Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>CN(C)C=O.C(#N)C.C(O)C>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][C:34]=4[O:35][CH3:36])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][C:34]=4[O:35][CH3:36])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(NC(C)=O)cc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CC#N
Product: COc1ccc(NC(C)=O)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (3.94 g, 15.4 mmol), K2CO3 (3.67 g, 26.6 mmole), N-[3-(3-bromopropoxy)-4-methoxyphenyl]acetamide (5.56 g, 18.6 mmol) in dimethylformamide (75 ml) and acetonitrile (100 ml) was heated at 100° C. for 3 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (500 ml). The organic solution was washed with water (500 ml) and brine (400 ml), dried, then concentrated to a crude oil. The purification was effected by flash chromatography over a silica gel column (SiO2, 65 g, eluted with 1% CH3OH:dichloromethane, 1.2 l; and 3% CH3OH:dichloromethane, 500 ml). The material thus obtained weighed 2.33 g (34.3 %) as an oil. This material was dissolved in ethanol and treated with a solution of fumaric acid (661 mg) in ethanol. The N-[3-[3-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1-piperidinyl]propoxy]4-methoxyphenyl]acetamide hemifumarate was obtained as off-white crystals weighing 2.17 g, m.p.=205°-206° C.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:4].[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([NH:4][NH:3][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)=[O:25])[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NNc1ccccn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a mixture of 2-hydrazinopyridine dihydrochloride (2.49 g, 13.7 mmol) and 1-Boc-piperidine-4-carboxylic acid (3.14 g, 13.7 mmol) in 30 mL of CH2Cl2 was added DIPEA (5.96 mL) followed by HOBT (2.22 g, 16.4 mmol) and EDC (3.93 g, 20.5 mmol) at rt. After stirring at rt for 18 h, the reaction mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure afforded the title compound (3.3 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 1.47 (s, 9H), 1.68-1.76 (m, 2H), 1.86-1.88 (m, 2H), 2.44 (m, 1H), 2.70-2.90 (br, 2H), 4.15-4.22 (br, 2H), 6.71 (d, J=8.5 Hz, 1H), 6.81 (t, J=6.4 Hz, 1H), 7.56 (m, 1H), 8.11 (d, J=5.0 Hz, 1H), 8.20˜8.55 (br s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Li+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][S:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:13][CH:12]=1)(=[O:16])=[O:15]
Reactant: O=S([O-])c1ccc(CN2CCOCC2)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN4CCOCC4)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of lithium 4-(morpholinomethyl)benzenesulfinate (2.0 g, 8.10 mmol, 1.43 equiv), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (1.5 g, 5.66 mmol, 1.00 equiv) and potassium carbonate (780 mg, 5.65 mmol, 1.00 equiv) in N,N-dimethylformamide (60 mL) was stirred overnight at 70° C. The reaction mixture was cooled to room temperature and the product was precipitated by the addition of 150 mL of ice and water. The solid was collected by filtration, washed with 2×20 mL of water and dried in a vacuum oven to afford 1.5 g (57%) of methyl 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a white solid. LC-MS: (ES, m/z): 512 [M+CH3CN+H]+, 471 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 8.04 (d, J=8.0Hz, 2H), 7.90 (d, J=8.0Hz, 2H), 7.72 (d, J=7.6Hz, 2H), 7.52 (d, J=7.6Hz, 2H), 4.67 (s, 2H), 3.88 (s, 3H), 3.55 (s, 6H), 3.31-3.29 (d, 4H), 2.32 (s, 4H), 2.15 (s, 3H).
Reaction SMILES: [C:1]([C:11]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:12]=1[C:13](N(C)OC)=[O:14])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:25]([Mg]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:1]([C:11]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:12]=1[C:13](=[O:14])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)Cc1ccccc1
Yield: 91 %

Procedure:
2-(1-Decyn-1-yl)-N-methyl-N,4-bis(methyloxy)benzamide (192) (0.80 g, 2.41 mmol) was treated with benzylmagnesium chloride in THF to give 0.80 g (91%) of compound 193 as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.85-0.90 (m, 3H), 1.20-1.37 (m, 8H), 1.40-1.50 (m, 2H), 1.55-1.65 (m, 2H), 2.45 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 4.45 (s, 2H), 6.83 (dd, J1=8.7 Hz, J2=2.7 Hz, 1H), 6.98 (d, J=2.8 Hz, 1H), 7.70-7.26 (m, 3H), 7.27-7.33 (m, 2H), 7.66 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 363 (M+H)+, m/z 361 (M−H)−.
Reaction SMILES: [C:1]([N:20]([CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1)[CH2:21][CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN1C(=O)N(C)[CH2:49][CH2:48][CH2:47]1.C(Br)C#C>C1COCC1.C1(C)C=CC=CC=1>[C:1]([N:20]([CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:32][CH:33]=1)[CH2:21][CH2:22][O:23][CH2:49][C:48]#[CH:47])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCN(C)C1=O
Reactant: OCCN(CCOCc1ccc(-c2nc3ccccc3o2)cc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCOCCN(CCOCc1ccc(-c2nc3ccccc3o2)cc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
Dry N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-hydroxyethanamine (8.7 g; 15.7 mmol) is dissolved in THF (50 ml). NaH (1 g; 25 mmol) is added and stirred vigorously at 0° C. for 1 minute then brought to room temperature for 45 minutes. DMPU [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone] (5 ml) is added followed by propargyl bromide (80 wt %/toluene; 2.1 ml) and stirred for 48 hours. To this is added 0.6 g NaH and 1.5 ml propargyl bromide. After stirring vigorously, an additional 48 hours the reaction mixture is quenched with MeOH, concentrated and purified by column chromatography using 10 Et3N/10 CH2Cl2 /80 petroleum ether. The product is triturated with ether to give solid N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(prop-2-ynyloxy)ethanamine which is used directly in Step F.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:28])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH3:27])[CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2S(C)(=O)=O)=[CH:3][CH:2]=1.[CH3:39][O:40][C:41](=[O:50])[C:42]1[CH:47]=[C:46]([OH:48])[CH:45]=[CH:44][C:43]=1[CH3:49].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:39][O:40][C:41](=[O:50])[C:42]1[CH:47]=[C:46]([O:48][C:9]2[N:8]([CH2:7][C:4]3[CH:5]=[CH:6][C:1]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:2][CH:3]=3)[C:12]3[CH:13]=[C:14]([F:28])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH3:27])[CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=2)[CH:45]=[CH:44][C:43]=1[CH3:49]
Reactant: COC(=O)c1cc(O)ccc1C
Reactant: Cn1ccc2cc(-c3c(F)cc4c(nc(S(C)(=O)=O)n4Cc4ccc(-c5ccccc5)cc4)c3F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2nc3c(F)c(-c4ccc5c(ccn5C)c4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)ccc1C
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A solution of 1-biphenyl-4-ylmethyl-4,6-difluoro-2-methanesulfonyl-5-(1-methyl-1H-indol-5-yl)-1H-benzoimidazole (1088 mg, 2.1 mmol), 5-hydroxy-2-methyl-benzoic acid methyl ester (513 mg, 3.1 mmol) and potassium carbonate (580 mg, 4.2 mmol) in DMF (20 mL) was stirred at room temperature under nitrogen. After 18 h, the reaction mixture was transferred to a microwave vial and heated under microwave at 130° C. for 10 min. The cooled reaction mixture was diluted with EtOAc and washed 3 times with saturated ammonium chloride, dried (MgSO4), filtered, and concentrated. Chromatography over silica gel afforded the desired product as a colorless foam.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:15][C:16]([C:18]1[S:19][C:20]([C:23]2[C:24]3[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:21][CH:22]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:15][C:16]([C:18]1[S:19][C:20]([C:23]2[C:24]3[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:21][CH:22]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14]
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N[C@H](CN)Cc4ccc(Cl)cc4Cl)s3)c21
Reaction time: 2 h
Yield: 94.9 %

Procedure:
10% Pd/C (6 mg) was added to a solution of N-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide (59 mg, 0.121 mmol) in methanol (2.5 mL). The solution was put under vacuum and purged with H2 (3×), and then the reaction mixture was stirred under a hydrogen atmosphere for 2 hours. LC-MS analysis of the reaction mixture showed no more starting material. The reaction mixture was filtered and concentrated to yield N-((S)-1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide as a foam (53 mg, 95%). m/z 461 (M+); 1H NMR (DMSO d6) δ (ppm) 8.91 (s, 1H), 8.58-8.56 (m, 1H), 7.90 (br s, 2H), 7.84 (d, 1H, J=4.3 Hz), 7.78 (d, 1H, J=4.1 Hz), 7.60 (m, 1H), 7.39-7.33 (m, 2H), 4.55-4.42 (m, 1H), 3.87-3.77 (m, 1H), 3.19-2.84 (m, 6H), 2.33-2.26 (m, 1H), 1.88-1.82 (m, 1H), 1.18 (d, 3H, J=6.9 Hz).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N+:35]([O-])[CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40]([NH2:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:42])[CH3:41].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>FC(F)(F)C1C=CC=CC=1.CCOC(C)=O>[Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][C:36]([NH:49][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH3:42])[CH3:41])=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(N)c1ccccc1
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc[n+]([O-])c3)N2C(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc(NC(C)(C)c4ccccc4)nc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(1-oxidopyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (0.465 g, 0.835 mmol) in trifluorotoluene (15 ml) was cooled to 0° C. Cumylamine (0.282 mL, 2.09 mmol) was added, followed by p-toluenesulfonic anhydride (0.273 g, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 minutes, additional cumylamine (0.282 mL, 2.09 mmol) was added, followed by p-toluenesulfonic anhydride (0.273 g, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 minutes, a third addition of cumylamine (0.282 mL, 2.088 mmol) was carried out, followed by p-toluenesulfonic anhydride (273 mg, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 hours, the reaction was diluted with EtOAc (250 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with 0-100% EtOAc/hexanes to afford tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}{6-[(2-phenylpropan-2-yl)amino]pyridin-3-yl}methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (349.1 mg, 62%). LC-MS=674.4 (M+1)+. 1H NMR (600 MHz, CD3OD) δ −0.07 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.15-1.92 (m, 20H), 2.75 & 2.46 (2 multiplets, 1H), 3.87 (m, 4H), 4.06 (bs, 1H), 5.31 & 5.12 (2 singlets, 1H), 6.00-6.10 (m, 1H), 7.07 (m, 5H), 7.23 (bs, 1H), 7.36 (bs, 2H), 7.81 (bs, 1H), 7.90 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C(Cl)Cl>[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([N:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:7]4[NH:6][C:5](=[O:27])[C:4]5[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=5[O:2][CH3:1])[N:8]=4)=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[O:41])=[CH:38][CH:37]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5ccc(F)cc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and 4-fluorobenzoyl chloride (0.04 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 0% to 10% of MeOH/EtOAc, to afford the title compound (0.080 g, 45%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.11 (d, J=8.8 Hz, 2H), 7.44-7.62 (m, 2H), 7.21-7.39 (m, 2H), 7.04 (d, J=9.0 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.64-3.94 (m, 8H), 3.22-3.60 (m, 6H); APCI MS m/z 489 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])C.[OH-].[Na+]>C(O)C.O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:7]1[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1
Reactant: CCOC(=O)Cn1c(-c2ccccc2Cl)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2ccccc2Cl)nc2cccnc21

Procedure:
A mixture of 9.7 g (0.0308 mole) of 2-(2-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester, 2.5 g (0.0339 mole) of sodium hydroxide (pellets), and 100 ml of ethanol-water (1:1) was refluxed for 1 hr. The ethanol was evaporated and the residual aqueous solution was extracted with methylene chloride (2×30 ml). The aqueous layer was acidified with concentrated hydrochloric acid and filtered. The filter cake was recrystallized from ethanol-water to give 7.0 g (79%). A 2.0-g portion was recrystallized from ethanol-isopropyl ether to give white needles, mp 227°-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17](O)=O)[CH2:13][CH2:12]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C(Cl)Cl>[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:13][CH2:12]1
Reactant: COC1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1S
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Product: COC1CCC(c2nc3ccccc3s2)CC1

Procedure:
A mixture of 2-amino-benzenethiol (796 mg, 6.32 mmol), 4-methoxy-cyclohexanecarboxylic acid (1.0 g, 6.32 mmol) and Lawesson reagent (889 mg, 2.2 mmol) was heated to 160˜190° C. for 1 h. Then the mixture was diluted with DCM (100 ml) and washed with 10% aqueous NaOH solution (2×10 mL), brine, and dried over Na2SO4. The organic layer was concentrated and purified by flash column chromatography to give 2-(4-methoxy-cyclohexyl)-benzothiazole which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CCOc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)COc1ccc2c(c1)OCCC2(C)C
Yield: 99.3 %

Procedure:
4,4-Dimethylchroman-7-ol (1.4 g, 8.0 mmol), potassium carbonate (3.3 g, 24.0 mmol) and ethyl bromoacetate (1.0 mL, 9.2 mmol) were treated in the same procedure described in Example 33(d). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 4/1) to furnish 2.1 g (98% yield) of the title compound as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4][CH2:3]1.[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:29]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[C:13]([F:14])=[CH:12][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:10][C:9]=3[F:26])[CH2:6][CH2:7]2)[O:1][CH2:27][CH2:28]1
Reactant: OCCO
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Yield: 77 %

Procedure:
The compound was prepared by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.5 mmol), ethylene glycol (0.5 mmol), p-toluene sulfonic acid (0.3 mmol) in toluene and by purifying on silica gel column chromatography to provide title compound in 77% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29])=[O:21].O1CCOCC1>C(#N)C>[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH:31][C:32]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)=[O:33])(=[O:29])=[O:30])=[O:21]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(CSc2ccccn2)nc(N)n1
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(CSc2ccccn2)cc(OC)n1

Procedure:
7.0 g of 2-amino-4-methoxy-6-(pyridin-2-ylthiomethyl)-pyrimidine and 6.8 g of 2-methoxycarbonylphenylsulfonylisocyanate are stirred in 50 ml of abs. acetonitrile for 2 hours at 20°-25° C. The turbid solution is filtered, and the solvent evaporated off in vacuo. The residue is crystallised from dioxane to thus obtain 5.5 g (37% of theory) of N-(2-methoxycarbonylphenyl-sulfonyl)-N'-[4-methoxy-6-(pyridin-2-ylthiomethyl)-pyrimidin-2-yl]-urea, which crystallises with 0.5 mol of dioxane, m.p. 175°-181° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS1C2N=CC=CC=2N=C1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:65](=[O:68])[NH:66][CH3:67])[CH2:59][C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(NC(C)C)(C)C>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:65](=[O:68])[NH:66][CH3:67])[CH2:59][C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O[SH]1C=Nc2cccnc21
Solvent: ClCCl
Solvent: O
Solvent: CC(C)NC(C)C
Product: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.30 g; 1.22 mmol) was dissolved in methylene chloride (10 ml). 1-Hydroxy-7-azabenzotiazole (0.17 g; 1.22 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26 g; 1.34 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)-3-(2-naphthyl)propionamide (0.50 g; 1.22 mmol) in methylene chloride (10 ml) was added to the reaction mixture. Diisopropylamine (0.21 ml; 1.22 mmol) was added. The reaction mixture was stirred 12 hours at room temperature. Water (10 ml) and methylene chloride (10 ml) were added. The phases were separated and the organic phase was washed with aqueous sodium hydrogensulfate (10%; 20 ml), saturated aqueous sodium hydrogencarbonate (20 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The crude product was chromatographed on silica (2×20 cm) using ethyl acetate/methylene chloride (1:1) as eluent to afford 0.66 g of ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[CH2:13]=[C:14]1[CH2:17][C:16]2([CH2:20][CH2:19][CH2:18]2)[CH2:15]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:13][C:14]3([CH2:17][C:16]4([CH2:20][CH2:19][CH2:18]4)[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CC2(CCC2)C1
Reactant: ON=CC#Cc1cccc(Cl)c1
Product: Clc1cccc(C#CC2=NOC3(C2)CC2(CCC2)C3)c1

Procedure:
The title compound was prepared following the procedure described for Compound 3c, using Compound 31e instead of Compound 3b and Compound 97a instead of Compound 3a. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; Petroleum Ether-EtOAc 97:3; then DCM 100%) to give the title compound as a white-yellowish solid. Yield: 20.7%.