Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[ClH:9].[CH3:10][O:11][NH2:12].CO.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:9].[CH3:10][O:11][N:12]=[C:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CON
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CON=C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
1-Methyl-4-piperidone (5 g, 44.2 mmol) and methoxyamine hydrochloride (3.69 g, 44.2 mmol) were taken into 25 mL of methanol and stirred at room temperature for 2 days. The reaction mixture was evaporated in vacuo to afford a solid residue. The residue was dissolved in water, made basic with solid potassium carbonate, and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated to give a clear, yellow liquid that was purified on silica gel, eluting with dichloromethane-methanol (95:5)to afford 2.55 g of the desired product. Treatment with ethereal hydrogen chloride gave the hydrochloride salt, 2.99 g, mp 145°-147° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[SH:10].[OH-].[Na+].[C:13](=S)=[S:14]>C(O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[S:10][C:13]([SH:14])=[N:1][C:2]=2[CH:7]=1
Reactant: S=C=S
Reactant: COc1ccc(S)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2sc(S)nc2c1
Yield: 78.9 %

Procedure:
A mixture of 2-amino-4-methoxybenzenethiol (7.0 g, 0.045 mole), sodium hydroxide (4.4 g, 0.11 mole) and carbon disulfide (8.06 g, 0.11 mole) in 90% aqueous ethanol (100 ml.) was heated at reflux for 2 hours, filtered, diluted with ice-water and acidified with hydrochloric acid to give 7.0 g of 5-methoxy-2-benzothiazolethiol which melts at 192°-4° C. after recrystallization from benzene.
Reaction SMILES: O=[C:2]([CH3:20])[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=O.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:27][CH:28]=1)[N:26]=[C:2]([CH3:20])[C:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)=[C:4]2[OH:6]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(C)=O
Reactant: Nc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A round-bottomed flask equipped with a Dean-Stark apparatus was charged with ethyl 3-oxo-2-(4-(trifluoromethyl)benzyl)butanoate (7.00 g, 24.3 mmol, Intermediate 26: step a), 4-bromoaniline (4.20 g, 24.2 mmol), para-toluenesulfonic acid (0.418 g, 2.4 mmol), and toluene (121 mL). The mixture was heated to 125° C. After 16 hours, the flask was cooled to room temperature. The toluene was removed by rotary evaporation to provide an orange colored solid. A mixture of the solid and diphenyl ether (48.4 mL) was heated to 220° C. After 60 minutes, the mixture was cooled to room temperature at which point a yellow solid crashed out of solution. Hexanes (150 mL) were added. The mixture was filtered through filter paper, rinsing with hexanes. The yellow solids were collected, dried, and then used in the next step without further purification.
Reaction SMILES: C(O)C.Cl.[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[NH:7])[NH2:6].[O-]CC.[Na+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:12]([O:11][C:9]([C:8]1[CH:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=2)[NH:7][C:5]=1[NH2:6])=[O:10])[CH3:13]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]c1N
Temperature: 25 °C
Yield: 103.1 %

Procedure:
After adding 700 ml of ethanol to 50.7 g of ethyl 2-amidinoacetate hydrochloride (a publicly known compound described in Liebigs Ann. Chem., 1895 (1977)), the mixture was stirred at room temperature, 22.3 g of sodium ethoxide (1 equivalent with respect to ethyl 2-amidinoacetate hydrochloride) was added, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. To this there was added 49.9 g of 1-(4-benzyloxyphenyl)-2-bromoethanone (publicly known compound described in Journal of Heterocyclic Chemistry, vol. 2, 310 (1965) and Journal of Medicinal Chemistry, vol. 17, 55 (1974)), and the mixture was stirred for 36 hours at room temperature under a nitrogen atmosphere. Water was added, ethyl acetate was used for liquid separation and extraction, and then the organic layer was dried over sodium sulfate and concentrated to dryness to obtain 56.7 g of the title compound.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20](O)=[O:21].CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20]([N:3]1[CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)=[O:21]
Reactant: COC(=O)C1Cc2ccccc2CN1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2ccccc2CN1C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate hydrochloride (2.0 g, 9 mmol) and 3,5-dimethylbenzoic acid (1.6 g, 10 mmol) in DMF (15 ml) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.9 ml, 10 mmol). The reaction mixture is slowly warmed to r.t. and stirring continued for 2 hours. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 1:3 to give methyl N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate as a colorless oil. This material is hydrolized with 1M sodium hydroxide in THF to give N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid as a white solid.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>O>[CH:1]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:7])[OH:8])=[O:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Solvent: O
Solvent: CO
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
The preparation of N-formyl-L-aspartic anhydride was repeated several times in order to prepare multiple first reaction mixtures. To each of these first reaction mixtures was added 100 ml of one of the alkyl ester or hindered alcohol solvents listed in Table 1 followed by the addition of 44.6 grams (0.27 mole) of L-phenylalanine. The resulting slurries were maintained at room temperature for 5 hours for completion of the in situ coupling process. As the reaction proceeded, the slurries became more and more solidified in each reaction and a quantity of a methanol and water solution (10:1) was added in order to dissolve all the solids therein. 2.0 grams aliquots were analyzed in each reaction mixture by HPLC. The resulting α/β ratios of N-formyl-L-aspartyl-L-phenylalanine formed in each reaction are as follows:
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:11][CH:12]=1)[CH3:6]>O.C(O)(=O)C>[CH2:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15](=[O:22])[C:16](=[N:1][OH:3])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: CCOC(=O)CC(=O)CCc1cccc(CC)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of sodium nitrite (6.3 g) in water (10 ml) was added to a stirred solution of the product from step (iii) (20.6 g) in acetic acid (30 ml) at <30° C. The reaction mixture was stirred at room temperature for 18 hours. Water (150 ml) was added and the mixture was stirred for 2 hours and extracted with diethyl ether. The combined extracts were washed with water and saturated aqueous sodium bicarbonate solution. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=2)[C:12]([OH:14])=[O:13])=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[O:8]=[C:9]1[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[CH:15]=[CH:16][NH:17]1
Reactant: COc1ccc(COc2cc(C(=O)O)ccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Compound 1 (20.4 g, 84.0 mmol) obtained in Reference Example 12 was dissolved in trifluoroacetic acid (168 mL), and anisole (91.1 mL, 0.840 mol) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was reslurried with ethyl acetate to afford 2-oxo-1,2-dihydropyridine-4-carboxylic acid (6.99 g, 60%) as a white solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].C[O-].[Na+].[Na].[CH:10]12[O:15][CH:11]1[CH2:12][CH2:13][CH2:14]2>CO>[OH:15][C@@H:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: C1CC2OC2C1
Reactant: O=C(O)CS
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(O)CS[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Mercaptoacetic acid (22.5 g 0.244 mole) was added to a cold (+5° C.) solution of sodium methoxide [prepared from sodium (11.2 g, 0.488 mole)]in methanol (125 ml). After stirring for 20 minutes, cyclopentene oxide (19.5 g, 0.23 mole) was added dropwise over 20 minutes to the cold solution. The ice bath was removed and the reaction was refluxed for 45 minutes. The reaction was cooled to room temperature and made acidic by the addition of 4N hydrochloric acid. Water (100 ml) was added and the mixture was extracted twice with 150 ml of diethyl ether. The combined diethyl ether extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12.[CH:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:33][O:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:30](O)=[O:31])[N:28]=1)=[O:22]>>[CH:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:33][O:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:30]([NH:1][CH:2]2[C:19](=[O:20])[N:4]3[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]4[NH:15][N:14]=[N:13][CH:12]=4)[CH2:7][S:8][C@H:3]23)=[O:31])[N:28]=1)=[O:22]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Yield: 67.7 %

Procedure:
7-Amino-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.7 g.) and 2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.) were treated in a similar manner to that of Example 20-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.).
Reaction SMILES: C(=O)=O.CC(C)=O.[NH3:8].C([O:11][C:12]([C:14]1[O:25][C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([CH3:26])[C:16]=2[C:15]=1[O:27][CH3:28])=O)C>O1CCCC1>[CH3:28][O:27][C:15]1[C:16]2[N:17]([CH3:26])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]=2[O:25][C:14]=1[C:12]([NH2:8])=[O:11]
Reactant: CCOC(=O)c1oc2c3ccccc3n(C)c2c1OC
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1c(C(N)=O)oc2c3ccccc3n(C)c12
Temperature: 0 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A flask fitted with a Dewar condenser containing dry ice/acetone was cooled in a dry ice/acetone bath and charged with 350 ml of anhydrous ammonia. A few crystals of hydrated ferric nitrate catalyst were added, and the cooling bath was removed. Lithium amide was then generated by the addition, over one hour, of 1.78 g (0.26 mole) of freshly cut lithium metal ribbon. After the addition of 65 ml of cold tetrahydrofuran, a solution of 16.5 g (0.060 mole) of 3-methoxy-4-methyl-4H-furo[3,2-b]indole-2-carboxylic acid ethyl ester in 75 ml of tetrahydrofuran was added over 30 minutes. The Dewar condenser was removed, and the mixture was stirred for 16 hours as the excess ammonia evaporated. The total reaction mixture was added to 600 g of ice/water, and the crude amide product was filtered and washed with water. Recrystallization from aqueous ethanol yielded 11.7 g (79% yield) of final product, mp 174°-177° C. An additional recrystallization as above yielded an analytically pure sample, mp 179°-182° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:17]1[O:19][CH2:18]1.[ClH:20]>C(O)C.CCOCC>[ClH:20].[OH:19][CH2:18][CH2:17][N:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[CH2:12]1
Reactant: C1CO1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2c(c1)CN(CCO)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 8-nitro-2,3,4,5-tetrahydro-1H-2-benzazapine (5.08 g, 22.2 mmol) in ethanol (200 ml) at 0° C. was added 2.5M sodium hydroxide solution (10.0 ml). To this solution, in a pressure bottle, was added ethylene oxide (4.2 ml) and the bottle was capped and stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the residue was partitioned between dichloromethane and dilute sodium hydroxide. The organic phase was dried (magnesium sulfate) and concentrated to give a yellow solid. This solid was taken up in ethanol and acidified with hydrochloric acid in ethanol. Addition of ether effected precipitation of the title salt as an orange solid (2.69 g, 44%), m.p. 193.5-4.5° C.
Reaction SMILES: Cl[C:2]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([NH2:6])=O.CO.[ClH:15]>C1COCC1.C1COCC1.CO>[Cl:15][C:8]1[CH:9]=[CH:10][C:2]([O:11][CH3:12])=[C:3]([CH:7]=1)[CH2:4][NH2:6]
Reactant: COC1(Cl)C=CC=CC1C(N)=O
Reactant: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cl)cc1CN
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of the above 2-chloro-2-methoxy-benzamide (1.0 g, 5.4 mmol) in anhydrous THF (10 mL) was added dropwise 1M BH3-THF complex (12.8 mL, 12.8 mmol) at 0° C. After 10 min. of stirring at 0° C., the reaction mixture was heated at 65° C. for 4 h. MeOH (approximately 10 mL) was then added to the cooled reaction mixture at 0° C. The reaction was warmed to room temperature and stirred for 10 min. The reaction solution was concentrated in vacuo to yield an oily product. The product was dissolved in 50% THF/MeOH (10 mL) and 4M HCl (10 mL) was added slowly to the solution. After 10 min. the mixture was partitioned between water (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted with CH2Cl2 (10 mL) and the organic layers were discarded. The aqueous layer was basified to pH 9 with 5M NaOH solution. The solution was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to afford 0.36 g (39%) of 5-chloro-2-methoxy-benzylamine as a white solid.
Reaction SMILES: Br[C:2]1[N:3]([CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CCN(CC)CC>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]3[CH2:19][CH2:20][CH2:21]/[C:22](=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])/[C:2]=23)=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/CCCn1c(Br)c(Cc2ccc(Cl)cc2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C1/CCCn2c1c(Cc1ccc(Cl)cc1)c1ccccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a vigorously stirred solution of 0.13 g of the product from Step 5 in 4 mL of DMF under N2 atmosphere was added sequentially 0.75 g of n-Bu4NCl, 0.1 mL of Et3N and 0.022 g of Pd(AcO)2. The mixture was stirred for 1 hour at 75° C. and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluted with 6:1 hexane/EtOAc to give 0.07 g of the more mobile isomer followed by 0.06 g of the less mobile isomer.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[N:35]1C=CC(CO)=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:20][C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][N:35]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: OCc1ccncc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccn1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed 4-pyridylmethanol (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 2-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (11 mg, 0.023 mmol). The solid was dissolved in ethyl acetate (2 mL) and 1.0N HCl in ether (0.1 mL) was added slowly. The precipatate was collected through filtration under nitrogen to give 4-pyridylmethyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate hydrochloride (12 mg, 0.023 mmol). 1H NMR (DMSO-d6) δ 1.91(m, 2H), 2.16(m, 2H), 3.55 (m, 2H), 3.90 (s, 3H), 4.03 (m, 2H), 4.92 (m, 1H), 5.34 (s, 2H), 7.06 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 7.73 (m, 1H), 7. 81 (m, 1H), 7.87 (s, 1H), 8.46(s, 1H), 8.76 (d, J=5.6 Hz, 1H), 9.05 (s, 1H). LC/MS: MH+=475.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:15]O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:12].[CH3:23][NH:24]CCC(C1C=C2C(=CC=1)NC=C2C#N)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:15][NH:24][CH3:23])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:12]
Reactant: N#Cc1c[nH]c2c(F)cc(C(CCO)c3ccccc3)cc12
Reactant: CNCCC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Product: CNCCC(c1ccccc1)c1cc(F)c2[nH]cc(C#N)c2c1

Procedure:
7-Fluoro-5-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile LXXXIX (197 mg) was prepared from 7-fluoro-5-(3-hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile using the procedure described above for preparation of 5-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile LXVI (Example 16). MS (M+H)=308.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])C([O-])=O.[Na+].CN(C=O)C>[Cu]I.C1(C)C=CC=CC=1>[F:16][C:12]([F:17])([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]([F:19])([F:18])[F:10]
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 160 °C
Yield: 52.3 %

Procedure:
A mixture of 4-iodobenzonitrile (10.0 g, 43.7 mmol), sodium pentafluoroproprionate (15.4 g, 82.9 mmol), and copper(I) iodide (16.6 g, 87.3 mmol), DMF (160 mL), and toluene (60 mL) was heated at 160° C. for 16 h, allowing most of the toluene to distil off. After cooling, ethyl acetate (200 mL) was added, and the mixture was filtered through diatomaceous earth, and the filtrate was partitioned between ethyl acetate/heptane and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (5.05 g 52%). Yellow oil, MS (EI) 221.1 (M+).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:16][N:17]([CH3:21])[C:18]([N:7]1[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCS(C)(=O)=O)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCS(C)(=O)=O
Yield: 54.6 %

Procedure:
2 g (8.0 mmole) of 3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole, 0.8 ml (8.8 mmole) of dimethylcarbamoyl chloride, 1.25 ml (9.0 mmole) of triethylamine and 0.1 g (0.8 mmole) of 4-dimethylaminopyridine were dissolved in 20 ml of tetrahydrofuran and refluxed for 4 hours. After removal of the solvent the mixture was partitioned between ether and water, dried over magnesium sulfate and concentrated under vaccum. After chromatography on silica gel, trituration with ether afforded 1.4 g of 1-dimethylcarbamoyl-3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole. m.p. 109°-110° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O>O>[Cl:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:7][CH:8]=[C:9]([Cl:13])[CH:10]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCCNc1ncc(Cl)cc1Cl
Solvent: O
Product: Cc1ccc(Cc2cnc(NCCCNc3ncc(Cl)cc3Cl)[nH]c2=O)cn1

Procedure:
2-(3-Aminopropylamino)-3,5-dichloropyridine (1.0 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.04 g) were fused together on an oil bath at 140° C. for 5 hr. On cooling, water was added, the pH adjusted to 7 and the resulting solid filtered off. Chromatography (silica gel, chloroform/methanol, graded elution 50:1 to 35:1) and recrystallisation from methanol afforded 2-[3-(3,5-dichloropyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone, (0.55 g; 33%) m.p. 147°-48° C.