Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2>>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[C:32](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:33](=[O:39])[NH:34]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 70.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (70 mg, 70.7%) as an orange solid.
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:36])[C@@H:23]([CH3:35])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:34])([CH3:33])[C@@H:28]([OH:32])[C@@H:29]([OH:31])[CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:36])[C@@H:23]([CH3:35])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:34])([CH3:33])[C@@H:28]([OH:32])[C@@H:29]([OH:31])[CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CNC4=O)C[C@]13C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To Compound (49a) (43 mg, 0.088 mmol) dissolved in 3.0 ml of methanol was added 9 mg of palladium-carbon, and the mixture stirred under hydrogen atmosphere for 2 hours at room temperature. After the palladium-carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=10:1) and further by crystallization from diethyl ether to give 32 mg (91%) of Compound (50a).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([NH:32][NH2:33])=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)CCC>[Si:1]([O:8][CH2:9][C@@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]2[C:30]([C:27]3([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)[CH2:29][CH2:28]3)=[N:32][N:33]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CSC1=NCCS[C@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CC1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@]1(C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
The compound (2.07 g, 6.54 mmol) obtained in Example 3-1) and the compound (1.38 g, 6.54 mmol) obtained in Example 1-1) were dissolved in 1-butanol (10 mL), and the mixture was stirred at 140° C. for 5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=30% to 80%) to obtain the title compound (1.27 g, 42%) in a white solid form.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pt]>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Reaction time: 2 h
Yield: 104.6 %

Procedure:
(7-Benzyloxy-3-nitroquinolin-4-yl)-(2-phenoxyethyl)amine (14.24 g, 34.28 mmol) was dissolved in toluene (900 mL) with heating and added to a Parr vessel charged with 5% platinum on carbon (6.7 g, 34.28 mmol) and toluene (100 mL). The vessel was placed under hydrogen pressure (35 psi, 2.4×105 Pa) and shaken for two hours. The catalyst was removed by filtration and washed with hexanes and dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol, isolated by filtration, washed with hexanes, and dried under high vacuum to provide 13.82 g of 7-benzyloxy-N4-(2-phenoxyethyl)quinoline-3,4-diamine as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:34])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:34])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 25.2 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-acrylonitrile (2.3 g, 8 mmol) prepared in Example 64a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.02 g, 25%).
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]C(C)(C)C)=[O:8])=[CH:5][CH:4]=[C:3]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1>Cl.O1CCOCC1>[N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccnc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cccnc2)cn1

Procedure:
A solution of tert-butyl 3,3′-bipyridine-6-carboxylate (3.2 g, 12.5 mmol) in 4 M HCl in dioxane (100 ml) was stirred at 110° C. overnight. The reaction mixture was evaporated completely under reduced pressure and triturated twice from diethyl ether. Yield 3.2 g. 1H-NMR (400 MHz; D2O): δ 8.23-8.27 (m, 1H), 8.50 (d, 1H), 8.84 (d, 1H), 8.93 (d, 1H), 8.98 (d, 1H), 9.16 (s, 1H), 9.26 (s, 1H).
Reaction SMILES: CN(C)C=[C:4]([F:24])[C:5]([C:7]1[C:12]([NH:13][C:14](=O)[O:15][C:16](C)(C)C)=[CH:11][C:10]([F:21])=[C:9](OC)[N:8]=1)=O.P(Br)(Br)[Br:27]>FC(F)(F)C(O)=O.ClCCl.O.C(=O)([O-])[O-].[K+].[K+]>[Br:27][C:11]1[C:10]([F:21])=[CH:9][N:8]=[C:7]2[C:12]=1[N:13]=[C:14]([O:15][CH3:16])[C:4]([F:24])=[CH:5]2
Reactant: COc1nc(C(=O)C(F)=CN(C)C)c(NC(=O)OC(C)(C)C)cc1F
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nc2c(Br)c(F)cnc2cc1F
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A solution of 1,1-dimethylethyl [2-[3-(dimethylamino)-2-fluoroacryloyl]-5-fluoro-6-(methyloxy)-3-pyridinyl]carbamate (2.15 g, 6.02 mmol) in trifluoroacetic acid/dichloromethane (20 ml/20 ml) was stirred at room temperature for 0.5 hour under argon and evaporated. The residue was treated with ˜50 ml 2M ammonia in methanol until basic and evaporated. This residue was dried in vacuo then chromatographed eluting with 0-10% methanol in ethyl acetate affording a solid (3.64 g), 8-hydroxy-3,7-difluoro-2-(methyloxy)-1,5-naphthyridine. 8-Hydroxy-3,7-difluoro-2-(methyloxy)-1,5-naphthyridine (3.64 g) was dissolved in N,N-dimethylformamide (20 ml) and treated with phosphorus tribromide (0.68 ml, 7.22 mmol). After 1 hour, more phosphorus tribromide (0.68 ml, 7.22 mmol) was added. After 0.5 hour the mixture was diluted with water and basified with solid potassium carbonate. Filtration and drying in vacuo afforded the product (0.95 g, 57%).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14]([O:16][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:13][CH:14]([OH:16])[CH2:15]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCOC(=O)c1csc(N2CC(O)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (5.31 g, 11.1 mmol) (obtained as described in Reference Example 41(1)) in anhydrous tetrahydrofuran (266 ml) was added a solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (13.3 ml, 13.3 mmol) in an ice bath. The mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (2.91 g, yield 100%) as pale brown crystals.
Reaction SMILES: C(OC)(=O)C1C=CC(C([O-])=O)=CC=1.[K+:14].[C:15]([O:28]CC)(=[O:27])[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.[OH-].[K+].C1(C)C=CC=CC=1>C(O)C>[C:20]([O:22][CH2:23][CH3:24])(=[O:21])[C:19]1[CH:25]=[CH:26][C:16]([C:15]([O-:28])=[O:27])=[CH:17][CH:18]=1.[K+:14]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)cc1
Agent: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(=O)[O-])cc1

Procedure:
This compound was prepared by the procedure described for potassium monomethyl terephthalate. Typical reagent levels were as follows: 77.0 gm (0.346 mole) of diethyl terephthalate, 19.4 gm of potassium hydroxide, 150 ml of toluene and 100 ml of ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.[CH3:13][O:14][C:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[CH:17][N:16]=1.CC([O-])=O.[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([O:14][CH3:13])[CH:20]=2)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2cc(Cl)c3cnn(C)c3n2)ccn1
Temperature: 120 °C
Yield: 51.5 %

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.5 g, 4.9 mmol) was dissolved in acetonitrile (8 mL) and 2-methoxypyridine-4-boronic acid (0.4 g) and 1 M KOAc (8 mL) were added in a microwave tube. Nitrogen was bubbled through the solution for 5 minutes. 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (1.21 g) was added and the resultant mixture was then heated by microwave at 120° C. for 5 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography (30% EtOAc in hexane) to provide 4-chloro-6-(2-methoxypyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.37 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]1[C:23]2[C@@H:22]3[CH2:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH2:27][C@H:21]3[C:20]([CH3:32])([CH3:31])[O:19][C:18]=2[CH:17]=[C:16]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:15]=1.O[N:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45].CCOC(C)=O>C(Cl)Cl>[OH:13][C:14]1[C:23]2[C@@H:22]3[CH2:24][C:25]([C:28]([O:30][N:39]4[C:43](=[O:44])[CH2:42][CH2:41][C:40]4=[O:45])=[O:29])=[CH:26][CH2:27][C@H:21]3[C:20]([CH3:31])([CH3:32])[O:19][C:18]=2[CH:17]=[C:16]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:15]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C(=O)O)C[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C(=O)ON3C(=O)CCC3=O)C[C@@H]21

Procedure:
In an alternate approach, 2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) as the coupling reagent in the reaction of (XI) were mixed with 1.5 equivalents of N-hydroxysuccinimide in CH2Cl2 at reflux for 24 h. Dilution of the resulting reaction mixture with EtOAc, washing with water, saturated NaHCO3, saturated NaCl, drying over Na2SO4 and evaporation in vacuo then gave a gum. This was subjected to chromatography on silica, eluting with EtOAc-hexanes (1:1) to give (XII) as an off-white foam, [α]D -208° (CHCl3), (M+H)+ (FAB) 442.2260 (Calc 442.2230).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:5][C:6]1[NH:11][C:10](=[O:12])[NH:9][C:8](=[O:13])[C:7]=1[CH:14]([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].[I-].[Li+].CS([CH2:33]/[CH:34]=[CH:35]/[CH3:36])(=O)=O>CN(C=O)C.CCOCC>[CH2:33]([N:11]1[C:6]([O:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:19]=[C:18]([CH3:20])[CH:17]=2)=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8](=[O:13])[NH:9][C:10]1=[O:12])[CH:34]=[CH:35][CH3:36]
Reactant: C/C=C/CS(C)(=O)=O
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC=CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 15 h
Yield: 75 %

Procedure:
To a stirred solution of 6-(3,5-dimethyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (114) (prepared using the methods of WO9518109, herein incorporated by reference in its entirety for all purposes; 274 mg, 1 mmol) anhydrous powdered K2CO3 (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol) in DMF (5 mL), was added 1-methanesulfonyl-trans-2-butene (141 μL, 1.2 mmol). After stirring for 15 hrs., the reaction mixture was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:dichloromethane:hexane (1:1:2)) to afford 247 mg (75%) of a white solid. m.p. 141-143° C.; 1H-NMR (200 MHz, CDCl3) δ1.13 (6H, d, J=7.0 Hz), 1.59 (3H, d, J=6.0 Hz), 2.29 (6H, s), 2.72 (1H, m), 4.20 (2H, d, J=5.5 Hz), 5.34-5.61 (2H, m), 6.51 (2H, s), 6.75 (1H, s), 9.00 (1H, s); m/z (EI) 328(M+).
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH2:23]Br)=[N:21][N:20](C(OC(C)(C)C)=O)[C:17]2=[N:18][CH:19]=1>CN(C=O)C.O>[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH2:23][N:7]3[CH2:8][CH:4]([CH:3]=[C:2]([F:10])[F:1])[CH2:5][C:6]3=[O:9])=[N:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cc(Br)cnc21
Reactant: O=C1CC(C=C(F)F)CN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(C=C(F)F)CN1Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
To a solution of 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.86 mmol, 2 eq, 0.42 g) in dry DMF (5 ml) maintained at 0° C. is added natrium hydride (60% dispersion in oil; 2.86 mmol, 2 eq, 0.114 g). The resulting mixture is stirred at room temperature for 0.5 hour and tert-butyl 5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155 (1.43 mmol, 1 eq, 0.56 g) dissolved in DMF (2 ml) is added. The resulting mixture is stirred overnight at room temperature. The mixture is poured in water and extracted with AcOEt. The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture is purified twice by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 98/2/0.2) to afford pure 1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 221 (0.025 g).
Reaction SMILES: O1CCOCC1.Cl.C(OC([N:15]1[CH2:19][C@@H:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][C@H:16]1[C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:32][N:31]([CH3:33])[C:30]([C@@H:16]1[CH2:17][C@H:18]([S:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH2:19][NH:15]1)=[O:34]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@@H]2CN[C@H](C(=O)N(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
1 ml of a 4N dioxane solution of hydrogen chloride was added, whilst ice-cooling, to a solution of 385 mg of (2S, 4S)-1-(t-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (3) above] dissolved in 1 ml of ethyl acetate, and the mixture was stirred at room temperature for 1.5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate to make it weakly basic, and it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 1:2 by volume mixture of ethyl acetate and methanol), to afford 163 mg of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC>C1COCC1.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>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:19](=[O:28])[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:26]4=[O:27])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(-c2ccccn2)c1

Procedure:
To a solution of 2-[1-(3-bromo-phenyl)-1H-benzimidazole-5-ylmethyl]-isoindole-1,3-dione (1.0 g, 2.31 mmol) in anhydrous THF (20 ml) was added 2-tributylstannylpyridine (0.82 ml, 2.54 mmol) and a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (60 mg) and the resultant mixture was stirred at reflux in a nitrogen atmosphere for 3 days. The reaction mixture was quenched with aqueous ammonia and extracted with ethyl acetate. The organic extract was dried over magnesium sulphate and concentrated in vacuo. The concentrate was eluted through silica gel with ethyl acetate to afford the desired product. 0.24 g (24%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:37])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:36])[CH2:12][CH2:13][C@@:14]3([CH2:31][CH2:32][N+:33]([O-])=O)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:39])[CH3:38])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.CCOC(C)=O.[Ni](Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:37])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:36])[CH2:12][CH2:13][C@@:14]3([CH2:31][CH2:32][NH2:33])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:38])[CH3:39])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(CC[N+](=O)[O-])CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(CCN)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(2-nitroethyl)-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (27) (10 g, 18.46 mmol) and nickel(II) chloride (7.18 g, 55.4 mmol) in methanol (100 ml) was added sodium borohydride (6.98 g, 185 mmol) portionwise during 1 hour. The reaction mixture was stirred at 0° C. for 1 h. The mixture was diluted with EtOAc (250 mL). The organic phase was washed with sat. NH4Cl (50 mL) until the organic layer change to colorless. The combined organic layers were dried over anhydrous Na2SO4, and concentrated in vacuo to get the crude product (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-aminoethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (34) (7 g, 12.63 mmol, 68.4% yield), which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ=9.15 (dd, J=4.9, 11.4 Hz, 1H), 8.12 (br. s., 2H), 7.97-7.81 (m, 1H), 7.63-7.49 (m, 1H), 7.26-7.15 (m, 1H), 7.15-7.04 (m, 1H), 6.98 (d, J=18.6 Hz, 1H), 6.81-5.38 (m, 47H); LC/MS: m/z calculated 511.4. found 512.3 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][S:5][C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Si:11]([O:10][CH2:9][C:6]1[S:5][S:4][C:3]([CH2:2][O:1][C:20]2[CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=[CH:24][C:19]=2[Cl:18])=[CH:8][CH:7]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1=CC=C(COc2cc(C(F)(F)F)ccc2Cl)SS1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(hydroxymethyl)-6-[(tert-butyldimethylsilyloxy)methyl]-1,2-dithiin (U.S. Ser. No. 08/212,096) (200 mg, 0.688 mmol) in 5 mL dry THF was added a solution of 2-chloro-5-(trifluoromethyl) phenol (271 mg, 180 μL, 1.38 mmol) in 5 mL of THF, followed by the addition of triphenylphosphine (220 mg, 0.83 mmol). The resulting solution was cooled to 0° C., then 140 μL (155 mg, 0.89 mmol) of diethylazodicarboxylate was added, and the reaction mixture was kept at 0°-5° C. for 30 min and then the ice-water bath was removed. The reaction mixture was stirred at rt for 17 h. For isolation of the products the reaction mixture was chromatographed directly on a silica gel column, using ethyl acetate-hexane (1:3) as eluant, to yield 3-[(tert-butyldimethylsilyloxy)methyl]-6-[(2-chloro-5-trifluoromethyl-phenyloxy)methyl]-1,2-dithiin, 200 mg (62%); 1H NMR(CDCl3):δ7.54 (d, J=8, 1 H), 7.23 (d, J=8.4, 1 H), 7.16 (s, 1 H), 6.54 (d, J=6.4, 1 H), 6.42(d, J=6.4, 1 H), 4.78(s, 2 H), 4.31 (s, 2 H), 0.9 (s, 9 H), 0.1 (s, 6 H); MS (EI):m/z 468.1.