Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[N:20]=[C:19](C(OCC)=O)[O:18][N:17]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[N:20]=[CH:19][O:18][N:17]=1
Reactant: CCOC(=O)c1nc(-c2ccncc2Nc2ccc(I)cc2F)no1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(I)ccc1Nc1cnccc1-c1ncon1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 3-{3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}-1,2,4-oxadiazole-5-carboxylate (1.80 g; 3.96 mmol; 1.00 eq.) in THF-H2O (1:1) was added lithium hydroxide (0.19 g; 7.93 mmol) Stirred for 2 h at room temperature. After work up, 1.42 g of (2-Fluoro-4-iodo-phenyl)-(4-[1,2,4]oxadiazol-3-yl-pyridin-3-yl)-amine was obtained in 92% yield. MS m/z: 383 M+1
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](O)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:25])=O.C(OCC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([Cl:25])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC(O)C(Cl)(Cl)Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(Cl)C(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A stirred solution of Example 37C (20.0 g, 70.8 mmol) in CH2Cl2(300 mL) at 0° C. was treated with pyridine (10 mL). The reaction mixture was treated dropwise with thionyl chloride (10.4 mL, 141 mmol), and the reaction flask was equipped with a calcium chloride drying tube. The reaction mixture was warmed to ambient temperature and stirred for 4 hours. Concentration of the reaction mixture to a reduced volume and addition of diethyl ether (100 mL) resulted in a precipitate which was filtered off, and the filtrate was concentrated and dried under reduced pressure to provide 19.0 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[CH2:34]([C:41]1[O:45][CH:44]=[C:43]([CH2:46]Br)[CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH2:46][C:43]3[CH:42]=[C:41]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:45][CH:44]=3)=[O:11])[C:8]2([CH3:13])[CH3:14])=[CH:15][CH:16]=1
Reactant: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O
Reactant: BrCc1coc(Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)OCc1coc(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a mixture of 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid (2.77 mmol) (as prepared in, for example, Example 1 or 2), potassium carbonate (3.25 mmol) and hexamethylphosphoric triamide (HMPT) (3 ml), with stirring and under nitrogen, at RT, is added 5-benzyl-3-furylmethyl bromide (2.77 mmol) in THF. The reaction is stirred at RT for about 48 hr and then worked up by partition between water/ether. The organic phase is washed with water and brine, dried over potassium carbonate, filtered and the solvent is removed from the filtrate. The residue is plated on prep. TLC plates developing with 10% ether/hexane to yield 5-benzyl-3-furylmethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([CH:13]1[CH2:15][CH2:14]1)[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.CN(C=O)C.[H-].[Na+]>C(O)(=O)C>[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7][N:8]3[CH:13]3[CH2:15][CH2:14]3)=[CH:3][C:2]=2[F:1])[CH2:23][CH2:22]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN1CCC(Oc2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 80.3 %

Procedure:
To a mixture of 530 mg of 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 690 mg of N-methyl-4-piperidinol and 8 ml of DMF was added 320 mg of 60% sodium hydride while the former was stirred under ice cooling. After the resultant mixture was stirred for 10 minutes at room temperature, 480 mg of acetic acid was added. DMF was distilled off under reduced pressure. To the residue was added 15 ml of n-hexane. The resultant mixture was thoroughly shaken and mixed. The supernatant was discarded. To the resultant precipitate was added 8 ml of ethanol, followed by stirring. A precipitate thus precipitated was collected by filtration, whereby 578 mg of the title compound was obtained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[ClH:10].[CH3:11][CH2:12]O>>[ClH:10].[CH2:11]([O:8][C:7](=[O:9])[C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1)[CH3:12]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
Trans-4-hydroxy-L-proline was treated with EtOH and HCl gas, and the mixture was evaporated to give trans-4-hydroxy-L-proline ethyl ester hydrochloride. This product was treated with TsCl in pyridine to give, after aqueous workup, N-(toluene-4-sulfonyl)-trans-4-(TsO)-L-proline ethyl ester. This product was treated with NaN3 in DMF and H2O to give, after aqueous workup and flash chromatography, N-(toluene-4-sulfonyl)-cis-4-azido-L-proline ethyl ester. This product was treated with NaOH in CH3OH and H2O to give, after acidification, extraction, drying with MgSO4, filtration and evaporation, N-(toluene-4-sulfonyl)-cis-4-azido-L-proline. This product was treated with 10% Pd on C in THF, AcOH and H2O, and the mixture was shaken under 50 psi H2. The mixture was filtered through Celite and evaporated to give N-(toluene-4-sulfonyl)-cis-4-amino-L-proline. This product was treated with Boc2O and Et3N in t-BuOH and H2O to give, after evaporation, acidification, extraction, drying with MgSO4, filtration, and evaporation, N-(toluene-4-sulfonyl)-cis-4-(t-butoxycarbonylamino)-L-proline. This product was treated with HCl.Phe-O-t-Bu, BOP, arid NMM in DMF to give, after aqueous workup and flash chromatography, N-(toluene-4-sulfonyl)-cis-4-(t-butoxycarbonylamino)-Pro-Phe-O-t-Bu. This product was treated with TFA to give after evaporation the trifluoroacetate salt of the title compound as a clear oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.Br[CH2:21]C1C=CC=CC=1C>>[CH3:14][O:13][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:7]([S:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:2][C:3]=2[CH3:21])=[CH:12][N:11]=1
Reactant: Cc1ccccc1CBr
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Product: COc1cc(SCc2ccccc2C)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using 1-(bromomethyl)-2-methylbenzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([C:36]([F:39])([F:38])[F:37])([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:41]([O:43][C:44](=[O:52])[CH2:45][C:46]1[N:47]=[C:48](Br)[S:49][CH:50]=1)[CH3:42].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:41]([O:43][C:44](=[O:52])[CH2:45][C:46]1[N:47]=[C:48]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:4][CH3:5])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:35])([C:36]([F:38])([F:39])[F:37])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:1][CH3:2])=[CH:7][C:8]=2[CH3:21])[S:49][CH:50]=1)[CH3:42]
Reactant: CCOC(=O)Cc1csc(Br)n1
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1csc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
Degassed N,N-dimethylformamide (0.25 mL) was added to (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 22.9 mg, 0.0401 mmol), (2-bromo-thiazol-4-yl)-acetic acid ethyl ester (Example 42; 17.8 mg, 0.071 mmol), tetrakis(triphenylphosphine)palladium (0) (5.9 mg, 0.0051 mmol) and potassium phosphate (19.2 mg, 0.0904 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 95 to 105° C. for five hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/dichloromethane=1/4) to give the title compound (9.7 mg, 39%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[C:25](=[O:31])[NH:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([CH3:32])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[CH:27]1([NH:26][C:25]([C@@H:21]2[CH2:22][CH2:23][CH2:24][N:20]2[C:18](=[O:19])[CH2:17][O:16][C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH3:32])=[CH:11][CH:12]=3)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=2)=[O:31])[CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccc(C)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.5 g 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid ethyl ester in 20 ml of THF, 5.7 ml of a 1M aqueous sodium hydroxide solution was added and stirred for 16 h at RT. The reaction mixture was acidified with 1M hydrochloric acid to pH 3 and the solvents were evaporated under reduced pressure. The residue was dissolved in a mixture of methanol/DCM and the solids were filtered off. The filtrate was evaporated under reduced pressure to yield the product which was pure enough for the next reaction step. Yield: 2.0 g.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[OH:13]>C(O)C.C1COCC1.[OH-].[Pd+2].[OH-]>[NH2:10][C:4]1[C:3]([OH:13])=[C:2]([F:1])[C:7]([O:8][CH3:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(N)c(O)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
A suspension of 2-fluoro-3-methoxy-6-nitrophenol (300 mg) and 5% palladium hydroxide (40 mg) in ethanol (10 mL) and THF (5 mL) was stirred at room temperature for 15 hr under a hydrogen atmosphere (1 atm). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (220 mg).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.N1C=CC=CC=1.Cl[S:38]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])(=[O:40])=[O:39]>CCCCCC.C(OCC)(=O)C>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][S:38]([NH:11][C:8]1[CH:7]=[C:6]([CH:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[C:5]([Cl:4])=[CH:10][N:9]=1)(=[O:40])=[O:39])[CH3:46]
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.4 %

Procedure:
To a methylene chloride (10 ml) solution of the [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (331 mg, 0.771 mmol) obtained in Example 196 and pyridine (94 μl, 1.16 mmol) was added a methylene chloride (2 ml) solution of ethyl chlorosulfonylacetate (216 mg, 1.16 mmol) at 0° C. After the resulting mixture was stirred at room temperature for 12 hours, pyridine (94 up, 1.16 mmol) and a methylene chloride (2 ml) solution of ethyl chlorosulfonylacetate (216 mg, 1.16 mmol) were added sequentially at 0° C. The resulting mixture was stirred at room temperature for 9 hours and then, the reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate. The resulting mixture was washed sequentially with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=3:1) eluate was concentrated under reduced pressure to give the title compound (239 mg, 0.412 mmol, 53%) as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].C[O:10][C:11]([C:13]1[O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]=1[CH2:18]Br)=[O:12].[OH-].[Na+].Cl>CN(C=O)C>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:18][C:17]1[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][C:13]=1[C:11]([OH:12])=[O:10]
Reactant: COC(=O)c1oc2ccccc2c1CBr
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1oc2ccccc2c1COCC(F)(F)F
Reaction time: 8 h

Procedure:
Sodium hydride (15 mg, 0.56 mmol) was suspended in anhydrous DMF and stirred under N2(g). 2,2,2-Trifluoroethanol (270 μL, 3.7 mmol) was added and after stirring the reaction mixture for 15-20 min., 3-bromomethylbenzofuran-2-carboxylic acid methyl ester was added. After 8 h, 1N NaOH (aq.) was added and the reaction mixture was stirred for 10-15 min. The reaction mixture was acidified reaction to pH 3 with aqueous hydrochloric acid and the product was extracted with EtOAc. The organic layer was dried organic over Na2SO4 and concentrated in vacuo to give 3-(2,2,2-trifluoroethoxymethyl)benzofuran-2-carboxylic acid (38 mg) which was then used without purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:17]#[N:18])=[CH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:19]([Mg]Br)[CH2:20][CH:21]=[CH2:22].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][P:4]([CH:9]([C:17]#[N:18])[CH:10]([CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[CH2:22][CH2:21][CH:20]=[CH2:19])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C=CCC[Mg]Br
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(C1CCOCC1)C(C#N)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the oil isolated in Step A (51.26 g, 188 mmol) in THF (200 mL) at −30° C., 3-butenylmagnesium bromide in THF (0.5 M, 394 mL, 197 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight. Aqueous saturated ammonium chloride solution (300 mL) was then added. The reaction mixture was stirred 30 min at room temperature and then was extracted with ethyl acetate (400 mL) once. The organic solution washed with saturated ammonium chloride solution three times, with brine one time and then was dried over magnesium sulfate. The reaction mixture was then filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield [1-cyano-2-(tetrahydro-pyran-4-yl)-hex-5-enyl]-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][N:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1.[CH2:13]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[CH:17]1)[CH2:14][CH3:15]>>[CH2:4]1[CH:5]2[N:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:11][CH2:12][CH:3]1[CH2:2][O:1][C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([CH2:13][CH2:14][CH3:15])[CH:17]=1)=[O:26]
Reactant: CCCn1cc(C(=O)O)c2ccccc21
Reactant: OCC1CCN2CCCCC2C1
Product: CCCn1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21

Procedure:
eq-2-Hydroxymethylquinolizidine (N. J. Leonard et al, J. Org. Chem,1957, 22, 1445) was reacted with the acid chloride of 1-n-propylindole-3-carboxylic acid using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate. The resulting yellow oil was crystallised from n-pentane to afford the title compound (E17) as a white solid mp 75°-76° C.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[NH2:17][C:18]1[CH:40]=[CH:39][C:21]([C:22]([N:24]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[CH:35]1[C:26]2[CH2:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[CH2:30][N:24]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:7]([CH:1]4[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]4)=[O:8])=[CH:40][CH:39]=3)=[O:23])[C:25]=2[CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)C1CC=CCC1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)C1CC=CCC1
Reaction time: 18 h
Yield: 67.1 %

Procedure:
A mixture of 208 mg of 3-cyclohexene-1-carbonyl chloride (prepared from 3-cyclohexene-1-carboxylic acid and thionyl chloride) and 145 mg of triethylamine in 3 ml of methylene chloride is added to a solution of 377 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 7 ml of methylene chloride. The mixture is stirred for 18 hours, washed with water, 1N HCl, water, 1M NaHCO3 and brine then dried with Na2 SO4. The organic layer is passed through a short column of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 340 mg of the desired product as a crystalline solid, m.p. 234°-236° C.
Reaction SMILES: [CH:1]1([S:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>>[CH:1]1([S:6][CH2:7][C:8]([Cl:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CSC1CCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CSC1CCCC1
Temperature: 70 °C

Procedure:
The product from Example 143B (6.56 g) was combined with thionyl chloride (50 mL, 685 mmol) and the reaction mixture was heated at 70° C. for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was dissolved in CHCl3 (50 mL) and concentrated again to remove excess thionyl chloride. The residue was distilled under vacuum (air bath 100-110° C./˜10 mm) to provide the title compound, used directly for the next step.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2Cl)[N:7]([CH3:16])[C:6]1=[O:17])[C:2]#[C:3][CH3:4].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.Cl>C(#N)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:12]2[N:11]=[C:10]([Cl:15])[N:9]=[C:8]3[C:13]=2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:6](=[O:17])[N:7]3[CH3:16])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC#CCn1c(=O)n(C)c2nc(Cl)nc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC#CCn1c(=O)n(C)c2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 60.2 %

Procedure:
7-(2-Butynyl)-2,6-dichloro-9-methyl-7,9-dihydropurin-8-one (334 mg) was dissolved in acetonitrile (5 mL), piperazin-1-carboxylic acid t-butyl ester (300 mg) and triethylamine (190 μL) were added, and this reaction solution was stirred at room temperature for 96 hours. After completion of the reaction, 1 N hydrochloric acid (3 mL) and water (10 mL) were added to the reaction solution, and this was extracted with ethyl acetate. The obtained organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The resulting organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (312 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.C(OCC)C.CO.C(Cl)Cl>[CH3:19][N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[NH:28])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:20]
Reactant: CN1CCCC1CCN1C(=O)CCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CN1CCCC1CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-amino-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one (1.15 g, 4.21 mmol) in absolute ethanol (25 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (2.40 g, 8.42 mmol) and stirred at room temperature for 18 hours. The reaction was diluted with diethyl ether (150 mL) and the precipitate collected by vacuum filtration. The precipitate was washed with ether (50 mL). The yellow solid was dissolved in water (50 mL) and transferred to a separatory funnel. The reaction was treated with 1N NaOH (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give a yellow oil which was subjected to flash chromatography on silica gel using 0-5% 2M NH3 in MeOH/CH2Cl2 to give a yellow foam. Yield: 1.11 g of yellow foam (69%). 1H-NMR (DMSO-d6) δ: 7.73 (d, J=3.0 Hz, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.10-7.02 (m, 2H), 6.72-6.75 (m, 2H), 6.45 (br s, 2H), 3.91-3.80 (m, 2H), 2.96-2.90 (m, 1H), 2.82-2.78 (m, 2H), 2.19 (s, 3H), 2.08-1.80 (m, 6H), 1.66-1.49 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.[OH-].[Na+].C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[N:10]([CH3:11])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][C:6]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1ccc(C(=O)OC)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21

Procedure:
Prepared analogously to example 113a from 3-amino-4-methylamino-benzoic acid methyl ester and 1,3-dichloro-2-isothiocyanato-benzene with DCC in DMF and NaOH in ethanol.