Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH2:25]([O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1)[CH3:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:31]4[CH:30]=[N:29][C:28]([O:27][CH2:25][CH3:26])=[N:33][CH:32]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: CCOc1ncc(B(O)O)cn1
Product: CCOc1ncc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cn1
Yield: 2.5 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-ethoxypyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 84 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(2-ethoxy-pyrimidin-5-yl)-benzoic acid (3 mg, 3%). LCMS analysis indicated that the material was ˜69% pure, as measured by UV at 214 nm. LRMS m/z 471.8 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:20][C@@H:19]2[CH2:21][OH:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[CH2:20][C@@H:19]2[CH:21]=[O:22])=[CH:16][CH:17]=1
Reactant: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (17.50 mL, 2 M in DCM, 35.0 mmol) in DCM (150 mL) under nitrogen atmosphere and cooled to −78° C. was added drop wise DMSO (4.97 mL, 70.0 mmol), followed with the dropwise addition of a solution of the product from Example 34D, ((1S,2S)-2-(4-bromophenyl)cyclopropyl)methanol (5.3 g, 23.34 mmol) in DCM (100 mL). The mixture was stirred 30 minutes at −78° C. Then the mixture was treated with triethylamine (13.01 mL, 93 mmol), and then the reaction temperature was raised to ambient temperature. The mixture was partitioned between DCM (400 mL) and H20 (400 mL). The organic layer was separated, washed with water, dried and concentrated under reduced pressure to provide the title product. 1H NMR (300 MHz, CDCl3): δ 1.48 (m, 1H), 1.65 (dt, J=9 Hz, J=6 Hz, 1H), 2.15 (m, 1H), 2.57 (m, 1H), 6.98 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H), 9.46 (d, J=4.5 Hz, 1H). MS (DCl—NH3) m/z 226 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:13][CH:12]3[CH:9]([C:10](=[O:41])[N:11]3[C@H:14]([C:31]([CH2:33][O:34]C(=O)C(F)(F)F)=[CH2:32])[C:15]([O:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C(Cl)Cl>[C:1]1([C:7]2[O:13][CH:12]3[CH:9]([C:10](=[O:41])[N:11]3[C@H:14]([C:31]([CH2:33][OH:34])=[CH2:32])[C:15]([O:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(COC(=O)C(F)(F)F)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(c3ccccc3)OC21
Solvent: ClCCl
Solvent: CO
Product: C=C(CO)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(c3ccccc3)OC21
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
To a solution of 240 mg of diphenylmethyl (2R)-2-(3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-3-trifluoroacetyloxymethyl-3-butenoate in 10 ml of a mixture (4:1) of methanol and methylene chloride is added 4.8 g of silica gel containing 10% water, and the mixture stirred for 30 minutes and filtered. The filter cake, silica gel, is washed several times with a mixture of methanol and methylene chloride. The combined filtrate and washings are evaporated under reduced pressure. The oily residue is chromatographed on 12 g of silica gel. Elution with a mixture (2:1) of benzene and ethyl acetate yields 106 mg of diphenylmethyl (2R)-2-(3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-3-hydroxymethyl-3-butenoate in 53% yield and 90 mg of the starting material in 35% recovery.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[NH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)N>>[CH2:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:23]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccncc1
Product: CCc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccncc3)n2)c1
Yield: 47 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-ethyl-phenyl)-1H-pyridazin-4-one (A-4) and 4-hydrazinopyridine according to the method described for Example 1 in 47% yield. MS: M=344.1 (M+H)+
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[Cl:6][C:7]1[CH:8]=[C:9]([NH2:15])[C:10]([NH2:14])=[CH:11][C:12]=1[I:13]>O.CCO>[Cl:6][C:7]1[C:12]([I:13])=[CH:11][C:10]2[NH:14][C:3](=[S:5])[NH:15][C:9]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(I)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1

Procedure:
KOH (15.7 g, 238 mmol) in water (50 mL), followed by carbon disulfide (14.4 mL, 238 mmol), was added to a solution of 4-chloro-5-iodobenzene-1,2-diamine (50 g, 198 mmol) in EtOH (300 mL). The mixture was heated at reflux for 3 h, cooled and filtered. To the filtrate was added water (300 mL) and then AcOH (25 mL) in water (50 mL). The precipitate was collected, washed with water and a small amount of EtOH and dried to afford the desired product as a brown powder, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[CH2:28]([O:35][C:36]1[CH:37]=[C:38](B(O)O)[C:39]([F:42])=[N:40][CH:41]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([O-])(=O)C.[K+]>O.CCO>[CH2:28]([O:35][C:36]1[CH:37]=[C:38]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)[C:39]([F:42])=[N:40][CH:41]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: OB(O)c1cc(OCc2ccccc2)cnc1F
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(OCc4ccccc4)cnc3F)n2)cc1
Temperature: 100 °C
Yield: 41.8 %

Procedure:
A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.150 g, 0.390 mmol), 5-(benzyloxy)-2-fluoropyridin-3-ylboronic acid (0.107 g, 0.432 mmol), Amphos (Aldrich) (0.014 g, 0.020 mmol), potassium acetate (Strem) (0.119 g, 1.22 mmol), EtOH (3 mL), and water (0.3 mL) was sealed under N2 and heated in a microwave at 100° C. for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 10% to 20% EtOAc in hexanes) to give the product as a white solid (0.090 g). m/z (ESI, +ve ion) 552.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J=7.31 Hz, 1H); 8.01 (br. s., 1H); 7.31-7.48 (m, 5H); 7.23 (d, J=7.89 Hz, 4H); 6.87 (t, J=7.60 Hz, 4H); 5.13 (s, 2H); 4.81 (d, J=6.28 Hz, 3H); 3.81 (d, J=8.33 Hz, 6H); 2.55 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1>O1CCOCC1>[CH2:20]([O:19][C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:2]2[N:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][N:3]=2)[CH2:12][CH2:13]1)=[O:18])[CH3:21]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 60 °C
Yield: 49.3 %

Procedure:
(2-Chloropyrimidin-5-yl)boronic acid (2 g, 13 mmol) and ethyl piperidine-4-carboxylate (1.94 mL, 13 mmol) were dissolved in 1,4-dioxane (20 mL) and heated to 60° C. under microwave irradiation for 1 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness, to afford the title compound (1.79 g, 51%) as a yellow gum. Method C HPLC-MS: MH+ m/z 280, RT 0.94 minutes (89%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34].C(N(CC)CC)C.O>CN(C)C=O>[CH2:12]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][CH:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C1OCCC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OCCC1N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
Dissolved in 40 ml of dimethylformamide were 8.54 g of L-phenylalanine benzyl ester p-toluenesulfonate and 3.40 g of 2-bromo-γ-butyrolactone. After a dropwise addition of 4.04 g of triethylamine, the resultant mixture was heated and stirred at 70° C. for 18 hours. The reaction mixture was poured into chilled water, followed by extraction with ethyl acetate. The extract was washed successively with water, a 2% aqueous solution of sodium hydrogencarbonate, and water. After drying the extract over anhydrous sodium sulfate, it was distilled under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (toluene:ethyl acetate=20:1-5:1). From initial fractions of the column effluent, 1.75 g of N-(2-oxo-3-tetrahydrofuranyl)-L-phenylalanine benzyl ester (Isomer A) was obtained as a colorless oily substance.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]4[S:21][CH:20]=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:22])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23]1(=[N:27][S:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])[CH2:26][CH2:25][CH2:24]1>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]4[S:21][C:20]([C:23]5([NH:27][S:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[O:29])[CH2:24][CH2:25][CH2:26]5)=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:22])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cncs2)c1
Reactant: CC(C)(C)S(=O)N=C1CCC1
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC3)s2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added IDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CCN(C(C)C)C(C)C.[Cl:21][CH:22]([CH3:26])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23](=[O:24])[CH:22]([Cl:21])[CH3:26]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)C(C)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To methyl anthranilate (5 g, 33.1 mmol) stirring in DCM at 0° C. under N2 was added DIEA (5.1 g, 39.7 mmol) in one portion followed by the dropwise addition of 2-chloropropionyl chloride (4.2 g, 33.1 mmol). The reaction was allowed to stir at 0° C. for 30 min. then warmed to room temperature, stirring for an additional 3 h. The reaction was treated with saturated aqueous solution of NaHCO3 and the resulting biphasic mixture transferred to a separatory funnel. The layers separated and the aqueous layer was extracted twice more with DCM (25 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under vacuum to afford the desired product (7.75 g, 97% yield), which was used without further purification. 1H-NMR (CDCl3): δ 11.8 (br, 1H), 8.72 (dd, 1H), 8.08 (dd, 1H), 7.58 (m, 1H), 7.15 (m, 1H), 4.56 (q, 1H), 3.97 (s, 3H), 1.85 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([CH:19]=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 5.6 %

Procedure:
25.8 g (0.1 mol) of 4,4'-dibromostilbene, 10 g (0.1 mol) of ethyl acrylate, 18.5 g (0.1 mol) of tri-n-butylamine, 0.224 g (0.001 mol) of palladium acetate and 0.6 g (0.002 mol) of tri-o-tolylphosphine are added under argon to 50 ml of p-xylene. The reaction mixture is stirred at 90° C. for 4 hours. Working up gives 2 g (6% of theory) of ethyl 4-bromostilbene-4'-acrylate. Melting point 166.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[NH2:21][CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24].CO.C(Cl)(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:26][C:23]([CH3:25])([CH3:24])[CH2:22][NH2:21])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CC(C)(N)CN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NC(C)(C)CN)c1C
Reaction time: 24 h
Yield: 57.6 %

Procedure:
A stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (4.42 g, 20.0 mmol) in 50 mL of anhydrous DMF, under N2, was treated with triethylamine (5.58 mL, 40.0 mol) and 1,2-diamino-2-methylpropane (2.10 mL, 20.0 mmol). After stirring for 24 h, the reaction mixture was concentrated under reduced pressure. The resulting oil was treated with CH2Cl2 (200 mL) and H2O (100 mL). The aqueous layer was made basic (pH˜12) by addition of concentrated NH4OH solution. The layers were separated and the aqueous portion was extracted with an additional 100 mL of CH2Cl2. The combined organic portions were washed with H2O (2×) and brine. The organic portion was dried with Na2SO4 and concentrated to give an orange oil that solidified on standing. Column chromatography (SiO2, 2% MeOH/CHCl3) gave N′-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-2-methylpropane-1,2-diamine (3.14 g) as a yellow solid.
Reaction SMILES: CS/[C:3](/[N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)=[O:15])[C@@H:10]([C:27]([O:29][CH3:30])=[O:28])[CH2:9]1)=[CH:4]\[N+:5]([O-:7])=[O:6].C(O)C.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[N+:5](/[CH:4]=[C:3](/[N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)=[O:15])[C@@H:10]([C:27]([O:29][CH3:30])=[O:28])[CH2:9]1)\[N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)([O-:7])=[O:6]
Reactant: COC(=O)[C@H]1CN(/C(=C/[N+](=O)[O-])SC)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Reactant: C1CCNCC1
Solvent: CCO
Product: COC(=O)[C@H]1CN(/C(=C/[N+](=O)[O-])N2CCCCC2)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 70.5 %

Procedure:
To a stirred solution of methyl(3R,4S)-1-[(Z)-1-(methylthio)-2-nitrovinyl]-4-[(3R)-3-phenylpyrrolidin-1-yl]carbonylpiperidine-3-carboxylate (81.0 mg, 0.000187 mol) in ethanol (3.0 mL, 0.051 mol) was added piperidine (92.8 uL, 0.000934 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 17 h 45 min. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 0-8% MeOH/CH2Cl2 to give the product as a yellow solid (62 mg, 71% in yield). MS (ESI): (M+H)+=471.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[CH2:20]([OH:22])[CH3:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:22][CH2:20][CH3:21])[N:3]=1
Reactant: CCO
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCOc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a stirred suspension of 300 mg (1.10 mmol) 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile in 15 ml dry DME were added 0.23 ml (3.86 mmol) ethanol and 0.25 ml (1.65 mmol) DBU and stirring continued for 2 hours at room temperature. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/4) followed by trituration in ether/hexane afforded 21 mg (8%) 2-amino-6-ethoxy-4-furan-2-yl-pyridine-3,5-dicarbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 254 (M+, 90), 226 (100), 198 (44), 143 (26).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1cc(Br)ncc1F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)ncc1F
Yield: 77 %

Procedure:
2-Bromo-5-fluoroisonicotinic acid (500 mg, 2.27 mmol) was dissolved in ethanol (22.7 mL), and the solution was stirred under heat and reflux for 1 hour after adding thionyl chloride (0.829 mL, 11.3 mmol). The solvent was then evaporated under reduced pressure. The residue was extracted with chloroform after adding a sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→4/1) to give ethyl 2 bromo-5-fluoroisonicotinate (434 mg, yield 77%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[C:10]1([CH:17]=[CH:16][C:14](O)=[CH:13][CH:12]=1)[OH:11]>O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][C:14]1[CH:16]=[CH:17][C:10]([OH:11])=[CH:12][CH:13]=1)=[O:8]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: Oc1ccc(O)cc1
Solvent: O
Product: O=C1CC[C@@H](C(=O)Oc2ccc(O)cc2)N1
Reaction time: 18 h

Procedure:
129 g (1 mol) of (l)-pyroglutamic acid and 110 g (1 mol) of hydroquinone are intimately mixed, the mixture is stirred at 175° under a stream of nitrogen for 18 hours, the temperature is lowered to 50° and the mixture is diluted with water (300 ml) and extracted with ethyl acetate (3×400 ml). A crude product is thus prepared which is purified by being made into a paste twice with ethyl acetate (250 ml) to give the title derivative in the form of crystals melting at 179°/82°. In TLC, the product shows a single spot of Rf(i)=0.33.
Reaction SMILES: C(OC(C1C(OCCC2CCN(C(OC(C)(C)C)=O)CC2)=NC(C#N)=NC=1Cl)=O)C=C.C1C2(CCC(CN)CC2)CC1.C(N(CC)CC)C.C([O:53][C:54]([C:56]1[C:57]([O:75][CH2:76][CH2:77][CH:78]2[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:80][CH2:79]2)=[N:58][C:59]([C:73]#[N:74])=[N:60][C:61]=1[NH:62][CH2:63][CH:64]1[CH2:72][CH2:71][C:67]2([CH2:70][CH2:69][CH2:68]2)[CH2:66][CH2:65]1)=[O:55])C=C.N1CCOCC1>C(C#N)C.CCOC(C)=O.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>[C:87]([O:86][C:84]([N:81]1[CH2:82][CH2:83][CH:78]([CH2:77][CH2:76][O:75][C:57]2[C:56]([C:54]([OH:55])=[O:53])=[C:61]([NH:62][CH2:63][CH:64]3[CH2:72][CH2:71][C:67]4([CH2:70][CH2:69][CH2:68]4)[CH2:66][CH2:65]3)[N:60]=[C:59]([C:73]#[N:74])[N:58]=2)[CH2:79][CH2:80]1)=[O:85])([CH3:90])([CH3:88])[CH3:89]
Reactant: C=CCOC(=O)c1c(NCC2CCC3(CCC3)CC2)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CCOC(=O)c1c(Cl)nc(C#N)nc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: NCC1CCC2(CCC2)CC1
Solvent: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CCC4)CC3)c2C(=O)O)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-6-chloro-2-cyanopyrimidine-5-carboxylic acid allyl ester (1.1 mmol) and C-Spiro[3.5]non-7-yl-methylamine (1.4 mmol) in C2H5CN (10 mL) is added triethylamine (2.8 mmol) at room temperature. After stirring at 80° C. for 1 h, the reaction mixture is cooled to room temperature and diluted with AcOEt. The organic layer is washed with H2O and aq. KHSO4 and brine. The organic layer is dried over MgSO4 and evaporated in vacuo, which is directly used for the next reaction without further purification. To a solution of the crude 4-[2-(1-tert-butoxy carbonylpiperidin-4-yl)ethoxy]-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidine-5-carboxylic acid allyl ester (1.1 mmol) in THF (5 mL) are added morpholine (3.4 mmol) and Pd(PPh3)4 (0.06 mmol) successively. After stirring at the same temperature for 0.5 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The residue is purified by silica gel column chromatography to give a 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidine-5-carboxylic acid as yellow pale solid; 1H-NMR (CDCl3), δ: 0.97-1.08 (2H, m), 1.15-1.29 (5H, m), 1.48 (9H, s), 1.48-1.86 (15H, m), 2.69 (2H, t), 3.39 (2H, t), 4.11 (2H, m), 4.66 (2H, t), 9.42 (1H, br t).