Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:10]([Br:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1.C(#N)CC>>[Br:11][C:10]1[C:5]([C:2]#[N:3])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: N#C[Cu]
Reactant: Clc1cnc(Br)c(Br)c1
Solvent: CCC#N
Product: N#Cc1ncc(Cl)cc1Br
Yield: 83.2 %

Procedure:
A microwave vial was charged with copper (I) cyanide (1.089 g, 12.16 mmol), 2,3-dibromo-5-chloropyridine (3 g, 11.06 mmol), and propionitrile (15 mL). The vial was capped and irradiated in a microwave reactor at 150° C. for 2.5 hours. The solution was concentrated, diluted with DCM (25 mL), and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography, eluting with 0-30% EtOAc in heptanes, to afford the title compound (2 g, 9.20 mmol). MS m/z=219 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Br)nc(C)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1cc(-c2cc(C)c(Br)c(C)c2)nc(C)n1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 4-bromo-2,6-dimethyl-pyrimidine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=1.01 min; Mass spectrum (ESI+): m/z=291/293 (Br) [M+H]+.
Reaction SMILES: CO[CH:3]([O:14][CH3:15])[CH2:4][O:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.C1(C)C=C[C:20]([S:23](O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:6]([O:5][CH2:4][CH:3]1[S:23][CH2:20][CH2:15][O:14]1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(COC(=O)c1ccccc1)OC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Yield: 5173.6 %

Procedure:
Aliquots of 2-benzoyloxyacetaldehyde dimethyl acetal (50.0 g) prepared according to Example 1,2-mercaptoethanol (20.4 g), p-toluenesulfonic acid monohydrate (0.90 g) and toluene (250 mL) were placed in a three-neck flask, followed by heating. By-produced methanol was distilled off with the solvent. After distilling off about 150 mL, the reaction mixture was cooled to room temperature, was washed with a saturated aqueous sodium hydrogen carbonate solution and water and was dried over anhydrous sodium carbonate. After filtration and vacuum distillation at 144-147° C. and at 0.60 mmHg, the target compound (54.9 g) was obtained in a yield of 100%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([O:11][CH:12]([F:14])[F:13])[CH:6]=1)=[O:4].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[Cl:15][C:6]1[C:7]([O:11][CH:12]([F:14])[F:13])=[N:8][N:9]([CH3:10])[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(OC(F)F)nn1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)c(OC(F)F)nn1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of 400 mg (1.94 mmol) of methyl-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate in 10 ml of N,N-dimethylformamide is admixed at 0° C. with 389 mg (2.91 mmol) of N-chlorosuccinimide and then stirred for 8 hours at 80° C. The reaction solution is poured onto water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. This gives 466 mg of methyl 4-chloro-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate (99%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[C:19]#[CH:20]>CO>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:21][CH2:18][C:19]#[CH:20])#[N:2]
Reactant: C#CCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CO
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The mixture of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea (10.0 g; 0.0371 mole) and distilled propargylamine (20 ml; 0.325 mole) in methanol (50 ml) was stirred at reflux, under a positive pressure nitrogen atmosphere (nitrogen sweep), for 20.5 hours. The solvent and excess amine were then removed by evaporation to leave a yellow-brown oil that readily crystallized. Trituration of the crude product under isopropanol (30 ml) gave the title compound as an off-white, friable solid (8.11 g, 79%); m.p. 146°-148.5°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7][C:6]=2[C:5]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+:28]>O>[Na+:28].[Na+:28].[Na+:28].[NH2:1][C:2]1[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:7][C:6]=2[C:5]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)[O-])c2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Temperature: 25 °C

Procedure:
To a warm solution of 23.8 g of 80.5% 8-amino-1,3,5-naphthalenetrisulfonic acid in 25 ml of water and 25 ml of 5 N sodium hydroxide are slowly added 125 ml of absolute ethyl alcohol with vigorous stirring. The mixture is cooled to room temperature, is filtered and washed with 50 ml of 80% aqueous ethyl alcohol, then ethyl alcohol and ether. The material is dried overnight at 110° C. to give 21.0 g of 8-amino-1,3,5-naphthalenetrisulfonic acid trisodium salt as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH:21][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: Nc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)CCCNc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
A mixture of 7-Chloro-2-(5-aminobenzofuran-2-yl)-quinoline (0.17 g), sodium bicarbonate (0.2 g), ethyl 4-bromobutyrate (0.12 g) in hexamethylphosphoric triamide ml) was stirred at ambient temperature for 1 day. The resulting mixture was poured into ice-water. The appeared precipitates were collected by filtration, washed with water, and recrystallized from ethanol to give 7-chloro-2-[5-(3-ethoxycarbonylpropylamino)benzofuran-2-yl]quinoline (0.13 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[CH3:24][C:25]([NH2:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]>>[CH3:24][C:25]([NH:33][C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3)=[O:22])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: CC(C)(N)c1ccccc1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccccc1
Yield: 68 %

Procedure:
The title compound was prepared in a yield of 68% in a similar manner to that described in Example 37 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1-methyl-1-phenylethylamine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:29])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OC(C)(C)C)[C@H:16]([OH:28])[CH2:15]2)=[N:4][CH:3]=1.[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:20][C@H:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:29])[CH2:15][C@H:16]1[OH:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl {(3R,4S)-1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-3-hydroxy-4-piperidinyl}carbamate (240 mg, 0.5905 mmol) was dissolved in DCM (10 ml) and the solution was treated with 4M hydrogen chloride in 1,4-dioxane (2 mL). Effervescence and formation of a precipitate was observed. After 2 h, the solvents were removed under reduced pressure and the residue was dried under reduced pressure overnight, to give 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one dihydrochloride as an off-white solid (220 mg).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:27]#[N:28])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[NH2:26])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:27]([NH2:28])=[O:35])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[NH2:26])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2S)-2-aminocyclohexylamino)pyrazine-2-carbonitrile (28 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (26 mg). MS 394.4 (M+H); UV 201.7, 262.8, 304.6, 359.2 nm; t 0.520 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[O:26][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CCCC1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CCCC3)n(Cc3ccccc3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 2-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-5-chloro-phenol (Example 48, intermediate a) and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Colorless powder (33%). MS (Turbo Spray): m/z=453.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>CN(C)C=O>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cccc(C#N)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cccc(C#N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture of 3-methyl-2-nitrobenzonitrile from Example 1c (5.72 g) and tert-butoxy-bis(dimethylamino)methane (9.5 ml) in dimethylformamide (30 ml) was heated to 90° with stirring for 1.5 hours. After cooling to ambient temperature the mixture was partitioned between ethyl acetate and water. The layers were separated with the aqueous phase further extracted using two portions of ethyl acetate. The combined ethyl acetate layer was washed with water then brine. The solution was dried over MgSO4 and filtered through a small pad of silica gel. After concentrating the material a very dark brown solid was obtained. Recrystallization from ethyl acetate/hexane gave the title product (6.99 g, 91%) as dark brown crystals.
Reaction SMILES: [CH3:1][C@H:2]([CH2:9]CCS([O-])(=O)=O)[CH2:3][CH2:4]S([O-])(=O)=O.[NH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].O>[CH3:1][C@@H:2]1[CH2:3][CH2:4][N:16]([C@@H:17]([CH3:20])[CH2:18][OH:19])[CH2:9]1
Reactant: C[C@H](N)CO
Reactant: C[C@H](CCCS(=O)(=O)[O-])CCS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
(R)-2-Methylbutane-1,4-diyldimethanesulfonate (37.5 g, 0.144 mol, from step 2 of Intermediate 11) was added to neat (S)-2-aminopropan-1-ol (54.8 g, 0.730 mol). The mixture was stirred in a room temperature water bath to minimize the exotherm. After 24 h, the reaction was diluted with DCM (150 mL), sat'd K2CO3 solution (150 mL), and just enough water (60 mL) to dissolve the resulting ppt. The organic layer was separated, and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give (S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (17.9 g) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (t, 1H), 3.48 (m, 1H), 3.18 (m, 1H), 2.79 (dd, 1H), 2.58 (m, 1H), 2.48 (m, 1H), 2.26 (m, 1H), 2.08 (m, 1H), 2.01 (dd, 1H), 1.88 (m, 1H), 1.20 (m, 1H), 0.98 (d, 3H), 0.96 (d, 3H); LCMS: 144.3 (M+H)+.
Reaction SMILES: [K].[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[NH:8][C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[N:8]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3]
Reactant: CCC1(C)CC2(NC(=O)NC2=O)C(C)C(C)(CC)N1
Reactant: CCCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCCCCCN1C(=O)NC2(CC(C)(CC)NC(C)(CC)C2C)C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 70 ml of dimethylformamide were added 8 g of the potassium salt of 7,9-diethyl-6,7,9-trimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 1) and 5.2 g of octyl bromide; the mixture was heated, with stirring, at 60° C for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and benzene was added to the residue. The resulting benzene solution was washed with water and then dried over magnesium sulphate. After removing the benzene, the resulting oily product was first purified by column chromatography on silica gel (eluent: benzene containing 5% of triethylamine) and then by recrystallization from hexane, giving 3.0 g of Compound 5, mp 65° - 67° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=O)[CH3:2].C(O[C:23]([C:25]1[C:26](C2C=CC=CC=2F)=[N:27][O:28][C:29]=1C)=O)C>>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:7]1[C:6]([CH2:4][O:3][C:1]2[CH:2]=[CH:23][C:25]([C:29]([NH:8][CH:7]([CH3:12])[CH3:6])=[O:28])=[CH:26][N:27]=2)=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2ccccc2F)noc1C
Reactant: CCOC(=O)c1c(-c2cc(F)ccc2F)noc1C
Product: Cc1onc(-c2cc(F)ccc2F)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 21 %

Procedure:
As described for example 84d, 3-(2,5-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (18 g, 67.4 mmol) was converted, instead of 3-(2-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (3.25 g, 21%) which was obtained as a yellow oil. MS: m/e=226.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[CH3:26][O:27][C:28]([CH:30]1[CH2:33][CH2:32][CH:31]1[C:34](O)=O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:34]([CH:31]5[CH2:32][CH2:33][CH:30]5[C:28]([O:27][CH3:26])=[O:29])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)C1CCC1C(=O)O
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (830 mg), (1RS, 2SR)-2-(methoxycarbonyl)cyclobutanecarboxylic acid (406 mg), HATU (1.33 g), N,N-diisopropylethylamine (0.611 ml) and DMF (20 ml) was stirred at room temperature for 2 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. Then a mixture of the obtained residue and AcOH (20 ml) was stirred at 80° C. for 30 min. After concentration of the mixture, the residue was poured into saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residual solid was washed with IPE to give the title compound (172 mg) as a brown solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Nc1ccc(O)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(NS(C)(=O)=O)cc1
Yield: 22.2 %

Procedure:
A solution of 22.63 g (0.25 mol) of acryloyl chloride in 250 ml of methylene chloride was added over a period of 35 minutes to a mixture of 46.81 g (0.25 mol) of N-(4-hydroxyphenyl)methanesulfonamide, 25.30 g (0.25 mol) of triethylamine and 750 ml of methylene chloride at 0° C. The resultant solution was stirred at reduced temperature for 2.17 hours, washed three times with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene and drying gave 13.4 g (22.2 percent yield) of N-(4-acryloyloxyphenyl)methanesulfonamide; m.p.=136.5° to 139.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([C:17](O)=[O:18])[N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[NH2:44][C@H:45]([C:49]([OH:51])=O)[CH2:46][CH2:47][SH:48]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([C:17](=[O:18])[NH:44][CH:45]3[CH2:46][CH2:47][S:48][C:49]3=[O:51])[N:13]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2
Reactant: N[C@@H](CCS)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](C(=O)NC1CCSC1=O)N(C(=O)OC(C)(C)C)C2
Reaction time: 16 h
Yield: 56.8 %

Procedure:
A solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,5-(S),6-tri-carboxylic acid 3,6-di-tert-butyl ester (0.30 g, 0.75 mmol) and triethylamine (0.21 mL, 1.51 mmol) in tetrahydrofuran (10 mL) was cooled to −20° C. before isobutyl chloroformate (0.103 mL, 0.75 mmol) was added. The reaction mixture was stirred 15 min at −20° C. before homocystein hydrochloride (116 mg, 0.75 mmol) was added. The cooling bath was removed and the reaction mixture was left for 16 hours at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography (SiO2, Flash 40, heptane/ethyl acetate 2:1) to give 212 mg (56%) of 2-amino-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1([CH3:30])[CH2:8][O:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)=[CH:11][CH:10]=2)=[N:5]1.[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40]Br)([CH3:34])([CH3:33])[CH3:32]>CS(C)=O>[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40][O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[O:7][CH2:8][C:4]([CH3:30])([CH3:3])[N:5]=3)=[CH:14][CH:13]=2)([OH:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC1(C)COC(c2ccc(C(O)(c3ccccc3)c3cccc(O)c3)cc2)=N1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1(C)COC(c2ccc(C(O)(c3ccccc3)c3cccc(OCCCNC(=O)OC(C)(C)C)c3)cc2)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of powdered KOH (45 mg, 0.8 mM) in anhydrous DMSO (2.5 mL) at room temperature was added 3-{[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-hydroxy-phenyl-methyl}-phenol (2, 150 mg, 0.4 mM) and (3-Bromo-propyl)-carbamic acid tert-butyl ester (96 mg, 0.4 mM). The reaction mixture was stirred at room temperature for 3 h. Then the reaction mixture was extracted with ethyl acetate (3×25 mL) and the combined extract was dried over anhydrous Mg2SO4. The residue obtained on evaporation of the solvent was purified by silica gel chromatography using hexane/EtOAc (1:1) as an eluent. Evaporation of the solvent gave 3. Yield: >220 mg (quantitative yield). Mass: 531 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(O)(C)C>O>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Solvent: CC(C)O
Solvent: O
Product: CC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a 0.33 g. sample of 5-amino-2-nitro-3-phenylbenzofuran is added 1 ml. of acetic anhydride, and the mixture is heated for 5 minutes on a steam bath. About 10 ml. of isopropanol is added, and the mixture is again heated on a steam bath to dissolve the solid. It is then saturated with hot water and cooled to provide yellow needles of 5-acetamido-2-nitro-3-phenylbenzofuran, m.p. 204°-207° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C[Si](N[Si](C)(C)C)(C)C>[NH:7]1[CH:6]=[CH:5][CH:4]=[C:8]1[CH:9]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:2][CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: O=C1Nc2ccccc2C1=Cc1ccc[nH]1
Yield: 276.3 %

Procedure:
(NH4)2SO4 (0.09 g, 0.67 mmol) was added into a stirred mixture of 8 (1.0 g, 6.61 mmol) in HMDS (20 mL, 20 P) at room temperature. The reaction mixture was then heated to reflux and maintained at that temperature for no less than 5 hours. Monitor the reaction by GC. After the reaction is completed, 14 (1.1 g, 3.77 mmol) and TMSOTf (0.29 g, 1.32 mmol) were added. Then the mixture was stirred, once the reaction was complete (as indicated by HPLC analysis) it was quenched with water (6 mL, 6 P.) and MeCN (30 mL). The mixture was filtrated and the filtrate cake was washed with MeCN (20 mL) and EtOH (5 mL), then it was dried under vacuum at 40° C. overnight to give the goal product 15 (1.92 g, 97% yield) as a yellow to brown powder with about 82.1% HPLC purity.