Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:23]2[C:14](=[CH:15][C:16]3[O:21][CH2:20][CH2:19][O:18][C:17]=3[CH:22]=2)[O:13][CH2:12]1.[NH:24]1[C:32]2[C:27](=CC=C[CH:31]=2)[C:26]2([C:36]3=[CH:37]C4OCOC=4C=C3OC2)C1=O.Br.BrCC1C=CC=CN=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:31][C:32]1[CH:27]=[CH:26][CH:36]=[CH:37][N:24]=1)[C:8](=[O:11])[C:7]12[C:23]2=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=[C:14]2[O:13][CH2:12]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Product: O=C1N(Cc2ccccn2)c2c(F)cccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 7′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (38%) as a colorless solid: mp 205-207° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ8.55 (d, J=4.8 Hz, 1H), 7.69-7.63 (m, 1H), 7.23-7.16 (m, 2H), 6.99-6.89 (m, 3H), 6.50 (s, 2H), 5.35 (d, J=16.4 Hz, 1H), 5.17 (d, J=16.4 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.22-4.19 (m, 2H), 4.15-4.13 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.5, 155.7, 155.1, 149.6, 144.7, 138.4, 136.7, 124.0, 124.0, 122.4, 121.0, 120.7, 119.7, 119.6, 116.7, 116.5, 112.1, 99.3, 80.3, 64.5, 63.9, 58.4, 47.0; MS (ES+) m/z 405.0 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[NH2:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:36])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29](C=O)=[CH:28][C:27]=1[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:7])([CH3:6])[CH3:5]>N1C=CC=CC=1.O>[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[NH2:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:36])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29](=[N:2][OH:3])[CH2:28][C:27]=1[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:5])([CH3:7])[CH3:6]
Reactant: NO
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)C1=C(OC)CC(=NO)C=C1
Reaction time: 0.33 h

Procedure:
137 mg (1.97 mmol) of hydroxylamine hydrochloride were added to a solution of 398 mg (0.879 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Example 110) in 5 ml of pyridine, and the resulting mixture was stirred for 20 minutes. At the end of this time, the reaction mixture was diluted with water, and the diluted aqueous mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. In order to remove the pyridine remaining in the residue, it was dissolved in toluene and the solvent was azeotropically distilled off. Repetition of this procedure gave 414 mg (a quantitative yield) of the title compound as a foam-like substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[N-:15]=[C:16]=[S:17].[K+].BrBr.O>C(O)(=O)C>[NH2:15][C:16]1[S:17][C:7]2[CH:6]=[C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: [N-]=C=S
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)c1ccc2nc(N)sc2c1
Yield: 48.4 %

Procedure:
The said starting material was also prepared by dissolving 154.6 g of ethyl 2-(p-aminophenyl)propionate [Arzneim. Forsch, Vol. 23, p. 1090 (1973)] in 95% acetic acid and 261 g of potassium isothiocyanate were added with stirring. A solution of 149.4 g of Br2 in 750 ml of 95% acetic acid was then added dropwise at 18°-25° C. over 2 hours and the mixture was stirred for an extra half hour, then poured into 8 liters of water. The mixture was filtered through celite and then neutralized to pH 5-6 using 6+ liters of 20% Na2CO3 solution. The product was then extracted with CH2Cl2 and the organic layer was separated, washed with water, dried over MgSO4 and finally filtered and evaporated to dryness. The crude product was dissolved in 300 ml of hot ethyl acetate and an equal volume of petroleum ether (40°-60° C.) was added. On cooling, cream colored crystals were formed which were filtered off, washed with ethyl acetate/petroleum ether and dried to obtain 97 g (48.5% yield) of the ethyl 2-amino-α-methylbenzothiazole-6-acetate melting at 146° C. A second crop of 29 g was obtained from the mother liquors for a total yield 63%.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-])=O)[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCOC(C)=O.CCO.[Pt]=O>[NH2:35][C:31]1[CH:30]=[C:29]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:1])([CH3:38])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])[CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Yield: 107.1 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{(3-nitro-phenyl)methoxy}ethoxy]hexyl}-1,3-oxazolidin-2-one (9.50 g) in EtOAc (120 ml) and EtOH (120 ml) was hydrogentated over platinum oxide (0.20 g) for 1.75 h. The mixture was filtered through celite and washed with EtOH. Solvent evaporation in vacuo gave the title compound (9.60 g). LCMS RT=3.25 min, ES+ve 499 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[S:19]>CN(C)C=O>[CH3:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CNC(=S)Nc1ccc(C2=NNC(=O)NC2C)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2 g) and methylisothiocyanate (0.788 g) in dimethylformamide (20 ml) was heated with stirring at 110° C. for 4 hours, followed by after-treatment in the same manner as Example 8 to give 6-[4-(3-methyl-thioureido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.7 g).
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.Cl[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][S:53][CH2:52][CH2:51]1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][S:53][CH2:52][CH2:51]1)[CH2:23][CH2:22]2
Reactant: ClCCN1CCSCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCSCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(2-chloroethyl)thiomorpholine hydrochloride (prepared as describe in WO 2009058859) as the alkylating reagent in Step 1. The product was isolated as a white solid (3 mg, 0.85%). LCMS: m/e 659.37 (M+H)+, 2.38 min (method 13). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 5.32-5.19 (m, 1H), 4.77 (s, 1H), 4.65 (s, 1H), 3.11-2.98 (m, 1H), 2.89 (m, 5H), 2.75 (m, 5H), 2.67-2.57 (m, 1H), 2.31-2.16 (m, 1H), 2.14-1.85 (m, 6H), 1.71 (s, 7H), 1.59-1.40 (m, 6H), 1.38-1.15 (m, 8H), 1.08-0.96 (m, 10H), 0.94 (s, 3H)
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:18]1[CH2:17][CH:16]1[CH2:14][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: BrCC1CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Yield: 76.9 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (6.2 g, 33.29 mmol), epibromohydrin (5.4 g, 39.42 mmol) and potassium carbonate (5.5 g, 39.79 mmol) in acetonitrile (70 ml) was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to afford tert-butyl 4-oxiranylmethylpiperazine-1-carboxylate (6.2 g, yield 77%) as a colorless oil.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([C:36]4[N:37]=[C:38]([C@@H:41]5[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]5C(OC(C)(C)C)=O)[NH:39][CH:40]=4)=[CH:32][CH:31]=2)[CH:24]=[CH:23]3)[N:19]=1)=O)(C)(C)C>O1CCOCC1.CO>[CH3:46][C@@H:44]1[CH2:43][NH:42][C@H:41]([C:38]2[NH:39][CH:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:18]6[N:19]=[C:15]([C@@H:10]7[CH2:11][C@H:12]([CH3:14])[CH2:13][NH:9]7)[NH:16][CH:17]=6)[CH:21]=5)[CH:26]=4)=[CH:31][CH:32]=3)[N:37]=2)[CH2:45]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@H](C)CN7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@H](C)CN7)n6)ccc5c4)cc3)c[nH]2)C1
Reaction time: 2 h

Procedure:
A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl (2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate (200 mg. 0.285 mmol) in MeOH (5 mL) and stirred at ambient conditions for 2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 185 mg). LC-MS retention time 2.64 min; calcd. for C32H35N6: 503.29 m/z Found 503.20 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:23]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:24]([C:28](ON1C(=O)CCC1=O)=[O:29])[CH:25]([CH3:27])[CH3:26].CCN(CC)CC>CN(C=O)C>[NH:23]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C@H:24]([C:28]([NH:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:29])[CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1

Procedure:
H-Thr(Bzl)-OBzl hemioxalate (58 g, 168.4 mmol) was suspended in DMF (700 ml) and stirred with Boc-Val-OSu (48 g, 153.1 mmol) and Et3N (16 ml) at 0° C for 1 hr, 4° C for 72 hrs and 25° C for 24 hrs. It was necessary during this time to add at intervals additional Et3N in order to maintain the pH between 7 and 8. The reaction mixture was worked up as in Example 2 to yield an oil which crystallized from EtOAc with petroleum ether, yield 40.8 g (53.5%); mp 99°-100.5° C; [α]D25 -26.0° (c 1, MeOH). Anal. Calcd for C28H38N2O6 (498.62): C, 67.45; H, 7.68; N, 5.62. Found: C, 67.57; H, 7.55; N, 5.70.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([NH:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:13]2)=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:47][O:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][O:50]1>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]3([NH:22][C:21](=[O:23])[C:20]4[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30]([NH:47][O:48][CH:49]5[CH2:54][CH2:53][CH2:52][CH2:51][O:50]5)=[O:31])[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CCCC3(C2)NC(=O)c2cc(/C=C/C(=O)O)ccc2O3)c2ccccc21
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1cc(CN2CCCC3(C2)NC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)c2ccccc21

Procedure:
A suspension of (±)-(E)-3-{1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (150 mg, 0.348 mmol) in DCM (4 ml) was treated with TEA (0.070 ml, 0.52 mmol) and then with EDC (99 mg, 0.52 mmol), HOBt (70 mg, 0.52 mmol) and NH2OTHP (49 mg, 0.42 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)acrylamide as a white solid [LC-MS: (ES+) MH+: 531]. The solid was suspended in DCM (5 ml) and treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C to give, after purification by preparative HPLC, (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl]-N-hyroxy-acrylamide (40 mg, trifluoroacetic salt) as a brown solid.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH2:1]([NH:7][C:28]([C:17]1[N:18]([CH3:27])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: CCCCCCNC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 9, Step B, but using hexylamine (0.020 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].Cl>O.C(Cl)Cl>[OH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccccc2)c(O)c1
Reaction time: 24 h

Procedure:
To a 1,000-mL, three-neck, nitrogen-purged flask was added 26.5 g (0.21 mole) of 3-methoxyphenol, 215 mL of methylene chloride, 32 g (0.24 mole) of aluminum chloride and 32 mL (0.26 mole) of phenyl chloroformate. This mixture was heated to reflux. After 24 hours, the mixture was cooled to 20°-30° C. and 400 mL of water and 32 mL of 37% hydrochloric acid were added. The layers were separated and the organic layer washed with two 100-mL portions of 5N hydrochloric acid. The organic layer was dried with anhydrous magnesium sulfate, filtered, then the solvent stripped off under vacuum. The crude product was recrystallized from heptane. The yield of phenyl 2-hydroxy-4-methoxybenzoate (white, m.p. 61.5°-62.5° C.) obtained was 49%.
Reaction SMILES: [C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:24])[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3ccccc31)CCN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a stirred solution of 2-benzoyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (3.0 g, 10.9 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (0.52 g, 13.1 mmole). After 10 min, methyliodide (7.80 g, 55 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (50 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (3.14 g, 99%) as a white solid: MS (ES) m/e 291 (M+H)+.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][OH:12])=[N:8][CH:7]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:9]1[S:10][C:6]([CH2:5][O:4][CH3:3])=[CH:7][N:8]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1cnc(CO)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1cnc(COS(C)(=O)=O)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-(methoxymethyl)thiazol-2-yl)methanol (201 mg, 1.26 mmol) in dry CH2Cl2 (10.0 mL) was treated at 0° C. with Et3N (0.23 mL, 1.63 mmol) followed by DMAP (15.6 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.59 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (10 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 300 mg of crude (5-(methoxymethyl)thiazol-2-yl)methyl methanesulfonate as an orange oil. LC-MS-conditions 07: tR=0.59 min, [M+H]+=238.07. A solution of this crude material (300 mg) in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (1.50 g of a 9.6% solution in DMF, 1.26 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.43 mL, 2.53 mmol) and the reaction mixture was stirred for 24 h at 50° C. Water (10 mL), followed by EA (10 mL) was added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.29. LC-MS-conditions 07: tR=0.70 min, [M+H]+=255.85.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15]O)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(NCCCO)c(=O)c1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOc1c(NCCCS(=O)(=O)c2ccccc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A solution of 1-butoxy-2-(3-hydroxypropylamino)-1-cyclobutene-3,4-dione [prepared in Example 7] (1.14 g, 5.0 mmol) and pyridine (0.65 mL, 8.0 mmol) in 6.0 mL of dichloromethane cooled to 0° C. was treated dropwise with benzenesulfonyl chloride (0.65 mL, 5.1 mmol). The mixture was stirred at ambient temperature for 3 hours, then washed with water (4 times), dried and evaporated under reduced pressure to give 1.53 g (83% yield) of title compound which was used without purification in the subsequent reaction.
Reaction SMILES: [CH2:1]([CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]([OH:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].[CH3:35]O>S(=O)(=O)(O)O>[CH2:19]([CH:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:16]([O:18][CH3:35])=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)C(=O)OC
Temperature: 55 °C
Reaction time: 24 h

Procedure:
144 mg of 2-(tetradecyl)hexadecanoic acid was dissolved in 25 ml of methanol. After the addition of a few drops of concentrated sulfuric acid, the solution was stirred at 55° C. for one day, neutralized with 10% sodium hydroxide and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:50) to obtain methyl 2-(tetradecyl)hexadecanoate.