Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[CH3:49][N:50]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:51](Cl)=[O:52]>C(Cl)Cl>[C:5]([O:4][C:3](=[O:9])[N:2]([CH3:1])[C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:51]([N:50]([CH3:49])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:52])[CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)N(C)c2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Intermediate 7 (175 mg, 0.322 mmol) is dissolved in anhydrous CH2Cl2 (15 mL), to which DIEA (70 μL, 0.40 mmol) is added. The solution is cooled to 0° C. and N-methyl-N-phenylcarbamoyl chloride (66 mg, 0.39 mmol) is added, the solution is subsequently warmed to room temperature for 4 h. N-Methyl-N-phenylcarbamoyl chloride (66 mg, 0.39 mmol) and DIEA (70 μL, 0.40 mmol) are added and the solution is stirred at room temperature for 15 h at room temperature. The solution is diluted with CH2Cl2 (50 mL) and washed with sat. NaHCO3 and brine. The solution is dried (MgSO4), filtered, and the solvent removed under reduced pressure to give the crude product as an oil. This material is purified by flash chromatography on silica gel (0-5% MeOH/CH2Cl2). The title compound is isolated as a white foam (168 mg, 77% yield): 1H NMR δ (CDCl3) 6.60-7.60 (m, 10H), 4.19-5.20 (m, 5H), 3.62 (“br d”, 1H, Jobs=13.2 Hz), 3.52 (“br d” 1H, Jobs=13.4 Hz), 2.56-3.28 (m, 10H), 1.72-2.10 (m, 5H), 1.47 and 1.45 (s, 9H total), 1.24-1.32 (br m, 3H), 0.88-1.12 (m, 2H), 1.09 (br d, 1H, J=6.7 Hz), 0.90 (dd, 2H, J=7.0, 2.6 Hz), 0.78 (br d, 2H, J=6.7 Hz), 0.66 (br d, 2H, 6.7 Hz; LCMS (APCl+) 678.6 (MH+, 100%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23](OCC)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:30].Cl.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:30])[NH:4][C:5]=4[CH:11]=3)[CH2:18][CH2:17]2)=[CH:29][CH:28]=1)[CH3:33]
Reactant: CCOC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Saponification of 390D was performed using the general procedure for hydrolysis of carboxylic esters. The resulting carboxylic acid and ethylamine hydrochloride were used in the general procedure for coupling an amine to a carboxylic acid to give the title compound as a pinkish, tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.13-1.31 (m, 2H) 1.40 (d, J=6.82 Hz, 3H) 1.56-1.72 (m, 3H) 2.44 (d, J=6.82 Hz, 2H) 2.62-2.78 (m, 2H) 3.17-3.29 (m, 2H) 3.76-3.89 (m, 2 H) 4.61 (q, J=6.82 Hz, 1H) 6.63-6.78 (m, 2H) 6.88 (dd, J=15.41, 8.59 Hz, 3H) 7.68 (d, J=9.09 Hz, 2H) 8.13 (t, J=5.43 Hz, 1H) 10.59 (s, 1H). ESI-MS: m/z 408.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[C:52]([O:53][CH3:54])=[CH:51][C:49]([NH2:50])=[C:48]([O:55][CH3:56])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N>CC(O)C.Cl.CO>[N:34]1([CH:40]2[CH2:41][CH2:42][N:43]([C:46]3[C:52]([O:53][CH3:54])=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=5[F:29])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([O:55][CH3:56])[CH:47]=3)[CH2:44][CH2:45]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1N
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: CO
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 40.3 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-(1,4′-bipiperidin-1′-yl)-2,5-bis(methyloxy)aniline (0.166 g, 0.520 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (4 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo. The resulting residue was taken up in DCM and purified by column chromatography using basic alumina. The desired combined fractions were concentrated and the resulting solid was triturated with DCM and hexane, filtered and air dried to give the title compound (0.130 g, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (br. s., 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.73 (d, J=9.2 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.43-7.50 (m, 1H), 7.36-7.42 (m, 1H), 7.34 (s, 1H), 7.20 (t, J=8.1 Hz, 2H), 6.94-7.00 (m, 1H), 6.66 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.43 (d, J=11.7 Hz, 2H), 2.51-2.58 (m, 2H), 2.26-2.35 (m, 1H), 1.77 (d, J=13.6 Hz, 2H), 1.53-1.64 (m, 2H), 1.48 (s, 4H), 1.38 (s, 2H). MS (M+H, ES+) 745.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].I[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: ICCn1cnc(-c2ccccc2)c1
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(CCn1cnc(-c2ccccc2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of Ethyl 2-(methylsulfonyl)propanoate (377 mg, 2.09 mmol, 1 eq) and 1-(2-iodoethyl)-4-phenyl-1H-imidazole (623 mg, 2.09 mmol, 1 eq) in DMF (7 mL) was added Cs2CO3(1.70 g, 5.22 mmol, 2.5 eq) and the reaction mixture was allowed to stir overnight at RT, then for a further 24 h at 45° C. EtOAc was added and the mixture was washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The crude product mixture was purified by flash chromatography on silica gel eluting with 10-95% ethyl acetate in heptanes to give ethyl 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanoate (335 mg, 46% yield). LC-MS M+H+351.1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[O:4][C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH:11]1([CH2:10][N:7]2[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[O:4][C@H:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:2]([NH:1][C:38](=[O:39])[C@H:36]([CH3:37])[NH:35][C:33](=[O:34])[CH2:32][C:27]3[CH:28]=[C:29]([F:31])[CH:30]=[C:25]([F:24])[CH:26]=3)[C:8]2=[O:9])[CH2:13][CH2:12]1
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a stirred solution of (2R,3S)-3-amino-5-(cyclopropylmethyl)-2-phenyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (72b) (150 mg, 0.486 mmol) in dichloromethane (4 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (130 mg, 0.534 mmol), HOBt (75 mg, 0.555 mmol), NMM (60 mg, 0.594 mmol) and EDAC-HCl (103 mg, 0.537 mmol). After stirring at ambient temperature under nitrogen overnight the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 5:1 (v/v) dichloromethane:ethyl acetate to afford the title compound (230 mg, 88%) as a white solid. TLC Rf=0.22 (5:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.20 (m, 1H), 0.36-0.64 (m, 3 h), 1.14 (m, 1H), 1.21 (d, 3H, J=7.0 Hz), 3.47 (s, 2H), 3.52 (m, 1H), 4.10-4.29 (m, 2H), 5.05 (t, 1H, J=7.0 Hz), 5.68 (d, 1H, J=7.4 Hz), 5.90 (d, 1H), 6.24 (d, 1H), 6.68-6.85 (m, 3H), 7.28 (s, 4H), 7.36, s, 5H). MS APCI, m/z=534 (M+1). LC/MS: 2.78 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.[C:9]([C:12](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[CH3:10]>>[Cl:25][C:21]1[CH:20]=[C:19]([CH:18]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:10])[NH:1][C:2]3[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]2=3)[CH:24]=[CH:23][CH:22]=1
Reactant: CCn1nccc1N
Reactant: CCOC(=O)C(=Cc1cccc(Cl)c1)C(C)=O
Product: CCOC(=O)C1=C(C)Nc2c(cnn2CC)C1c1cccc(Cl)c1
Temperature: 130 °C
Yield: 34.9 %

Procedure:
A mixture of 5-amino-1-ethylpyrazole (250 mg) and ethyl 2-acetyl-3-(3-chlorophenyl)acrylate (568 mg) was heated at 130° C. for 3 hours. After cooling, the residue was evaporated. The residue was diluted with CHCl3 and washed with saturated NaHCO3, water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:7)-to give ethyl 4-(3-chlorophenyl)-1-ethyl-6-methyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (271 mg) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[N:38][CH:39]=1>ClCCl.CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[N:38][CH:39]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: Cc1ccc(N)cn1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccc(C)nc4)c3cc2OC)c1
Yield: 36 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (100 mg, 0.22 mmol) with 5-amino-2-methylpyridine (28 mg, 0.26 mmol) and chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 36% yield (40 mg).
Reaction SMILES: Br[C:2]1[O:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C.ClCCl>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:2]2[O:6][C:5]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=3[C:3]=2[C:13](=[O:26])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(Br)oc2c1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(N3CCN(C)CC3)oc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-bromo-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (20 mg, 0.047 mmol) in a mixture of acetonitrile/dichloromethane; 1:1 (2 mL) was added N-methylpiperazine (50 μL, excess) and the reaction mixture was stirred at room temperature for 1 hour. After this time the solvent was removed by distillation under vacuum and the product was purified by PTLC (eluent=hexane/ethyl acetate; 4:6+1% triethylamine) to give the title compound as a green yellow paste which was crystallized by freeze drying in t-butanol to give a yellow solid; (8 mg, 43%); 1H NMR (300 MHz, CDCl3) δ 7.07(s, 2H, benzoyl Hs), 6.93(d, 1H, J=8.60 Hz), 6.84(d, 1H, J=2.25 Hz), 6.65(dd, 1H, J=8.64, 2.30 Hz), 3.92(s, 3H, OMe), 3.83(s, 6H, 2×OMe), 3.78(s, 3H, OMe), 3.66-3.64(bm, 4H), 2.65-2.63(bm, 4H), 2.40(s, 3H, N-Me); 13C NMR (75 MHz, CDCl3) δ 188.76(CO), 162.24, 155.88, 152.72, 149.06, 141.09, 135.36, 121.68, 119.64, 110.42, 106.11, 155.88, 95.63, 60.64, 55.88, 55.44, 53.88, 47.06, 45.29.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44]([O:47][CH3:48])([CH3:46])[CH3:45])[C:39](=[O:49])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][C:44]([O:47][CH3:48])([CH3:46])[CH3:45])[C:39](=[O:49])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(C)(C)Cn1ccc(Br)cc1=O
Product: COC(C)(C)Cn1ccc(-c2ccc(C(C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(2-methoxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75 Method 1. Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][OH:24])[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC(Cl)(Cl)C(=N)O[C:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>C1COCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][OH:24])[C:20]([O:22][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][CH:33]=3)([CH3:31])[CH3:30])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: CC(C)(OC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxypropanoic acid (Compound SP827, Fmoc-Ser-OH) (96.0 g, 292 mmol) was azeotropically distilled with THF (100 ml) eight times. This was dissolved in dehydrated THF (200 ml) under a nitrogen atmosphere, 2-(4-(trifluoromethyl)phenyl)propan-2-yl 2,2,2-trichloroacetimidate (Compound SP853) (67.9 g, 195 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by amino silica gel column chromatography (DCM) and concentrated under reduced pressure. The residue was further purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=95/5→0/100) to afford (S)-2-(4-(trifluoromethyl)phenyl)propan-2-yl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxypropanoate (Compound SP826, Fmoc-Ser-OPis(4-CF3)) (38%, 38.4g).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1.C(O[C:22](OCC)(OCC)[CH2:23][CH3:24])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:23]([C:24]1[O:8][C:7]2[C:2]([N:1]=1)=[CH:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=2)[CH3:22]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCOC(=O)c1cc(N)c(=O)[nH]c1C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)c1cc2nc(CC)oc2nc1C(=O)OCC
Yield: 84.8 %

Procedure:
Diethyl 5-amino-1,6-dihydro-6-oxo-pyridine-2,3-dicarboxylate (7.57 g, 0.030 mol), is suspended in 60 mL triethylorthopropionate (TEOP 0.30 mol). A small amount of p-toluenesulfonic acid is added and the mixture is heated at reflux for 65 hours. The triethylorthopropionate is removed in vacuo and the resulting oil is purified by column chromatography. The tractions containing the pure desired product are combined and stripped to a honey-colored oil weighing 7.38 g, yield 84.8%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([NH:29][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: NCCCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and 3-phenylpropylamine in DME. ES-MS m/e (%): 330 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([OH:20])=O)=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:26][N:27]1[C:31]([NH2:32])=[CH:30][C:29]([CH3:33])=[N:28]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:32][C:31]4[N:27]([CH3:26])[N:28]=[C:29]([CH3:33])[CH:30]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Cc1cc(N)n(C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2ccccc2Sc2ccc3nc(NC(=O)C4CC4)cn3n2)n(C)n1
Yield: 69.2 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (150 mg, 0.42 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (130 mg, 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (130 mg, 70%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9](O)[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl>[F:27][CH:9]1[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2)=NC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2)=NC1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A well stirred suspension of 6.0 g (0.018 mole) of 7-bromo-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one in 250 ml methylene chloride was cooled to -70°, and 7.5 ml (0.06 mole) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm slowly to -10° over a period of 30 min., and held at -10° for 20 min., until most of the solid had dissolved. The reaction mixture was poured into 500 ml of ice water and stirred until the yellow color faded. The organic layer was separated, dried over MgSO4, and evaporated to dryness under reduced pressure. The residue was dissolved in 300 ml of hot benzene and filtered hot. The filtrate was mixed with 400 ml hexane and cooled. The crystals that separated were collected on a filter, washed with hexane, and dried in air to give 5.28 g (88%) of 3-fluoro-7-bromo-1,3-dihydro- 5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 207°-209° (dec.); 19F nmr (acetone-d6) δ -162.6 ppm (d, J=57 Hz); 1H nmr (acetone-d6) δ 5.86 ppm (d, J=57 Hz, 1H), 7.2-8 ppm (m, 8H), 9.90 ppm (NH); ir (KBr) 5.84μ (C=O). A sample was dried in a vacuum oven for analysis.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: COc1cccc(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1cccc(OC)c1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and 3-methoxybenzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.5 g of product m.p. 154-56° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 3.48 (m, 1H; 3.81 (s, 3H); 4.82 (d, 2H, J=2.2 Hz); 6.15 (s, 1H); 6.90-7.26 (m, 5H); 7.10 (d, 1H, J=8.9 Hz); 7.65 (d, 1H, J=8.9 Hz).
Reaction SMILES: C(O[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][C:13]=1F)CCCCCCCCC.S(=O)(=O)(O)O>N1C=CC=CC=1.CO>[CH:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:19]#[C:18][C:15]2[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=2)=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(OCCCCCCCCCC)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: c1ccncc1
Product: C(C#Cc1ccccc1)#Cc1ccccc1
Temperature: 25 °C
Yield: 225.9 %

Procedure:
To a 50 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was added 300 mg 4-decyloxy-3-fluorophenylacetylene and 43 mg cupric acetate in 40 ml 1:1 pyridine/MeOH. The reaction mixture was refluxed for 2 hrs, allowed to cool to room temperature and then added dropwise into a stirred 9 M aqueous sulfuric acid solution at ice bath temperature. The resulting cream-like suspension was extracted with ethyl ether and sequentially washed with water (3x) and brine and dried with anhydrous magnesium sulfate yielding 289 mg of a yellow-brown solid. Flash chromatography (1% ethyl acetate/hexane) and recrystallization of the residue from 95% ethanol afforded 248 mg diphenyldiacetylene (V), 4,4'-didecyloxy-3,3'-difluoro diphenyldiacetylene, as pale yellow needles.