Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:10][CH:9]1[C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]#[N:44])[CH2:33][CH2:32]1)=[O:30])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:21][C:18]([Cl:19])([Cl:20])[CH2:17][O:16][C:14](=[O:15])[N:13]([CH:11]1[CH2:10][CH:9]([C:29]([N:31]2[CH2:32][CH2:33][N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]#[N:44])[CH2:35][CH2:36]2)=[O:30])[NH:8][CH2:12]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(N(Cc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)N1CCN(c2ccccc2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(N(Cc3ccccc3)C(=O)OCC(Cl)(Cl)Cl)CN2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-4-[(benzyl)-(2,2,2-trichloroethoxycarbonyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester and CF3COOH are stirred at rt for about 5 h, and then concentrated to give {5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidin-3-yl}-(benzyl)-carbamic acid 2,2,2-trichloro-ethyl ester (22).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: Cc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)nc1
Yield: 53.8 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.82 g) and 2-amino-5-methylpyridine (1.08 g) as starting materials, 5-benzyloxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.00 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[C:35]([Cl:40])=[C:34]([Cl:41])[CH:33]=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH2:42][C:43]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=3[CH3:1])=[O:44])[C:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:39][CH2:38][C:37]=3[C:36]=2[C:35]=1[Cl:40]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Reactant: Cc1cccc(N)c1C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Cn2c3c(c4c(Cl)c(Cl)ccc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
DMAP (89 mg, 0.73 mmol), 2,3-dimethylaniline (98 mg, 0.81 mmol) and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional 2,3-dimethylaniline (0.049 mL, 0.40 mmol) and THF (2 mL) was added. The reaction was diluted with EtOAc after 25 h followed by washing with 10% aqueous citric acid (75 mL), saturated aqueous NaHCO3 (40 mL), and brine (40 mL). A precipitate in the combined organic layers was filtered to yield 0.22 g (58%) white solid: mp 232.5-233.0° C.; 1H NMR (DMSO, 400 MHz) δ 9.77 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 7.03 (m, 2H), 5.11 (s, 2H), 3.64 (m, 4H), 3.39 (m, 2H), 3.03 (m, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.41 (s, 9H); IR (diffuse reflectance) 2977, 1692, 1659, 1541, 1474, 1451, 1412, 1366, 1303, 1269, 1201, 1174, 1112, 791, 773 cm−1; MS (EI) m/z 515 (M+), 376, 226, 224, 212, 189, 149, 133, 119, 55, 52; HRMS (EI) calcd for C27H31Cl2N3O3 515.1743, found 515.1747.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](F)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (134.3 mg, 1.6 mmol) in 7.8 mL water was added 2-aminoethanethiol hydrochloride (97.5 mg, 0.86 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25d (170.3 mg, 0.78 mmol) in 7.8 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 205.8 mg (96% from 24d) of clean 26d as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[CH:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1>[C:36]([O:17][CH:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[CH:19]=1)[C:15]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1([CH3:14])[CH3:13])=[O:35])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 4.5 h
Yield: 96.2 %

Procedure:
To a solution of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)1H-pyrrol-3-yl]-2-hydroxy-ethanone (867 mg, 1.86 mmol) in dry pyridine (5 mL) was added acetic anhydride (0.42 mL, 4.5 mmol). After 4.5 hours at ambient temperature, the mixture was partitioned between 1N aqueous NaHSO4 (25 mL) and EtOAc (25 mL). The EtOAc layer was washed with 1N pH7 phosphate buffer (25 mL) two times, H2O (25 mL), and brine (25 mL), dried over Na2SO4, and evaporated to give 0.91 g (100%) of 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl]-ethanone as an amorphous solid that was used without further purification. An analytical sample was obtained upon flash column chromatography with 0-2% EtOAc/CH2Cl2 gradient eluent. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=7.0 Hz), 7.48-7.24 (m, 1H), 7.10 (t, 1H, J=2.6 Hz), 6.46 (dd, 1H, J=1.7, 2.8 Hz), 6.25 (s, 1H), 3.98-3.93 (m, 1H), 3.81 (d, 1H, J=9.2 Hz), 3.64-3.60 (m, 1H), 3.42 (d, 1H, J=13.6 Hz), 2.96 (dd, 1H, J=11.6, 13.8 Hz), 2.22 (s 3H), 1.78 (s, 3H), 1.55 (s, 3H). Anal. Calculated for C32H32N2O4: C, 75.57; H, 6.34; N, 5.51. Found: C, 75.47; H, 6.37; N, 5.45.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([CH3:32])([CH3:31])[OH:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:34][CH2:35][CH:36]([CH2:42][CH3:43])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]([S:34][CH2:35][CH:36]([CH2:42][CH3:43])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:30])([CH3:32])[CH3:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccccc1CCC(O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reactant: CCOC(=O)C(CC)CS
Product: CCOC(=O)C(CC)CSC(CCc1ccccc1C(C)(C)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Yield: 64 %

Procedure:
Starting from the diol of Example 5, Step 1, and using the procedure of Example 1, Method B, Step 7, but substituting the thiol of Step 2 for ethyl 2-(mercaptomethyl)butanoate, the title compound was prepared. Yield: 64%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([NH2:24])=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:6]([O:8]CC)=O.[CH:25]([NH2:27])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[N:24]=[CH:25][NH:27][C:6]2=[O:8]
Reactant: CCOC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1N
Reactant: NC=O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 125 °C
Yield: 68 %

Procedure:
A solution of ethyl 3-methoxy-4-(3-morpholinopropoxy)-6-aminobenzoate (130 g, 384 mmol) in formamide (280 ml) was heated at 180° C. for 3 hours, during which time a small amount (25 ml) of liquid distilled out of the reaction. The reaction was cooled to 125° C. and the excess formamide was evaporated in vacuo. Trituration of the solid residue with isopropanol (100 ml), followed by drying in vacuo, yielded 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (83.0 g, 68% yield) as a pale brown solid:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[NH2:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>O>[NH2:16][C:17]1[CH:22]=[C:21]([O:15][C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]

Procedure:
1.26 G. 57% sodium hydride in oil suspension in 20 ml. dimethylformamide is treated with 3.9 g. p-chlorophenol. When the mixture becomes homogenous, 2.5 g. 2-amino-4-chloro-1-nitrobenzene is added and the mixture heated for five hours at 130°-135° C. The crude product is obtained by diluting the reaction mixture with water and filtering and washing with water and hexane. Recrystallization from methanol gives pure 2-amino-4-(4-chlorophenoxy)-1-nitrobenzene.
Reaction SMILES: CC1C=CC(S([CH:11]([C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH3:22])[C:13]=2[CH3:23])(=O)=O)=CC=1.[OH-].[Na+].[CH3:32][N:33](C)[CH:34]=O>>[CH3:32][N:33]([CH:11]([C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][CH:28]=1)[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH3:22])[C:13]=1[CH3:23])[CH3:34]
Reactant: CCn1c(C)c(C(c2cccn2C)S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)c(C(c2cccn2C)N(C)C)c2ccccc21

Procedure:
A mixture containing 1.4 g. of 3-[(4-methylphenylsulfonyl)(1-methyl-2-pyrrolyl)methyl]-1-ethyl-2-methyl-1H-indole, 5 ml. of N,N-dimethylformamide and 30 ml. of 20% aqueous sodium hydroxide was heated 3 hours at 50° C. The reaction mixture was then cooled and diluted with 100 ml. of water and the product extracted with toluene. The toluene extracts were washed with water and evaporated to dryness affording 3-[(dimethylamino)(1-methyl-2-pyrrolyl)methyl]-1-ethyl-2-methyl-1H-indole as a brown gummy material, the infrared and nuclear magnetic resonance spectra of which were consistent with the assigned structure. A toluene solution of this product when contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[N:8]3[C:9](=[N:14][C:15]([CH3:16])=[C:7]3[C:6]1=[O:17])[CH:10]=[CH:11][CH:12]=2.C(N(CC)CC)C.[F:25][C:26]([F:33])([F:32])[CH2:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:16][C:15]1[N:14]=[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[N:8]2[C:7]=1[C:6](=[O:17])[N:5]3[CH2:4][CH2:3][CH2:2][NH:1][S:28]([CH2:27][C:26]([F:33])([F:32])[F:25])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cc1nc2cccc3n(CCCN)c(=O)c1n23
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cccc3n(CCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 58.5 %

Procedure:
To a solution of 0.43 g (1.87 mmol) of 1-[3-(amino)propan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.39 ml (2.80 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.41 g (2.26 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 412 mg of the desired compound (58.6%, white powdery).
Reaction SMILES: [CH3:1][CH:2]1[C@H:6]([CH:7]=O)[C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:4][N:3]1[C@H:16]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:17]([O:19]CC1C=CC=CC=1)=[O:18].FC(F)(F)C(O)=O.[CH2:38]([C:45]1[CH:49]=[C:48]([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[N:47]([CH2:56][CH3:57])[N:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:1][CH:2]1[C@H:6]([CH2:7][N:53]2[CH2:54][CH2:55][CH:50]([C:48]3[N:47]([CH2:56][CH3:57])[N:46]=[C:45]([CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:49]=3)[CH2:51][CH2:52]2)[C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH2:4][N:3]1[C@H:16]([CH2:27][CH:28]1[CH2:29][CH2:30]1)[C:17]([OH:19])=[O:18]
Reactant: CCn1nc(Cc2ccccc2)cc1C1CCNCC1
Reactant: CC1[C@H](C=O)[C@@H](c2cccc(F)c2)CN1[C@H](CC1CC1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(Cc2ccccc2)cc1C1CCN(C[C@H]2C(C)N([C@H](CC3CC3)C(=O)O)C[C@@H]2c2cccc(F)c2)CC1
Yield: 46.1 %

Procedure:
2-(R)-(2-Methyl-3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propionic acid, benzyl ester (54 mg, 0.13 mmol, from Step D) and 4-(3-benzyl-1-ethyl-(1H-pyrazol-5-yl))piperidine trifluoroacetate (58 mg, 0.17 mmol, from Example 1, Step C) were reacted via the procedure described in Example 1, Steps D and E to afford 34.3 mg (46% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ0.04-0.11 (m, 1H), 0.14-0.20 (m, 1H), 0.41-0.49 (m, 1H), 0.51-0.57 (m, 1H), 0.68-0.75 (m, 1H), 1.23 (t, 3H), 1.63 (d, 3H), 1.80-2.10 (m, 6H), 2.65-2.78 (m, 1H), 2.84-2.98 (m 2H), 3.00-3.10 (m, 2H), 3.16-3.23 (m, 1H), 3.30-3.40 (m, 1H), 3.50-3.68 (m, 4H), 4.02 (s, 2H), 4.15-4.20 (m, 1H), 4.20-4.30 (m, 3H), 5.24 (d, 1H), 5.39 (d, 1H), 5.93 (s, 1H), 7.02-7.44 (m, 14 H); ESI-MS (M+H): 663.9; HPLC A: 2.04 min.
Reaction SMILES: CN([CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1)C.CI.[I-]>CO>[CH2:4]=[C:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1
Reactant: CN(C)CC1CCc2onc(-c3ccccc3)c2C1=O
Agent: [I-]
Solvent: CI
Solvent: CO
Product: C=C1CCc2onc(-c3ccccc3)c2C1=O
Yield: 82 %

Procedure:
6,7-Dihydro-5-dimethylaminomethyl-3-phenyl-1,2-benzisoxazole-4(5H)-one free base (3.0 g) was dissolved in 3 ml of methanol and added in one portion to 5 ml (excess) of methyl iodide. As the quaternary iodide began to separate, additional methanol was added to facilitate stirring. After stirring overnight the reaction mixture was poured into 5% sodium bicarbonate solution and extracted with ether. The organic phase was washed with 5% HCl and then dried, evaporated, and recrystallized from hexane to give 2.05 g of 6,7-dihydro-5-methylene-3-phenyl-1,2-benzisoxazol-4(5H)-one, m.p. 97°-99° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH:22]2[CH2:27][C:26](=[O:28])[NH:25][CH:24]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[CH3:36])[C:23]32[C:44]2[C:39](=[CH:40][C:41]([Cl:45])=[CH:42][CH:43]=2)[NH:38][C:37]3=[O:46])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:45][C:41]1[CH:40]=[C:39]2[NH:38][C:37](=[O:46])[C:23]3([CH:22]([C:16]4[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=4[O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH2:27][C:26](=[O:28])[NH:25][CH:24]3[C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[CH3:36])[C:44]2=[CH:43][CH:42]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCN(C(=O)OC(C)(C)C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 105.5 %

Procedure:
A solution of racemic (2′S,3S,4′R)-4′-[2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.7 g, 1 mmol) in TFA (10 mL) was stirred at r.t. for 0.5 h. The solution was diluted with DCM, washed with 1N Na2CO3 aq. (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated to give title compound as a yellow solid (Yield: 0.6 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11](Br)[N:10]=1)=[O:8].[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[CH3:1][S:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[C:11]([S:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:10]=1)=[O:8]
Reactant: Sc1ccccc1
Reactant: CSc1ccccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Solvent: CCN(CC)CC
Product: CSc1ccccc1CNC(=O)c1nc(Sc2ccccc2)c2cccnc2c1O
Temperature: 135 °C

Procedure:
To a 5 mL pyrex pressure vessel with a stirring bar was added 8-hydroxy-5-bromo-[1,6]naphthyridine-7-carboxylic acid 2-methylsulfanylbenzylamide (0.22 g, 0.54 mmol), thiophenol (0.181 g, 1.63 mmol) and triethylamine (0.557 mL, 4.00 mmol). The vessel was sealed under nitrogen and the stirred mixture heated in a 135° C. oil bath for 24 h. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed by reverse phase HPLC using water/acetonitrile as eluant to give 8-hydroxy-5-phenylsulfanyl-[1,6]naphthyridine-7-carboxylic acid 2-methylsulfanylbenzylamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[C:11]([C:17]([O:19]C)=[O:18])[CH:10]=1.CO.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=1
Reactant: C=Cc1cc(C(=O)OC)cc(-c2ccc(C)cc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1cc(C(=O)O)cc(-c2ccc(C)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 mL flask charged with methyl ester from step C above (20 g, 74 mmol) in THF (250 mL) was added MeOH (100 mL) and aq. 3N NaOH (74 mmol, 25 mL). The mixture was stirred overnight at rt and an additional 15 mL NaOH added. Reaction stirred for 16 h, the pH was then adjusted 4-5 and the mixture extracted repeatedly with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give 18.5 g of product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[O:11])=[CH:4][CH:3]=1.Cl.Cl.[Cl:30][C:31]1[C:32]([O:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([NH:16][CH2:17][C:18]([N:42]2[CH2:43][CH2:44][CH:39]([O:38][C:32]3[C:31]([Cl:30])=[CH:36][C:35]([Cl:37])=[CH:34][N:33]=3)[CH2:40][CH2:41]2)=[O:20])=[O:15])=[O:11])=[CH:6][CH:7]=1
Reactant: Clc1cnc(OC2CCNCC2)c(Cl)c1
Reactant: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)/C=C/c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCC(Oc2ncc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.4 %

Procedure:
To a mixture of {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenoyl]amino}-3-(2-pyridyl)propanoyl]amino}acetic acid (0.19 g), 3,5-dichloro-2-(4-piperidinyloxy)pyridine dihydrochloride (0.16 g), 1-hydroxybenzotriazole (0.084 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g) in N,N-dimethylformamide (2.5 ml) was added dropwise N,N-diisopropylethylamine (0.27 ml) at 8° C. The mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (231 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=O)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:31]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:41]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[S:41])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:31]=1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
Dissolve 0.50 g (0.12 m mole) of 8-chloro-11-[1-(1-(3-pyridyl)methylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridine (Example 2 of Table 2) and 0.5 g (0.12 m mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) in 15 mL of toluene and stirr for 18 hours at room temperature and 18 hours at 80° C., under nitrogen. Filter the reaction mixture and concentrate under vacuo. Disolve the residue in 50 mL of 1N HCl and extract with 200 mL of CH2Cl2. The water layer was neutralized with Na2CO3 and extracted with CH2 Cl2. The organic layer was dried over MgSO4 and concentrated under vacuo giving the product as a white solid, mp=92°-93° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:10][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(I)cc2C=O)C1
Yield: 59.9 %

Procedure:
In a manner similar to the method described in example 4a, 5-iodosalicylaldehyde (5 g, 20 mmol) (Aldrich) reacted with (S)-3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (7 g, 26 mmol) prepared in Example 48a and K2CO3 in N,N-dimethylformamide to give (R/S)-3-(2-formyl-4-iodo-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam (Yield 5 g, 60%).