Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)C>C1COCC1.CO>[OH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][CH2:7][C:6]([OH:18])=[O:5])=[O:17]
Reactant: CCOC(=O)CNC(=O)c1cccc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
LiOH (75 mg in 2 mL water) was added to (3-hydroxy-benzoyl amino)-acetic acid ethyl ester (100 mg, 0.45 mmol) in a mixture of THF and MeOH mixture. This was followed by the addition of to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The THF and MeOH were then evaporated under reduced pressure and the resulting residue was acidified to pH 2 using 10% citric acid solution. The product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford (3-hydroxy-benzoyl amino)-acetic acid in 89% yield. 1H NMR (DMSO-D6): δ 12.4 (s, 1H), 9.6 (s, 1H), 8.7 (t, 1H), 7.2 (d, 3H), 6.9 (m, 1H), 4.0 (d, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:16]([CH3:24])([CH2:17][CH2:18][C:19]=32)[C@@H:11]([C@H:12]([CH3:15])[CH:13]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:25].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:27]1([CH2:15][C@H:12]([C@@H:11]2[C@:16]3([CH3:24])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:20]([C:19]=4[CH2:18][CH2:17]3)([CH3:23])[CH2:21][CH2:22][C@H:2]([OH:1])[C:3]5([CH3:26])[CH3:25])=[CH:9][CH2:10]2)[CH3:13])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@H](CN1CCOCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al was treated with morpholine and sodium tris(acetoxy)borohydride as described in Example 1h). (20S)-20-[(morpholin-4-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[N:10][C:5]2=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:27]3[C:26]([CH3:28])=[N:25][N:24]([CH:29]4[CH2:31][CH2:30]4)[C:23]=3[C:22](=[O:32])[NH:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:27]3[C:26]([CH3:28])=[N:25][N:24]([CH:29]4[CH2:31][CH2:30]4)[C:23]=3[C:22](=[O:32])[N:21]2[C:2]2[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[N:10][C:5]3=[C:4]([CH3:12])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Reactant: Cc1cc(Cl)nc2c1nnn2C
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnn(C)c3n1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 102 using 5-chloro-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine (Step 109.4) and 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.6). The reaction mixture was quenched with a saturated aq. NaHCO3 solution (75 mL) and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. The crude material was first purified by silica gel chromatography (hexane/EtOAc 25-45%). tR: 5.69 min (HPLC 1); tR: 1.26 min (LC-MS 2); ESI-MS: 434 [M+H]+ (LC-MS 2); Rf=0.58 (EtOAc/hexane 1:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.11 (m, 2H) 1.19-1.27 (m, 2H) 1.91 (s, 3H) 2.68 (s, 3H) 3.78-3.87 (m, 1H) 4.08 (s, 3H) 6.58 (s, 1H) 7.31 (d, J=8.6 Hz, 2H) 7.43 (d, J=8.2 Hz, 2H) 8.21 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].[H-].[Na+].[C:21]1([C:27]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:28]2[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=3)=[N:31][N:30]=[N:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:53]1([C:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:28]2[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[CH:44]=[CH:43][C:42]([CH2:45][O:1][C:2]4[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=4[N+:16]([O-:18])=[O:17])[C:5]([N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)=[O:6])=[CH:41][CH:40]=3)=[N:31][N:30]=[N:29]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(c1ccc([N+](=O)[O-])c(O)c1)N1CCOCC1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc([N+](=O)[O-])c(OCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
The compound ([3]-(32)-587) (0.99 g) prepared in Example 36 was dissolved in dry N,N-dimethylformamide (19 ml), and 50% sodium hydride (0.20 g) was added to the solution. The mixture was stirred at room temperature for 15 minutes. A solution of N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (2.19 g) in N,N-dimethylformamide (6.5 ml) was added to the solution. The mixture was stirred at room temperature for 39 hours. The reaction mixture was added to water (50 ml), and extracted with chloroform (100 ml). The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated to obtain the compound (2.72 g) as a light yellow solid. The product was purified by silica gel column chromatography (Kieselgel 60=190 g, chloroform/ethyl acetate=7/3) to obtain the compound ([3]-(33)-587) (1.41 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+:33]>C(O)C>[CH3:28][Si:2]([CH3:1])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O-:13])=[O:12])=[CH:14][CH:15]=1.[Na+:33]
Reactant: CCCCCCCCCCCC[Si](C)(C)CCCNc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCC[Si](C)(C)CCCNc1ccc(C(=O)[O-])cc1

Procedure:
To a solution of 6.79 g (16.7 mmol) of 4-(4,4-dimethyl-4-sila-hexadecylamino)benzoic acid in 10 ml of ethanol is added an aqueous solution of 1.5 g (17.8 mmol) of sodium bicarbonate (in about 50 ml of water). The mixture is heated to 60° and the resultant clear solution evaporated, under vacuum, to obtain the title product as a white crystalline solid, m.p. above 300°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:34])=[C:4]([C:8]2[N:9]=[C:10]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]3([CH3:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:43]([C:37]3[C:38]([F:42])=[CH:39][CH:40]=[CH:41][C:36]=3[F:35])(=[O:45])=[O:44])[C:3]=2[F:34])[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 5 h
Yield: 81.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (200 mg, 0.397 mmol) in pyridine (2 mL) was added 2,6-difluorobenzenesulfonyl chloride (130 mg, 0.612 mmol) and the reaction mixture was stirred for 5 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extract was dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to obtain the title compound (220 mg). MS (ESI): 680.4 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N1C2C(=CC=CC=2)N=CC=1.[N+]1([O-])C2C(=CC=CC=2)[N+]([O-])=CC=1.C(Cl)(=O)C.O[C@@H:40]1[CH2:44][N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:42]([C:52]([O:54][CH3:55])=[O:53])[CH2:41]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:12][C@H:40]2[CH2:44][N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:42]([C:52]([O:54][CH3:55])=[O:53])[CH2:41]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1nc2ccccc2nc1Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [O-][n+]1cc[n+]([O-])c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3nc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of 3-chloroquinoxalin-2-ol (1.44 g, 7.97 mmol) (Yusuf Ahmad et al., Quinoxaline Derivatives, XI. The Reaction of Quinoxaline 1,4-Dioxide and Some of Its Derivatives with Acetyl Chloride, 38(12) J. ORG. CHEM. 2176 (1973)) and 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.05 g, 8.37 mmol) in THF (190 ml) was cooled to 0° C., then treated with PPh3 (2.51 g, 9.57 mmol). DIAD (1.86 ml, 9.57 mmol) was added dropwise, and the mixture was stirred at 20° C. for 1 hour. After evaporation of the volatiles, the residue was purified on SiO2 (gradient elution, 0-70% EtOAc/petroleum ether) to afford the title compound (2.5 g, 77%). LCMS (ES+) m/z 408 (M+H)+
Reaction SMILES: O[C:2]1([C:21]2[C:30]([OH:31])=[CH:29][C:24]3[C:25]([CH3:28])=[N:26][O:27][C:23]=3[CH:22]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:3]1=[O:20].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[OH:31][C:30]1[C:21]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:3]2=[O:20])=[CH:22][C:23]2[O:27][N:26]=[C:25]([CH3:28])[C:24]=2[CH:29]=1
Reactant: COc1ccc(CN2C(=O)C(O)(c3cc4onc(C)c4cc3O)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)C(c3cc4onc(C)c4cc3O)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 26 h
Yield: 92.4 %

Procedure:
To a stirred suspension of 3-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (0.84 g; 2.0 mmol) in triethylsilane (3.0 mL, 18.7 mmol) was added trifluoroacetic acid (15.0 mL). The reaction mixture was stirred at 50° C. for 26 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to afford 3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (0.74 g, 92%): 1H NMR (300 MHz, CDCl3) δ 7.34-6.80 (m, 10H), 5.29 (s, 1H), 4.87 (ABq, 2H), 3.74 (s, 3H), 2.45 (s, 3H); MS (ES+) m/z 400.9 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[C@H:10]([NH:13]C(OC(C)(C)C)=O)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.Cl.[OH-].[Na+]>O>[NH2:13][C@H:10]([CH2:11][OH:12])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N[C@H](CO)C(=O)NCc1ccccc1
Yield: 73.52 %

Procedure:
To a 500 mL four-neck round bottom flask, 34.0 g (R)-N-benzyl-2-(tert-butoxycarbonylamino)-3-hydroxypropionamide and 350 mL dichloromethane were added, and the mixture was stirred to obtain a clear solution. At 20-25° C., 40.0 g concentrated hydrochloric acid (having a mass concentration of 36.0%) was added, and the reaction was continued. TLC tracking was performed, till the raw materials were completely converted. After the reaction was completed, the temperature was decreased to 20° C. The mixture was suction-filtered, to obtain a white needle-like crystal. The obtained white crystalline solid was dissolved in 50 g water. At 20-25° C., 30% sodium hydroxide solution was added to adjust the pH value of the system to 8-9. After the addition, the solution was stirred continuously, and a white flaky crystal was precipitated. The mixture was suction-filtered, and the filter was washed and dried, to obtain a target product of 16.5 g (0.085 mol). The molar yield was 73.52%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].[CH2:11]([O:13][CH:14]([O:19][CH2:20][CH3:21])[C:15](=[NH:18])OC)[CH3:12]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:15](=[NH:18])[CH:14]([O:19][CH2:20][CH3:21])[O:13][CH2:11][CH3:12]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Cl)cc1Cl
Temperature: 70 °C
Yield: 80.7 %

Procedure:
(2,4-Dichlorophenyl)methanamine (2 g, 11.4 mmol) was added to a solution of methyl 2,2-diethoxyacetimidate (2.04 g, 12.6 mmol) in methanol (10 ml). The mixture was heated at 70° C. for 1 h. The mixture was purified by chromatography (Biotage: 100% ethyl acetate). The desired fractions were concentrated to yield N-(2,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2.8 g, 9.2 mmol, 72.7% yield) as a colorless viscous oil. 1H NMR (500 MHz, DMSO-D6) δ ppm 7.27-7.70 (m, 3H), 4.77 (s, 1H), 4.14-4.35 (m, 2H), 3.45-3.68 (m, 4H), 1.09-1.29 (m, 6H). LC/MS RT=2.03; [M+H]+=304.9.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CN(C=O)C>[CH3:4][C:3]([CH3:6])([CH3:5])[CH:2]([S:15][C:13](=[O:16])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC([O-])=S
Reactant: CC(C)(C)C(Br)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC(c1ccccc1)C(C)(C)C
Temperature: 50 °C
Yield: 99.1 %

Procedure:
(1-Bromo-2,2-dimethyl-propyl)-benzene (1.00 g, 4.40 mmol) was dissolved in dry DMF (5 mL) under an argon atmosphere. Potassium thioacetate (2.51 g, 22.0 mmol) was added and the reaction was heated to 50° C. for 7 days. The solution was then concentrated and the product purified by column chromatography to obtain the desired thioester (970 mg, 99%). TLC (Hexane:CH2Cl2, 7:3 v/v): Rf=0.40. 1H NMR (400 MHz, CDCl3): δ 7.33-7.22 (m, 5H), 4.52 (s, 1H), 2.32 (s, 3H), 1.00 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 193.9 (q), 140.4 (q), 129.0, 127.2, 126.4, 58.7, 34.9 (q), 30.2, 27.6. HRMS (m/z): [M+Na]+ calcd. for C13H18ONaS 245.0976; found, 245.0972.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9].C(N(CC)CC)C>CS(C)=O>[CH:2]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=[O:1]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(CO)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reaction time: 5 h
Yield: 75 %

Procedure:
The product from Example 76D (2.3 g, 4.6 mmol) and triethylamine (4.48 mL, 32.1 mmol) in DMSO (25 mL) was treated with sulfur trioxide pyridine complex (2.92 g, 18.4 mmol). After 5 hours, the mixture was partitioned between ethyl acetate and 1N HCl. The separated organic phase was washed with 1N HCl, brine, and concentrated under reduced pressure. The residue was dissolved in THF (30 mL) and saturated aqueous Na2CO3 solution (30 mL) was added. After stirring vigorously for 1 hour, the separated aqueous layer was acidified and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound as a pale yellow solid (1.73 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[S:21]([C:24]1[N:28]=[CH:27][NH:26][N:25]=1)(=[O:23])=[O:22]>O1CCCC1>[CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[C:8]([O:11][S:21]([C:24]3[N:28]=[CH:27][NH:26][N:25]=3)(=[O:23])=[O:22])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2ccc(O)cc21
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(OS(=O)(=O)c3nc[nH]n3)cc21

Procedure:
5.4 g of 3,3-dimethyl-5-hydroxy-2,3-dihydrobenzofuran was dissolved in 30 ml of tetrahydrofuran, and then 4.6 ml of triethylamine was added while stirring the solution. Then, 5.0 g of 3-chlorosulfonyl-1,2,4-triazole was gradually added while cooling with ice and stirring the solution. Then, this was stirred for 14 hours. Tetrahydrofuran was evaporated, and 2N hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate, and the solvent was removed, so that coarse crystals were obtained. This was then recrystallized from n-hexane/ethyl acetate, so that 2.7 g of the titled compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[OH:19][CH2:18][C:14]1[CH2:15][CH2:16][O:17][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:21][C:12]=2[CH:13]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(CO)CCO3)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
Into a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (841 mg) and triethylamine (0.42 ml) in THF (15 ml) was added dropwise at −5° C. a solution of ethyl chloroformate (0.29 ml)/THF (2 ml). The resulting mixture was stirred at −5° C. for 30 minutes, and an insoluble material was removed by filtration. Into the filtrate was added dropwise under ice cooling a solution of sodium borohydride (284 mg)/water (6 ml). After stirring at room temperature for 1.5 hours, the reaction mixture was mixed with 1 N hydrochloric acid and was extracted with ethyl acetate. The extract was washed successively with water, a 1 N aqueous solution of sodium hydroxide, water and an aqueous solution of sodium chloride, was dried (anhydrous magnesium sulfate) and was then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/diethyl ether/hexane to obtain 4-hydroxymethyl-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine (708 mg) as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH:26]([CH3:28])[CH3:27])[C:22]4=[O:29])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH:26]([CH3:27])[CH3:28])[C:22]4=[O:29])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C)c4=O)cc3)CC2)cc1
Agent: Br
Solvent: O
Product: CC(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 86 %

Procedure:
A mixture of 4.7 parts of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylethyl)-3H-1,2,4-triazol-3-one and 75 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 3 hours. The reaction mixture was evaporated and the residue was dissolved in a mixture of methanol and water. The whole was neutralized with a sodium hydrogen carbonate solution and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was triturated in 2-propanol, yielding 3.9 parts (86%) of 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylethyl)-3H-1,2,4-triazol-3-one, mp. 208.4° C. (intermediate 10).
Reaction SMILES: [CH2:1]([SiH:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:26]=[CH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:18]([Si:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC[SiH](CCCCCCCC)CCCCCCCC
Reactant: C=CCCCCCC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](CCCCCCCC)(CCCCCCCC)CCCCCCCC

Procedure:
A mixture of 2.0 grams trioctylsilane and 10 grams 1-octene in 5 milliliters of toluene was reacted for 2 hours at 75°-80° C. in the presence of 0.009 gram of chlorotris(triphenylphosphine)rhodium(I) to yield 80 weight percent tetraoctylsilane.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[N:6]([CH:21]([CH3:23])[CH3:22])[C:5]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(C)(C)O2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)N(C(C)C)C(=O)C(C)(C)O2
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a solution of 2,2-dimethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.0 g) in dimethylformamide (60 ml) were added 60% sodium hydride (in oil) (0.61 g) and 2-iodopropane (2.38 g) and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 2,2-dimethyl-6-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C=O)C>[CH3:15][Si:13]([CH3:16])([CH3:14])[CH2:12][CH2:11][O:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([NH:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:3]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=1
Reactant: COC(=O)CBr
Reactant: C[Si](C)(C)CCOC(=O)COc1ccc(N)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-trimethylsilanylethyl (4-amino-3-benzyloxyphenoxy)acetate (4.56 g, 12.2 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in DMF (25 mL) is added methyl bromoacetate (1.87 g, 12.2 mmol). The mixture is stirred at 60° C. for 1 h then is allowed to cool to RT. It is poured into water and extracted with EtOAc and the organic phase is washed with water (1×), brine (5×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.