Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[C:23](=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)NCc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1)S(C)(=O)=O
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A flask is charged with N-[5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide (670 mg, 1.49 mmol), DMF (10 mL), dimethyl carbonate (403 mg, 4.47 mmol) and potassium carbonate (319 mg, 2.31 mmol), and the mixture is stirred at 150° C. for 5 h. The mixture is cooled to room temperature and purified using Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give N-[5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.74 (s, 3H), 3.02 (s, 3H), 4.35 (s, 2H), 7.04 (dd, J=8.5, 1.9 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.14 (t, J=2.1 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 9.05 (d, J=2.3 Hz, 1H), 11.92 (s, 1H). HRMS (ESI) m/z 350.0738 [(M+H)+ Calcd for C16H17ClN3O2S: 350.0730].
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2].[CH3:26]C[O-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:26])[C:16]2=[O:25])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1[N+](=O)[O-]
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)ccc1[N+](=O)[O-]

Procedure:
using ethyl 2-nitro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate with sodium ethylate in ethanol there is obtained ethyl 2-nitro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 188°-190° C.,
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:6]1)=[O:4].[OH-].[Li+].Cl>CO>[O:30]=[C:11]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:10][N:7]1[CH2:8][CH2:9][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 18 h

Procedure:
1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid methyl ester (compound 11 from Step 8, 3.3 gm, 8.06 mmol) was dissolved in methanol and 10 ml of 1N lithium hydroxide added. The reaction mixture was stirred for 18 hrs. 10 ml of 1N HCl was added to the reaction mixture and evaporated to a white solid (3.94 gm)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:11](=[S:13])[NH2:12])[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)[C:11]2[S:13][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(C(CCc2cccc(Br)c2)C(N)=S)cc1
Product: COC(=O)c1ccc(C(CCc2cccc(Br)c2)c2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Yield: 89.6 %

Procedure:
By a reaction in the same manner as in Example 178b and using the compound (3.15 g, 8.03 mmol) obtained in Example 181b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (3.22 g, 12.0 mmol), the title compound (4.03 g, 90%) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH:22](C(OC(C)(C)C)=O)[CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CCC(NCCc1cccc(N)c1)C(=O)OC(C)(C)C
Product: CCCNCCc1cccc(NS(=O)(=O)c2ccccc2F)c1

Procedure:
Using procedure 4, 2-fluorobenzenesulfonyl chloride was added to 2-(3-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine (13) to give the title compound as a solid, m.p. 165-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 77 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.41 (s, 1H), 7.30–7.27 (m, 6H), 6.96 (m, 2H), 3.51 (q, 1H, J=7.2 Hz), 3.50–3.30 (m, 2H), 3.02 (d, 1H, J=10.8 Hz), 2.92 (d, 1H, J=13.6 Hz), 2.50 (m, 1H), 2.41–2.34 (m, 4H), 1.99–1.94 (m, 2H), 1.86–1.58 (m, 8H), 1.51 (d, 3H, J=7.2 Hz), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 470.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:20][CH:21]([CH2:25][CH3:26])[C:22]([NH:1][C@H:2]([C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:3][OH:4])=[O:23]
Reactant: N[C@@H](CO)c1cc(F)cc(F)c1
Reactant: CCC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Cl)C(=O)N[C@@H](CO)c1cc(F)cc(F)c1
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-amino-2-(3,5-difluorophenyl)ethanol (2.60 g, 15.0 mmol, described in Intermediate 10) and triethylamine (4.19 mL, 30.0 mmol) in CH2Cl2 (150 mL) at 0° C. was slowly added 2-chlorobutyryl chloride (1.71 mL, 15.0 mmol). After 60 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—70:30 to 0:100, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH2:10]([NH:7][C:5](=[O:6])[CH:4]1[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)C1CCNCC1
Yield: 51.7 %

Procedure:
To a suspension of isonipecotamide (12.3 g, 96 mmol) in 200 mL of dichloromethane, was added, benzaldehyde (10.6 g, 100 mmol) and sodium triacetoxyborohydride (29.7 gm, 140 mmol) and the mixture was stirred at room temperature for 5 days. The thick white mixture was diluted with 100 mL water and extracted with EtOAc (2×20 mL). The aqueous phase was basified with 1N NaOH to pH>12. The resulting white precipitate was collected by suction filtration. The white solid was subsequently taken up in 50 mL of EtOAc, and was washed with 20 mL of brine, then dried (MgSO4), filtered and concentrated to give 10.84 g (50%) of the desired product. 1H-NMR (400 MHz, CDCl3) δ7.85 (m, 5H), 5.45 (s, 1H), 5.34 (s, 1H), 3.5 (s, 2H), 2.93 (d, J=10.96 Hz, 2H), 2.16 (t, J=12.13 Hz, 1H), 2.01 (t, J=11.74 Hz, 2H), 1.87 (d, J=12.52 Hz, 2H), 1.76 (q, J=12.52 Hz, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:11]=1[O:12][C:13]1[C:14]2[N:15]([CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:17][CH:18]=1>C(Cl)(Cl)Cl>[Br:1][C:21]1[CH:20]=[CH:19][N:15]2[C:14]=1[C:13]([O:12][C:11]1[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:10]=1[F:9])=[CH:18][CH:17]=[N:16]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(Oc2ccnn3cccc23)c(F)c1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Oc2ccnn3ccc(Br)c23)c(F)c1
Reaction time: 4 h
Yield: 28.4 %

Procedure:
N-Bromosuccinimide (1.49 g, 8.42 mmol) was added to a solution of 4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine (2.30 g, 8.42 mmol) in anhydrous chloroform (70 mL) at 0° C. and stirred for 4 hours. Upon completion of the reaction, the resulting mixture was washed by adding water thereto. The organic layer was separated, dried with magnesium sulfate, and then filtered. The filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to give the target compound as a yellow solid (840 mg, 2.39 mmol, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21]>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1cc(F)cc(NC(=O)c2c(Cl)ncnc2Cl)c1
Reactant: N
Solvent: C1COCCO1
Product: COc1cc(F)cc(NC(=O)c2c(N)ncnc2Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4,6-Dichloro-N-(3-fluoro-5-methoxyphenyl)pyrimidine-5-carboxamide (800 mg, 1.42 mmol) was dissolved in dioxane (5 ml) and cooled in an ice bath. Ammonia solution (1 ml, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h and overnight at room temperature. After evaporation of the solvent under reduced pressure, the residue (458 mg, 100%) was used in the next synthetic step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([N:23]2[C:27](=[O:28])[CH:26]=[CH:25][C:24]2=[O:29])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(N(CC)CC)C>[CH:17]1([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([S:11][C:9]3[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[C:24]2=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C1C=CC(=O)N1C1CCCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC2CC(=O)N(C3CCCCC3)C2=O)cc(C(C)(C)C)c1O
Yield: 50.3 %

Procedure:
The procedure of Example 1 is repeated using 11.95 grams of 2,6-di-tert-butyl-4-mercaptophenol, 8.96 grams of N-cyclohexylmaleimide, and 0.5 grams of triethylamine. The residue is recrystallized from a heptane-toluene mixture to give 10.5 grams of a white solid, m.p. 94°-98° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[Cl:38])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=3[Cl:38])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cc1ccc(C(=O)CCCCCBr)c(Cl)c1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)cc2Cl)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-chloro-4-methylphenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-chloro-4-methylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][OH:14].[Br:15][CH:16]([CH3:20])[C:17](Br)=[O:18]>C(Cl)(Cl)Cl>[Br:15][CH:16]([CH3:20])[C:17]([O:14][CH2:13][C:9]1[O:8][CH:12]=[CH:11][CH:10]=1)=[O:18]
Reactant: CC(Br)C(=O)Br
Reactant: OCc1ccco1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)OCc1ccco1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
Triethylamine (5.26 g, 0.052 mol) is added to an ice-cooled solution of 2 furylmethanol (5.10 g, 0.052 mol) in 70 ml of chloroform. This is followed by the gradual addition of 2-bromopropionyl bromide (9.93 g, 0.046 mol) in 10 ml of chloroform. The reaction mixture is stirred at RT for 24 h. To workup, the reaction mixture is washed with water (1 times 80 ml), 10% sulfuric acid (1 times 80 ml) and with saturated NaHCO3 solution (2 times 50 ml). The organic phase is dried over magnesium sulfate, concentrated and dried in a high vacuum. The yield is 67%.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[Na+].[C:14](=[O:16])=[O:15]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 180 °C
Yield: 75 %

Procedure:
p-Acetaminophenol 15 g, sodium hydroxide 37.5 g, and Y-type molecular sieve 15 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 2.0 MPa and heated to 180° C., maintained for 3 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve sodium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% of hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 99.5% and the yield is 75%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[CH:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)NCCc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 71.7 %

Procedure:
tert-Butyl 2-(2-cyano-4-pyridyl)ethylcarbamate (3.0 g, 12 mmol) and methyl thiosalicylate (3.6 g, 21 mmol) were dissolved in toluene (12 ml), and triethylamine (6.0 ml, 43 mmol) was added thereto. The mixture was refluxed for 8 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:1, v/v) were collected, concentrated and recrystallized from hexane-ethanol to give the titled compound (3.3 g, 71%) as white crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:29][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:7]=2[C:6]=1[CH3:30])=[O:4].[OH-].[Na+]>C(O)C.ClCCl.Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:30])=[C:5]([C:3]([OH:4])=[O:2])[S:29][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OCC3CCOCC3)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OCC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl-4-(4-fluoro-2-((tetrahydro-2-H-pyran-4-yl)methoxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (82 mg) and NaOH (2M; 0.5 ml) was dissolved in ethanol (2 ml). The reaction was stirred at room temperature overnight. Then the reaction mixture was diluted with dichloromethane and HCl (2M). The suspension was filtered, washed with brine and ether. The residue was dried in vacuo over P2O5.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:21]=[CH:20][C:9]2[C:10]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[N:11][O:12][C:8]=2[CH:7]=1>S(=O)(=O)(O)O.CCOCC.C(Cl)Cl>[Cl:5][C:6]1[C:21]([N+:1]([O-:4])=[O:2])=[CH:20][C:9]2[C:10]([O:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[N:11][O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C(C)Oc1noc2cc(Cl)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)Oc1noc2cc(Cl)c([N+](=O)[O-])cc12
Reaction time: 1 h

Procedure:
Nitric acid (70%, 3.0 mL, 47 mmol) is slowly added to a mixture of methyl 2-[(6-chloro-1,2-benzisoxazol-3-yl)oxy]propionate (6.0 g, 23.5 mmol) in concentrated sulfuric acid (50 mL) while maintaining the temperature below 10° C. The reaction mixture is stirred for 1 hour on an ice/water bath and poured onto ice. The resultant aqueous mixture is diluted with ether, stirred for several minutes and the ether is allowed to evaporate overnight. The resultant mixture is filtered to obtain a solid which is dissolved in methylene chloride. The methylene chloride solution is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a solid which is recrystallized from an ether/hexanes solution to give the title product as a solid, mp 98°-101° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH2:22](Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH3:22])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(2S)—N-(tert-Butoxycarbonyl)-3-(pyridin-3-yl)alanine (25.00 g, 93.88 mmol) is dissolved in 300 ml of dichloromethane under argon. Methanol (11.4 ml, 9.02 g, 281 mmol, 3 equivalents) and one grain of DMAP are added. The mixture is then cooled to 0° C. EDC (19.80 g, 103 mmol, 1.1 equivalents) is added. After 5 min, the ice bath is removed and the mixture is left to stir at RT over 1 h. The mixture is then concentrated in vacuo, and ethyl acetate is added to the residue and the mixture is extracted against a saturated sodium hydrogen carbonate solution. The aqueous phase is reextracted once with ethyl acetate, then the combined organic phases are washed with 0.5 M citric acid and then once again with a saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. An oil remains, which crystallizes during drying in an oil-pump vacuum. Yield: 23.60 g (90% of theory).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH:4]([OH:28])[C@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[C:2]([CH3:29])([CH3:3])[CH3:1]
Reactant: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(O)C(C)(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4R)-2,2-dimethyl-4-(trityl-amino)-hexan-3-ol (0.57 g, 1 eq, 1.47 mmol) in DCM (10 mL) under an argon atmosphere at room temperature, was added trifluoroacetic acid (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated from ether (3 mL) with hexane (20 mL) with sting to give a yellow oil. The solvent was decanted from the oil, and the oil was washed with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil; Yield: 0.21 g (100%). (55% de 3S,4R: 45% de 3R,4R) 1H-NMR (d6-DMSO, 250 MHz): δ 0.84-0.99 (m, 3H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 1.25-1.29 (m, 9H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 1.20-1.72 (m, 2H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 3.14 (m, 1H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 3.39 (m, 1H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 3.65 (m, 1H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 7.43, 7.77+8.54 (3×bs, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>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.[Pd]>[C:7]([O:11][C:12]([NH:14][C@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:1]=[O:4])[CH:22]=2)=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)[C@@H](Cc1ccc(-c2cccc(C=O)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 35 %

Procedure:
100 ml (201 mmol) of an aqueous 2M potassium carbonate solution and 4.4 g (3.80 mmol) of tetrakis palladium are introduced into a solution containing 33 g (77.3 mmol) of methyl (R)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl)propionate, and 15 g (100 mmol) of 3-boronic acid-benzaldehyde (Example 28b) in 300 ml of ethylene glycol dimethyl ether. The reaction medium is heated at 85° C. for 20 h and, after a return to ambient temperature, extracted with ethyl acetate. The organic phase is washed with water and then a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with a 7/3 heptane/ethyl acetate mixture. 10.2 g of coupled product are obtained with a 35% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:17])[C:13]([O:15]C)=[O:14])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].CO.Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:17])[C:13]([OH:15])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)Nc1ccccc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccccc1NC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate (154 g, 655 mmoles) and MeOH (1000 mL). The resulting mixture was stirred at a moderate speed at room temperature. A solution of 1N NaOH/MeOH (800 mL) was added dropwise to the reaction mixture via addition funnel. After 1 hour, agitation was stopped, and the suspension transferred to a filtration funnel and filtered to afford a white solid. This solid was then taken up in water (1200 mL) and the pH adjusted to 1.5–2 with addition of conc. HCl with stirring. After mixing for 1 hour, filtration and drying yielded the title compound as a white crystalline mass (127 g, 574 mmoles, 87.6%). TLC (silica F254, 3/1 v/v dichloromethane/MeOH, detection 254 nm) showed one spot and HPLC confirmed that. MP 110.9–112.6° C.; IR (KBr) 3405, 2973, 1688, 1548, 1300, 757 cm−1; 1H NMR (300 MHz, CDCl3): δ (ppm): 9.37 (br, 1H), 7.91 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.44 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.25 (m, 2H), 1.46 (s, 9H); 13C (300 MHz, CDCl3): δ (ppm): 160.87, 155.24, 141.18, 133.19, 126.92, 126.69, 126.63, 124.24, 34.21, 30.49.