Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)O)cc1F
Temperature: 80 °C
Yield: 72 %

Procedure:
Methyl 3-fluoro-4-isopropoxybenzoate (from step 1), 1,4-dioxane (31 mL), and NaOH (31 mL of 1.0 M, 31 mmol) were combined and the mixture was heated at 80° C. for 20 min. The solvent was evaporated under reduced pressure. The crude mixture was dissolved in water and was washed with EtOAc (3×). The combined organics were discarded. The aqueous layer was acidified and was extracted with EtOAc (3×). The organic layer was dried over sodium sulfate, filtered and the concentrated under reduced pressure to yield 3-fluoro-4-isopropoxy-benzoic acid (1.25 g, 72%) as a white solid. ESI-MS m/z calc 198.1, found 199.3 (M+1)+. Retention time: 1.34 minutes (3 min run).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=O)=O)(C)(C)C.C[N:25](C=O)C.S(Cl)(Cl)=O>C1COCC1.N1C=CC=CC=1>[C:21]([CH:9]1[NH:8][CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1)(=[O:23])[NH2:25]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Temperature: 40 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
1,4-Bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.0 g, 3.03 mmol) was suspended in THF (5 mL) and pyridine (0.36 mL), DMF (0.1 mL) was added, followed by thionyl chloride (0.23 mL, 3.03 mmol). The reaction mixture was stirred at 40° C. for 4 h and then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 and transferred to a sealed tube. A saturated solution of ammonia in dioxane (10 mL) was added to the compound and the resulting reaction mixture was stirred at 40° C. for 2 h followed by room temperature stirring for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1.5 N HCl. The aqueous layer was washed with diethyl ether and then basified with 1N sodium hydroxide solution. The organic product was extracted with CH2Cl2. The combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to get tert-butyl 3-carbamoylpiperazine-1-carboxylate (340 mg, yield 49%), which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 6.70 (br s, 1H), 5.51 (br s, 1H), 4.06-4.03 (m, 1H), 3.77 (m, 1H), 3.37-3.33 (m, 1H), 3.11-2.95 (m, 3H), 2.81-2.76 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9](=[CH2:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH:2]=1.[CH3:16][NH:17][C:18](=[O:21])[CH2:19][SH:20].[N-]=C=O>ClCCl.C(N(CC)CC)C>[CH3:16][NH:17][C:18]([CH2:19][S:20][CH2:15][CH:9]([C:7](=[O:8])[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:21]
Reactant: CNC(=O)CS
Reactant: C=C(CC(=O)OC)C(=O)c1cccnc1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)CSCC(CC(=O)OC)C(=O)c1cccnc1
Reaction time: 24 h

Procedure:
A solution of methyl 3-(3-pyridylcarbonyl)but-3-enoate in dichloromethane (0.5 mL, 0.1 mM), triethylamine in dichloromethane (0.5 mL, 0.1 mM) and N-methyl-2-sulfanylacetamide (0.6 mL, 0.12 mmol) was stirred for 24 h. PS isocyanate resin (60 mg) was added to the reaction mixture and stirred for 24 h. The solution was filtered and concentrated to give the title compound in quantitative yield, ESMS, (M+1)+311.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)=[N:5][N:4]=1)#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C>CO>[OH:23][B:14]1[C:13]2[CH:24]=[C:9]([O:8][C:6]3[S:7][C:3]([C:1](=[NH:2])[NH:27][OH:28])=[N:4][N:5]=3)[CH:10]=[C:11]([CH3:25])[C:12]=2[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C#N)s3)cc(C)c21
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C(=N)NO)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 2-(6-(5-cyano-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.63 g, 4.54 mmol, 1 eq.) and hydroxylamine hydrochloride (0.79 g, 11.35 mmol, 2.5 eq.) in methanol was added triethylamine (2.22 ml, 15.88 mmol, 3.5 eq.). After stirring at room temperature for one hour, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and then washed with water. The organic layers were collected, dried with Na2SO4 and evaporated to give the crude product (1.73 g, yield 97.2%). The crude was used in subsequent steps without further purification.
Reaction SMILES: N[C@H:2]1CCCN(C(OC(C)(C)C)=O)[C@H:3]1C1C=CC=CC=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][CH2:35][C:36]2[CH:41]=[C:40]([CH:42]([C:47](F)([F:49])[F:48])C(F)(F)F)[CH:39]=[CH:38][C:37]=2[O:51][CH3:52])[C@@H:29]1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][CH2:35][C:36]2[CH:41]=[C:40]3[C:39]([CH2:2][CH2:3][C:47]([F:48])([F:49])[CH2:42]3)=[CH:38][C:37]=2[O:51][CH3:52])[C@@H:29]1[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:27])([CH3:23])([CH3:24])[CH3:22]
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Product: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)CC(F)(F)CC2

Procedure:
This compound was prepared from Compound 96 and Compound 12 in the same manner of Compound 13.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10].O>C(O)(=O)C>[CH3:7][C:6]1[N:16]([C:15]2[CH:17]=[CH:18][C:12]([O:11][CH2:9][CH3:10])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(-n2c(C)ccc2C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of acetonyl acetone (1.95 mL, 16.5 mmol) in acetic acid (100 mL) was added 4-ethoxy-2-nitroaniline (3.0 g, 16.5 mmol) and the red mixture heated at reflux overnight. After cooling to rt, the now black solution was poured into water and extracted with EtOAc (2×200mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to an oil. Purification by flash chromatography (10% EtOAc/hexanes) gave 2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole as a red oil: 1H NMR (CDCl3, 500 MHz) δ 7.46 (d, 1H), 7.27 (t, 1H), 7.19 (dd, 1H), 5.91 (s, 2H), 4.15 (q, 1H), 1.96 (s, 6H), 1.50 (t, 3H); MS (ESI) 261 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>C(#N)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[CH:11]=3)[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)=[CH:13][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(Br)ccc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C#C[Si](C)(C)C)ccc2c1=O
Temperature: 0 °C

Procedure:
To a solution of 25.4 g ethyl 7-bromo-1,4-dihydro-1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxylate in 975 ml acetonitrile at 40°-50° C. was added 1.4 g cuprous iodide and 325 ml triethylamine. The air in the reaction was replaced by argon, and 1.4 g bis-triphenylphosphine palladium dichloride and 15.5 ml trimethylsilylacetylene were added. The reaction mixture was heated at reflux for one hour, then chilled to 0° C, and the product was collected to give 23.4 g ethyl 1,4-dihydro-1-(4-fluoro- phenyl)-4-oxo-7-(trimethylsilylethynyl)-3-quinolinecarboxylate. A sample of the compound was further purified by recrystallization from DMF to give a colorless solid, m.p. 247°-249° C. The corresponding carboxylic acid, obtained by hydrolysis of the ester with ethanolic hydrogen chloride, was obtained as a light-tan powder, m.p. 289° C. (decompn.).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18]CC)=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([OH:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(=O)O)c2c1-c1nc(N)ncc1CC2
Yield: 73.4 %

Procedure:
Ethyl 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (275 mg, 1 mmol) was to suspended in anhydrous ethanol (10 mL) and treated with a 2 M solution of sodium hydroxide (0.5 mL, 1 eq.) at reflux temperature for 1 hour. Solvent was evaporated to dryness and the residue dissolved in water. After treatment with acetic acid and the resulting precipitate was collected by filtration to give the title compound (180 mg, 74% yield) as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH:4]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH3:18])[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.O>[NH:4]([C:11]1[N:12]=[C:13]([CH3:18])[CH:14]=[C:15]([O:2][CH3:1])[N:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)nc(Nc2ccccc2)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
2.9 g of 28% methanolic solution of sodium methylate was dissolved in 40 ml of methanol, and thereto was added 3.3 g of 2-anilino-4-chloro-6-methylpyrimidine. After 2 hours of reaction with stirring at room temperature the reaction liquid was poured in water The solids deposited were filtered, dried, and recrystallized from n-hexane to afford 2 9 g of 2-anilino-4-methyl-6-methoxypyrimidine (yield 92 %). Melting point: 75°-76° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([N:30]3[CH2:31][CH2:32][O:33][CH:28]([CH2:27][CH2:26][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:29]3)=[O:3])[C:5]=12
Reactant: C1CCN(CCC2CNCCO2)CC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Agent: Cl
Product: Cc1scc2c1N(C(=O)N1CCOC(CCN3CCCCC3)C1)c1ccccc1NC2=O
Yield: 74 %

Procedure:
Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[2-(1-piperidinyl)ethyl]morpholine in a yield of 74% of theory. Rf 0.48 (conditions as in Example 58). The colourless hydrochloride melted at 254°-256° C. (D.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:15](OC)=[O:16])[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:15][OH:16])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2cccc(OC)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(CO)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 5 b), by reducing methyl 4,8-dimethoxy-naphthalene-2-carboxylate (J.Chem.Soc. 1959, 1024) by means of lithium aluminium hydride there was obtained (4,8-dimethoxy-naphthalen-2-yl)-methanol, MS: 218 (M)+, as a colourless solid.
Reaction SMILES: BrC1C=C2C(=CC=1)N(S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.Cl[S:30]([C:33]1[C:41]2[C:36](=[C:37]([N+:42]([O-:44])=[O:43])[CH:38]=[CH:39][CH:40]=2)[N:35](S(C2C=CC=CC=2)(=O)=O)[C:34]=1[C:54]([O:56]CC)=[O:55])(=[O:32])=[O:31].[O:59]([CH2:66][C@H:67]1[O:72][CH2:71][CH2:70][NH:69][CH2:68]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[N+:42]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:36]=1[NH:35][C:34]([C:54]([OH:56])=[O:55])=[C:33]2[S:30]([N:69]1[CH2:70][CH2:71][O:72][C@H:67]([CH2:66][O:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH2:68]1)(=[O:31])=[O:32])([O-:44])=[O:43]
Reactant: c1ccc(OC[C@@H]2CNCCO2)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cccc([N+](=O)[O-])c2n1S(=O)(=O)c1ccccc1
Agent: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Product: O=C(O)c1[nH]c2c([N+](=O)[O-])cccc2c1S(=O)(=O)N1CCO[C@H](COc2ccccc2)C1

Procedure:
Following the procedure described in Steps B and C of Example 2, replacing in Step B ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole-2-carboxylate and replacing morpholine with (S)-2-(phenoxymethyl)morpholine from Step A of Example 23, the title compound was obtained. ESI+MS: 461.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C1Cc2cc(-c3cccc(Cl)c3)ccc2N1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of the 5-bromoxindole (0.5 g, 2.4 mmol) and tetrakis(triphenylphosphine) palladium (0.14 g, 0.12 mmol) in dimethoxyethane (10 cm3) was stirred under N2 for 20 min. To this mixture was then added 3-chlorophenylboronic acid (0.44 g, 2.83 mmol) and sodium carbonate (0.75 g, 7.1 mmol) in water (4 cm3). The solution was brought to reflux for 6 h then cooled to RT, poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:3) to afford the title compound (0.49 g, 2.0 mmol, 86%) as a tan solid: m.p. 169-171° C., 1H NMR (THF-d8) δ 3.45 (s, 2H), 6.85 (d, 1H J=8.1 Hz), 7.25 (d, J=8.0 Hz, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.50 (s, 1H), 7.59 (dd, J=1.78, 1.78 Hz, 1H), 9.5 (br s, 1H); 13C NMR (THF-d8) δ 36.39 (t), 109.80, 123.97, 125.55, 127.19 (d), 127.68 (s), 130.89 (d), 133.73, 135.29, 144.23, 145.09, 176.45 (s); MS (EI) m/z 243, 245 (M)+; Anal. (C14H10ClNO)C, H, N.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:14]([C:24]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)=[C:25]([CH2:26][CH3:27])[C:12]3=[CH:11][CH:10]=1)=C(C(O)=O)C=2C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([O:45][C:46](=[O:48])[CH3:47])(=[O:44])[CH3:43]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:14]([C:24]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:32][CH:33]=4)=[C:25]([CH2:26][CH3:27])[C:12]3=[CH:11][CH:10]=1)=[C:47]1[C:46](=[O:48])[O:45][C:42](=[O:44])[C:43]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)O)c(C(=O)O)c3c(OCc4ccccc4)ccc1n32
Solvent: c1ccncc1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c3c(c4c(OCc5ccccc5)ccc1n42)C(=O)OC3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7Benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid (34.00 g, 60 mmol) was dissolved in 200 ml of pyridine under a nitrogen atmosphere. Acetic acid anhydride (8.8 ml, 90 mmol) was added and the mixture was stirred at room temperature for 21/2 hours. The reaction mixture was allowed to cool to room temperature and the product was filtered off, and washed with petroleum ether. This gave 25.63 g (81%) of the title compound as yellow crystals. M.p. 229-231° C. MS(SP): m/z 527 (M+). 1H-NMR (CDCl3, and DMSO-d6, 300 MHz) δ: 1.47 (t, 3H); 3.20 (q, 2H); 5.18 (s, 2H); 5.59 (s, 2H); 7.19 (d, 2H); 7.30-7.55 (m, 9H); 7.62 (d, 2H); 7.79 (d, 2H); 7.98 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH2:34][NH2:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:34][NH:35][C:10](=[O:12])[C@@H:9]2[CH2:13][C@@H:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Reactant: NCc1cccc2ccccc12
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)NCc1cccc2ccccc12

Procedure:
The title compound was prepared using the procedure in Example 1 step H using N-t-butoxycarbonyl-4(R)-benzyloxyproline and naphth-1-ylmethylamine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[N:9][N:10]=2)[N:7]=1.[SH-:11].[K+]>C(O)C>[SH:11][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[N:9][N:10]=2)[N:7]=1
Reactant: [SH-]
Reactant: Clc1ccc2nnnn2n1
Agent: [K+]
Solvent: CCO
Product: Sc1ccc2nnnn2n1

Procedure:
A mixture of 21.3 g. (0.137 mole) of 12 and 20 g. (0.25 mole) of potassium hydrosulfide in 200 ml. of ethanol was refluxed for 2 hours and evaporated to dryness. The residue was dissolved in 100 ml. of water and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 1 with dil. hydrochloric acid to precipitate (13) as colorless needles which were collected by filtration, washed with 20 ml. of water and dried. Yield 9.80 g. (47%). M.p. 140°-141° C. (dec.).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][O:52][C:53](=[O:55])[NH2:54])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][O:52][C:53](=[O:55])[NH2:54])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCOC(N)=O)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
2.67 ml of trifluoroacetic acid and 122 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 417 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (ii) above] in 753 μl of anisole, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was repeatedly washed with diethyl ether by decantation. After the residue had been dried in vacuo, 325 mg of the title compound were obtained, as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30]C4C=CC=CC=4)=O)=[CH:23][C:22]=3[O:37][CH3:38])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:41][NH:42][C:43]([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl>[C:43]([N:42]([CH3:41])[C:28](=[O:30])[NH:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:8]2[C:7]3[CH:39]=[CH:40][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[N:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:9]2=[O:17])(=[O:19])=[O:20])=[C:22]([O:37][CH3:38])[CH:23]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CNC(C)(C)C
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)Oc2ccccc2)cc1OC
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)N(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of the compound obtained in EXAMPLE 16 step A), 1 ml of N-methyl-tert-butylamine and 20 ml of DCM is stirred for 2 hours at RT. The solvent is evaporated off under vacuum and the residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.13 g of the expected product after crystallization from an iso ether/ AcOEt mixture (65/35; v/v). M.p.=208° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=O)[CH3:2].[C:9]([O:12][C:13](=O)C)(=O)[CH3:10].C([O-])(=O)C.[Pb+2].C([O-])(=O)C.COCC=O>O1CCCC1>[CH3:13][O:12][CH2:9][CH:10]=[C:5]1[C:6](=[O:7])[O:8][C:1]([CH3:2])=[N:4]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: COCC=O
Agent: [Pb+2]
Solvent: C1CCOC1
Product: COCC=C1N=C(C)OC1=O

Procedure:
A flask equipped with a mechanical stirrer, reflux condenser, dropping funnel, and drying tube was charged with 38.5 g (0.33 mol) of N-acetylglycine (2), 134 g (1.3 mol) of acetic anhydride, 54 g (0.166 mol) of lead acetate, and 450 ml of tetrahydrofuran (THF). The mixture was heated with stirring at reflux temperature for 1 hr. A solution consisting of 37 g (0.5 mol) of methoxyacetaldehyde (1) and 220 ml of THF was then added dropwise over a 21/2 hr period. The resultant mixture was heated with stirring at reflux temperature for an additional 4 hrs. The reaction was allowed to cool, diluted with 1 l. of ether, and filtered through a pad of Celite®. The filtrate was concentrated in vacuo and the dark brown fluid residue was distilled under reduced pressure. The fraction boiling at 60°-83°/0.5 mm consisted mainly of 4-(2-methoxyethylidene)-2-methyl-5-oxazolone (3): NMR (CDCl3) δ 6.5 (m, 1H, --CH2CH=), 4.35 (m, 2H, --CH2CH--), 3.3 (s, 3H, CH3O--), 2.2 ##STR5##
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O.O>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.64 g, 26.97 mmol) in DMF (100 mL) was added NIS (6.68 g, 29.67 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h at ambient temperature, the reaction was treated by water (150 mL). The precipitate was filtered off and the filter cake was washed with water. The desired product was obtained as a yellow solid (10.34 g, 86.0% yield). 1H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 7.42 (d, J=10.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.63 (dd, J=15.0, 8.7 Hz, 1H), 3.97 (s, 3H).