Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:25][N:26](C)C)[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:36]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:36][NH:26][CH:25]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2ccc(Cl)cc2)ccn1
Yield: 97 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 10.1 g (25.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-1-(4-chlorophenyl)-3-dimethylamino-2-propen-1-one obtained in Example 23-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 9.01 g of the title compound as a pale yellowish white powder. (Yield: 97%)
Reaction SMILES: C(OC([NH:8][N:9]1[CH2:14][C:13](/[CH:15]=[N:16]/[O:17][CH3:18])=[N:12][N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=O)(C)(C)C.C(Cl)(=O)C.C([O-])(O)=O.[Na+]>CO>[NH2:8][N:9]1[CH2:14][C:13](/[CH:15]=[N:16]/[O:17][CH3:18])=[N:12][NH:11][C:10]1=[O:26]
Reactant: CO/N=C/C1=NN(C(=O)OC(C)(C)C)C(=O)N(NC(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Product: CO/N=C/C1=NNC(=O)N(N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-6-[(E)-methoxyiminomethyl]-3-oxo-5H-1,2,4-triazine-2-carboxylate (12.4 g, 30.0 mmol) in MeOH (120 mL) at 0° C. was slowly added acetyl chloride (10.7 mL, 150 mmol). After completion of the addition, the reaction mixture was stirred at this temperature for another 30 min before it was allowed to warm to room temperature. After additional 20 h stirring at room temperature, the reaction mixture was carefully neutralized with sat. NaHCO3. The volatiles were removed in vacuo and the residual was repeatedly diluted with acetonitrile and evaporated. The remaining material were stirred for 10 min with hot acetonitrile and filtered. Concentration of the filtrate furnished the desired product as an off-white solid. LCMS (Method K) RT 0.42 min. [M+H]+ 172.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](NS(C)(=O)=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol), in anhydrous CH2Cl2 (5 mL) under argon were added methane sulfonyl chloride (0.23 mL, 2.99 mmol) and Pyridine (0.30 mL, 3.73 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with 1 N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.40 g, 58%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19](O)=[O:20].[CH:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][C:33]=2[C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>C(Cl)Cl>[Cl:17][C:4]1[CH:5]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:18][C:19]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:28]2[CH2:27][CH2:26][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:30][CH2:29]2)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)=[O:20]
Reactant: O=C(O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3c(Cl)cc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 7 but using (2,6-dichloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (WO 03/099771). Title compound: ES-MS: 604.9/606.9 [M+H]+; tR=3.89 min (System 1); Rf=0.23 (CH2Cl2/(2N NH3 in MeOH), 95:5).
Reaction SMILES: [N:1]([CH:4]([CH:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[NH2:1][CH:4]([CH:10]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:21])[CH3:20])[C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(N=[N+]=[N-])C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 113 %

Procedure:
A mixture of 5.6 g of ethyl 2-azido-3-t-butyl-dimethylsilyloxy-3-(2-chloropyridin-3-yl)propionate (prepared as described in Preparation 77), 7.5 g of triphenylphosphine and 18 ml of a 8: 1 by volume mixture of tetrahydrofuran and water was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate and subsequently a 50:1 by volume mixture of methylene chloride and methanol as the eluent, to give 5.9 g of the title compound having Rf=0.59 (on silica gel thin layer chromatography using a 15:1 by volume mixture of methylene chloride and methanol as the developing solvent).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.C([Li])CCC.FC(Cl)(Cl)C([Cl:22])(F)F>O1CCCC1>[Cl:22][C:10]1[C:4]2[O:3][C:2]([F:1])([F:11])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: FC(F)(Cl)C(F)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC1(F)Oc2cccc(Cl)c2O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
2,2-Difluorobenzo[d][1,3]dioxole (6.3 g, 39.8 mmol) was dissolved in tetrahydrofuran (66 mL) and cooled to −78° C. n-Butyllithium (2.5 M solution in hexanes; 16.74 mL, 41.8 mmol) was added dropwise, keeping the temperature below −70° C. The reaction mixture was then stirred at −78° C. for 1 h to ensure complete deprotonation. 1,2,2-Trifluorotrichloroethane (14.93 g, 80 mmol) was dissolved in tetrahydrofuran (33 mL) and cooled to −65° C. The lithiate was transferred via cannula into the solution of 1,2,2-trifluorotrichloroethane at a rate that allowed the temperature to remain between −60° C. and −65° C. during the addition. The reaction mixture was then allowed to warm to room temperature and partitioned between diethyl ether and water. The organic phase was concentrated and the product was flashed through 100 g of silica gel using hexane as a solvent to provide the title compound as a clear oil (5.74 g, 74.8%): 1H NMR (400 MHz, CDCl3) δ 7.08 (dd, J=8.2, 1.4 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.97 (dd, J=7.9, 1.5 Hz, 1H); EIMS m/z 192.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[F:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[Cl:23][C:24]1[N:29]=[C:28]([C:30](OC)=[O:31])[CH:27]=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[N:29]=[C:28]([C:30]([C:22]2[C:17]([F:16])=[N:18][CH:19]=[CH:20][N:21]=2)=[O:31])[CH:27]=[CH:26][CH:25]=1
Reactant: Fc1cnccn1
Reactant: COC(=O)c1cccc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccc(Cl)n1)c1nccnc1F
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
2,2,6,6-tetramethylpiperidine (1.729 g, 2.066 mL, 12.24 mmol) was dissolved in THF (20.00 mL) and cooled to −30° C. under nitrogen. BuLi (4.488 mL of 2.5 M, 11.22 mmol) was added dropwise and the reaction allowed to warm to 0° C. Stir at this temperature for 10 minutes then cooled to −78° C. A solution of 2-fluoropyrazine (1 g, 10.20 mmol) in THF (4.000 mL) was added slowly and the mixture stirred at −78° C. for 1 h. Methyl 6-chloropyridine-2-carboxylate (1.750 g, 10.20 mmol) in THF (6.000 mL) was added dropwise at between −78 and −70° C., stirred at −78° C. for 1 h. Reaction quenched with 5% citric acid at −78° C. then allow to warm to ambient temperature. Diluted with EtOAc and separated layers. Extracted with EtOAc (x1) then wash combined organics with NaHCO3 (x1), brine (x1). Dried (MgSO4), filtered and concentrated. Crude product purified by ISCO companion (80 g SiO2, 0 to 50% EtOAc/petrol) to leave title compound as an orange oil (1.12 g, 46%). 1H NMR (DMSO-d6) δ 7.90 (dd, 1H), 8.22-8.15 (dd, 2H), 8.67 (dd, 1H), 8.84 (dd, 1H). ES+238.13.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:21])[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.O>C1COCC1.[OH-].[Na+]>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[C:23]([NH:22][CH:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:21])[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)C(C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (2.38 g) in THF (20 ml), 0.5N aqueous sodium hydroxide solution (14.7 ml) was added, and the resulting mixture was stirred at room temperature for 1 hour. Water (120 ml) was added to the reaction solution and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid thereto and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (2.06 g).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.[H-].[Na+].Cl[C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=2)[N:14]=1>C1COCC1.CN(C=O)C>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:25][CH3:26])[N:14]=[C:13]([N:2]1[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][CH:1]1[CH2:6][CH2:5]3)[CH:22]=[N:21]2
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: O=C1NC2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncc(N3C(=O)C4CCC3CC4)nc2cc1OC
Temperature: 80 °C
Yield: 34.9 %

Procedure:
2-Azabicyclo[2.2.2]octan-3-one (228 mg, 2.3 mmole) is dissolved in a mixture of THF/DMF (5 mL/3 mL) and treated with NaH (60%, 184 mg, 4.6 mmole). The resulting mixture is heated at 60° C. for 0.5 hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (344 mg, 1.5 mmole). After being heated at 80° C. overnight, the reaction mixture is concentrated . The residue is chromatographed on silica gel (50% ethyl acetate/hexane) to give 164 mg (23%) of a yellow solid (m.p. 158-159° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[CH3:24])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cccc(-c2c(C)[nH]c3ccc(O)cc23)c1
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3cccc(C)c3)c2c1

Procedure:
The above compound was prepared from 2-methyl-3-(3-methyl-phenyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20]O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:26][C:25]([F:27])([F:28])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([C:2]([F:30])([F:1])[F:29])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20][N:35]2[C:31](=[O:41])[C:32]3[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:34]2=[O:36])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1
Reactant: OCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)isochroman-1-yl)ethanol (100 mg, 0.230 mmol), phthalimide (50.8 mg, 0.345 mmol), and tetrahydrofuran (2 mL) at 0° C. was added diethylazodicarboxylate (0.055 mL, 0.345 mmol) dropwise. The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of saturated ammonium chloride and extracted with ethyl acetate (2×) which was washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (8%-->12% EtOAc/Hex) gave 105 mg (81%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.55-7.80 (m, 7H), 7.12 (d, J=7.6 Hz, 1H), 7.01 (m, 3H), 4.66 (qAB, JAB=13.1 Hz, 2H), 4.03 (m, 2H), 3.74 (m, 2H), 3.72 (qAB, JAB=10.4 Hz, 2H), 3.02 (m, 1H), 2.66 (m, 1H), 2.30-2.50 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 168.2, 141.2, 136.6, 134.9, 133.7, 132.2, 131.7 (q, J=33.6 Hz), 129.2, 127.4, 126.8, 126.3, 125.5, 123.4 (q, J=273 Hz), 123.0, 121.5, 77.4, 76.1, 72.2, 60.4, 35.5, 33.5, 29.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([OH:25])=[O:24])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)CC(C)(C)Cc1cc(F)c(OCCCNc2ccccn2)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)O)Cc1cc(F)c(OCCCNc2ccccn2)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of STEP 9 (0.254 g, 0.54 mmol) was dissolved in 10 ml methanol and 10 ml 1 N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, and acidified with trifluoroacetic acid (5 ml). Solvents were evaporated and residue was purified on HPLC using acetonitrile gradient 10-50% in 30 min to yield 0.213 g. NMR spectra of the product were consistent for the proposed structure. FAB-MS:(M+2)=441.3. H MNR (CDCl3) δ1.05 (s, 6H), 2.20 (p, 2H), 2.22 (s, 2H), 2.63 (s, 2H), 2.68 (q, 2H), 4.20 (t, 2H), 6.74 (t, 1H), 6.93 (dd, 1H), 6.97 (s, 1H), 7.15 (s, 1H), 7.83 (m, 2H), 9.66 (br, 1H); Anal Calcd. for C20H24N2O3FBr plus 1.75 CF3COOH: C, 44.18; H, 4.06; N, 4.38. Found: 44.05; H, 4.16; N, 4.25.
Reaction SMILES: [CH:1](=[O:8])[CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH3:7].[CH:9]([C:11]([CH3:13])=[O:12])=[CH2:10].C(N(CC)CC)C>>[CH3:13][C:11](=[O:12])[CH2:9][CH2:10][C:1](=[O:8])[CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH3:7]
Reactant: CCC#CCCC=O
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Product: CCC#CCCC(=O)CCC(C)=O

Procedure:
22.0 g (0.2 mol) of hept-4-in-1-al, 14 g (0.2 mol) of methyl vinyl ketone, 5.4 g (0.02 mol) of Cat. 1 and 12.6 g (0.12 mol) of triethylamine are brought together in the manner described in Example 26. After 12 hours' reaction time at a surrounding temperature of 80° C in a nitrogen atmosphere, the mixture is worked up in the manner described in Example 21. On subsequent fractionation, undec-8-ine-2,5-dione is obtained.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17]O)[C:10]=1[CH:19]([OH:28])[C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)C1C=CC=CC=1.C(OCC)(=O)C.[OH-].[Na+].[ClH:37]>>[ClH:37].[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]2[CH2:16][CH2:17][O:28][CH:19]([C:20]3[CH:21]=[CH:22][C:23]([S:26][CH3:27])=[CH:24][CH:25]=3)[C:10]=12
Reactant: CSc1ccc(C(O)c2c(OCc3ccccc3)c(=O)ccn2CCO)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CSc1ccc(C2OCCn3ccc(=O)c(O)c32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.99 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[hydroxy-(4-methylthio-phenyl)-methyl]-1H-pyridin-4-one are boiled under reflux for 45 minutes in 60 ml of 6N hydrochloric acid. The reaction mixture is cooled to room temperature and covered with 10 ml of ethyl acetate. With vigorous stirring, the reaction mixture is neutralised with dilute sodium hydroxide solution until the product precipitates in the form of crystals. The reaction mixture is left to stand overnight in a refrigerator and then filtered. The crystals are washed with a small amount of cold alcohol. Drying yields 9-hydroxy-1-(4-methylthio-phenyl)-3,4-dihydro-1H-pyrido[2,1-c]-[1,4]oxazin-8-one hydrochloride, M.p.: 235°-238° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1ccc(C(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)NCCc1ccc(CO)cc1

Procedure:
4-(2-Acetamidoethyl)-benzoic acid is reduced, via a mixed anhydride, with sodium borohydride to give 4-(2-acetamidoethyl)-benzyl alcohol (m.p. 72°-73° C.) and then oxidized with activated manganese dioxide to give 4-(2-acetamidoethyl)-benzaldehyde (m.p. 81°-83° C.). Subsequent reaction with malonic acid gives 4-(2-acetamidoethyl)-cinnamic acid (m.p. 206°-208° C.), which is hydrogenated to give β-[4-(2-acetamidoethyl)-phenyl]-propionic acid (m.p. 132°-133° C.). This is then subjected to acidic saponification and reacted directly with ethanol to give ethyl β-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride (m.p. 165°-167° C.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>CC(C)=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:22](=[O:23])[NH:21][CH:18]([CH3:20])[CH3:19])[CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)N=C=O
Reactant: CCC1CNC(c2cccc(C(F)(F)F)c2)O1
Solvent: CC(C)=O
Product: CCC1CN(C(=O)NC(C)C)C(c2cccc(C(F)(F)F)c2)O1

Procedure:
Four and four-tenths grams of 2-(m-trifluoromethylphenyl)-5-ethyl-1,3-oxazolidine was dissolved in dry acetone and 1.8 ml of isopropyl isocyanate was added dropwise. The mixture was heated at reflux for two hours, cooled and stripped on the rotary evaporator. Yield was 5.9 g of a thick, sticky gum. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH2:19][CH3:20])[C:4]=1[NH:21][C:22](=[O:37])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[C:25]([N+:34]([O-])=O)[CH:24]=1)[CH3:2]>C(O)C.[Pd]>[NH2:34][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)[C:22]([NH:21][C:4]1[C:5]([CH2:19][CH3:20])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:16])([F:17])[F:15])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:37]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1NC(=O)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(CC)c1NC(=O)c1ccc(-n2cncn2)c(N)c1
Reaction time: 15 h
Yield: 74 %

Procedure:
A solution of N-[2,6-diethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethylethyl)phenyl]-3-nitro-4-(1,2,4-triazol-1-yl)benzamide (473 mg, 0.89 mmol) (Example I2) in ethanol (9 ml) was charged with palladium on carbon (10%) (140 mg, 0.13 mmol) and was stirred under a atmosphere of hydrogen for 15 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:4) to give Compound No. B2 of Table B (328 mg, 74% yield) and Compound No. C1 of Table C (18 mg, 4% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([NH:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12]2)[CH:5]=1.Br[CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([N:10]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12]2)[CH2:22][CH2:23][CH3:24])[CH:5]=1
Reactant: CCCBr
Reactant: Cc1cn(Nc2cc(Cl)ncn2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(c1cc(Cl)ncn1)n1cc(C)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60% in oil, 1.52 g) in 40 ml dimethylformamide (hereafter DMF) at ice bath temperature was added 9.0 g of 6-chloro-N-(3-methyl-1H-indol-1-yl)-4-pyrimidinamine dropwise, in 50 ml DMF. After addition was complete, the reaction was stirred for 5 minutes and then 3.45 ml of 1-bromopropane was added dropwise to the cool mixture. Reaction was allowed to proceed for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1([N:12]2[CH2:16][CH2:15][CH:14]([C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]#[N:19])[CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-:32].[NH4+]>C(OCC)(=O)C>[CH:6]1([N:12]2[CH2:16][CH2:15][CH:14]([C:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]([NH2:19])=[O:32])[CH2:13]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(C2CCCCC2)C1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(C2CCCCC2)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 80 ml. of concentrated sulfuric acid was added 20 g. (0.057 mole) of α-(cyclohexyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile. The mixture was shaken until solution occurred while being cooled in an ice bath until heat was no longer evolved. The solution was heated at 70° C. for 48 hours, poured on ice and made basic with ammonium hydroxide. The resulting white solid precipitate was taken up in ethyl acetate and the solution dried over sodium sulfate. The solution was concentrated and the residual oil taken up in hot ligroin, filtered and allowed to stand overnight at room temperature. The resulting crystals were recrystallized from ligroin. Yield 9.0 g. (42.5%); m.p. 119°-121° C.