Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:23])=[CH:11][C:12]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2].N1C=CC=CC=1.[CH:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[C:10]([NH:23][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([CH:33]([CH3:34])[CH3:35])=[CH:37][CH:38]=2)=[CH:11][C:12]([O:15][Si:16]([CH3:21])([CH3:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2cccc(C#N)c2)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-4-(dimethyl-t-butylsiloxy)-1,2-benzenediamine (2.63 g, 7.17 mmol) and CH2Cl2 (45 mL) at 0° C. was added pyridine (0.65 mL, 8.0 mmol) followed by a solution of the 4-isopropyl benzoyl chloride (10.1 mmol) in CH2Cl2 (90 mL). The reaction was allowed to warm to room temperature and stirred for 10 m. The reaction was diluted with CH2Cl2 (200 mL) and washed with sat. aq. NH4Cl (2×50 mL). The organic layer was MgSO4 dried filtered, and concentrated. The residue was chromatographed (10% EtOAc/hexanes to 20% EtOAc/hexanes) to give the title compound as a solid (3.04 g, 83%); IR(CHCl3): 2962, 1656, 1610, 1513, 1473, 1295 cm−1; NMR(300 MHz, CDCl3): δ0.16 (s, 6H), 0.95 (s, 9H), 1.29 (s, 3H), 1.31 (s, 3H), 3.00 (m, 1H), 6.68 (d, 1H, J=9.0), 6.86 (s, 1H), 7.38 (d, 2H, J=8.1), 7.50 (d, 1H, J=9.0), 7.61 (m, 1H), 7.81 (d, 1H, J=6.3), 7.89 (d, 2H, J=7.1), 8.16 (d, 1H, J=9.3), 8.29 (s, 1H), 8.58 (br s, 1H), 9.40 (br s, 1H); MS(FD): 513.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:2]1=2.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24]OS(C)(=O)=O>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:24][CH2:23][C:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:16][C:12]=3[CH3:11])[C:2]1=2
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: Oc1cccc2ccsc12
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc2ccsc12

Procedure:
In analogy to the procedures described in example 91 a] and b], benzo[b]thiophen-7-ol [J. Chem. Soc., Perkin Trans. 1 (1983), (12), 2973-7] was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002]) to yield 4-[2-(benzo[b]thiophen-7-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole. Treatment of 4-[2-(benzo[b]thiophen-7-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with dichloromethyl methyl ether and titanium tetrachloride then gave 7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophene-4-carbaldehyde as a yellow solid. NMR: (CDCl3, 1H, δ, TMS, 300 MHz) 2.45 (s, 3H), 3.12 (t, J=6, 2H), 4.55 (t, J=6, 2H), 6.92 (d, J=8, 1H), 7.39-7.46 (m, 3H), 7.66 (d, J=5, 1H), 7.80 (d, J=8, 1H), 7.95-7.99 (m, 2H), 8.35 (d, J=5, 1H), 10.1 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([OH:17])([CH3:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[H-].[Na+].[CH3:22]I>C1COCC1>[F:19][C:2]([F:1])([F:18])[C:3]([O:17][CH3:22])([CH3:16])[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: CI
Reactant: CC(O)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(CN1C(=O)c2ccccc2C1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirring solution of 2-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)isoindoline-1,3-dione (250 mg, 0.915 mmol)) at 0° C. in THF (8 ml), NaH (80 mg, 2 mmol) was added. After 30 minutes methyl iodide (1.299, 9.15 mmol) was added. The reaction mixture was left stirring in a ice-bath and allowed to warm to 25° C. over 3.5 hours. The reaction was quenched with sat. NH4Cl and the mixture extracted with DCM. The organic extract was separated using a phase separator and purification by chromatography on silica, eluting in a 0% to 30% iso-hexane:EtOAc afforded the title product; 1H NMR (400 MHz, Methanol-d4) δ 7.91 (2H, m), 7.85 (2H, m), 3.97 (2H, m), 3.44 (3H, s), 1.42 (3H, s);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:25]([F:28])([F:27])[F:26])[N:6]2[CH2:23][CH2:22][N:21]([CH3:24])[C:8]3([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]3)[C:7]=12)#[N:2].[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[ClH:29].[CH3:24][N:21]1[CH2:22][CH2:23][N:6]2[C:5]([C:25]([F:28])([F:26])[F:27])=[CH:4][C:3]([C:1]#[N:2])=[C:7]2[C:8]21[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2
Reactant: CN1CCn2c(C(F)(F)F)cc(C#N)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCn2c(C(F)(F)F)cc(C#N)c2C12CCNCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 8-cyano-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (278.9 mg, 0.7 mmol) in DCM (4 mL) was added HCl in dioxane (2 mL of 4 M, 8.0 mmol). The mixture was stirred at room temperature for 30 min. The solvent was evaporated and the crude material was used directly in next step without further purification. ESI-MS m/z calc. 298.1, found 299.5 (M+1)+; Retention time: 0.88 minutes (3 minute run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:26])=[C:11]([F:25])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:33](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:33][N:17]1[C:18]2[C:13](=[CH:12][C:11]([F:25])=[C:10]([F:26])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14](=[O:24])[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16]1
Reactant: CCOC(=O)c1cnc2c(OCc3ccccc3)c(F)c(F)cc2c1O
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2c(OCc3ccccc3)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
After a mixture of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformamide (10 ml) was stirred at room temperature for 3 hours, O-(2,4-dinitrophenyl)hydroxylamine (260 mg) was added. The mixture was stirred at room temperature for further 6.5 hours. After removal of the solvent under reduced pressure, water (12 ml) was added to the residue, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with cold water and then with ether to give 405 mg of ethyl 1-amino-8-benzyloxy-6,7-difluoro-4-oxo-1,4-dihydro -3-quinolinecarboxylate. An analytical sample, mp 143°-144° C.; MS m/z 374 (M+), was prepared by recrystallization from methanol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N:5]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24].O>ClCCl>[Cl:20][CH2:21][CH2:22][C:23]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:7][CH2:8]2)=[O:24]
Reactant: O=C(Cl)CCCl
Reactant: CCOC(=O)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCCc2cc(C(=O)CCCl)ccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Aluminum chloride (23.5 g, 176 mmol) was added to a solution of ethyl 3,4-dihydro-1(2H)-quinoline carboxylate (14.5 g, 70.4 mmol) and 3-chloropropionyl chloride (7.39 ml, 77.4 mmol) in dichloromethane under cooling with water-bath, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into iced water and extracted with dichloromethane. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resulting residues were purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1) and crystallized from hexane, whereby the title compound (15.6 g) was obtained as colorless powder with a mp. of 78 to 79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][CH:34]=2)=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (550 mg), (4-methoxycarbonylphenyl)boronic acid (300 mg), triethylamine (1.0 ml) and powdered 4 Å molecular sieves (600 mg) in dichloromethane (8 ml) was added copper(II) acetate (255 mg), and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 4-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]benzoate (185 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:28])[N:19]([C@H:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH2:35](I)[CH3:36]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:28])[N:19]([C@H:23]5[CH2:27][CH2:26][N:25]([CH2:35][CH3:36])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1
Reactant: CCI
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@H]1CCNC1
Product: CCN1CC[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S)-1-ethylpyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S)-pyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 114) and ethyl iodide at rt following General Procedure S.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[O:6].[CH3:25][O:26]C1C=CC(C(Cl)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:26][C:24]1[CH:23]=[CH:22][C:4]([C:5]([NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[O:6])=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc[nH]4)c3c2)cc1
Yield: 102.9 %

Procedure:
2,2-Dimethyl-propionic acid 5-amino-3-(1H-pyrrol-2-yl)-indazol-1-yl ester (0.38 mmol) (from Example 25) was coupled with 4-methoxy-benzoyl chloride (0.4 mmol) and triethylamine in DCM at 0° C. to give 130 mg of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([F:9])=[CH:4][N:3]=1.[CH:10]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:12][CH2:11]1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH:17]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[N:14]=[CH:15]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: Fc1cnc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [Cs+]
Solvent: CCCC#N
Product: Fc1cnc(Cl)cc1-n1cnc(C2CC2)c1
Yield: 295.4 %

Procedure:
A suspension 2-chloro-5-fluoro-4-iodopyridine (1.8 g, 1.00 mmol), 4-cyclopropyl imidazole (982 mg, 9.10 mmol), Cu2O (100 mg, 0.700 mmol), 8-hydroxyquinoline (152 mg, 1.05 mmol), cesium carbonate (4.60 g, 14.0 mmol), and PEG-3350 (1.4 g) in butyronitrile (50 mL) was heated at 65° C. for 16 hours. The reaction mixture was filtered through Celite, concentrated and the residue was partitioned between dichlormethane and water. The layers were separated and the aqueous layer washed twice with dichloromethane. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (15→60% EtOAc in hexanes) to afford 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine (702 mg, 42% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1.[F-:24].[Cs+].CS(C)=O>CCOC(C)=O>[F:24][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3ncccn3)n2)cc1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2cc(F)cc(-c3ncccn3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 2 dram vial equipped with a stir bar and charged with 2-(4-chloro-6-(4-isopropoxyphenyl)pyridin-2-yl)pyrimidine (all material from step 1) was added CsF (200 mg, 1.32 mmol) and DMSO (0.7 mL). The vial was sealed with a septum cap and then placed in a 140° C. heating block with stirring for 18 hours. The reaction mixture was allowed to cool to room temperature and then was transfered to a 125 mL separatory funnel. The mixture was diluted with EtOAc (50 mL) and twice washed with water:brine (25 mL:25 mL). The organic solution was dried over MgSO4; filtered; then concentrated in vacuo to afford a solid amber residue. This material was subjected to silica gel purification (hexanes:EtOAc) to afford 2-(4-fluoro-6-(4-isopropoxyphenyl)pyridin-2-yl)pyrimidine as a white solid (15 mg, 27% over two steps). 1H-NMR (400 MHz, CDCl3) δ 8.96 (d, J=5.0 Hz, 2H), 8.12 (dd, J=9.5, 2.3 Hz, 1H), 8.09-8.04 (m, 2H), 7.50 (dd, J=9.8, 2.3 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 7.02-6.97 (m, 2H), 4.65 (spt, J=6.0 Hz, 1H), 1.38 (d, J=6.0 Hz, 6H); MS: MS m/z 310.2 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[O:22][CH2:23][C:24]([O:26]CC)=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O1CCCC1>O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[O:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2C2=CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(cyclohex-1-en-1-yl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 8a (97 mg, 0.18 mmol) and lithium hydroxide (100 mg, 4.2 mmol) were added to 25 mL of a mixed solvent of tetrahydrofuran and water (V:V=1:1), and then the reaction solution was stirred for 1 h. The reaction solution was extracted with dichloromethane (50 mL×3), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(cyclohex-1-en-1-yl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid 8b (69 mg, a colorless oil) in 75% yield.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[C@@H:10]([NH2:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([NH:40][C@@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42](O)=[O:43])(=[O:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:36])[C@@H:10]([NH:35][C:42](=[O:43])[C@@H:41]([NH:40][C:37](=[O:39])[CH3:38])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:33])=[O:34])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](N)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Reaction time: 1 h

Procedure:
The title A compound, (S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (79 mg, 0.155 mmol) and (S)-2-acetylamino-3-phenyl-propionic acid (33.7 mg, 0.162 mmol) are dissolved in CH2Cl2 (3.1 mL). HOBt (24.8 mg, 0.162 mmol) is added as a solid, followed by EDCl (31.0 mg, 0.162 mmol) and TEA (0.023 mL, 0.162 mmol) in a slurry of CH2Cl2 (1 mL). After 1 h, EtOAc (100 mL) is added and the mixture is washed three times with 2N aqueous HCl (50 mL) followed by saturated aqueous NaHCO3 (50 mL). The EtOAc layer is dried over anhydrous Na2SO4 and concentrated to yield (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a white powder.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C([Li])CCC.[Br:17]Br.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:17][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[NH:1][N:2]=[N:3][N:4]=1
Reactant: BrBr
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccccc1-c1nnn[nH]1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To (tetrazol-5-yl)benzene (0.29 g) in THF (10 ml) at -25° C. was slowly added n-butyllithium (2 mL, 2.5M in hexanes) while maintaining the reaction temperature below -15° C. When the addition was over in 10 to 15 minutes, the mixture was aged at -10° C. for 30 minutes. The reaction mixture was cooled to -60° C. and bromine (0.2 mL) was added dropwise. To the reaction mixture was added aqueous 10% sodium sulfite (5 mL). An HPLC assay showed a starting material/products ratio of 3.5/96.5. The product was precipitated by the addition of water (20 mL) and acidification with 2N HCl to pH 2. The mixture was aged at 0° C. for 1 hour and filtered. The yield was 0.427 g (95%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][C:3]=1C(O)=O.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>CC(N(C)C)=O.C(OCC)C>[Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][CH:3]=1
Reactant: COc1ccc(F)c2c(Cl)c(C(=O)O)sc12
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: COc1ccc(F)c2c(Cl)csc12
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A mixture of 3-chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (1.09 g, 4.19 mmol) and diazobicycloundecane (DBU) (2 mL) in dimethylacetamide (15 mL) was heated in a sealed vessel in a microwave (300W, 100%) for 1 h. After cooling to room temperature the mixture was diluted with diethyl ether (100 mL) and washed with brine (2×100 mL). The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:diethyl ether [10:1] to yield a white solid (520 mg, 57%); δH (300 MHz, CDCl3) 7.24 (1H, s, Ar), 7.05-6.92 (1H, m, Ar), 6.70-6.60 (1H, dd, Ar), 3.96 (3H, s, OCH3).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[S:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:20][C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[OH:27][C:7]1[C:8]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:18][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:11][C:6]=1[C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2sc(-c3ccccc3)nc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 7-hydroxy-2,4-diphenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (93 mg, 0.25 mmole) and glycine (372 mg, 4.95 mmole) in 0.5 M sodium methoxide/methanol (9.4 ml) was refluxed for 4 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (50 ml) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (7 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (79 mg). 1H NMR (DMSO-d6, 200 MHz): δ=13.28 (br s, 1H), 9.42 (t, 1H, J=6.2 Hz), 8.16 (m, 4H), 7.62 (m, 6H), 4.07 (d, 2H, J=5.8 Hz); MS: (+) m/z 406.27 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]1[C:17]([CH2:22]Br)=[CH:18][CH:19]=[CH:20][CH:21]=1>O1CCCC1>[C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:22][C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15]1)([O:9][CH2:10][CH3:11])=[O:8]
Reactant: BrCc1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)Cc2ccccc2C1
Temperature: 5 °C
Yield: 73.5 %

Procedure:
Dissolve diethyl malonate (7.6 mL, 50 mmol) in anhydrous tetrahydrofuran (500 mL) and place under an argon atmosphere. Cool to 5° C., add sodium hydride (1.2 g, 50 mmol) and stir briefly until homogeneous. Add α,α'-dibromo-o-xylene (13.2 g, 50 mmol) and stir an additional 15 minutes. Add additional sodium hydride (1.2 g, 50 mmol) and stir for 16 hours while warming to room temperature. Filter, evaporate the solvent in vacuo and purify by silica gel chromatography (1:1 methylene chloride/hexane) to give 2,2-dicarboethoxyindan (9.64 g, 74%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:16][C:15]=2[C:14]([OH:26])=[CH:13][CH:12]=1)[CH2:5][CH2:6][Cl:7].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C)C=O.O>[Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:16][C:15]=2[C:14]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:13][CH:12]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=c1c2ccccc2sc2c(O)ccc(OCCN(CCCl)CCCl)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCCN(CCCl)CCCl)c2c(=O)c3ccccc3sc12

Procedure:
A solution of 0.50 g of 1-(N,N-bischloroethylaminoethoxy)-4-hydroxythioxanthone in 10 ml of dimethylformamide is mixed with 0.22 g of tert-butyldimethylsilyl chloride, 0.20 g of imidazole and a catalytic amount of dimethylaminopyridine, and stirred at room temperature for 12 h. The solution is then added over water and extracted with ethyl acetate. The ethyl acetate extract is washed sequentially with saturated sodium bicarbonate and water, dried over sodium sulfate, concentrated and dissolved in a mixture of ethyl acetate: hexanes (1:4) and passed through a plug of alumina. The solid obtained after concentration is pure and weighed 0.48 g (70%).