500 mL). Extract the aqueous layer with EtOAc (2×75 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound (14.0 g, 91%) as an off-white solid that was used without further purification. MS (ES+) m/z: 310 (M+H)+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]=[CH:13][C:12]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19]O>C(O)(=O)C>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]=[CH:13][C:12]=3[CH:18]=2)=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: C1=Cc2cc(Sc3ccccc3)ccc2OCC1
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1ccc2c(c1)C=CCCO2
Reaction time: 2 h

Procedure:
6.00 g (23.6 mmol) of 2,3-dihydro-7-phenylthio-1-benzoxepin are introduced at 15°-20° C. into 59 ml of glacial acetic acid and, at this temperature, 5 ml of aqueous hydrogen peroxide solution (30% strength) are added dropwise. The mixture is stirred at this temperature for about 2 hours until all the precursor has reacted (TLC check). The mixture is then stirred into sodium bicarbonate/ice-water and extracted several times with diethyl ether. The combined ether phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and filtered, and the solvent is evaporated off in vacuo. 6.2 g of oil remain and are reacted without further purification.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C[Si]([N:33]=[C:34]=[O:35])(C)C.O>ClCCl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:34]([NH2:33])=[O:35])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: O
Solvent: ClCCl
Product: NC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Yield: 99.9 %

Procedure:
The (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (20.0 mg, 47.2 μmol) obtained in Step 1 of Example 2 was dissolved in dichloromethane (1 mL), and trimethylsilyl isocyanate (25.0 μL, 188 μmol) was then added to the obtained solution. The obtained mixture was stirred for hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→20%) to obtain the captioned compound (22.0 mg, 99%) in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[CH:26]=[CH2:27].O>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:6][CH:7]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CCOC(=O)c1c(-c2ccc(O)cc2)noc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc(-c2noc(C)c2C(=O)OCC)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
The mixture of ethyl 3-(4-hydroxyphenyl)-5-methylisoxazole-4-carboxylate (Preparation C) (0.474 g, 1.92 mmol), Cs2CO3 (0.937 g, 2.88 mmol) and allyl bromide (0.27 mL, 3.12 mmol) in 10 mL of THF was sealed in a 150-mL pressure vessel and stirred at 90° C. overnight. The reaction mixture was cooled to room temperature. Water (150 mL) and ethyl acetate (150 mL) were added to the reaction mixture. Layers were separated and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic extract was dried over anhydrous sodium sulfate. Solvent was evaporated in vacuo to give 0.66 g of crude product, which was used in the next step without purification. LCMS (method B) RT 3.34 min., MH+288. 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J=8.5Hz, 2H), 6.96 (d, J=8.5Hz, 2H), 6.12-6.00 (m, 1H), 5.46-5.26 (m, 2H), 4.58 (d, J=5.2Hz, 2H), 4.25 (q, J=7.2Hz, 2H), 2.71 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35])[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=2)[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2ccc(Cl)cc2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1ccc(Cl)cc1)CC(=O)NC2c1cccc(Cl)c1
Yield: 95 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.35 g, 0.97 mmol) prepared in example 9b was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(4-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow solid (Yield 0.5 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[F:14][C:15]1[CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22].[F-].[K+]>C(#N)C.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([F:23])([F:24])[F:22])=[C:15]([F:14])[CH:16]=2)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(C(F)(F)F)c(F)c2)cc(N)c1Cl
Yield: 57.4 %

Procedure:
Methyl 4-amino-3,6-dichloropicolinate (630 mg, 2.85 mmol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.06 g, 3.65 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II) chloride (209 mg, 0.30 mmol, 0.1 equiv), and potassium fluoride (510 mg, 8.8 mmol, 3 equiv) in acetonitrile/water (8 mL, 3:1) was capped in a 25-mL vial on a Biotage Initiator™ microwave reactor for 20 min at 115° C., with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude compound was loaded onto a Celite™ cartridge and dried in vacuum oven. Purification by reverse-phase flash chromatography (0-60, 60, 60-100% acetonitrile/water) afforded the title compound as a white solid (0.57 g, 57%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@H]1[C@H](NC)CCCC1>[Cu]I.CN(C=O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cncn2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 120 °C
Yield: 6.7 %

Procedure:
In a tube were added successively (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK, 0.1 g, 0.19 mmol), 1,2,4-triazole (11 mg, 0.155 mmol), potassium phosphate (71 mg, 0.326 mmol), CuI (7 mg, 0.037 mmol), (1R,2R)-diaminomethylcyclohexane (2.3 mg, 0.015 mmol) and DMF (1 ml). The mixture was heated under argon at 120° C. for 24 hours. The reaction mixture was cooled to room temperature and quenched with water/dichloromethane. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over silicagel: eluent: heptane/ethylacetate: 0-100% to provide the title compound as a light grey solid (5 mg, 6%), MS (m/e): 480.4 (M+H, 100%)
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH3:30])[N:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C:21]=3[CH3:22])[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[C:21]([CH3:22])=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[CH:7][N:6]4[CH2:5][C:4]([OH:31])=[O:3])=[CH:10][CH:11]=3)[N:18]([CH3:30])[N:19]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3c(C)c(-c4ccc(Cl)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cc1c(-c2ccc(Cl)cc2)nn(C)c1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[5-(4-chloro-phenyl)-2,4-dimethyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[5-(4-chloro-phenyl)-2,4-dimethyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:27]=2)[CH:25]=[O:26])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]([C:24]1[CH:27]=[C:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[CH:21]=[N:22][CH:23]=1)=[O:26]
Reactant: COc1cc(Br)ccc1C#N
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2cncc(C=O)c2)ccc1C#N
Temperature: 90 °C
Yield: 90.2 %

Procedure:
A mixture of 4-bromo-2-methoxybenzonitrile (0.424 g, 2.000 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (0.466 g, 2.000 mmol), tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.050 mmol) and sodium carbonate (2M in water, 2.00 mL, 4.00 mmol) in DME (50 mL) was heated to 90° C. for 6 h. After filtration through a pad of dry Na2SO4 and concentration, the residue was purified by column and yielded a colorless solid (430 mg). 1H NMR (400 MHz, CDCl3): δ 4.04 (s, 3H), 6.99 (s, 1H), 7.27 (d, J=4.7 Hz, 1H), 7.71 (d, J=7.9 Hz, 1H), 8.34 (t, J=2 Hz, 1H), 9.07 (d, J=2.36 Hz, 1H), 9.12 (d, J=1.9 Hz, 1H), 10.22 (s, 1H).
Reaction SMILES: O1CCOCC1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([CH3:37])=[C:17]([CH2:19][CH2:20][O:21][C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH2:24][CH2:25][CH:26]=[C:27]4[CH2:32][CH2:33][C:34]([NH2:36])=O)[N:18]=2)=[CH:10][CH:9]=1.FC(F)(F)C(O)=O>N1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]([CH3:37])=[C:17]([CH2:19][CH2:20][O:21][C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH2:24][CH2:25][CH:26]=[C:27]4[CH2:32][CH2:33][C:34]#[N:36])[N:18]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2nc(CCOc3cccc4c3CCC=C4CCC(N)=O)c(C)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1ccc(-c2nc(CCOc3cccc4c3CCC=C4CCC#N)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dioxane (15 ml) solution of the compound prepared in Example 10, pyridine (363 μl) and trifluoroacetic acid (423 μl) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid, water and a saturated saline in this order, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to thereby obtain the title compound (533 mg) having the following physical data.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:6][C:7]1[C:8]([C:4]#[C:3][C@@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: C#C[C@H](C)O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](C)O)c21

Procedure:
Using Method C above, (S)-but-3-yn-2-ol (38 mg, 0.54 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (16 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was obtained after silica gel column with a 0-10% MeOH in CH2Cl2 gradient and trituration with Et2O. (Yield 21 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[N:18]1([C:23]2[CH2:27][CH2:26][CH2:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([C:24]2[CH2:25][CH2:26][CH2:27][C:23]=2[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: C1=C(N2CCCC2)CCC1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1=C(N2CCCC2)CCC1)c1cccnc1Cl
Reaction time: 21 h

Procedure:
Dissolve 2-chloronicotinoyl chloride (0.10 mole) in CHCl3 (90 ml). Add the resulting solution to a 5° C. solution of triethylamine (0.10 mole) and an enamine, 1-(1-pyrrolidinyl)-1-cyclopentene (0.10 mole), dissolved in CHCl3 (90 ml). Allow C-acylation to proceed for 21 hrs., while the temperature of the reaction mixture rises to 25° after the second hour. Monitor the course of the reaction by thin-layer chromatography as needed. Wash the resulting solution with water, aqueous NaHCO3 solution, and with water. After drying, carefully evaporate solvent to obtain the enaminoketone, (2-chloro-3-pyridinyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]methanone, m.p. 102.5°-104.0° C., after recrystallization from ethyl acetate. This compound is referred to in Examples 1 and 3 below as Compound 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C[OH:10]>>[C:1]([NH2:2])(=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: CO
Product: NC(=O)c1cccnc1
Reaction time: 0.17 h

Procedure:
A reaction mixture comprising 3-cyanopyridine (0.5 M; 0.500 ml), nitrile hydratase solution (0.697 μmol/min; 0.025 ml) and different buffers in the pH range from 4 to 11 (0.1 M; 0.0475 ml) was incubated at 20° C. for 10 min. The reaction was stopped by adding MeOH. The amount of nicotinamide produced was determined by means of HPLC according to Example 1. The pH optimum of nitrile hydratase was in the range from 6.0 to 6.5 (FIG. 16).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@@H:52]1[O:64][C@H:63]([CH2:65][O:66][C:67](=[O:69])[CH3:68])[C@@H:58]([O:59][C:60](=[O:62])[CH3:61])[C@H:53]1[O:54][C:55](=[O:57])[CH3:56])(=O)C>COCCOC>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:52]2[O:64][C@H:63]([CH2:65][O:66][C:67](=[O:69])[CH3:68])[C@@H:58]([O:59][C:60](=[O:62])[CH3:61])[C@H:53]2[O:54][C:55](=[O:57])[CH3:56])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: COCCOC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN4CCCCC4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide (200 g, 0.426 moles) (Preparation 23) in anhydrous 1,2-dimethoxyethane (800 ml) under an atmosphere of nitrogen was added a solution of trimethylsilyl trifluoromethanesulfonate (200 g, 0.900 moles) in anhydrous 1,2-dimethoxyethane (200 ml) over a period of 15 minutes. During the addition, all the solid dissolved to give a deep red/amber solution and the reaction temperature rose from 20° C. to 31.5° C. The resultant mixture was heated to 55-60° C. and a solution of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (163 g, 0.512 moles) in anhydrous 1,2-dimethoxyethane (400 ml) was added over a period of 40 minutes. The addition apparatus was rinsed through into the reaction mixture with anhydrous 1,2-dimethoxyethane (200 ml). The reaction mixture was heated at 60° C. for 3 hours and was allowed to cool to ambient temperature. This crude reaction solution was held at ambient temperature for 18 hours. The resulting mixture containing the title compound may be used directly without further purification.