Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(-c4ccccc4)c23)C1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Intermediate 1a (228 mg) obtained in Example 1-1, Step A was added with phenylboronic acid (122 mg, Aldrich), tetrakis(triphenylphosphine)palladium(0) (116 mg), 1,2-dimethoxyethane (5 ml) and 2 N aqueous sodium carbonate (2 ml), and the mixture was refluxed by heating for 5 hours under a nitrogen gas atmosphere. The reaction mixture was cooled to room temperature, then added with water (25 ml), and extracted 3 times with ethyl acetate (20 ml for each time), and the combined organic layer was washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (158 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][O:17][C:18]=2[C:19](OCC)=[O:20])=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1oncc1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1oncc1-c1ccc(F)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a stirred mixture of LiAlH4 (259 mg, 6.82 mmol, 2.01 equiv) in anhydrous tetrahydrofuran (10 mL) maintained under nitrogen at −60° C. was added dropwise a solution of ethyl 4-(4-fluorophenyl)-1,2-oxazole-5-carboxylate (800 mg, 3.40 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). The reaction mixture was stirred at −35° C. for 1 h and then quenched by 2.5 mL of saturated NH4Cl solution. The solid material was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 10-15% of ethyl acetate in petroleum ether to give 300 mg (46%) of (4-(4-fluorophenyl)isoxazol-5-yl)methanol as a yellow oil. 1H-NMR (300 MHz, CDCl3): δ 8.53 (s, 1H), 7.55-7.50 (m, 2H), 7.20-7.07 (m, 2H), 4.87 (s, 2H) ppm. LCMS (method C, ESI): RT=0.79 min, m/z=194.0 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[C:11]([CH3:19])=[CH:10]3)=[N+]=[N-].[H][H].[ClH:23]>O1CCCC1.[Pd]>[NH2:1][CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[C:11]([CH3:19])=[CH:10]3.[ClH:23]
Reactant: [H][H]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CN=[N+]=[N-])O3
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CN)O3
Yield: 73.4 %

Procedure:
2-Azidomethyl-5,8-dimethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (2.76 g, 10.2 mmol) was dissolved in tetrahydrofuran (200 ml), to which 10% palladium-on-carbon (2.76 g) was added. The mixture was stirred at room temperature for 2 hours in the atmospher of hydrogen. The catalyst was filtered off, and the filtrate was condensed. The residue was converted to a hydrochloric acid salt, and then subjected to recrystallization (methanol-ether) to obtain 2.10 g of the title compound as yellow crystals (73.4%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)[C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=[O:20].C[O-].[Na+].Cl>CO>[CH3:17][O:16][C:10]1[C:9](=[O:20])[NH:8][C:12](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]=1[O:14][CH3:15]
Reactant: CS(C)=O
Reactant: COc1cnn(-c2ccccc2)c(=O)c1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=Nc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
12 parts by weight of 2-phenyl-4,5-dimethoxypyridazin-3-one were suspended in 150 parts by volume of dimethyl sulfoxide, and 9 parts by weight of a 30% strength solution of sodium methylate in methanol were added dropwise. The mixture was stirred for 20 hours at room temperature, after which it was stirred into 1 liter of ice water and rendered neutral by adding concentrated hydrochloric acid, and the product was filtered off under suction. 11.4 parts by weight of 2,5-dihydro-3,4-dimethoxy-5-phenyliminopyrrol-2-one of melting point 141°-143° C. were obtained (compound No.1).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23])[CH3:11]>>[CH2:10]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[S:23][CH2:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)[CH3:11]
Reactant: CCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1(CCl)CCCC1
Agent: Cl
Product: CCc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1

Procedure:
2-Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(2-ethyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:15]1([C:14]([NH:13][S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:11])=[O:12])=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1ccccc1
Yield: 85.6 %

Procedure:
The title compound was prepared in the some way as that described in Example 11, Step 1, using 3-nitrobenzenesulphonamide (10.1 g, 50 mml), benzoic acid (6.1 g, 50 mmol), 4-dimethylaminopyridine (6.1 g, 50 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (9.59 g, 50 mmol) and anhydrous dichloromethane (400ml). The title compound (13.1 g, 86%) was afforded as a colourless solid. mp 181°-183° C. 1H NMR (360 MHz, D6 -DMSO) δ 7.49 (2H, m), 7.61-7.66 (1H, m), 7.86-7.89 (2H, m), 7.96 (1H, dd, J=8.0 and 8.0 Hz), 8.43 (1H, m), 8.56 (1H, m), 8.71 (1H, m).
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]2[CH:25]3[CH2:26][CH2:27][CH2:28][CH:21]2[C:22](=[CH:30]O)[C:23](=O)[CH2:24]3)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[CH2:1]([N:8]1[C:23]2[CH2:24][CH:25]3[N:20]([S:17]([C:14]4[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=4)(=[O:19])=[O:18])[CH:21]([CH2:28][CH2:27][CH2:26]3)[C:22]=2[CH:30]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NNCc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnn(Cc3ccccc3)c1C2

Procedure:
Prepared as described in Example 5 using benzylhydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:51]1[S:52][CH:53]=[CH:54][N:55]=1.C([O-])([O-])=O.[K+].[K+]>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:10]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:7][C:6]3[CH:22]=[C:2]([C:51]4[S:52][CH:53]=[CH:54][N:55]=4)[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]=3[O:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COC(=O)c1cc(-c2nccs2)cc2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (250 mg, 0.608 mmol, 1 eq.) Pd(PPh3)4 (70 mg, 0.06 mmol, 0.1 eq.), bis(pinacolato)diboron (200 mg, 0.79 mmol, 1.3 eq.) and KOAc (90 mg, 0.912 mmol, 1.5 eq.), then Pd(PPh3)4 (70 mg, 0.06 mmol, 0.1 eq.), 2-bromo-thiazole (110 mg, 0.67 mmol, 1.1 eq.) and K2CO3 (420 mg, 3.04 mmol, 5 eq.) were used according to GP6 to yield the title product as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][N:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[O:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:1]=[C:2]1[N:7]([CH:35]2[CH2:36][CH2:37][O:32][CH2:33][CH2:34]2)[C:6](=[O:8])[C:5]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][N:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: N#Cc1ccc(-n2nccc2-c2cn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]c2=O)cc1
Reactant: OC1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2nccc2-c2cn(-c3cccc(C(F)(F)F)c3)c(=O)n(C3CCOCC3)c2=O)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(5-(2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 53) (30 mg) in THF (2 ml) were added tetrahydro-2H-pyran-4-ol (0.014 ml), triphenylphosphine (37 mg) and diethyl azodicarboxylate (2.2 M toluene solution, 0.065 ml) and the resulting mixture was stirred at room temperature for fifteen minutes. The reaction solution was concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and reversed phase liquid chromatography (eluent: TFA water/acetonitrile) to afford-4-(5-(2,4-dioxo-3-(tetrahydro-2H-pyran-4-yl)-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (7 mg).
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)(=O)=O.[NH3:18].C1COCC1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]([NH2:18])[N:6]=[N:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)c1nncc(-c2ccc(F)cc2)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nncc(-c2ccc(F)cc2)n1
Yield: 74 %

Procedure:
5-(4-Fluorophenyl)-1,2,4-triazin-3-amine (2.80 g, 74%) was prepared from 3-(methylsulfonyl)-5-(4-fluorophenyl)-1,2,4-triazine (5.00 g, 19.7 mmol) and 0.5 M ammonia in THF (100 mL, 50.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH3:15])[CH2:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1.CO.Cl>O.C(Cl)(Cl)Cl>[OH:11][C:12]1[CH:13]=[C:4]([OH:3])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:15])[CH2:9][C:10]([OH:1])=[O:14]
Reactant: CC1CC(=O)Oc2cc(O)ccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(CC(=O)O)c1ccc(O)cc1O
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Sodium hydroxide (5.0 M, 27 ml, 135 mmol) was added to a suspension of 7-hydroxy-3,4-dihydro-4-methylcoumarin (Compound of formula B1) (8.0 g, 45 mmol) in water (40 ml) at room temperature and the resulting solution stirred for 20 min. At this time, TLC (4% methanol:chloroform) showed the clean formation of product at the expense of starting material. The solution was cooled to 5° C. and carefully acidified with concentrated HCl to pH less than about 1, keeping the temperature at less than about 15° C. throughout the addition. The solution was extracted with ethyl ether (4×100 ml), the organic layers washed with saturated NaCl (4×50 ml), combined, dried (Na2SO4), filtered and the solvent removed to give a pale orange oil. Further purification by filtering through a short pad of silica gel and eluting with ethyl acetate afforded pure product as a white solid (8.3 g, 94%): m.p. 92-94° C.; 1H NMR (DMSO-d6) d 1.13 (d, JJ=7.0, 3H), 2.33 (dd, JJ=15.0, 8.9, 1H), 2.52 (dd, JJ=15.5, 7.3, 1H), 3.32 (m, 1H), 6.16 (dd, JJ=8.2, 2.4, 1H), 6.28 (d, JJ=2.4, 1H), 6.84 (d, JJ=8.2, 1H), 9.08 (s, 1H), 9.59 (s, 1H), 11.87 (s, 1H); 13C NMR (DMSO-d6) d 20.39, 28.97, 41.0, 102.58, 106.01, 122.55, 127.27, 155.19, 156.18, 173.74; m/z (EI; TMS derivatized; M+) 412; IR (neat; cm−1) 3360.1, 2974.1, 2935.1, 2876.4, 1748.0, 1713.8, 1625.9, 1606.3, 1518.4, 1459.8, 1381.6, 1347.4, 1283.9, 1254.6, 1239.9, 1156.9, 1117.8, 1025.0, 981.0, 937.1, 849.1, 810.1.
Reaction SMILES: [OH:1][CH:2]([C:9]1[S:10][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:12][N:13]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7]>C1COCC1.O=[Mn]=O>[O:1]=[C:2]([C:9]1[S:10][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:12][N:13]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH3:7])[CH3:8]
Reactant: CN(C)CCCC(O)c1ncc(S(N)(=O)=O)s1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CN(C)CCCC(=O)c1ncc(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A mixture of 2-(1-hydroxy-4-(N,N-dimethylamino)butyl)-5-thiazole sulfonamide (0.35 mmol, 0.098 g) and MnO2 (5.27 mmol, 0.46 g) in THF was stirred at rt overnight. The mixture was filtered through celite and the solvent removed. The residue was subjected to flash chromatography (10% MeOH/NH3 /CHCl3) to afford 34.4 mg (35%) of 2-(1-keto-4-(N,N-dimethylamino)butyl)-5-thiazole sulfonamide.
Reaction SMILES: [C:1]([CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:32]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:32]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:11](=[O:13])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(CC(C(=O)O)c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 0.01 mole sample of 3-benzoyl-2-(phenyl)propionic acid is dissolved in tetrahydrofuran and 0.01 mole of N,N-carbonyldiimidazole added. After stirring 3 hours at room temperature, 0.01 mole of L-proline t-butyl ester is added. After 24 hours the solvent is removed and 1-[3-benzoyl-2-(phenyl)-propionyl]-L-proline t-butyl ester isolated. The preceding compound is reacted with trifluoroacetic acid to remove the t-butyl group. Separation of isomers A and B is carried out as described for Example 69. Reaction of the isomers with bromine is acetic acid and reaction of the 1-[3-bromo-3-benzoyl-2-(phenyl)propionyl]-L-proline isomers with sodium thioacetate in acetonitrile as for Example 69 gives the products of the example. The product from isomer A is separated by chromatography to give [S-(R*,R*)] and [S-(R*,S*)]-1-[3-acetylthio-3-benzoyl-2-(phenyl)propionyl]-L-proline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCc3ccccc3)cc2C(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)c2cc(OCc3ccccc3)ccc2C1
Temperature: 25 °C

Procedure:
To 500 mg (1.41 mmol) 6-benzyloxy-4-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XL) in 8 mL DCM are added 618 mg (1.41 mmol) Dess-Martin periodinane and stirred at r.t. over night. After that time, the reaction mixture is diluted with water and extracted with DCM. The organic layer is concentrated by evaporation and the residue is purified by HPLC (ACN/H2O/HCOOH).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])([O-:14])=[O:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 49.7 %

Procedure:
Using 5-bromosalicylic acid and 4-nitro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=4[CH:34]=3)[CH2:19]2)=[N:14]1.CCN(CC)CC.Br[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>CN(C=O)C>[C:47]([O:46][C:44](=[O:45])[CH2:43][N:22]([CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][N:13]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=4)[N:9]=[CH:8][CH:7]=3)[N:14]=2)[CH2:19]1)[CH2:23][C:24]1[CH:25]=[CH:26][C:27]2[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(N(CC(=O)OC(C)(C)C)Cc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Temperature: 50 °C
Yield: 25.6 %

Procedure:
To a solution of 6-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one (50 mg, 0.1 mmol) in DMF (600 μL) was added Et3N (19 μL, 0.13 mmol) and tert-butyl bromoacetate (19 μL, 0.13 mmol). The reaction mixture was heated at 50° C. overnight. The crude was purified directly by basic reverse phase HPLC to afford 15 mg (24%) of the title compound. MS (ESI): exact mass calculated for C31H34N6O4S, 586.24; m/z found, 587.23 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([C:13](=[O:16])[NH:14][CH3:15])[C:6]=2[CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.Cl.[CH3:53][NH:54][O:55][CH3:56]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([C:10]([N:54]([O:55][CH3:56])[CH3:53])=[O:12])=[C:7]([C:13]([NH:14][CH3:15])=[O:16])[C:6]=2[CH:17]=1
Reactant: CNC(=O)c1c(C(=O)O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C(=O)N(C)OC)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 5-bromo-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylic acid (1 g, 2.47 mmol), HOBT (500 mg, 3.70 mmol) and EDCI (946 mg, 4.94 mmol) in DMF (20 mL) was stirred at room temperature under N2 for 2 h. Et3N (1.25 g, 12.34 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.03 g, 12.34 mmol) were added, then the mixture was stirred for 18 h. The mixture was concentrated, diluted with water, extracted with EA, the organic layers were washed with Na2CO3 (a.q.), brine, dried over Na2SO4, concentrated. The residue was purified by column chromatography (DCM:EA=20:1) to get product 5-bromo-N2-methoxy-N2,N3-dimethyl-6-(N-methylmethylsulfonamido)benzofuran-2,3-dicarboxamide (0.68 g, yield: 62%). 1H-NMR (CDCl3, 400 MHz) δ 8.83 (s, 1H), 8.74 (s, 1H), 7.72 (s, 1H), 3.89 (s, 3H), 3.42 (s, 3H), 3.34 (s, 3H), 3.08 (s, 3H), 2.98 (d, J=4.8 Hz, 3H). MS (M+H)+: 448/450.
Reaction SMILES: O=CC[O:4][C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]([O:18]CC)=O)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1.[OH-].[Li+].[Cl-].ClC=[N+:26](C)C.[OH-].[NH4+]>O.O1CCCC1>[OH:4][C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]([NH2:26])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: C[N+](C)=CCl
Reactant: CCOC(=O)c1ccc(-c2cccc(OCC=O)c2)s1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2cccc(O)c2)s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The mixture of ethyl 5-{3-[(2-oxoethyl)oxy]phenyl}-2-thiophenecarboxylate (1.3 g, 4.48 mmol), 2N aqueous lithium hydroxide solution (5 ml, 10 mmol) and tetrahydrofuran (10 ml) was heated to reflux for 12 h. The reaction mixture was cooled, concentrated in vacuo to remove tetrahydrofuran, acidified to pH1-2 with 2N HCl, and extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The solid residue (0.75 g) was dissolved in dry tetrahydrofuran (15 ml) and cooled to 0° C. (Chloromethylene)dimethylammonium chloride (Aldrich, 0.52 g, 4 mmol) was added in one portion. The mixture was stirred at 0° C. for 4 h. The pre-cooled (0° C.) mixture of 28% ammonium hydroxide aqueous solution (2.5 ml) and water (2.5 ml) was added, and the reaction mixture was stirred at the room temperature. Tetrahydrofuran was removed in vacuo and the residue was extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (80% ethyl acetate in hexanes) to give the title compound as a brown solid.