Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[C:8](I)[CH:9]=1)=[O:4].[F:12][C:13]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)=[O:16].C(=O)(O)[O-].[Na+].O>[Pd].C1(C)C=CC=CC=1.CCOC(C)=O.C(O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[C:8]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C:14]3[C:13]([F:12])=[CH:36][CH:35]=[CH:34][C:33]=3[F:37])=[CH:19][CH:20]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(I)c(C)s1
Reactant: CC1(C)OB(c2ccc(NC(=O)c3c(F)cccc3F)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c(C)s1
Temperature: 100 °C
Yield: 12.9 %

Procedure:
A mixture of 4-Iodo-5-methyl-thiophene-2-carboxylic acid methyl ester (d, 1 mmol), 2,6-Difluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (c, 1 mmol), palladium catalyst (0.1 mmol), sodium bicarbonate (1 mmol) in a mixture of toluene (5 mL), water (1 mL), ethanol (1 mL) was heated at 100° C. for 24 h. The mixture was taken up with EtOAc (100 mL), washed with water (2×100 mL) and dried (Na2SO4). The oil obtained on concentration was purified by flash chromatography to give 4-[4-(2,6-Difluoro-benzoylamino)-phenyl]-5-methyl-thiophene-2-carboxylic acid methyl ester as a yellowish solid (50 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
580 mg of (2R,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-[2-{2-[2-(3,4-difluorophenyl)ethyl]-4-fluorophenoxy}ethyl]pyrrolidine [prepared as described in step (a) above] were dissolved in 5 ml of tetrahydrofuran, and then 0.31 ml of tetrabutylammonium fluoride were added to the resulting solution. The resulting mixture was then stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrated oily substance was purified by silica gel column chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 280 mg (yield 61%) of the title compound as a colorless solid substance.
Reaction SMILES: [CH:1]1([C:7]2([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:12][C:11](=[O:13])[CH:10]=[C:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:10]1[C:11](=[O:13])[O:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:8][C:9]=1[OH:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(C2CCCCC2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(C3CCCCC3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The title compound was prepared as described in General Method 9 from 6-cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example NN; 156 mg, 0.499 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 250 mg, 0.546 mmol), K2CO3 (303 mg, 2.195 mmol), and DMF (4 mL). The reaction was stirred at room temperature for 2.5 hours and then worked up in the usual manner. The crude product was flash chromatographed using CH2Cl2 : MeOH (98:2) to give the desired product as a solid, m.p. 138-139° C. (dec.). 1H NMR (CDCl3) δ 1.0-2.1 (m, 13 H), 1.58 (s, 9 H), 2.03 (s, 3 H), 2.6-2.7 (m, 3 H), 3.05 (d, 1 H), 4.6 (s, 2 H), 6.69-6.74 (d, s, 3 H), 6.98 (d, 2 H), 7.34 (s, 1 H), 7.74 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][C:7](OC)=[O:8])#[N:2]>CO.[Ni]>[O:5]1[C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[CH2:1][NH:2][C:7](=[O:8])[CH2:6]1
Reactant: COC(=O)COc1ccccc1C#N
Agent: [Ni]
Solvent: CO
Product: O=C1COc2ccccc2CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
The methanol solution of methyl (2-cyanophenoxy)acetate (40 g, 0.209 mol) was added to the mixture of Raney Ni (80 g) in 500 mL of methanol. The reaction mixture was stirred at room temperature overnight under hydrogen atmosphere. Raney Ni was removed by filtration, and the filtrated was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (methanol/dichloromethane, 1:50) to give 23 g of product. MS obsd. (ESI+) [(M+H)+] 164.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:9][S-:10].[Na+].O>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([S:10][CH3:9])[CH:7]=1
Reactant: C[S-]
Reactant: Clc1cnnc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cnnc(Cl)c1
Yield: 76 %

Procedure:
3,5-Dichloropyridazine, which is known in the art, (2.0 g, 0.0135 moles) and sodium thiomethoxide (1.14 g, 0.0162 moles) were stirred in THF (50 mL) at RT under N2 for 2 h. The mixture was then poured into water and extracted 2×100 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated in-vacuo to give a crude solid which was recrystallized from cyclohexane/ethyl acetate to give 3-chloro-5(methylthio)pyridazine (1.64 g, 76% yield) as a brown solid, mp=98° C.-100° C.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:24]([N:26]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25]>>[CH2:24]([N:26]([CH:37]1[CH2:42][CH2:41][N:40]([CH2:1][C@@H:3]2[CH2:5][C@@:4]2([CH2:12][N:13]([CH3:23])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:39][CH2:38]1)[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25]
Reactant: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1C=O)S(=O)(=O)c1ccccc1
Product: CCN(C(=O)OCc1ccccc1)C1CCN(C[C@@H]2C[C@@]2(CN(C)S(=O)(=O)c2ccccc2)c2ccccc2)CC1

Procedure:
N-{[(1S,2R)-2-formyl-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide and benzyl ethyl(piperidin-4-yl)carbamate (incorporating by reference as needed Bioorg. and Med. Chem. Lett., 11 (2001), 2475) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, DMSO-d8) δ 7.70-7.56 (m, 5H), 7.40-7.17 (m, 10H), 5.09 (s, 2H), 3.88 (d, J=13.3 Hz, 1H), 3.75 (m, 1H), 3.19 (q, J=6.6 Hz, 2H), 3.09-3.05 (m, 1H), 2.91-2.87 (m, 1H), 2.83 (d, J=13.3 Hz, 1H), 2.58-2.52 (m, 1H), 2.52 (s, 3H), 2.44-2.38 (m, 1H), 2.08-1.92 (m, 2H), 1.77-1.58 (m, 4H), 1.41-1.37 (m, 0.1H), 1.07 (t, J=6.6 Hz, 3H), 1.07-0.99 (m, 1H), 0.78 (m, 1H). ES-LCMS m/z 576.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]2[CH:19]=[C:20]([CH:22]=[C:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])[O:21][C:17]=2[CH:16]=1>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]2[CH:19]=[C:20]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])[O:21][C:17]=2[CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(C=C3SC(=O)NC3=O)oc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CC3SC(=O)NC3=O)oc2c1
Reaction time: 16 h
Yield: 37.9 %

Procedure:
A mixture of 5-[6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-2-benzofuranylmethylidene]-2,4-thiazolidinedione (0.80 g), palladium-carbon (5%, 1.60 g) and tetrahydrofuran (250 ml) was subjected to catalytic reduction at room temperature under a hydrogen pressure of 3.2 kgf/cm2 for 8 hours. After the catalyst was filtered off, the filtrate was subjected to catalytic reduction under constant conditions for additional 16 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform (1:5, v/v), crystals of 5-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranylmethyl]-2,4-thiazolidinedione (0.305 g, 38%) were obtained, which was then recrystallized from dichloromethane-methanol to yield yellow needles having a melting point of 179° to 180° C.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:26]4[CH:25]=[N:24][C:33]5[C:28]([CH:27]=4)=[CH:29][CH:30]=[CH:31][CH:32]=5)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cnc4ccccc4c3)sc2n1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (90 mg, 0.208 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 3-quinolinylboronic acid (72.1 mg, 0.417 mmol), bis(triphenylphosphine)palladium(II) chloride (14.63 mg, 0.021 mmol) and potassium carbonate (101 mg, 0.730 mmol) and the reaction mixture heated at 100° C. for 30 min using a microwave reactor. The mixture was then filtered through celite, washing with DCM (30 mL×2) and the filtrate dried (phase separation cartridge) and concentrated. This residue was then purified by MDAP (basic conditions) and then further triturated with MeOH (2 mL) and dried, to afford the title compound (31.61 mg). LCMS (A) m/z: 480 [M+1]+, Rt 1.23 min (acidic).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].[CH3:32][N:33]([CH3:48])[C:34]1[CH:47]=[CH:46][C:37]([CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][C@@H:42](O)[CH2:41]2)=[CH:36][CH:35]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.CCOCC>[CH3:48][N:33]([CH3:32])[C:34]1[CH:35]=[CH:36][C:37]([CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][C@H:42]([O:28][C:27](=[O:29])[C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)[CH2:41]2)=[CH:46][CH:47]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)c1ccc(CCN2CC[C@@H](O)C2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)c1ccc(CCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C

Procedure:
Triphenylphosphine (1.72 g, 5.13 mmol) and 4-nitrobenzoic acid (0.86 g, 5.13 mmol) were added to a solution of (R)-1-(4-dimethylaminophenethyl)-3-hydroxypyrrolidine in anhydrous tetrahydrofuran (20 ml) under argon atmosphere. 40% solution (2.32 ml, 5.13 mmol) of diethyl azodicarboxylate in toluene was added dropwise in the obtained mixture under stirring at room temperature. After stirring at room temperature for 2 hours, 60 ml of ether was added to the reaction liquid. The reaction mixture was washed with water, then with saturated aqueous sodium hydrogencarbonate solution and finally with saturated aqueous sodium chloride solution. The organic layer was dried, and the solvent was evaporated under reduced pressure. Ethyl acetate and hexane were added to the obtained residue, and the crystals thus formed were taken by the filtration. The filtrate was evaporated under reduced pressure, and the residue was distributed in dichloromethane and 1 M-HCl. 4M-NaOH was added to the aqueous layer to make it strongly alkaline. After the extraction with dichloromethane, the organic layer was dried and the solvent was distilled under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1), then with a mixture of the same solvents (3:1) and finally with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain the title compound in the form of a light yellow oil (860 mg, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].N1CCCC1.[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)=[O:23])=[CH:20][C:19]=1[C:33]([F:36])([F:35])[F:34].Cl>ClCCl.C(OCC)(=O)C.CO>[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([N:24]2[CH2:25][CH2:26][C:27]3([CH2:9][C:8](=[O:10])[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[O:1]3)[CH2:28][CH2:29]2)=[O:23])=[CH:20][C:19]=1[C:33]([F:36])([F:34])[F:35]
Reactant: CC(=O)c1ccccc1O
Reactant: COc1ccc(C(=O)N2CCC(=O)CC2)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N2CCC3(CC2)CC(=O)c2ccccc2O3)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
1-(2-Hydroxyphenyl)ethanone (1.80 g, 13.3 mmol) was added portion wise at 25° C. to pyrrolidine (2.20 mL, 26.6 mmol) followed by portion-wise addition of 1-(4-methoxy-3-(trifluoromethyl)benzoyl)piperidin-4-one (4.00 g, 13.3 mmol). Anhydrous methanol (868 μL) was then added and the red slurry was heated at 80° C. for 3 hours. The reaction was cooled to 25° C. and was stirred overnight. Ethyl acetate (5 mL) and 1M HCl (aq, 5 mL) were added. The aqueous layer was separated and discarded. 1M NaOH (aq, 5 mL) was added and the aqueous layer was separated and discarded. A brine solution was added (10 mL) and the aqueous layer was separated and discarded. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated to provide an oil. The crude oil was dissolved in dichloromethane and was purified by column chromatography using 0-50% ethyl acetate/hexanes to provide 1′-(4-methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4′-piperidin]-4-one (4.4 g, 79%) as a off-white solid. ESI-MS m/z calc. 419.4. found 420.2 (M+1)+. Retention time: 2.63 minutes (4 min run).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:15]([O-])=O)=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[H][H]>CO.[Pd]>[NH2:12][C:5]1[CH:4]=[C:3]([NH2:15])[C:2]([F:1])=[CH:7][C:6]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N)c(CC(=O)O)cc1F
Yield: 99.9 %

Procedure:
(5-Fluoro-2,4-dinitro-phenyl)-acetic acid 3b (10 g, 38.7 mmol) was dissolved in 150 ml of methanol under stirring, and added with palladium on activated carbon (1.5 g, 5%) to the solution at room temperature. The reaction mixture was hydrogenated under 0.3 Mpa of hydrogen. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered twice, and concentrated under reduced pressure to obtain the title compound (2,4-diamino-5-fluoro-phenyl)-acetic acid 3c (7.12 g) as a brown solid to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](C=O)=[CH:8][CH:7]=[CH:6]2.[CH2:15]1COC[CH2:16]1>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:15]=[CH2:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C=O)cccc2c1
Reactant: C1CCOC1
Solvent: CCOCC
Product: C=Cc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
6-Methoxy-naphthaldehyde (432 mg, 2.35 mmol) is added to a solution of instantaneous ylide (Ph3P+Br−+NaNH2, 1.48 g, 2.4 mmol) in anhydrous THF (5 ml). After one hour of stirring at ambient temperature, it is diluted with ether, it is filtered on Celite, and it is chromatographed (hexane/AcOEt 5:1) to obtain 6-methoxy-2-vinyl-naphthalene (390 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cccc(C(C)O)n1
Temperature: -10 °C
Yield: 100 %

Procedure:
To a −60° C. solution of 6-methyl-pyridine-2-carbaldehyde (25 g, 206 mmol) in tetrahydrofuran (200 mL) was added methyl magnesium bromide (200 mL, 1.4 M in tetrahydrofuran/toluene, 1.36 equiv) over 40 minutes. The reaction mixture was slowly warmed to −10° C. over 90 minutes, and then slowly quenched with saturated aqueous ammonium chloride (75 mL). The liquid phase was decanted from the solids and concentrated in vacuo. The resulting residue was dissolved in methylene chloride, dried over magnesium sulfate, and concentrated in vacuo to yield the title compound (28 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-])=O)=[C:4]([F:13])[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][NH2:8])=[C:4]([F:13])[CH:3]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: NCCc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-fluoronitro styrene (1 equivalent) in THF (0.2 M) was cooled to 0° C. and treated with 1.0 M BH3 in THF (5 equivalents). The reaction was heated to reflux overnight. The reaction was cooled to 0° C. and quenched with H2O then 1 N HCl until a pH of about 2 was achieved. The reaction was stirred for 30 minutes at room temperature and then extracted with ether (3×). The aqueous layer was made basic with 5% NaOH solution. The aqueous layer was then extracted into ether (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude 2-(4-bromo-2-fluorophenyl)ethylamine. Purification by flash chromatography eluting with 2%-5%-10% MeOH/CH2Cl2 gradients containing 1% concentrated ammonia afforded the desired compound. MS m/z 219.8 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:6]([N+:19]([O-])=O)=[CH:5][CH:4]=1.[Sn]>CO.Cl>[NH2:19][C:6]1[C:7]([CH2:9][S:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccccc2)n1
Agent: Cl
Agent: [Sn]
Solvent: CO
Product: COc1ccc(N)c(CS(=O)(=O)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
A stirred mixture of 6-methoxy-3-nitro-2-[(phenylsulfonyl)methyl]-pyridine (6.17 g, 20.0 mmol) in methanol and concentrated HCl (50 mL) is treated with thin strips of tin foil (10.0 g, 84.2 mmol), heated at 60° C. for 20 h, and filtered hot. The filtrate is poured over ice and 2.5N aqueous NaOH, stirred for 0.5 h and filtered. The filtercake is air-dried to afford the title compound as a white solid 5.26 g (94% yield), identified by mass spectral and HNMR analyses.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[Cl:19][C:20]1[CH:36]=[CH:35][C:23]([CH2:24][N:25]2[C@H:29]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:33])[NH:27][C:26]2=[O:34])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C@H:29]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:33])[N:27]([CH2:2][C:3]3[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[C:26]2=[O:34])=[CH:35][CH:36]=1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: CC(C)[C@@H]1C(=O)NC(=O)N1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1C(=O)N(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)C(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
To a solution of 0.5 g (1.63 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in DMF (5 ml) are added 0.653 g of (2.45 mmoles) of (R)-1-(4-chloro-benzyl)-5-isopropyl-imidazolidine-2,4-dione and 0.293 g (2.12 mmoles) of K2CO3 at ambient temperature under N2 atmosphere. The mixture is stirred at ambient temperature for 15 hours. The mixture is diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The crude product is purified by silica gel column chromatography to give 0.644 g of desired 6-[(R)-3-(4-chloro-benzyl)-4-isopropyl-2,5-dioxo-imidazolidin-1-ylmethyl]-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]([OH:18])[CH2:16]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O.C(O)CCC>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:18][CH:15]([C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[Cl:12])[CH2:16][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: OCC(O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCO
Product: Clc1ccc(C2(CBr)OCC(c3ccccc3Cl)O2)cc1

Procedure:
A mixture of 11.5 parts of 2-bromo-p-chloroacetophenone, 10.4 parts of o-chloro-α-(hydroxymethyl)benzylalcohol, 0.2 parts of p-toluenesulfonic acid, 180 parts of benzene and 80 parts of butanol is stirred and refluxed overnight with water-separator. The solvent is removed in vacuo and the residue is dissolved in chloroform. The chloroform solution is stirred with silica gel for 30 minutes. The silica gel is filtered off and the solvent is removed in vacuo, yielding 2-(bromomethyl)-4-(o-chlorophenyl)-2-(p-chlorophenyl)-1,3-dioxolane as a residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][O:17]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:20]([NH2:25])([CH2:23][CH3:24])([CH3:22])[CH3:21]>C(O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:17])[CH2:18][NH:25][C:20]([CH3:22])([CH3:21])[CH2:23][CH3:24])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CO2)cc1
Reactant: CCC(C)(C)N
Solvent: CCO
Product: CCC(C)(C)NCC(O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
30 mg of the compound [7-2] was dissolved in 2 mL of ethanol, then 2 mL of tert-amylamine was added thereto, and the mixture was stirred overnight at 50° C. The reaction solution was concentrated, and then the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-20/80), to obtain 31 mg of tert-butyl[(1S)-1-(4-{2-[(1,1-dimethylpropyl) amino]-1-hydroxyethyl}phenyl)ethyl]carbamate [7-3] (hereinafter, referred to as the compound [7-3]) as a colorless oily product.