Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:4][N:3]=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.Cl>C(O)(C)C>[ClH:15].[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: COc1ccc(C2=NN=C(N)C2)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2cc(Nc3ncnc4cc(OCC5CCN(C)CC5)c(OC)cc34)n[nH]2)cc1
Temperature: 5 °C
Yield: 76.5 %

Procedure:
A solution of 3-amino-5-(4-methoxyphenyl)-4H-pyrazole (74 mg, 0.39 mmol), (Synthesis, 1984, 3, 276), in isopropanol (3.5 ml) was added to 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (110 mg, 0.34 mmol) followed by 5M hydrogen chloride in isopropanol (78 μl, 0.39 mmol) and the mixture was heated at reflux for 1.5 hours. After cooling to 5° C., the precipitate was collected by filtration washed with isopropanol, followed by ether and dried under vacuum at 60° C. to give 4-(5-(4-methoxyphenyl)pyrazol-3-ylamino)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline hydrochloride (133 mg, 72%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C([O:39][C:40](=[O:51])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[NH2:42])(C)(C)C.C(N1CCOCC1)C>ClCCl.CN(C)C=O>[CH:16]1([C:21]([NH:42][C@H:41]([C:40]([OH:51])=[O:39])[CH2:43][C:44]2[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=2)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(Cl)cc1)C(=O)O)C1CCCC1
Temperature: 0 °C

Procedure:
A cool solution of 15 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to a solution of 15 mmoles of cyclopentanecarboxylic acid in dichloromethane at -5° C. 15 mmoles of 4-chloro-phenylalanine t-butyl ester toluenesulfonate salt in dimethylformamide (DMF), which is neutralized with N-ethyl morpholine, is then added. The reaction mixture is stirred at 0° C. initially and then at room temperature until the reaction is completed as judged by TLC. Dicyclohexylurea is removed by filtration and 50 ml of ethyl acetate is added to the filtrate. The organic phase is washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator. The residue is crystallized from isopropanol and hexane.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[OH:20])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SCCC(O)C2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
By the method of Example 14, the aldehyde of Example 4 was reacted with 7.1 ml of 1.97M cyclohexyl magnesium bromide in tetrahydrofuran to give the title alcohol. Analysis calc. for C23H38O2S(378.60):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[OH-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH:36](Cl)(Cl)[Cl:37]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:37][C:36]1[CH:7]=[N:8][C:9]2[C:5]([C:6]=1[CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2
Reactant: ClC(Cl)Cl
Reactant: COc1ccc2[nH]cc(CCC3CCNCC3)c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Product: COc1ccc2ncc(Cl)c(CCC3CCNCC3)c2c1

Procedure:
The operation is as in Example 1, but starting from 15 g of 4-[2-(5-methoxy-3-indolyl)-ethyl]-piperidine and 0.25 g of triethylbenzylammonium chloride in 120 ml of chloroform and 18 g of sodium hydroxide in 35 ml of water. 1.85 g of 3-chloro-6-methoxy-4-[2-(4-piperidyl)-ethyl]-quinoline are finally obtained in the form of the dihydrochloride melting at 210° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[C:15](O)=[O:16])=[O:12])=[CH:9][CH:8]=1.[NH3:34]>>[NH2:34][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[C:10]1[CH:30]=[CH:31][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:33])([F:32])[F:1])=[CH:8][CH:9]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCCC(F)(F)F)cc1
Reactant: N
Product: NC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[4-(4,4,4-trifluorobutoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (360 mg) prepared in Example 82 (82a) and ammonia (600 μL, 2 M methanol solution) to give 122 mg of the title compound (white powder).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH3:23][N:24]1[C@@H:41]2[CH2:42][C:29]3[CH:30]=[CH:31][C:32]([O:43][CH3:44])=[C:33]4[O:34][C@H:35]5[C:36]([CH:38]=[CH:39][C@@H:40]2[C@:27]5([C:28]=34)[CH2:26][CH2:25]1)=[O:37].[CH3:45][N:46]1[C@@H:62]2[CH2:63][C:51]3[CH:52]=[CH:53][C:54]([O:66][CH3:67])=[C:55]4[O:56][C@H:57]5[C:58]([O:64][CH3:65])=[CH:59][CH:60]=[C:61]2[C@:49]5([C:50]=34)[CH2:48][CH2:47]1>>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH3:23][N:24]1[C@@H:41]2[CH2:42][C:29]3[CH:30]=[CH:31][C:32]([O:43][CH3:44])=[C:33]4[O:34][C@H:35]5[C@@H:36]([OH:37])[CH:38]=[CH:39][C@@H:40]2[C@:27]5([C:28]=34)[CH2:26][CH2:25]1.[CH3:45][N:46]1[C@@H:62]2[CH2:63][C:51]3[CH:52]=[CH:53][C:54]([O:66][CH3:67])=[C:55]4[O:56][C@H:57]5[C:58]([O:64][CH3:65])=[CH:59][CH:60]=[C:61]2[C@:49]5([C:50]=34)[CH2:48][CH2:47]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341

Procedure:
Hydrocodone has been prepared by reduction of codeinone (Arch. Pharm (1920), 258, 295; J. Am Chem. Soc (1950), 72, 3247, U.S. Pat. No. 5,571,685) or thebaine (DE Pat. No. 441,613). However, since codeinone is obtained by oxidation of codeine in low to moderate yields, and thebaine is a relatively scarce alkaloid, these methods have little practical value.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[CH3:12][O:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([C:22](=[S:24])[NH2:23])=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([C:22]2[S:24][CH:2]=[C:3]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:10]=3[CH3:11])[N:23]=2)=[CH:16][N:15]=1
Reactant: COc1ncc(C(N)=S)c(OC)n1
Reactant: Cc1ccncc1C(=O)CBr
Product: COc1ncc(-c2nc(-c3cnccc3C)cs2)c(OC)n1
Yield: 16.9 %

Procedure:
By the reaction in the same manner as in Example 25-ii) using 2,4-dimethoxy-5-pyrimidinecarbonitrile (1.32 g), crude 2,4-dimethoxypyrimidine-5-carbothioamide (1.92 g) was obtained as a brown powder. Then, by the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (1.07 g) and 2,4-dimethoxypyrimidine-5-carbothioamide (880 mg), the title compound (235 mg) was obtained as colorless powder crystals.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:3][N:4]([CH3:21])[C:5]1[CH:10]=[C:9]([O:11][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[CH:7][C:6]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1cc(O)ccc1-c1nc2ncccc2[nH]1
Agent: Cl
Product: CN(C)c1cc(OS(C)(=O)=O)ccc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 56 from 2-(2'-dimethylamino-4'-hydroxy-phenyl)-imidazo[4,5-b]pyridine dihydrochloride and methanesulfonyl chloride. The product was purified over silica gel column [eluant:first methylene chloride, then methylene chloride/ethanol (50:1)].
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1.C(O)(=O)C.Cl[C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[CH3:32][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:22]2[C:21](=[O:33])[NH:20][C:19](=[O:34])[C:18]=2[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:8][CH2:7][CH2:6][NH:5][C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:10]=2)=[CH:24]1
Reactant: Cn1cc(C2=C(c3cn(CCCN)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(C2=C(c3cn(CCCNc4ncccn4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 80 °C
Yield: 57.7 %

Procedure:
A mixture of 100 mg of 3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione acetate, containing an extra equivalent of acetic acid, 75 mg of 2-chloropyrimidine and 100 mg of sodium carbonate in 100 ml of DMSO was heated at 80° C. for 2 hours. 50 ml of water were added to the cooled solution and the precipitate was filtered off and chromatographed on silica gel with 5% methanol in dichloromethane to give 60 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(2-pyrimidinylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 214°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1>[OH-].[Na+].C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)cnc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
5-(p-Chlorophenyl)-2-methyl-3-ethoxycarbonylpyridine (25 g) was suspended in sodium hydroxide (3.99 g) in ethanol (100 ml) and water (50 ml). Stirring at room temperature for 3 hours gave a solution which was concentrated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate; its pH was then brought to 5. The product which precipitated was collected, washed well with water and then with acetone and then dried to give the title compound (20.94 g), m.p. 297°-300° (dec).
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[C:6]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([O:20]S(C2C=CC(C)=CC=2)(=O)=O)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.C(O)(=O)C.O>CO.CN(C=O)C>[OH:20][C:13]1[C:14]([C:16]([O:18][CH3:19])=[O:17])=[N:15][C:6]([N:5]([CH3:4])[S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CCS(=O)(=O)N(C)c1nc(C(=O)OC)c(OS(=O)(=O)c2ccc(C)cc2)c2ncccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CCS(=O)(=O)N(C)c1nc(C(=O)OC)c(O)c2ncccc12
Temperature: 50 °C

Procedure:
A solution of sodium methoxide (479 mg, 8.86 mmol) in dry methanol (18 mL) was added to methyl 5-[methyl(ethylsulfonyl)amino]-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (1.7 g, 3.54 mmol) dissolved in a minimum amount of DMF and the resulting solution was heated to 50° C. for 5 minutes. The reaction was cooled, glacial acetic acid (0.433 mL, 7 mmol) was added followed by water (0.936 mL) over 15 minutes at 25 degrees C. The resulting solid was collected by filtration and washed with 1:1 water methanol and dried in vacuo to give the desired product as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:44]=[CH:43][C:11]([CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]([N:20]([C:22]2[C:23]([Cl:42])=[C:24]([C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[N:35]=[C:34]([CH3:37])[CH:33]=[CH:32]3)[CH3:21])=[O:19])=[O:15])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:42][C:23]1[C:22]([N:20]([CH3:21])[C:18](=[O:19])[CH2:17][NH:16][C:14](=[O:15])[CH:13]=[CH:12][C:11]2[CH:43]=[CH:44][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:9][CH:10]=2)=[CH:40][CH:39]=[C:38]([Cl:41])[C:24]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([CH3:37])[CH:33]=[CH:32]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCCBr)cc4)c3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N5CCCC5=O)cc4)c3Cl)c2n1
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a stirred solution of 8-[3-[N-[4-(bromobutyramido)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (50 mg) in N,N-dimethylformamide was added potassium carbonate (30 mg) at ambient temperature and the resulting mixture was stirred at the same temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (methanol-ethyl acetate=1:12, V/V) to afford 8-[2,6-dichloro-3-[N-methyl-N-[4-(2-oxo-1-pyrrolidinyl)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (33.4 mg) as an amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]3[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:28]([C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[CH:7][CH:8]=3)[CH:13]=2)[N:17]([CH3:21])[C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(OCC(=O)O)cc3)ccc21

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(3-benzyl-1-methyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.139 g, 0.301 mmol) was reacted with 1N KOH (0.6 ml) in THF/MeOH (3 ml/2 ml) to give the product (0.075 g, 0.168 mmol, 56%) as a white solid, mp 179-181° C. 1H NMR (DMSO-d6) δ 3.63 (s, 3H), 4.05 (s, 2H), 4.69 (s, 2H), 6.97 (d, J=8.9 Hz, 2H), 7.08-7.12 (m, 3H), 7.19 (t, J=7.6 Hz, 2H), 7.43 (dd, J=1.5, 8.4 Hz, 1H), 7.46-7.58 (m, 9H); IR (solid) 3020, 2910, 1730, 1705, 1605, 1510, 1480, 1430, 1370, 1270, and 1230 cm−1; [ESI(+)], m/z 448 (M+H)+; Anal. Calcd. for C30H25NO3: C, 80.51; H, 5.63; N, 3.13; Found: C, 80.15; H, 5.62; N, 3.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CCCSc1cc(OC)c(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(SCCCC(=O)O)cc(OC)c1OC

Procedure:
A solution of 1.6 g of the compound obtained in Step B in 25 ml of 1M sodium hydroxide solution and 25 ml of methanol is stirred for 4 hours at 50° C., and then distilled under a partial vacuum, rendered acidic with 25 ml of 1M hydrochloric acid and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and then evaporated to dryness, enabling the expected product to be isolated.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.Cl.[NH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[O:36]>C1COCC1>[O:36]=[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=1)[CH2:34][NH:33][C:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:20][CH2:19]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
Add N-methylmorpholine (13.0 mL, 118 mmol) to a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11.2 g, 48.8 mmol) in THF (400 mL) at −10° C. and stir for 5 min. Add isobutyl chloroformate (5.1 mL, 38.8 mmol) and continue stirring at −10° C. for 2 h. Add 2-amino-1-(3-(trifluoromethyl)phenyl)ethanone hydrochloride (9.35 g, 39.0 mmol) and continue stirring for 1 h. Add methylene chloride (500 mL) to the mixture and filter. Wash the filtrate with sat. aqueous sodium bicarbonate (400 mL) and concentrate in vacuo. Purify the residue by silica gel chromatography (330 g RediSep column, eluting with a gradient of 0% to 100% ethyl acetate:hexane, 6.0 L) to provide tert-butyl 4-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (9.72 g, 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.I.O.[I-].[Na+]>C(#N)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (12.0 g, 46.3 mmol) was dissolved in 20 mL of anhydrous acetonitrile and 4-(trifluoromethyl)aniline was added (7.0 mL, 55.6 mmol), followed by 47% HI/H2O (2.0 L) and sodium iodide (10.3 g, 69.5 mmol). The mixture was heated at refluxed overnight and solvents were removed under vacuum. The residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to a yellow solid which was purified by silica gel flash chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as a brown oil (15 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].O.[NH2:13][C:14]1([C:24]#[N:25])[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[C:24]([C:14]1([NH:13][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:23][CH2:22][C:17]2([O:18][CH2:19][CH2:20][O:21]2)[CH2:16][CH2:15]1)#[N:25]
Reactant: N#CC1(N)CCC2(CC1)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: N#CC1(NC(=O)OCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Benzyl chloroformate (24.18 mL, 169.4 mmol) was added dropwise to a biphasic system of water (300 mL) and CH2Cl2 (150 mL) containing 8-amino-1,4-dioxaspiro[4.5]decane-8-carbonitrile (28 g, 154 mmol) and Na2CO3.H2O (22.9 g, 185 mmol) at 0° C. and stirred for 2 h. The mixture was then allowed to warm to room temperature and stirred for 18 h. The mixture was then diluted with CH2Cl2 (250 mL), washed with sat. NaHCO3 (200 mL), water (200 mL), followed by brine (100 mL) then dried (Na2SO4), filtered and concentrated to give a brown oil. Flash chromatography on silica gel (using a 5% to 40% ethyl acetate-hexane gradient) afforded the title compound as a white solid (45 g, 92% yield). 1H NMR (500 MHz, CDCl3) δ: 7.30-7.35 (m, 5H), 5.11 (s, 2H), 4.90 (brs, 1H), 3.86-3.96 (m, 4H), 2.36-2.41 (m, 2H), 1.84-2.01 (m, 4H), 1.73-1.76 (m, 2H). LCMS (M+H)=317.30.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:12][S:13]([C:16]1[CH:21]=[C:20]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(-c2cccc(S(C)(=O)=O)c2)n1
Yield: 47.7 %

Procedure:
Ethyl 2-bromothiazole-4-carboxylate (1 g), 3-(methylsulphonyl)phenyl-boronic acid (1.02 g, 1.2 equivalents) and potassium carbonate (1.76 g) are introduced in dioxane (12.5 ml). (1,3-Diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride (288 mg) is added, and the mixture is stirred under reflux under protective gas for 18 h. Dioxane is then removed in a rotary evaporator, and the residue is taken up in ethyl acetate and water. The organic phase is separated off and the aqueous phase is back-extracted twice with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate and concentrated. Purification by column chromatography on silica gel (ethyl acetate/hexane) results in a white solid (629 mg).
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[Cl:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Nc1ccc(I)cc1Cl
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Product: Cc1c(Nc2ccc(I)cc2Cl)c(C(=O)O)cn(C)c1=O

Procedure:
The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 2-chloro-4-iodoaniline instead of 2-fluoro-4-iodoaniline. The title compound is used for the next reaction without further purification.