Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:19]1(C(Cl)=O)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[NH:1]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C@H:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)COCc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H](COCc1ccccc1)NN1CCOCC1

Procedure:
Morpholino-Ser(OBn) was prepared from N-Fmoc-Ser(OBn). Esterification of N-Fmoc-Ser(OBn) with isobutylene in the presence of a catalytic amount of H2SO4 afforded N-Fmoc-Ser(OBn)-OtBu. The Fmoc group was removed with piperidine in CH2Cl2 to produce Ser(OBn)-OtBu. Reaction of Ser(OBn)-OtBu with 4-morpholinecarbonyl chloride in pyridine yielded morpholino-Ser(OBn)-OtBu. Morpholino-Ser(OBn)-OtBu was hydrolyzed with TFA in CH2Cl2 to yield morpholine-Ser(OBn).
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:36])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH:24]5[CH2:29][CH2:28][C:27](=[C:30]([CH3:35])[C:31]([O:33]C)=[O:32])[CH2:26][CH2:25]5)[CH2:22][CH:23]=4)[C:4](=[C:5]23)[CH:3]=1.[Li+].[OH-].Cl>O1CCCC1.CO>[F:1][C:2]1[CH:37]=[C:6]2[CH:7]=[CH:8][C:9]3=[N:10][NH:11][C:12]4[C:13](=[CH:14][N:15]([CH3:36])[CH2:16][C:17]=4[C:18]4[CH2:19][CH2:20][N:21]([CH:24]5[CH2:25][CH2:26][C:27](=[C:30]([CH3:35])[C:31]([OH:33])=[O:32])[CH2:28][CH2:29]5)[CH2:22][CH:23]=4)[C:4](=[C:5]23)[CH:3]=1
Reactant: COC(=O)C(C)=C1CCC(N2CC=C(C3=C4NN=C5C=Cc6cc(F)cc(c65)C4=CN(C)C3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(=O)O)=C1CCC(N2CC=C(C3=C4NN=C5C=Cc6cc(F)cc(c65)C4=CN(C)C3)CC2)CC1
Temperature: 65 °C

Procedure:
To a solution of Example 174B (110 mg, 0.151 mmol) in a mixture of tetrahydrofuran (1 mL) and methanol (0.5 mL) was added LiOH (1M aqueous solution, 453 μL, 0.453 mmol). This mixture was heated at 65° C. for 5 hours. After cooling, the reaction was neutralized with 1M aqueous hydrochloride acid. The formed solid was collected by filtration, washed with water and hexanes, and dried in vacuo to provide the title compound. 1H NMR (400 MHz, Pyridine-d5) δ 1.51-2.22 (m, 8H), 2.12 (s, 3H), 2.74 (d, J=13.3 Hz, 1H), 2.93 (s, 3H), 2.95-3.15 (m, 3H), 3.53-3.79 (m, 3H), 4.38 (s, 2H), 6.11 (d, J=3.4 Hz, 1H), 7.27 (td, J=8.3, 7.6, 4.2 Hz, 2H), 7.44 (d, J=5.3 Hz, 1H), 7.89 (dd, J=10.4, 3.0 Hz, 1H), 8.62 (d, J=5.2 Hz, 1H), 12.78 (s, 1H). MS (ESI+) m/z 487.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.O>N1C=CC=CC=1>[CH3:32][N:33]([CH3:38])[CH2:34][C:35]([O:31][CH2:30][CH2:29][NH:28][C:26]([C:15]1[N:14]=[N:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:27])=[O:36]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(F)c2)cc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCOC(=O)CN(C)C)c2COc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-fluorophenoxy)methyl]-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 498 in pyridine (10 ml) were added dimethylglycine (181 mg) and WSC (336 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate/hexane=1/1 to 2/1) and recrystallized from ethyl acetate to give the title compound as a colorless powder (432 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])#[CH:9].[CH2:14]([C:16]([C:27]1[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[C:29]([CH3:41])[CH:28]=1)([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:17][CH3:18])[CH3:15]>C(#N)C.[Cu]I.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>[CH2:14]([C:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:9]#[C:8][Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:29]([CH3:41])[CH:28]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#C[Si](C)(C)C)c(C)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
Triethylamine (25.1 mL, 180.09 mmol), ethynyltrimethylsilane (25.5 mL, 180.09 mmol), CuI (1.143 g, 6.00 mmol) and tetrakis(triphenylphosphine)palladium (0) (6.93 g, 6.00 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 25 g, 60.03 mmol) in acetonitrile (300 mL) at room temperature, and the mixture was stirred at 110° C. for 18 hours and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and a 1 N hydrochloric acid aqueous solution was added to adjust the pH to about 7. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=15/1) to give the title compound (16 g, 74%).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:18]=[CH:17][C:11](OCC(O)=O)=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([O:3][CH2:2][C:1]([Cl:6])=[O:5])=[CH:10][CH:9]=1
Reactant: Cc1ccc(OCC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(OCC(=O)Cl)cc1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (8.83 ml) and N,N-dimethylformamide (3 drops) were added at room temperature to a solution of 4-methylphenoxyacetic acid (6.73 g) in dichloromethane (70 ml), and the reaction mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, then the resulting acidic gas was removed as the toluene azeotrope, and the product was dried under reduced pressure to give 4-methylphenoxyacetyl chloride. A 1.61N solution of n-butyl lithium in hexane (25.2 ml) was added dropwise at −78° C. to a solution of (S)-4-benzyl-2-oxazolidinone (7.08 g) in tetrahydrofuran (70-ml), and after the completion of the dropwise addition, the reaction mixture was stirred at −78° C. for 30 minutes. To this resulting solution was added at −78° C. a solution of 4-methylphenoxyacetyl chloride obtained above in tetrahydrofuran (70 ml) followed by stirring at 0° C. for 1 hour. The resulting reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed successively with a 1N aqueous solution of hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate =3/1˜1/1) to afford the target compound (9.00 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)[S:14]([CH3:17])(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:20]3[CH:19]=[C:18]([N:13]([CH3:12])[S:14]([CH3:17])(=[O:15])=[O:16])[CH:23]=[CH:22][CH:21]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(c1cccc(B2OC(C)(C)C(C)(C)O2)c1)S(C)(=O)=O
Reactant: Nc1nc2c(Br)cccn2n1
Product: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as pale yellow solid (1.03 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.76-7.70 (m, 2H), 7.53 (d, J=7.9 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 3.34 (s, 3H), 2.86 (s, 3H), 1.35 (s, 12H). MS=312 (MH)+. 127b) N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500.0 mg, 2.347 mmol) and N-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (800.0 mg, 2.571 mmol) in a manner analogous to Example 2c. Product isolated as a white foam (0.529 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.57 (d, J=6.5 Hz, 1H), 8.13-8.10 (m, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 6.12 (s, 2H), 3.31 (s, 3H), 3.01 (s, 3H). MS=318 (MH)+. 127c) N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (67.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.033 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.6, 1H), 8.13 (s, 3H), 7.93 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.4 Hz, 1H), 7.56-7.45 (m, 3H), 7.44 (dd, J=8.2, 1.2 Hz, 1H), 6.98-6.92 (m, 3H), 6.64 (s, 1H), 3.42 (s, 3H), 3.19-3.14 (m, 4H), 2.89 (s, 3H), 2.63-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]2[S:8][C:9]([CH3:20])=[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:36][CH2:37][CH2:38][CH3:39].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH2:11][C:10]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[NH:43][S:40]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:22]=[CH:21][C:7]=2[S:8][C:9]=1[CH3:20]
Reactant: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl
Reactant: CCCCCS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
In the same manner as in Example 1, 5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]thiophene (440 mg, 1.25 mmol) was suspended in dimethylformamide and carbonyldiimidazole (305 mg, 1.88 mmol) was added, which was followed by stirring at room temperature for 1 hr. Then, 1-n-pentanesulfonamide (284 mg, 1.88 mmol) and DBU (286 mg, 1.88 mmol) were added and the mixture was refluxed under heating at 100° C. for 15 hr. The reaction mixture was concentrated under reduced pressure and water and 3N hydrochloric acid were added to acidify the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/2) and recrystallized from 2-propanol-n-hexane to give 3-(2,4-dichlorobenzyl)-2-methyl-5-(1-n-pentanesulfonylcarbamoyl)benzo[b]thiophene (410 mg, 68%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25](=[O:27])[CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1.[Na]>CN(C=O)C.CO>[CH3:1][N:2]1[C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([CH:25]([OH:27])[CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:14][CH:15]=2)=[N:5][CH:4]=[N:3]1
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(COCc2ncnn2C)c1
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(O)c1ccc2c(c1)ncn2-c1cccc(COCc2ncnn2C)c1
Yield: 46 %

Procedure:
To a solution of compound 21d (4.9 g, 13.9 mmol) in a mixture of DMF (90 ml) and methanol (10 ml) was added sodium boronhydride (0.53 g, 13.9 mmol). The resultant mixture was stirred at 60° C. for 1 hour. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and eluted through silica gel with a mixture of ethyl acetate and methanol (9:1 v/v). The pure fractions were concentrated and compound 23 was precipitated as the hydro chloride upon addition of etheral hydrogen chloride to the concentrate. Yield: 46%. LC-ESI-HRMS of [M+H]+ shows 364.1764 Da. Calc. 364.177325 Da, dev. −2.5 ppm
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:16][C:17](=[O:31])[CH:18]([NH2:30])[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:32][C@H:33]([CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51])[C:34](O)=[O:35]>>[CH2:22]([NH:21][C:19](=[O:20])[CH:18]([NH:30][C:34](=[O:35])[C@@H:33]([Br:32])[CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51])[C:17]([NH:16][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)[C@H](Br)CCCCN1C(=O)c2ccccc2C1=O
Reactant: NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1ccccc1)C(NC(=O)[C@@H](Br)CCCCN1C(=O)c2ccccc2C1=O)C(=O)NCCc1ccccc1

Procedure:
Prepare by the method of Example 3.3 using N,N′-diphenethyl-2-aminomalonamide trifluoroacetic acid salt (20 mmol) and (R)-2-bromo-6-phthalimidohexanoic acid (25 mmol) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[CH3:29][O:30][CH:31]1[CH2:34][NH:33][CH2:32]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:29][O:30][CH:31]1[CH2:34][N:33]([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:26])[CH2:32]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: COC1CNC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC1CN(C(=O)c2cnn(C)c2C(=O)Nc2ccn3nc(-c4ccccc4)nc3c2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-methoxyazetidine hydrochloride (37.5 mg, 304 μmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 3 hours at 70° C. under nitrogen atmosphere in a closed vessel, and then over the weekend at room temperature. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(3-Methoxyazetidine-1-carbonyl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (75 mg, 66.6%) as a very insoluble white solid. mp.: 269-270° C. MS: m/z=432.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17].Cl.C([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])C>>[F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31]([NH:51][CH2:50][CH2:49][C:48]([OH:47])=[O:52])=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17]
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Reactant: CCOC(=O)CCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)NCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 120D and β-alanine ethyl ester hydrochloride was processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.90 (t, 1 H), 6.87-7.35 (m, 11 H), 6.68 (m, 1 H), 6.48 (m, 2 H), 4.08 (s, 2 H), 4.05 (s, 2 H), 3.90 (t, 2 H), 3.64 (s, 1 H), 3.22 (dd, 2 H), 2.90 (s, 3 H), 2.35 (m, 2 H), 2.33 (s, 3 H), 2.19 (t, , 2 H), 1.87 (m, 2 H); MS (ESI) m/z 682 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[I:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[NH2:20].N1C=CC=CC=1>ClCCl>[I:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]([F:18])([F:19])[F:17])=[CH:11][C:10]=1[NH:20][C:2](=[O:3])[O:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1cc(I)c(N)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(I)c(NC(=O)OC(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
Add a solution of isopropyl chloroformate (99.6 mL, 99.6 mmol, 1M in toluene) dropwise to a solution of 2-iodo-4-methyl-5-trifluoromethylphenylamine (27.26 g, 90.55 mmol) and pyridine (14.6 mL, 181.1 mmol) in dichloromethane (350 mL) at 5° C. under an atmosphere of nitrogen and warm the mixture to room temperature. Stir for 3 h and wash the mixture with 2 N HCl (100 mL) and brine (100 mL). Dry over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a tan solid (33.59 g, 96%), which is used in the next step without purification. APCI MS m/z 388 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=2[CH:18]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[NH:22]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=3[CH:18]=2)=[CH:25][CH:24]=1)[C:19]([CH3:20])=[O:21]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CC1OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)C(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4-methyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH:5]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=1
Reactant: COC(=O)c1cccc(CCCNCCCc2cccc(Cl)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CCCN(CCCc2cccc(Cl)c2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 115.5 %

Procedure:
To a solution of 3-(3-{[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-benzoic Acid methyl ester (50.3 mg, 0.145 mmol) and triethylamine (32.4 mg, 0.32 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (18.3 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred for 24 h at room temperature and was diluted with CH2Cl2. The organic solution was washed consecutively with aqueous HCl (5.5%, 1×), H2O (1×), NaHCO3 (1×) and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford the title product of Step A as an oil (71 mg). MS 424 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:26])=[CH:4][C:5]2[N:11]([C:12](=[O:19])[CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:25]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([Br:26])=[CH:4][C:5]2[N:11]([C:12](=[O:19])[CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:10]3[N:20]=[CH:21][CH:22]=[CH:23][C:9]=3[C:8](=[S:28])[NH:7][C:6]=2[CH:25]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCN(CC)CC(=O)N1c2cc(Br)c(Br)cc2NC(=O)c2cccnc21
Solvent: c1ccncc1
Product: CCN(CC)CC(=O)N1c2cc(Br)c(Br)cc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 8,9-dibromo-6,11-dihydro-11-[(diethylamino)acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dibromo-6,11-dihydro-11-[(diethylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [CH:1]1([C:4]([CH:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])OC2=O)=[O:5])[CH2:3][CH2:2]1.[C:16](O)(C)(C)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:5])[CH2:6][C:11]([O:10][C:9]([CH3:13])([CH3:14])[CH3:16])=[O:12])[CH2:2][CH2:3]1
Reactant: CC(C)(C)O
Reactant: CC1(C)OC(=O)C(C(=O)C2CC2)C(=O)O1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC(=O)C1CC1
Temperature: 80 °C
Yield: 97.3 %

Procedure:
A mixture of 5-cyclopropylcarbonyl-2,2-dimethyl-1,3-dioxan-4,6-dione (23.9 g) and t-butanol (25 g) in dry toluene (80 ml) was stirred and heated at 80° C. for 4 hours. The cooled mixture was washed with water (3×30 ml), dried (anhydrous sodium sulphate), treated with decolourizing charcoal and filtered. The filtrate was evaporated to dryness and the residue was distilled to give t-butyl 3-cyclopropyl-3-oxopropionate (20.2 g) as a clear oil bp 80°-84° C./8 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([CH3:21])[CH:4]=1)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([CH3:21])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C=Cc1cccn1-c1ccc(C#N)cc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccn1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate (6C) (8.0 g, 28.6 mmol) in ethanol was added 10% Pd/C (0.8 g). The mixture was stirred under 1 atm of H2 for 30 min at room temperature and filtrated. The resultant filtrate was concentrated to dryness affording the crude product of ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (7.5 g), which was used for the next step without further purification: LC-MS m/z 283.0 [M+H]+, purity 68%.