Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H](C(O)=O)CO.[ClH:8].[CH3:9][O:10][C:11](=[O:16])[C@H:12]([CH2:14]O)[NH2:13].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[ClH:18].[CH3:9][O:10][C:11](=[O:16])[CH:12]([NH2:13])[CH2:14][Cl:8]
Reactant: COC(=O)[C@@H](N)CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Agent: N[C@@H](CO)C(=O)O
Product: COC(=O)C(N)CCl

Procedure:
The method which comprises derivatizing a β-hydroxy-α-aminocarboxylic acid into the corresponding β-hydroxy-α-aminocarboxylic acid ester, then halogenating the hydroxyl group thereof with a phosphorus halide to give the corresponding β-halogeno-α-aminocarboxylic acid ester, and hydrolyzing the ester group using a hydrohalogenic acid to give the objective β-halogeno-α-aminocarboxylic acid. Specifically, serine is derivatized into serine methyl ester hydrochloride, the ester salt is then treated with phosphorus pentachloride to give α-amino-β-chloropropionic acid methyl ester hydrochloride, which is further hydrolyzed with hydrochloric acid. The resulting α-amino-β-chloropropionic acid hydrochloride is isolated by concentrating the reaction mixture to dryness, followed by crystallization of the residue from a mixture of 1-propanol and hydrochloric acid [e.g. CHIRALITY, 8:197-200 (1996)]; and
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S([O-])(=O)=O.[CH2:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[C:21]1([CH:20]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)(C)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Product: CC(c1ccccc1)c1ccc(C(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
A 5 liter separable flask equipped with a stirrer, reflux condenser and dropping funnel was fed with 1340 g (10 moles) of tert-butylbenzene and 3 ml of trifluoromethane sulfonate, and the contents were maintained at 50° C. to 60° C. While stirring, 104 g (1 mole) of styrene was then added dropwise for 2 hours and, after the addition, the stirring was continued for further 30 minutes. After the reaction, the catalyst was deactivated with water and, through neutralization, water rinsing, drying and distillation, 1-phenyl-1-(4'-tert-butylphenyl)ethane was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:27]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([F:23])([F:21])[F:22])[CH:14]=3)[N:9]2[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C(F)(F)F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2ccc(C(F)(F)F)cc2C(C)(C)CC1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (5.0 g, 13.06 mmol) in N,N-dimethylformamide (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (1.1 g, 26.1 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min and then iodomethane (2.5 mL, 39.2 mmol) was added to the above mixture dropwise at 0° C. The solution was stirred at 0° C. for 2 h and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by ISCO combi-flash chromatography (gradient elution, 10% ethyl acetate/hexane) to afford 2-(3-bromo-phenyl)-1,4,4-trimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (3.6 g, 70%) as a yellow oil: MS obsd. (ESI+) [(M+H)+] 397.9 & 399.9.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[O:12]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:13][C:14]3([OH:12])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2nc(I)c3c(N)ncnc32)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.86 g, 0.0033 mol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.7 g, 0.0033 mol) and cesium carbonate (1.1 g, 0.0033 mol) in anhydrous N,N-dimethylformamide (30 mL) was stirred at 60° C. for 18 hours. The solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane (200 mL). The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with dichloromethane, and the solid was filtered to give tert-butyl 4-[(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl]-4-hydroxy-1-piperidinecarboxylate (0.66 g, 0.0014 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 8.7 min. MS: MH+ 475.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[C:48](OC(=O)C)(=[O:50])[CH3:49]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:48](=[O:50])[CH3:49])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:20])=[O:21])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(N)c(S(C)(=O)=O)c3S(C)(=O)=O)C(=O)OC(C)(C)C)c2c1
Reaction time: 0.25 h

Procedure:
To a solution of {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-[4-(4-amino(dimethanesulfonyl)phenyl)butyl] carbamic acid tert-butyl ester (from EXAMPLE 3.2 StepC, 60 mg in 3 mL dry methylene chloride) at 0° C. was added 0.025 mL pyridine followed by 0.020 mL acetic anhydride and the mixture stirred at low temperature. After 15 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed successively with a pH2 solution, saturated sodium bicarbonate and brine, then dried over sodium sulfate. Concentration in vacuo provided the crude title compound (65 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)(O)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:26]=1>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:26]=1
Reactant: COc1ccc2c(c1)CCCCC2(O)c1cc(OC)c(OC)c(OC)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)CCCC=C2c1cc(OC)c(OC)c(OC)c1
Yield: 90.9 %

Procedure:
A mixture of the 32 (800 mg, 2.23 mmol) in 20 mL of acetic acid and 100 mL of water, taken in a 250 mL round bottom flask were refluxed for 12 h. The reaction mixture was cooled and extracted with dichloromethane (3×25 mL) and the combined organic phases were dried over magnesium sulfate. The solvent evaporated and the crude product was purified by flash column chromatography (10:90 EtOAc:Hexanes), to afford 690 mg (91%) of 2 as white crystals. Rf: 0.43 (30:70, EtOAc:Hexanes).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[C:20](=[O:21])[N:12]2[C:13]3[C:18]([CH:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[CH2:24]([N:6]1[C:2]([CH3:1])=[C:3]([CH2:7][CH:8]2[C:20](=[O:21])[N:12]3[C:13]4[C:18]([CH:19]=[C:11]3[CH2:10][CH2:9]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:4]=[CH:5]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: Cc1[nH]cnc1CC1CCc2cc3ccccc3n2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CC2CCc3cc4ccccc4n3C2=O)ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
To a suspension of 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (500 mg) in N,N-dimethylformamide (5 ml) at room temperature was added sodium hydride (60% in mineral oil, 79 mg). After stirring at room temperature for 10 minutes and then at 5° C. for 5 minutes, the solution was treated with a solution of benzyl chloride (249 mg) in N,N-dimethylformamide (1 ml) at 5° C. The mixture was stirred at 5° C. for 10 minutes and then at room temperature for 2 hours. The reaction mixture was diluted with chilled water and extracted twice with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The oil obtained was purified by silica gel column chromatography (1% methanol-chloroform) to give 7-[(1-benzyl-5-methyl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (468 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(O)[CH3:7])[CH3:2].[I-].[K+].P(=O)(O)(O)O>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=P(O)(O)O
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A mixture of 32 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, 8.7 g. of potassium iodide, 5.2 g. of red phosphorus and 45 ml. of 85% phosphoric acid is stirred and heated to 130° for 7 hours. It is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid ethyl ester.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27]C(OC)=O)[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].O.Cl>CO>[ClH:1].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([OH:27])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (259 mg, 0.54 mmol), (prepared as described for the starting material in Example 12), in methanol (15 ml) containing 1M sodium hydroxide (1.6 ml) was stirred at ambient temperature for 1 hour. After addition of water (15 ml), concentrated hydrochloric acid (1 ml) was added and the mixture was stirred at ambient temperature for 15 minutes. After evaporation of methanol, the precipitate was filtered, washed with water and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (192 mg, 80%). m.p. 294-298° C. 1H NMR Spectrum: (DMSOd6) 2.2(s, 3H); 4.05(s, 3H); 5.35(s, 2H); 6.9(d, 1H); 7.12(d, 1H) 7.35-7.5(m, 4H); 7.55-7.6(m, 2H); 8.25(s, 1H); 8.8(s, 1H); 9.7(s, 1H); 11.35(s, 1H) MS-ESI: 406 [MH]+
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[NH2:11][NH2:12]>C1COCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[NH:11][N:12]=[CH:4][C:3]=12
Reactant: NN
Reactant: O=Cc1c(I)ccnc1F
Solvent: C1CCOC1
Product: Ic1ccnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2-fluoro-4-iodonicotinaldehyde (11.33 g, 45.1 mmol) in THF (200 mL) was added hydrazine (5.67 ml, 181 mmol) dropwise. The resulting mixture was stirred at RT under a nitrogen atmosphere for 5 h. The reaction was concentrated, diluted with 10:1 acetone/MeOH and filtered through a pad of silica gel. Removed most of the solvent in vacuo, then diluted with some hexanes and filtered resulting solid. Dried to yield 4-iodo-1H-pyrazolo[3,4-b]pyridine as an off-white solid. MS m/z=246 [M+1]+. Calc'd for C6H4IN3: 245.02.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].I[CH2:44][C:45]1([CH3:49])[CH2:48][O:47][CH2:46]1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3([CH3:49])[CH2:48][O:47][CH2:46]3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(CI)COC1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC1(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)COC1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS(m/e): 367.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:1](=[O:3])[CH2:2][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: CC(=O)c1cccs1
Reactant: c1c[nH]cn1
Product: O=C(Cn1ccnc1)c1cccs1

Procedure:
As illustrated in the following diagram, the thienyl compounds of this invention can be prepared by an initial bromination of 2-acetylthiophene 1, and reacting the resulting bromo derivative 2 with imidazole to produce the 1-(2-thienyl)-2-(1H-imidazol-1-yl)ethanone 3. Reaction of compound 3 with N-methylhyroxylamine hydrochloride provides the 1-(2-thienyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide 4 which is included in the subject matter of our co-pending application Ser. No. 900,856 filed Aug. 27, 1986 entitled "α-Substituted Ketonitrone Derivatives" whose disclosure is incorporated herein by reference. The nitrone compound 4 is then treated with styrene or an appropriate styrene (or allyl phenyl ether or alkyl phenyl thioether) derivative 5 to give a diastereomeric mixture of the desired cis- and trans-5-(phenyl, phenoxymethyl or phenylthiomethyl)-3-(2-thienyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine 6. ##STR3##
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]1.C(OC(C1C(C(=O)NC2C=CC(C)=C(I)C=2)CN(C2C=CC=CN=2)CC1)=O)C>CCOC(C)=O>[CH2:29]([O:28][C:26]([CH:25]1[CH2:31][CH2:32][N:22]([C:2]2[CH:21]=[CH:20][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][N:15]4[CH2:18][CH3:19])=[CH:11][CH:10]=3)=[CH:4][N:3]=2)[CH2:23][CH2:24]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Agent: CCOC(=O)C1CCN(c2ccccn2)CC1C(=O)Nc1ccc(C)c(I)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc4ccn(CC)c4c3)cn2)CC1

Procedure:
5′-(1-Ethyl-1H-indol-6-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 6-chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide and ethyl isonipecotate following a procedure similar to the one described in the synthesis of 5-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester above. The product was isolated by silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C24H28N4O3 [M+H]+: 421.2234. Found: 421.2234.
Reaction SMILES: CC(N(C)C)=O.CC(C)([O-])C.[Na+].[CH2:13]([C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:26])[C:24]=1[CH3:25])=[CH:21][C:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:19]([CH3:39])[CH:18]=2)[CH3:14].Cl[C:41]([O:43][CH3:44])=[O:42]>O>[C:41](=[O:42])([O:43][CH3:44])[O:26][C:23]1[C:22]2[C:17](=[CH:18][C:19]([CH3:39])=[C:20]([O:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=3)[CH:21]=2)[N:16]=[C:15]([CH2:13][CH3:14])[C:24]=1[CH3:25]
Reactant: COC(=O)Cl
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Dimethyl acetamide (694 ml), 35.2 g of sodium-t-butoxide, and 131 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one were added to a glass vessel equipped with a stirring device, a thermometer, and a reflux condenser and having a volume of 1000 ml under a nitrogen atmosphere, and the mixture was stirred at room temperature. Methyl chloroformate (34.4 g) was added dropwise thereto, and a reaction was allowed to proceed at room temperature for one hr. The reaction mixture was poured into 1735 ml of water contained in a 5-L plastic vessel, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was collected by a suction filter and was washed with water. The solid was dried in vacuo to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (149.5 g, yield 98.8%).
Reaction SMILES: FC(F)(F)[C:3]1C=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Br:22])[N:12]=2)=[O:10])[NH:6][N:7]=1.[NH:25]1C(N)=NC=N1>>[N:7]1[NH:6][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Br:22])[N:12]=2)=[O:10])=[N:25][CH:3]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Reactant: Nc1ncn[nH]1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1ncn[nH]1

Procedure:
The title compound was prepared analogously to 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide (Example 1) by replacing 3-(trifluoromethyl)-1H-pyrazol-5-amine with 1H-[1,2,4]triazole-5-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:39])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[C:21](=[O:28])[N:20]([CH2:29][C:30]([O:32]CC)=[O:31])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>Cl.C(OCC)C>[C:30]([CH2:29][N:20]1[C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:17](=[CH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([OH:39])[CH2:13][CH2:12]2)[C:18]2[CH:38]=[CH:37][CH:36]=[CH:35][C:19]1=2)([OH:32])=[O:31]
Reactant: CCOC(=O)CN1C(=O)c2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)c2ccccc2C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.4 %

Procedure:
4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethoxycarbonylmethyl-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol (Example 18) (1.0 g) was solved in 1M hydrogen chloride in diethyl ether and stirred at room temperature for 24 hours. Aqueous sodium hydroxide and ethyl acetate were added to the reaction mixture, the aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitation was filtered to give the titled compound (250 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:9][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(N)n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)ncc1Br
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 4-methylpyrimidine-2-ylamine (10.9 g, 100 mmol) in chloroform (400 mL) was added N-bromosuccinimide (17.8 g, 100 mmol). The solution was stirred in the dark for 15 hours, at which time it was added to CH2Cl2 (1400 mL), washed with 1N NaOH (3×200 mL) and NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 5-bromo-4-methylpyrimidine-2-ylamine (18.8 g, 99%). LCMS (m/z): 188.0/190.0 (MH+). 1H NMR (CDCl3): δ 8.22 (s, 1H), 5.02 (bs, 2H), 2.44 (s, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28]O)[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][N:38]4[C:37](=[O:39])[C:36]5=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]5[C:34]4=[O:44])[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.6 %

Procedure:
A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (6.9 g, 23.6 mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped to dryness. The residue was stirred in ether (200 ml) and the insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g, eluted with dichloromethane, DCM, and 1-2% CH3OH in DCM) and (100 g of SiO2 ; eluted with DCM, 1 l, and 1% CH3OH in DCM, 1.2 l). Two close compounds were separated and the top compound on TLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 g of white crystals, m.p. 86-88° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[N:15]([C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:31]2)[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:48](C=O)C>C([O-])(=O)C.[NH4+].C(O)(=O)C.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])[CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:29])[F:28])[CH:20]=3)[N:48]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N(CC(=O)c2ccc(F)c(C(F)(F)F)c2)[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Yield: 75 %

Procedure:
Heat a solution of 4-{((R)-1-benzyloxycarbonyl-piperidin-3-yl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (4.40 mmol; 2.86 g) in DMF (2.5 mL) and ammonium acetate saturated in acetic acid (15 mL) at 90° C. for 8 h. Dilute with EA, wash the organic phase 3× with water, saturated sodium bicarbonate, brine, dry over MgSO4 and filter. Purify the residue on 80 g silica gel with 5-20% EA/DCM to provide the title compound (2.08 g; 3.30 mmol; 75%). MS (ES+): m/z=631 (M+H).