Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[O:10][CH:11]=[CH:12][C:13]=1[C@H:14]([CH3:18])[C:15]([OH:17])=[O:16].O1CCOCC1.[C:25](Cl)([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26]>C([O-])([O-])=O.[Na+].[Na+].O>[C:25]([NH:8][C:9]1[O:10][CH:11]=[CH:12][C:13]=1[C@H:14]([CH3:18])[C:15]([OH:17])=[O:16])([O:27][CH2:28][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:26]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](C(=O)O)c1ccoc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@H](C(=O)O)c1ccoc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-2-amino-3-furylpropionic acid trifluoroacetic acid salt (0.47 g) was dissolved in 30 mL of 10% Na2CO3 and 5 mL of dioxane and was cooled to 0 C. A solution of FMOC-Cl (0.53 g) in 10 mL was added dropwise. The mixture was then stirred for 15 min. at 0° C. and 2 hr at room temperature. The mixture was diluted with H2O, extracted with diethyl ether, and acidified with citric acid. The mixture was filtered and washed with H2O until neutral. The solid was then dissolved in ethylacetate, dried over Na2SO4, concentrated in vacuo to give the product as a white foam.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Br[C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=2.[CH3:29]S(C)=O>>[CH2:13]([O:12][C:10](=[O:11])[C:9]1[CH:15]=[CH:16][C:6]([CH:2]([NH:1][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=3)[CH2:3][CH:4]([CH3:29])[CH3:5])=[CH:7][CH:8]=1)[CH3:14]
Reactant: Cc1ccc2cc(Br)cnc2c1
Reactant: CCCC(N)c1ccc(C(=O)OCC)cc1
Reactant: CS(C)=O
Product: CCOC(=O)c1ccc(C(CC(C)C)Nc2cnc3cc(C)ccc3c2)cc1
Yield: 15 %

Procedure:
To a reaction vial with 4-(1-Amino-3-methyl-butyryl)-benzoic acid ethyl ester (2) (440 mg, 1.9 mM) was added DMSO (6.33 mL), 3-bromo-7-methylquinoline (9) (420 mg, 1.9 mM), followed by Cul catalyst (36 mg, 0.19 mM) and CsOAc (726 mg, 3.78 mM). The mixture was purged with argon gas and then the tube was sealed. The reaction mixture was heated to 100° for 48 h. The reaction mixture was cooled, diluted with EtOAc (10 mL), washed with water (3×5 mL), dried (Na2SO4) and concentrated. The crude material was separated by a 40 g silica gel with 0-80% EtOAc in heptane to give a yellow color product (108 mg, 15%). 1H NMR (500 MHz, CDCl3) δ ppm 0.98 (d, J=6.34 Hz, 3H) 1.04 (d, J=6.34 Hz, 3H) 1.39 (t, 3H) 1.61-1.71 (m, 1H) 1.71-1.86 (m, 2H) 2.46 (s, 3H) 4.36 (q, 2H) 4.38-4.43 (m, 1H) 4.47-4.56 (m, 1H) 6.75 (d, J=1.95 Hz, 1H) 7.20 (d, J=8.29 Hz, 1H) 7.36 (d, J=8.05 Hz, 1H) 7.47 (d, J=8.29 Hz, 2H) 7.69 (s, 1H) 8.03 (d, 2H) 8.47 (br. s., 1H). LC-MS: m/z 377.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:22])=[O:21]>>[CH2:6]([N:9]([CH2:10][CH2:11][CH3:12])[C:3](=[O:4])[CH2:2][N:23]([S:20]([C:15]1[C:14]([CH3:13])=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:22])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH2:7][CH3:8]
Reactant: CCCNCCC
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2C)cc1
Product: CCCN(CCC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of 2-bromoacetyl bromide with di-n-propylamine and 2-methyl-N-p-tolyl-benzenesulfonamide
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[NH:9][C@@:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5]2.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH:21]=O.C(O)(=O)C.[Cl:36]CCCl>>[ClH:36].[ClH:36].[F:16][C:17]([F:30])([F:31])[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=1)[CH2:21][NH:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]2[NH:9][C@@:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5]2
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Reactant: ClCCCl
Solvent: CC(=O)O
Product: Cl
Product: FC(F)(F)c1cc(CN[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1R*,2R*,5S*)-2-Amino-1-phenyl-8-azabicyclo[3.2.1]octane (Description 6; 97 mg, 0.48 mmol) and 3,5-bis(trifluoromethyl)benzaldehyde (121 mg, 0.5 mmol) were dissolved in 1,2-dichloroethane (10 mL) and treated with acetic acid (30 μL). The solution was stirred at room temperature for 16 hours then concentrated. The residue was taken up in methanol (10 mL) and treated with sodium cyanoborohydride (60 mg), then heated at 80° C. for 2 hours, concentrated in vacuo and the residue suspended in saturated sodium bicarbonate solution (10 mL). This was extracted with dichloromethane (2×10 mL) and the extracts dried (MgSO4), then concentrated. The residue was taken up in ethyl acetate (10 mL) and treated with ethereal hydrogen chloride (1M, 2 mL). The suspension formed was concentrated in vacuo and the solid remaining recrystallized from methanol/diethyl ether, to give the title compound as a white solid (167 mg, 0.33 mmol).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[O:34][C:33](=[O:35])[C:32]5([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[N:31]=4)=[CH:26][CH:25]=3)[N:23]=2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH:6][C:33]([C:32]1([NH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:22]3[N:23]=[C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)[S:20][CH:21]=3)=[CH:25][CH:26]=2)=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)=[O:35]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CN1CCN(c2nc(-c3ccc(C4=NC5(CCCCC5)C(=O)O4)cc3)cs2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 33.3 %

Procedure:
200 mg (1.00 mmol) of L-methionine methyl ester hydrochloride was added to a solution of 411 mg (1.00 mmol) of 2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one and 258 mg (2.00 mmol) of N,N-diisopropylethylamine in 20 ml of dimethylformamide. After the mixture was stirred at 80° C. for 15 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 191 mg (33%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([CH2:17][O:12][C:3]2[C:2]([F:1])=[CH:7][C:6]([CH2:8][CH2:9][CH3:10])=[CH:5][C:4]=2[F:11])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: CCCc1cc(F)c(O)c(F)c1
Reactant: OCc1cc(F)cc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(F)c(OCc2cc(F)cc(F)c2)c(F)c1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
Into THF (85 mL), 2,6-difluoro-4-propylphenol obtained in (1-2) in Example 1 (17.2 g), 3,5-difluorobenzyl alcohol (17.2 g), triphenylphosphine (28.9 g) were dissolved, and the product was cooled to −10° C. DIAD (21.2 g) was added thereto at a rate which did not allow the internal temperature to exceed 15° C., and the product was stirred for 3 hours at room temperature. Then, 5 mL of water was added thereto, the solvent was distilled off under reduced pressure, hexane (300 mL) was added thereto, and the product was stirred. The precipitate was removed by filtration, the filtrate was washed with an aqueous solution of 50% methanol (200 mL) and a saturated salt solution in sequence, and sodium sulfate was added thereto for dehydration. The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography, thereby yielding a slightly yellow liquid that what 1,3-difluoro-5-[(2,6-difluoro-4-propylphenyloxy)methyl]benzene (19.1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:10][CH:9]=1)=[O:5]>CO>[CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:12][CH:13]=1)=[O:5].[CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Solvent: CO
Product: Cc1ccc(C(=O)OCc2ccc([C@@H](CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Product: Cc1ccc(C(=O)OCc2ccc([C@H](CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1

Procedure:
(S)-4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E145-S) and (R)-4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E145-R) were prepared from E145 according to the scheme in FIG. 10. 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate was dissolve in methanol and the R and S enantiomers separated by supercritical fluid chromatography (Chiralpak AS-H column, eluent: 18.8% MeOH, 0.2% dimethylethylamine, 80% CO2). The enantiomers were then each purified by column chromotagraphy (SiO2, 0-5% MeOH/CH2Cl2gradient). The enantiomeric excess for each enantiomer was >98%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH3:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)(=[O:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O.O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:15]([S:12]([NH:11][CH3:10])(=[O:13])=[O:14])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[F:9]
Reactant: CNS(=O)(=O)c1ccccc1B(O)O
Reactant: Fc1cc(I)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccccc1-c1ccc(Br)c(F)c1
Reaction time: 0.17 h

Procedure:
1-Bromo-2-fluoro-4-iodobenzene (6.30 g, 20.9 mmol) and (2-(N-methyl-sulfamoyl)-phenyl)boronic acid (4.50 g, 20.9 mmol) were added to a 250 mL flask equipped with a stir bar and reflux condenser. 1,4-Dioxane (50 mL) and Na2CO3 (2 M, 50 mL) were added. Argon was bubbled through the solvent while it was rapidly stirred for 10 minutes before Pd(dppf)Cl2.CH2Cl2 (766 mg, 1.05 mmol) was added and the reaction was stirred at 80° Celsius for 15 hours. The reaction was then diluted with 50 mL of water and extracted with ethyl acetate (1×50 mL, 3×100 mL). The combined organic extracts were dried with Na2CO3, filtered and concentrated to dryness. The crude product was purified by FCC to give 4′-bromo-3′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide. 1H NMR (500 MHz, CDCl3) δ 8.17-8.11 (m, 1H), 7.66-7.59 (m, 2H), 7.59-7.54 (m, 1H), 7.33-7.29 (m, 1H), 7.28-7.23 (m, 1H), 7.20-7.13 (m, 1H), 3.67-3.56 (dd, J=10.1, 4.5, 1H), 2.46-2.43 (d, J=5.3, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[CH:15][CH:14]=1.Cl([O-])=[O:26].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:26])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[CH:17][CH:18]=1
Reactant: CN1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: CN1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 4.1 %

Procedure:
To a solution of 6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carbaldehyde (crude, 0.23 g, 0.68 mmol) in acetonitrile (8 mL) and tert-butanol (8 mL) was added 2-methyl-2-butene (8 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (683 mg, 7.50 mmol) and sodium phosphate monobasic dihydrate (1.59 g, 10.2 mmol) in water (4 mL) dropwise. The reaction mixture was stirred at room temperature for two hours and treated with additional sodium chlorite (911 mg, 10.0 mmol) and sodium phosphate monobasic dihydrate (2.12 g, 13.6 mmol) in H2O (4 mL) and 2-methyl-2-butene (2 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified via prep-HPLC to give 6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylic acid (10 mg) as a solid. MS (ES+) 354.9 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.01 (m, 2H), 7.59 (s, 1H), 7.3-7.5 (m, 4H), 3.40-4.00 (m, 5H), 3.06 (s, 3H), 2.1-2.7 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[CH3:7][C:8]([CH3:10])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1>[CH:8]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)([CH3:10])[CH3:7]
Reactant: CC(C)=O
Reactant: Nc1cc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)Nc1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixture of 1H-pyrazol-3-ylamine (8.3 g, 100 mmol), acetone (7.4 mL, 100 mmol) and acetic acid (12 mL, 200 mmol) in THF (280 mL) was added, in portions, sodium triacetoxyborohydride (27 g, 120 mmol) while cooling with an ice-water bath. The mixture was stirred at room temperature for 1 h and then at 50° C. for 3 h. After cooling to room temperature, 10 N NaOH (40 mL) was added dropwise, and stirred gently for 1 h. The clear solution was isolated with decantation. The gummy residue was washed with THF (2×50 mL). All the THF solutions were combined and concentrated. The residue was purified by silica gel column chromatography (EtOAc), affording isopropyl-(1H-pyrazol-3-yl)-amine (8.5 g, 68%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.34 (d, 1H), 5.62 (d, 1H), 3.58 (m, 1H), 1.22 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([O:16][CH3:17])=[C:4]([O:18][CH3:19])[CH:3]=1.[C:20]([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:23]1)#[N:21].O.Cl>CS(C)=O.C(OCC)(=O)C>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:18][CH3:19])=[C:5]([O:16][CH3:17])[C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:1]=[C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:23]2)[N:21]=1
Reactant: CS(=O)(=O)Nc1cccc2c1CCN(C#N)C2
Reactant: COc1cc(N)c(C#N)c(-c2ccccn2)c1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nc(N3CCc4c(cccc4NS(C)(=O)=O)C3)nc(N)c2c(-c2ccccn2)c1OC
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a stirred solution of 6-amino-3,4-dimethoxy-2-(2-pyridyl)benzonitrile (see Example 2 or 2A, 7 g, 27 mmol) and N-(2-cyano-1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide (see Example 3 or 3A, 9 g, 36 mmol) in DMSO (21 ml) at room temperature, was added sodium-t-pentoxide (9.5 g, 92 mmol) portionwise over 20 minutes keeping the temperature below 30° C. The resulting slurry was then stirred for 2 hours. After this time, iced water (35 ml) was added over 1 minute followed by ethyl acetate (35 ml) before reducing the pH of the biphasic mixture to 8.0 with 2M aqueous HCl (20 ml). The aqueous phase was extracted with ethyl acetate (50 ml). The combined organics were washed with saturated NaCl solution (2×30 ml), reduced in volume and stirred for 3 hours. After this time, the resulting slurry was filtered to yield 10.2 g (74%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][S:14]([CH2:17][CH2:18][NH2:19])(=[O:16])=[O:15].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:6]
Reactant: CS(=O)(=O)CCN
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCNC(=O)c1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-amino-3-bromobenzoic acid (0.8 g, 3.70 mmol) and 2-(methylsulfonyl)ethanamine hydrochloride (0.709 g, 4.44 mmol, ChemBridge Inc.) in EtOAc (15 mL) followed by DIEA (1.61 mL, 9.26 mmol) and T3P (2.59 mL, 4.07 mmol, Sigma Aldrich). The mixture was stirred at RT for 2 h, then quenched with sat. NaHCO3. EtOAc (100 mL) was added and the layers were separated. The organic layer was washed with sat. NaHCO3 (20 mL), brine (15 mL), then dried (MgSO4), filtered and concentrated to give the crude product 485 mg. MS (ESI, pos. ion) m/z: 321 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([NH2:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([NH:12][C:13](=[O:16])[O:14][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(-c2ccccc2)on1
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2ccccc2)on1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 160.1 %

Procedure:
5-Phenylisoxazol-3-amine (428 mg, 2.67 mmol) in tetrahydrofuran (4.8 mL) was treated with potassium carbonate (481 mg, 3.47 mmol) and phenyl choloroformate (0.67 mL, 5.3 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through a celite pad, washed with ethyl acetate and concentrated to dryness. The residue was taken into chloroform, washed with brine, and the organics dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 8:2) to give phenyl 5-phenylisoxazol-3-ylcarbamate (599 mg, 80%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.92 (bs, 1H), 7.78 (d, 2H), 7.45 (m, 6H), 7.26 (m, 2H), 7.12 (s, 1H); LC-MS (ESI) m/z 281 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][CH2:13][O-:14].[Na+].[CH3:16][CH2:17][OH:18]>CCO>[CH2:13]([O:14][C:17](=[O:18])/[CH:16]=[CH:6]/[C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1)[CH3:12]
Reactant: CCO
Reactant: O=Cc1cc2ccccc2s1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1cc2ccccc2s1
Temperature: 25 °C
Yield: 113.5 %

Procedure:
To a solution of benzo[b]thiophene-2-carboxaldehyde (4.40 g, 27.1 mmol) and triethyl phosphonoacetate (16.6 mL, 83.2 mmol) in absolute EtOH (120 mL) was added a solution of EtONa/EtOH (made from 1.92 g of Na and 70 mL of EtOH) at 40° C. with stirring. The mixture was then heated at reflux for 40 min. After cooling to r.t. the mixture was concentrated to remove most of the solvent, mixed with crushed ice (60 mL) and water (60 mL), and was extracted with Et2O (3×450 mL). The combined extracts were washed with brine (2×200 mL), dried (MgSO4), and evaporated to dryness. The crude solid was purified by a flash chromatography on silica gel using 15% EtOAc/hexane as the eluent to give-(E)-3-(benzo[b]thien-2-yl)-2-propenoic acid ethyl ester (4.44 g, 19.1 mmol) in 71% yield as an amorphous solid.
Reaction SMILES: S(=O)(O)[O-].[Na+].[NH:6]([C:10]1[CH:15]=[C:14](S(O)=O)[CH:13]=[CH:12][C:11]=1[O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26](S(O)=O)=[CH:25][C:24]=1[NH:32]C(C)=O)C(C)=O.[CH2:36]1[O:38][CH2:37]1.N(C1C=C(S(CCO)(=O)=O)C=CC=1OCCOC1C=CC(S(CCO)(=O)=O)=CC=1NC(C)=O)[C:40]([CH3:42])=[O:41].S(=O)(=O)(O)O>>[NH2:32][C:24]1[CH:25]=[C:26]([CH2:42][CH2:40][OH:41])[CH:27]=[CH:28][C:23]=1[O:22][CH2:21][CH2:20][O:19][C:11]1[CH:12]=[CH:13][C:14]([CH2:37][CH2:36][OH:38])=[CH:15][C:10]=1[NH2:6]
Reactant: C1CO1
Reactant: CC(=O)Nc1cc(S(=O)(=O)CCO)ccc1OCCOc1ccc(S(=O)(=O)CCO)cc1NC(C)=O
Reactant: CC(=O)Nc1cc(S(=O)O)ccc1OCCOc1ccc(S(=O)O)cc1NC(C)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Product: Nc1cc(CCO)ccc1OCCOc1ccc(CCO)cc1N

Procedure:
328.4 parts of ethylene glycol bis-(2-acetaminophenyl)ether are reacted in accordance with Example 1 with 1,100 parts of chlorosulfonic acid and 250 parts of thionyl chloride to give ethylene glycol bis-(2-acetamino-4-chlorosulfonylphenyl)ether. After its isolation, this compound is reduced in the method described in Example 1 by means of 572 parts of 40% strength aqueous sodium bisulfite to ethylene glycol bis-(2-acetamino-4-sulfinophenyl)ether and, analogously to the method in Example 1, the resulting bis-sulfinic acid is converted, by means of 540 parts of ethylene oxide, into ethylene glycol bis-(2-acetamino-4-hydroxyethylsulfonylphenyl)ether. The crude product, as detailed in Example 1, is deacetylated by means of 1,500 parts of 5% strength aqueous sulfuric acid and ethylene glycol bis-(2-amino-4-β-hydroxyethylphenyl)ether is formed. This product, after drying, melts at 144°-146° C.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[C:15]([O:17][CH3:18])=[O:16])#[N:2].[CH3:19][NH:20][CH2:21]C(O)=O.[CH2:25]=O>C1(C)C=CC=CC=1>[C:1]([C@@H:3]1[CH2:25][N:20]([CH3:21])[CH2:19][C@H:4]1[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[C:15]([O:17][CH3:18])=[O:16])#[N:2]
Reactant: C=O
Reactant: COC(=O)c1ccc(C=CC#N)c(C(=O)OC)c1
Reactant: CNCC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc([C@@H]2CN(C)C[C@H]2C#N)c(C(=O)OC)c1
Temperature: 125 °C

Procedure:
A 100 mL round bottom flask was charged with dimethyl 4-(2-cyanovinyl)isophthalate (380 mg, 1.55 mmol), 2-(methylamino)acetic acid (276 mg, 3.1 mmol), paraformaldehyde (326 mg, 10.85 mmol) and toluene (5 mL). The reaction mixture was heated to 125° C. under nitrogen for 2 hours. Then the solution was transferred to another flask leaving the dark tar behind. 2-(Methylamino)acetic acid (276 mg, 3.1 mmol) and paraformaldehyde (326 mg, 10.85 mmol) were added. The reaction mixture was heated to 125° C. under nitrogen for another 2 hours. Then this was cooled and concentrated and partitioned between saturated NaHCO3(aq.) and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography with 80-100% ethyl acetate/hexane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.30 (d, J=1.9, 1H), 8.13 (dd, J=2.0, 8.3, 1H), 7.81 (d, J=8.3, 1H), 4.43-4.33 (m, 1H), 3.89 (d, J=5.7, 3H), 3.36 (q, J=8.1, 1H), 3.30 (s, 3H), 3.20-3.10 (m, 1H), 3.02-2.92 (m, 1H), 2.75 (dd, J=6.4, 9.2, 1H), 2.62 (dd, J=5.5, 9.5, 1H), 2.34 (s, 3H); MS (ESI+) m/z 302.9 [M+H]+.