Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[N:4]1)[CH3:2].[CH3:17][O:18]CCN1C=C(Br)C=N1>>[CH3:17][O:18][CH2:2][CH2:1][N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]2)[CH:5]=[N:4]1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCCn1cc(Br)cn1
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, using 1-(2-methoxyethyl)-4-bromo-1H-pyrazole (see Ivachtchenko, A. V., et al J. Het. Chem. 2004, 41, 931-939).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.Br[CH2:31][CH2:32][CH3:33]>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:31][CH2:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CCCBr
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Product: CCCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 78 %

Procedure:
In a manner similar to that of Example 17(d), starting with 700 mg (1.7 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]carbamate and 350 μl (3.8 mmol) of 1-bromopropane, 600 mg (78%) of the desired product are obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:10]2[C:9]([S:21][CH3:22])=[N:8][N:7]3[C:2]([NH2:24])=[CH:3][C:4]([CH3:23])=[N:5][C:6]=23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(Cl)cc1
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-3-(4-chloro-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-chloro-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([C:15]#[N:16])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:23]([C:26]1[CH:43]=[CH:42][C:29]([C:30]([O:32][C:33]([CH2:40][CH3:41])([C:36]([F:39])([F:38])[F:37])[C:34]#[CH:35])=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][C@@:33]([C:34]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:10][C:11]([C:15]#[N:16])=[N:12]4)=[CH:7][CH:6]=3)[CH:35]=2)([C:36]([F:37])([F:38])[F:39])[CH2:40][CH3:41])=[O:31])=[CH:42][CH:43]=1)([O-:25])=[O:24]
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CN=[N+]=[N-])cc2n1
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-phenylquinoline-2-carbonitrile (120 mg, 0.42 mmol) and 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (139 mg, 0.46 mmol, slower eluting enantiomer described in Example 1, step 2) in THF (5 mL) was added diisopropylethylamine (0.37 mL, 2.1 mmol) followed by copper iodide (120 mg, 0.63 mmol). The reaction was stirred at room temperature overnight and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with EtOAc/hexanes, 4:6) gave the title compound. MS (+ESI): 587 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].[C@H:27]12[CH2:33][C@H:30]([NH:31][CH2:32]1)[CH2:29][N:28]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(#N)C>[CH:14]([NH:13][C:11](=[O:12])[CH2:10][NH:9][C:7]([C:6]1[CH:17]=[C:2]([N:31]2[CH2:32][C@@H:27]3[CH2:33][C@H:30]2[CH2:29][N:28]3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:3]=[CH:4][C:5]=1[N+:18]([O-:20])=[O:19])=[O:8])([CH3:16])[CH3:15]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)CNC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 92.1 %

Procedure:
To a solution of 5-fluoro-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (1.0 g, 3.53 mmol) (Intermediate 2A) in acetonitrile (20 mL) was added potassium carbonate (1.46 g, 10.9 mmol) followed by (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.70 g, 3.53 mmol). The resulting suspension was heated to reflux at 90° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, then filtered and concentrated. The resultant crude material was purified by a 25 g silica column in neat ethylacetate (Biotage Snap cartridge). Fractions of the product were combined and reduced to dryness under reduced pressure to afford (1S,4S)-tert-butyl 5-(3-(2-(isopropylamino)-2-oxoethylcarbamoyl)-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.5 g, 3.25 mmol).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:9]([C:10]#[N:11])([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(C(F)(F)F)cc1

Procedure:
Prepare by the method of example 1.1.2 using 4-trifluoromethyl-phenylacetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=O)=[CH:5][CH:4]=1)#[N:2].[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH3:22])=C(Cl)[N:14]=1>>[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH3:22])=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:14]=1
Reactant: N#Cc1ccc(NC=O)cc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccc(C#N)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-cyano-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCOc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A mixture of ethyl 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (750 mg), 1 N aqueous sodium hydroxide solution (3 ml), ethanol (3 ml), and tetrahydrofuran (3 ml) was stirred at room temperature for one hour. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (610 mg, yield: 90%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 110–111° C.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:24]([OH:29])[CH2:25][CH2:26][C:27]#[CH:28]>CN(C=O)C.O>[Si:6]([O:29][CH2:24][CH2:25][CH2:26][C:27]#[CH:28])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 1265.9 %

Procedure:
Imidazole (9.29 g (136 mmol) was dissolved in 50 ml of DMF under nitrogen with stirring. To this solution was added 18.75 g (17.74 mmol) of t-butyldiphenylsilyl chloride and 5.27 g (5.55 mmol) of 4-pentyn-1-ol and the mixture was stirred at room temperature for 2 h. The mixture was carefully diluted with 300 ml of water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo to provide 22.66 g of a yellow oil which was purified by passing through 150 g pad of silica gel eluting with hexane and 3% ethyl acetate in hexane affording 17.56 g (86.8%) of the title compound as a clear oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1>C(Cl)Cl.CC(N(C)C)=O>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of acryloyl chloride (0.604 mL, 1M in CH2Cl2, 0.60 mmol) was added dropwise to 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxybenzene-1,3-diamine (Intermediate 164, 268 mg, 0.60 mmol) in CH2Cl2 (10 mL) and 10 mL DMA, which was cooled to −5° C. The resulting mixture was stirred at −5° C. for 1 h and was then diluted with CH2Cl2 (100 mL). The resulting solution was washed with sat. NaHCO3 (25 mL), water (25 mL), and then sat. brine (4×25 mL), and was then concentrated in vacuo. Purification by FCC, eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (135 mg, 45%) as a beige solid; 1H NMR (CDCl3) 1.98 (1H, s), 2.18 (1H, d), 2.94 (1H, s), 3.11 (4H, d), 3.88 (3H, s), 5.73 (1H, d), 6.40 (2H, d), 6.76 (1H, s), 7.17 (1H, d), 7.22-7.24 (1H, m), 7.41-7.46 (1H, m), 7.62 (1H, s), 8.16 (1H, s), 8.39 (1H, d), 8.45 (1H, s), 8.75 (1H, s), 8.86 (1H, s), 9.56 (1H, s); m/z: ES+ MH+ 498.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Yield: 83.6 %

Procedure:
At room temperature, 6.0 g of N-[2,6-dimethyl-4-{1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl}phenyl]3-aminobenzamide, 2.5 g of benzoyl chloride and 1.8 g of pyridine were introduced to 50 ml of tetrahydrofuran. After the loss of the starting material was confirmed through TLC, the reaction solution was filtered, and thus obtained filtrate was concentrated under reduce pressure. Thus obtained residue was purified by silica gel chromatography (eluent:hexane:ethyl acetate=3:1) to give 6.3 g (yield 85%) of the title compound as a powder form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[C:17]1[S:18][C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][N:21]=1.[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([C:17]4[S:18][C:19]([C:22]([F:23])([F:24])[F:25])=[N:20][N:21]=4)[CH:12]=3)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(F)(F)F)s2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(F)(F)F)s3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)-[1,1′-biphenyl]-4-ol (195 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (157 mg) and tributylphosphine (213 mg) in THF (5.0 mL) was added ADDP (226 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (298 mg) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:21]2[C:29]3[C:24](=[C:25]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[CH:32][C:31]=4[CH3:38])[CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].[O:46]1[C:48]2([CH2:53][CH2:52][S:51][CH2:50][CH2:49]2)[CH2:47]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:21]2[C:29]3[C:24](=[C:25]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([O:37][CH2:47][C:48]5([OH:46])[CH2:53][CH2:52][S:51][CH2:50][CH2:49]5)=[CH:32][C:31]=4[CH3:38])[CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: C1CC2(CCS1)CO2
Reactant: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(O)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(OCC5(O)CCSCC5)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (0.698 g, 1.1 mmol) in N,N-dimethylformamide (8 mL) were added 1-oxa-6-thiaspiro[2.5]octane (0.286 g, 2.20 mmol) and potassium carbonate (0.304 g, 2.20 mmol) under stirring at room temperature, and the mixture was stirred at 80° C. for 16 hr. To the reaction mixture were added reagents (1-oxa-6-thiaspiro[2.5]octane and potassium carbonate) in the same amount as mentioned above. After stirring for 8 hr, reagents (1-oxa-6-thiaspiro[2.5]octane and potassium carbonate) in twice the above-mentioned amount were added and the mixture was stirred for 16 hr. After cooling the reaction mixture, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give ethyl 3-(2-fluoro-4-{(4-{4-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2,6-dimethylphenyl}-2,3-dihydro-1H-inden-1-yl)[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate as a yellow oil. To the obtained oil dissolved in ethyl acetate (15 mL) was added m-chloroperbenzoic acid (70%, 0.459 g, 1.86 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was washed with saturated brine and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-90% ethyl acetate/hexane) to give the title compound (0.426 g, yield 72%, 2 steps) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:30][C:31]([F:34])([F:33])[F:32])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:30][C:31]([F:32])([F:34])[F:33])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A mixture of ethyl {2-[7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (780 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at 50° C. for 30 min. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (490 mg, yield 64%) as brown crystals. The crystals were recrystallized from ethyl acetate-hexane to give brown prism crystals. melting point 247-248° C. (decomposition).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=2[O:29][CH3:30])[C:14]([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[O:15])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]1(S(Cl)(=O)=O)C=CC=C[CH:34]=1>>[CH2:33]([O:22][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:11]([NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:12]=2)=[CH:18][CH:19]=1)[CH3:34]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2ccccc2)c1OC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3ccccc3)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=455.2 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using benzenesulfonyl chloride and yielded 4-[3-(benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C([O-])([O-])=O.[K+].[K+].C([O:14][C:15](=O)[CH:16](Br)[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)C.O>CCO>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH:16]2[S:5][CH2:4][CH2:3][NH:2][C:15]2=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(Br)c1ccc(Br)cc1
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1NCCSC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.1 %

Procedure:
To a solution of 2-aminoethanethiol hydrochloride (6.93 g; 61 mmol) in EtOH (400 mL) was added K2CO3 (16.86 g; 122 mmol), at RT, followed after 15 minutes by bromo-(4-bromo-phenyl)-acetic acid ethyl ester (12 mL; 61 mmol). The resulting mixture was stirred at RT for two days, subsequently, water was added and the resulting mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from EtOH to afford 2-(4-bromo-phenyl)-thiomorpholin-3-one (12.8 g).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([OH:11])[CH:8]([OH:10])[CH3:9].[C:12]([O:16][O:17][C:18]([CH2:20][CH2:21][C:22](Cl)=[O:23])=[O:19])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:18]([O:17][O:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:19])[CH2:20][CH2:21][C:22]([O:11][CH2:7][CH:8]([OH:10])[CH3:9])=[O:23]
Reactant: CC(C)(C)OOC(=O)CCC(=O)Cl
Reactant: CC(O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)COC(=O)CCC(=O)OOC(C)(C)C
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 97.5 %

Procedure:
A 250 mL 3-neck round-bottom flask, equipped with a magnetic stirrer, a thermometer, a cold water condenser and an addition funnel, was charged with 50 mL of methylene chloride, 4.2 g (0.052 mole) of pyridine and 19.0 g (0.25 mole) of 1,2-propanediol. The resulting vigorously stirred solution was cooled to 10° C. and to it was slowly added a solution of 11.5 g (0.050 mole) of 94% 3-(t-butylperoxycarbonyl)propionyl chloride in 10 mL of methylene chloride over a period of 20 minutes. The reaction mass was warmed to 20° C. and stirred at 20° C. for 210 minutes. The reaction mixture was washed at 10°-15° C. with 50 mL of aqueous 5% HCl solution and then twice with 100 mL portions of 5% aqueous NaHCO3 solution. The methylene chloride solution was then dried over 10% by weight of anhydrous MgSO4 and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 12.4 g (100% of theory, uncorrected) of a straw-color liquid. An infrared spectrum of the product showed a strong OH band, a strong and broad carbonyl band at ca. 1720-1780 cm-1 and a strong --OO-- band at ca. 850 cm-1. The product had a peroxyester Act[O] content of 6.29%. Based on a theoretical Act[O] of 6.45% for the desired title product, the assay was 97.5% and the corrected yield was 97.5%.
Reaction SMILES: ClC1C=C(C=CC=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[N+:83]([C:86]1[CH:87]=[C:88](B(O)O)[CH:89]=[CH:90][CH:91]=1)([O-:85])=[O:84]>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:88]4[CH:89]=[CH:90][CH:91]=[C:86]([N+:83]([O-:85])=[O:84])[CH:87]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2cccc([N+](=O)[O-])c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 7 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 3-nitrophenylboronic acid (44 mg, 0.2625 mmol) to produce the title compound (7 mg, 7% yield).