Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C([C:21](OO)=[O:22])C=1>ClCCl>[O:22]=[C:21]1[CH:10]2[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2C(=O)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 142.5 %

Procedure:
To the solution of N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine (110 g, 0.60 mol) obtained in Step 1 in 300 ml of dichloromethane, was added 3-chloroperbenzoic acid (m-CPBA; 311 g, 1.80 mol). The reaction mixture was stirred overnight at room temperature and filtered to remove benzoic acid produced. The resulting filtrate was washed with a saturated potassium carbonate solution, brine and distilled water. The resulting organic layer was dried and concentrated on magnesium sulfate to give the titled compound (180.6 g).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C@@:2]1([CH2:12][CH2:11][C@H:7]([C:8]([OH:10])=O)[C:4]1([CH3:6])[CH3:5])[CH3:3].C(Cl)(C)=O.CC(OC(C)=O)=O>>[C:1]1(=[O:13])[O:14][C:8](=[O:10])[CH:7]2[CH2:11][CH2:12][C@@:2]1([C:4]2([CH3:5])[CH3:6])[CH3:3]
Reactant: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Solvent: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: CC1(C)C2CC[C@@]1(C)C(=O)OC2=O

Procedure:
A mixture of (1R-cis)-1,2,2-Trimethylcyclopentane-1,3-dicarboxylic acid)[(1R,3S)-camphoric acid](40.0 g), AcCl (23.5 g), and Ac2O (81.6 g) was heated under reflux for 3 hr. The mixture was concentrated in vacuo, dissolved in CHCl3, washed with sat. NaHCO3, brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was triturated with i-Pr2O to give (1R)-1,8,8-Trimethyl-3-oxabicyclo[3.2.1]octane-2,4-dione[(1R)-camphoric anhydride (34.0 g) as crystals.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:38][C:15]2[N:16]=[CH:17][N:18]([CH2:21][C:22]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])([OH:29])[CH2:23][N:24]3[CH:28]=[N:27][CH:26]=[N:25]3)[C:19](=[O:20])[C:14]=2[CH:13]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:22]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[CH2:21][N:18]1[C:19](=[O:20])[C:14]2[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[S:38][C:15]=2[N:16]=[CH:17]1
Reactant: CC(=O)OCCCCCCCc1cc2c(=O)n(CC(O)(Cn3cncn3)c3ccc(F)cc3F)cnc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1c2cc(CCCCCCCO)sc2ncn1CC(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
6-(7-Acetoxyheptyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (3.00 g, 5.5 mmol) was dissolved in the mixture of methanol (10 ml) and water (2 ml). Then potassium carbonate (760 mg, 5.5 mmol) was added and the mixture was stirred at RT for 2 hours. Methanol was then removed on rotavapor, water (10 ml) was added to the reaction mixture and extracted with ethyl acetate (2×5 ml), dried, concentrated and purified by column chromatography to obtain the pure 3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(7-hydroxyheptyl)-thieno[2,3-d]pyrimidin-4(3H)-one (2.5 gm, 90.57%).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1.Cl>O1CCCC1.O>[CH3:28][S:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:26][CH:25]=1
Reactant: CSc1ccc(-c2oncc2CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(-c2oncc2CCC(=O)O)cc1
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of diethyl malonate (10.3 g) in tetrahydrofuran (80 ml) was gradually added sodium hydride (60%, oil, 2.34 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-methylthiophenyl)isoxazole (7.00 g) in tetrahydrofuran (70 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (50 ml) and acetic acid (100 ml), and heated under reflux for 5 hr. The reaction mixture was concentrated, and water was added to the residue to give colorless crystals (4.68 g, yield 61%) of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionic acid. The crystals were recrystallized from ethyl acetate-isopropyl ether to give a colorless prism. melting point: 124–125° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27]Br)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])[CH3:8].O>O1CCCC1>[CH2:7]([O:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1(CCCBr)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCN2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 62.5 °C

Procedure:
Piperidine (0.13 mL, 0.00132 mol) is added to a solution of 4-(3-bromopropyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (0.1 gm, 0.00026 mol) in tetrahydrofuran (5 mL). The reaction mixture is heated at 60-65° C. for 3 hours. It is then cooled to room temperature, treated with demineralized water (12 mL) and extracted with ethyl acetate (2×20 mL). Combined extract is dried over sodium sulphate and concentrated under reduced pressure to get a crude residue which is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane, 1:9) to yield 4-(3-piperidin-1-yl propyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:24][PH:25]([O-])([O-:29])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:5]1[CH:6]=[CH:7][C:2]([P:25]([CH3:24])(=[O:29])[O:26][CH2:27][CH3:28])=[CH:3][CH:4]=1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
To (R)—N—((R)-(4-bromophenyl)(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 20-c, (1 g, 2.5 mmol), ethyl methylphosphite (0.54 g, 5 mmol) and Et3N (0.63 g, 6.25 mmol) in THF (10 ml) was added PdCl2(dppf) (183 mg). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel to give compound, 20-d, (dichloromethane:methanol=50/1) to provide the product (866 mg, 81%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClC1C=CC=CC=1>[Br:20][C:3]1[C:2]([OH:1])=[C:11]([CH3:12])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: Cc1cc2ncccc2cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1cc2ncccc2c(Br)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
6-Hydroxy-7-methylquinoline (76 mg) was dissolved in chlorobenzene (7 ml) to prepare a solution. N-Bromosuccimide (180 mg) and 2,2′-azobisisobutyronitrile (23 mg) were added to the solution, and the mixture was stirred at 80° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give 5-bromo-6-hydroxy-7-methyl-quinoline (111 mg, yield 97%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[F:12][C:13]([F:22])([F:21])[C:14]([CH3:20])(O)[C:15]([F:18])([F:17])[F:16].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([O:3][C:14]([CH3:20])([C:15]([F:18])([F:17])[F:16])[C:13]([F:22])([F:21])[F:12])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)c1ccc(C=O)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A mixture of 41.1 g (274 mmol) 4-carboxybenzaldehyde, 50 g (274 mmol) 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, and 33.4 g (274 mmol) DMAP in 700 mL DCM was stirred until homogeneous (approximately 0.5 hr). The solution was cooled over an ice bath, under Ar, and 52.3 g (274 mmol) EDCI was added portion-wise. The reaction was stirred at RT for 48 hr. and concentrated to an oil on the rotovap. The oil was taken up with EA and washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to 25.5 g pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][N:36]([CH2:2][C:3]3[N:13]([CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[CH2:35][CH2:34]2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1ncc2cc(CBr)n(CCC3CCCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4cnc(C#N)nc4n3CCC3CCCCC3)CC2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71 %

Procedure:
To a solution of 6-bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (290 mg, 0.84 mmol) in DMF (1.7 ml), 2,8-Diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (201 mg, 0.84 mmol) and potassium carbonate (138 mg, 1.0 mmol) are added. The mixture is stirred at room temperature under nitrogen atomosphere for 14 h. The reaction mixture is diluted with water and extracted with AcOEt (twice). The combined organic layer is washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give 8-[2-Cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester in 71% yield. Rf=0.45(n-hexane:AcOEt=1:1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[C:23]([CH:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)#[N:24]>>[C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:27][CH2:26]1)#[N:24]
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: N#CC1CCC(=O)CC1
Product: N#CC1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-cyano-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][S:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: CSc1nc(-c2cccnc2)sc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1nc(-c2cccnc2)sc1N
Reaction time: 2 h

Procedure:
To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1(M+1), 324.1 (M-1).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=O)[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2].[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:66][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH:46]([O:51][CH2:52][CH2:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-propyloxy-4"-oxocyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry isopropyl alcohol (3 ml) is added benzyl amine (86.5 mg). The mixture is stirred at r.t. for 30 minutes, and cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([CH2:37][CH2:38][C:39]([N:22]2[CH2:23][CH2:24][N:19]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=4)[N:9]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[OH:18])[N:7]=3)[CH2:20][CH2:21]2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)CCC4CCCC4)CC3)nc(-c3ccccc3O)nc2c1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200 mg, 0.62 mmol) in CH2Cl2 (6.0 mL) was stirred under an N2 atmosphere. Then triethylamine (170 μL, 1.24 mmol) was added, and the reaction was cooled to −10 to −20° C. After adding 3-cyclopentylpropanoyl chloride (96 μL in 600 μL THF, 0.62 mmol), the reaction mixture was stirred for 30 minutes. CH2Cl2 was added, and the organic phase was washed 2× with H2O, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2: hexanes gave 3-cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one (240 mg, 86%). LC/MS: m/z 445.50 (M+H)+ at 3.07 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J=8.2, 1.8 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 3.95 (dd, J=19.9, 5.6 Hz, 4H), 3.74 (m, 4H), 2.52 (s, 3H), 2.38 (t, J=7.8 Hz, 2H), 1.76 (m, 3H), 1.55 (m, 6H), 1.16 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH2:25])=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cccnc2)sc1C(=O)NCc1ccccc1
Yield: 33 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use nicotinoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 33% yield. m.p. 224-226° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.17 (d, J=1.5 Hz, 1H), 8.76 (dd, J=1.5, 4.6 Hz, 1H), 8.63 (t, J=5.7 Hz, 1H), 8.40-8.36 (m, 1H), 7.55 (dd, J=4.6, 8.1 Hz, 1H), 7.33-7.19 (m, 5H), 4.38 (d, J=5.7 Hz, 2H), 2.51 (s, 3H); MS (ES+) m/z 353.2 (M+1).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][N:28]=[CH:29][C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([CH:29]=[N:28][OH:27])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: ON=Cc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C=NO)[n+]4c3)[C@H](C)[C@H]12
Yield: 2.1 %

Procedure:
The same procedure as in Example 1 was repeated except that 102 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 70 mg of 3-(hydroxyimino)methylimidazo[5,1-b]thiazole were used, thereby obtaining 2.3 mg of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:9])[CH3:8].Br[CH2:29][C:30]1[C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:33]([C:51]([F:54])([F:53])[F:52])=[CH:32][CH:31]=1.O>CN(C)C=O>[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:29][C:30]2[C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C:33]([C:51]([F:52])([F:53])[F:54])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)(=[O:9])[CH3:8]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C(C)=O)c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Cesium carbonate (209 mg, 0.644 mmol) was added to a solution of methyl (2-acetyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (122 mg, 0.429 mmol) obtained in Example (40-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (181 mg, 0.429 mmol) obtained in Example (28-5) in N,N-dimethylformamide (4 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate (three times). After the organic layer was successively washed with water (three times) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to give tert-butyl 6-[({2′-acetyl-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (93 mg, yield: 34%).