Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([C:28]([O:30]CC)=[O:29])=[CH:24][C:22]=4[N:23]=3)[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:33]([N:35]1[CH2:39][CH2:38][S:37][CH2:36]1)=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C=CC2OC(C3CCN([C@@H]4CN[C@H](C(N5CCSC5)=O)C4)CC3)=NC=2C=1)=O)C.O.[OH-].[Li+]>C(O)C.O.Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:22]=4[N:23]=3)[CH2:17][CH2:18]2)[CH2:10][C@H:9]1[C:33]([N:35]1[CH2:39][CH2:38][S:37][CH2:36]1)=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc2oc(C3CCN([C@H]4C[C@@H](C(=O)N5CCSC5)N(C(=O)OC(C)(C)C)C4)CC3)nc2c1
Agent: CCOC(=O)c1ccc2oc(C3CCN([C@@H]4CN[C@H](C(=O)N5CCSC5)C4)CC3)nc2c1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](N2CCC(c3nc4cc(C(=O)O)ccc4o3)CC2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 80.5 %

Procedure:
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-ethoxycarbonyl-2 -benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 309 (3), 4.51 g] was dissolved in ethanol (16 mL) and water (8 mL), and lithium hydroxide monohydrate (678 mg) was added. The mixture was stirred at room temperature for 3.5 hr. The reaction mixture was diluted with water, and 1 mol/L hydrochloric acid was added to adjust its pH to 7. The mixture was extracted with chloroform. The extract was dried and concentrated under reduced pressure to give 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carboxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (3.45 g) as a white powder.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3(O)[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: OC1(c2ccc(-c3ccccc3)cc2)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(c2ccc(-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
1-(4-Phenylphenyl)cyclopentan-1-ol (7.50 g, 31.5 mmol), p-toluenesulfonic acid (650 mg) and toluene (200 mL) were mixed together in a 500 mL 3 neck flask fitted with a thermometer and Dean Stark trap and stirred at reflux for 4 hours under a nitrogen atmosphere. The reaction was then allowed to cool to room temperature and concentrated under reduced vacuum. The resulting semi-solid was taken into methylene chloride, washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 7.73 g as a solid. This material was purified via silica gel chromatography employing the Water's Prep 2000 and eluting with a solvent of hexane/methylene chloride 4:1 to yield the intermediate title compound (4.71 g, 68%) as a white solid. Fd M.S. 220.1 (M*).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH2:13]O)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[C:4](=[CH2:13])[NH:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-DL-serine methyl ester {5.48 g, Reference Example 15(a)} in tetrahydrofuran (60 mL) was treated with triethylamine (3.48 mL) followed by carbonyldiilmidazole (4.05 g). The mixture was stirred at room temperature overnight and then evaporated. The residue was extracted several times with tert-butyl methyl ether. The combined extracts were evaporated to give a colourless oil which was subjected to flash chromatography on silica eluting with toluene to give the title compound (3.64 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CCc1cc(Cl)c(Cl)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(Cl)c(Cl)cc1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a stirring solution of 4,5-dichloro-2-ethylbenzenamine (600 mg, 3.15 mmol) in DMF at 0° C., NaH (150 mg, 3.78 mmol) was added in portions. After stirring for 30 min, ethyl 2-bromoacetate (789 mg, 4.74 mmol) was added to the mixture. The resulting mixture was stirred at 120° C. for 16 h. The mixture was allowed to cool to room temperature, poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford the desired product (380 mg, 44.7% yield) as a yellow solid.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([OH:16])=[O:15].[Cl-].[Cl-].[Cl-].[Al+3]>>[CH3:8][O:7][C:1]1[CH:6]=[C:5]2[C:4](=[CH:3][CH:2]=1)[C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=[CH:13]2
Reactant: COc1ccccc1
Reactant: O=C(O)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(C(=O)O)cccc2c1

Procedure:
This starts from anisole; this is reacted with furan-2-carboxylic acid in the presence of a large excess of aluminium trichloride to give 6-methoxy-naphthalene-1-carboxylic acid (see J. Am. Chem. Soc. 69, page 2262 and European Patent No. A1-200,840).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:31])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[N:23]=3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 4-Methoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 363.2 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:26][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([N+:27]([O-:29])=[O:28])[CH:3]=1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:36][O:35][C:33]([N:11]([C:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:26][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:27]([O-:29])=[O:28])(=[O:10])=[O:9])=[O:34]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])ccc2c1OCC1CC21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A solution of methyl (1aRS,7bSR)-5-(4-fluoro-2-nitrobenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 112, 0.25 g) in THF (10 mL) was added dropwise with stirring to a cooled suspension of sodium hydride (0.1 g) in THF (5 mL) at 0° C. On completion of the addition, the mixture was stirred at room temperature for 30 minutes. Methyl chloroformate (0.3 g) was added dropwise and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether to give methyl (1aRS,7bSR)-5-[N-(methoxycarbonyl)-N-(4-fluoro-2-nitrobenzenesulfonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.2 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: Oc1ccc(F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 336.3 parts of 4-fluorophenol, 417.5 parts of allyl bromide, 420 parts of potassium carbonate and 480 parts of acetone is stirred and refluxed for 8 hours. After cooling to room temperature, 2250 parts of water are added. The aqueous layer is separated and extracted twice with ether. The combined extracts are washed successively twice with sodium hydroxide solution 10% and twice with sodium chloride solution, dried over potassium carbonate, filtered and evaporated. The oil residue is distilled in vacuo, yielding 381.8 parts of 4-allyloxy-fluorobenzene; bp. 93° C at 23 mm. pressure; nD20 : 1.4950;d2020 : 1.070.
Reaction SMILES: I.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N:25]=[C:26]=[S:27])=[C:18]([F:28])[CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([NH:25][C:26]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]2)=[S:27])=[C:18]([F:28])[CH:17]=1
Reactant: C1CCNNC1
Reactant: O=[N+]([O-])c1cc(N=C=S)c(F)cc1Cl
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a stirred, cold (-5° C.) solution of 8.56 g (0.0400 mole) of perhydropyridazine hydroiodide in 150 mL of methylene chloride was added dropwise 12.2 g (0.120 mole) of triethylamine. This mixture was stirred for approximately 30 minutes. A solution of 8.0 g (0.034 mole) of 4-chloro-2-fluoro-5-nitrophenylisothiocyanate in methylene chloride was added dropwise to the reaction mixture while maintaining a reaction temperature of -20° C. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for two days. The solvent was removed from the mixture by evaporation under reduced pressure leaving a residue. The residue was subjected to column chromatography on silica gel, eluting with ethyl acetate:n-heptane (50:50), to yield 10.4 g of N-[(4-chloro-2-fluoro-5-nitrophenyl)aminothiocarbonyl]perhydropyridazine as a solid, mp 118°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][O:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH3:28].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][O:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([C:23]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:21][C:20]=1[CH3:28]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was placed 3,5-dimethyl-4-hydroxy benzaldehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) of product. To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150° C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:28])[C@@H:19]([NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:20]([CH3:22])[CH3:21])=[N:10][CH:9]=2)=[CH:4][C:3]=1[O:29][CH:30]([F:32])[F:31].[CH3:33][O:34][CH2:35][C@@H:36]1[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:38]([C:48]2[NH:52][C:51]3[C:53]4[C:58]([CH:59]=[CH:60][C:50]=3[N:49]=2)=[CH:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][CH:54]=4)[CH2:37]1.COC(N[C@@H](C(C)C)C(N1CCC[C@H]1C1NC2C3C(C=CC=2N=1)=CC(C1C=C2C(=CC=1)C1NC([C@@H]4C[C@H](COC)CN4C(=O)[C@@H](NC(=O)OC)C(C)C)=NC=1C=C2)=CC=3)=O)=O>>[F:31][CH:30]([F:32])[O:29][C:3]1[CH:4]=[C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:28])[C@@H:19]([NH:23][C:24]([O:25][CH3:26])=[O:27])[CH:20]([CH3:22])[CH3:21])=[N:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[C:56]1[CH:57]=[C:58]2[C:53](=[CH:54][CH:55]=1)[C:51]1[NH:52][C:48]([C@@H:38]3[CH2:37][C@H:36]([CH2:35][O:34][CH3:33])[CH2:40][N:39]3[C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42])=[N:49][C:50]=1[CH:60]=[CH:59]2
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)c(OC(F)F)c2)[nH]1)C(C)C
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(B5OC(C)(C)C(C)(C)O5)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8CCCN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5OC(F)F)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1

Procedure:
(2S,4S)-tert-Butyl 2-(7-(2-(difluoromethoxy)-4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate was prepared from methyl (S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate and (2S,4S)-tert-butyl 4-(methoxymethyl)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate using the same conditions employed in the synthesis of methyl {(2S)-1-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:17]C1C=C(C)C=CC=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH3:17][C:15]1[CH:14]=[C:5]([CH:4]=[CH:3][CH:2]=1)[CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1cccc(CBr)c1
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1cccc(C)c1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 3-bromomethyltoluene (15 g), a 2M ethanolic solution of sodium ethylate (44.5 cc) and ethyl 2-mercaptoacetate (9.7 g) in ethanol (100 cc). Ethyl (3-methylbenzylthio)-acetate (14.4 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23](C(Cl)=O)=[CH:22][CH:21]=1>>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:9]([N:7]2[CH2:8][C:4](=[N:3][O:2][CH3:1])[CH2:5][C@H:6]2[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:22][CH:21]=1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 31 %

Procedure:
Following the general methods as outlined in Example 4, starting from 1-tert-butyl 2-methyl(2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and [1,1′-biphenyl]-4-carbonyl chloride, the title compound was isolated, after flash-chromatography, as a mixture of two isomers as an oil in 31% yield (99% purity by HPLC).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:12]([CH:15]=[C:16](SC)[NH:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[NH:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: NCCCCc1ccccn1
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCCCc1ccccn1

Procedure:
When 2-(4-aminobutyl)pyridine is reacted with 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-ethylene in the procedure of Example 1 (a) (ii), the title compound is produced.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: NCCc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc(NCCc2ccc(Cl)cc2)[nH]c1=O
Temperature: 80 °C
Yield: 25.2 %

Procedure:
The mixture of ethyl 2-(methylthio)-6-oxo-1,6-dihyropyrimidine-5-carboxylate (333 mg, 1.554 mmol) and 2-(4-chlorophenyl)ethanamine (242 mg, 1.554 mmol) were dissolved in 10 mL of ethanol and heated at 80° C. overnight. After heating, the solution was run on thin layer chromatography and filtered. The precipitate was collected and stored. 1H-NMR confirmed the product (126 mg, 25.2% yield).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33](=[O:49])[C@H:34]([CH:46]([CH3:48])[CH3:47])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:22][CH2:23][C:24]([O:26][CH2:27]Cl)=[O:25])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:50].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33](=[O:49])[C@H:34]([CH:46]([CH3:48])[CH3:47])[NH:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:22][CH2:23][C:24]([O:26][CH2:27][I:50])=[O:25])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CCC(=O)OCCl)cc1OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CCC(=O)OCI)cc1OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 65 °C
Yield: 89.2 %

Procedure:
Chloromethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (1.9 g, 2.7 mmol) and sodium iodide (2 g, 13.3 mmol) were dissolved in acetonitrile (50 ml) and heated to 65° C. for 60 min. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and filtrated. Removal of the solvent and purification by chromatography (ethyl acetate-hexane, 2:5) gave pure title product (1.9 g, 90%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH:19]\2O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C(N(CC)CC)C.[C:52]([O-:55])(=[S:54])[CH3:53].[K+]>ClCCl.O>[C:52]([S:54][CH:19]1[CH2:18][CH2:17][N:16]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15]/[C:14]/1=[CH:13]\[C:10]1[CH:11]=[CH:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[N:9]=1)(=[O:55])[CH3:53]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)n1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (15.0 g) in dichloromethane (300 ml) were added successively methanesulfonyl chloride (2.5 ml) and triethylamine (4.5 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour and then evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in dimethyl sulfoxide (200 ml) was added potassium thioacetate (16.5 g) at room temperature, and the resulting mixture was stirred at 50° C. for 30 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane and dichloromethane (1:8:1) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}-1-(triphenylmethyl) piperidine (including impurities) as a yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][CH:6]=[CH:5]2>CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][CH2:6][CH2:5]2
Reactant: COc1cc2c(=O)[nH]ccc2cc1F
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1F)CCNC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
A suspension of 6-fluoro-7-methoxyisoquinolin-1(2H)-one (Cpd L, 0.531 g, 2.75 mmol) and 10% Pd/C in EtOH (20 mL) was stirred vigorously under a blanket of H2 (balloon) at room temperature for 2 days. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 6-fluoro-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (Cpd M, 430 mg, 80%) as a white powder.