Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]([CH2:15][C:16](OCC)=[O:17])(=O)[CH2:11][CH2:12][CH3:13].FC(F)(F)S(O)(=O)=O>O>[OH:2][C:1]1[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]2[C:3]=1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:15][C:16](=[O:17])[O:5]2
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Oc1cc(O)cc(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: CCCc1cc(=O)oc2cc(O)cc(O)c12
Temperature: 0 °C
Yield: 99.1 %

Procedure:
A suspension of anhydrous phloroglucinol (20.0 g, 0.159 mol) in ethyl butrylacetate (26.3 g; 0.167 mol) was added over 30 min to 50 g of constantly stirred trifluoromethanesulfonic acid cooled in an ice bath. A drying tube was then fined to the reaction vessel and the mixture was stirred for 16h at 25° C., after which the resulting thick paste was combined with ice (200 g) and water (300 mL) with brisk stirring. After 30 min the solid material was collected by vacuum filtration and recrystallised from 95% ethanol to yield coumarin 15 (34.7 g; 99%) as lemon yellow crystals. mp 236°-238° C. 1H NMR (CDCl3 /CD3OD 3:1): δ6.13(1H, d; J =2.3 Hz), 6.04(1H, d; J=2.3 Hz), 5.68(1H, s), 2.76(2H, t; J=7.4 Hz), 1.47(2H, tq; J =7.7, 7.4 Hz), 0.82(3H, t; J =7.7 Hz). 13C NMR (CDCl3 /CD3OD 3:1): δ163.1, 160.7, 160.6, 157.3, 156.7, 107.8, 102.5, 99.2, 95.0, 37.7, 22.5, 13.4. Anal. calc. for C12H12O4.(H2O): C, 60.50; H, 5.92. Found: C, 60.47; H, 5.92.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([CH3:47])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([CH3:47])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccc(OC)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.5 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-methoxy-3-methylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.31 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.67 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.96 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:15][CH2:14]3)[N:7]=2)[CH:3]=1.[CH3:16][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:12])[CH3:16])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:14][CH2:15]3)[N:7]=2)[CH:3]=1
Reactant: O=Cc1cc(Cl)cc2cn(C3CC3)nc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 0 °C

Procedure:
To a solution of 5-chloro-2-cyclopropyl-2H-indazole-7-carbaldehyde (0.30 g, 1.35 mmol) in tetrahydrofuran (5 mL) at −78° C. was added methyl magnesiumbromide (3 M in diethyl ether, 0.68 mL, 2.03 mmol). The reaction was allowed to gradually warm in the ice bath (ca. 1 h) to 0° C. The reaction which had been a suspension became a solution. The reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The ethereal was washed with water (2×), then brine, dried over sodium sulfate, and concentrated to give 240 mg (77%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 7.90 (s, 1H), 7.45 (m, 1H), 7.09 (m, 1H), 5.27 (q, J=6.6 Hz, 1H), 3.85-3.93 (m, 1H), 1.65 (d, J=6.6 Hz, 1H), 1.28-1.34 (m, 2H), 1.10-1.17 (m, 2H). Mass spec.: 237.28 (MH)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)[CH3:2].[O-:16][C:17]#[N:18].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:17]([NH2:18])=[O:16])[CH:10]=1)[CH3:2]
Reactant: N#C[O-]
Reactant: CCn1cccc1Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cccc1Cc1cccc(NC(N)=O)c1
Reaction time: 72 h
Yield: 65.2 %

Procedure:
1-Ethyl-2-(3'-aminobenzyl)pyrrole 5.6 g (28 mmol) was dissolved in a mixture of 500 ml of methylene chloride and 100 ml methanol; 3.92 g (60 mmol) of sodium cyanate were added to the solution and thereafter, in a dropwise fashion and at room temperature, 4.6 ml (59 mmol) of trifluoroacetic acid in 100 ml of methylene chloride. When the addition was completed, the resulting mixture was stirred for 72 hours, 10 g (90 mmol) of sodium carbonate were added thereto, the mixture stirred for 15 minutes and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on 300 g of silica gel, using methylene chloride-acetone (85:15) as eluant, to produce 4.44 g (65%) of the title compound, 1-ethyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)=[O:5])[CH3:2].CN(C=O)C.[H-].[Na+].I[CH:21]([CH2:23][CH3:24])[CH3:22]>O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH:21]([CH2:23][CH3:24])[CH3:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCC(C)I
Reactant: CCOC(=O)c1cccc(S)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(SC(C)CC)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
6-Mercapto-pyridine-2-carboxylic acid ethyl ester (0.25 g, 1.3 mmol) was added with DMF (7 mL), and the mixture was cooled to 0° C. NaH (0.065 g, 1.56 mmol) was added thereto, and the mixture was stirred for 30 minutes. 2-Iodobutane (0.2 mL, 1.56 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reactant was added with water and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and purified by column chromatography to obtain the title compound (0.17 g, 52%).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33]>C(Cl)Cl>[F:30][C:31]([F:38])([F:37])[C:32]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)=[O:33]
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Reactant: CCOC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.199 mmol, 62.1 mg) and triethylamine (0.399 mmol, 0.056 mL, 40.4 mg) in DCM (1.2 mL) was added a solution of ethyl 2,2,2-trifluoroacetate (0.199 mmol, 0.024 mL, 28.3 mg) and the whole stirred at room temperature for 60 h. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give a clear film (30.0 mg, 0.074 mmol, 36.9%). MS (ESI): m/z [M+H]+ 408.0.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[C:23]([O:27][C:28]([NH:30][C:31]([CH3:38])([CH3:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[CH3:39][NH:40][C@H:41]([CH2:64][C:65]1[CH:74]=[CH:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=1)[C:42]([N:44]([CH3:63])[C@@H:45]([C:57]1[O:61][N:60]=[C:59]([CH3:62])[N:58]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)=[O:43].FC(F)(F)C(O)=O.C(N(CC)CC)C>CN(C)C=O>[C:23]([O:27][C:28](=[O:29])[NH:30][C:31]([CH3:38])([CH3:37])/[CH:32]=[CH:33]/[C:34](=[O:36])[N:40]([C@@H:41]([C:42](=[O:43])[N:44]([CH3:63])[C@@H:45]([C:57]1[O:61][N:60]=[C:59]([CH3:62])[N:58]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)[CH2:64][C:65]1[CH:74]=[CH:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=1)[CH3:39])([CH3:24])([CH3:25])[CH3:26]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccc2ccccc2c1)c1nc(C)no1
Reactant: CC(C)(/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)/C=C/C(C)(C)NC(=O)OC(C)(C)C)n1

Procedure:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.31 g, 1.6 mmol) and 1-hydroxy-7-azabenzotriazole (0.22 g, 1.6 mmol) were added to a solution of (2E)-4-tertbutoxycarbonylamino-4-methylpent-2-enoic acid (0.37 g, 1.6 mmol) in N,N-dimethylformamide (5 ml). After 30 min at 20° C. a mixture of (2R)-2-methylamino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid (0.68 g, 1.2 mmol) and triethylamine (0.12 g, 1.2 mmol) in N,N-dimethylformamide (5 ml) were added. After 18 h at 20° C. the reaction mixture was poured on water (80 ml) and extracted several times with ethyl acetate (total 55 ml). The organic phases were collected and washed with aqueous citric acid (10%, 15 ml), a saturated solution of sodium hydrogencarbonate (3×15 ml) and water (3×15 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo and chromatographed on silica gel (80 g) using heptane and ethyl acetate (3:7) as eluent to give 0.75 g of {(2E)-1,1-dimethyl-3-[N-((1R)-1-{N-methyl-N-{(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl}carbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]allyl}carbamic acid tertbutyl ester.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:14][C:15]([N:18]1[C:22]([NH2:23])=[CH:21][C:20]([CH3:24])=[N:19]1)([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:21]3[C:20]([CH3:24])=[N:19][N:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:22]=3[N:23]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)(C)C
Reaction time: 3 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 33 using ethyl 4-cyclopropyl-2,4-dioxobutanoate (481 mg, 2.61 mmol), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (400 mg, 2.61 mmol), and toluene (20 mL), wherein the reaction time was 3 h. The crude product was purified via silica gel chromatography (eluent: 0 to 10% EtOAc:Hex). The final product was collected as 0.24 g (30%). LCMS E-S (M+H)=302.5. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.23 (m, 4 H) 1.47 (t, J=7.20 Hz, 3 H) 1.79 (s, 9 H) 2.19 (s, 1 H) 2.66 (s, 3 H) 4.49 (q, J=7.07 Hz, 2 H) 7.44 (s, 1 H).
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:34]=[C:33]([CH3:35])[C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([OH:32])=[C:22]([CH:31]=2)[C:23]([N:25]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH3:26])=[O:24])=[C:15]([CH3:36])[CH:14]=1)=[O:11])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:27]1([N:25]([CH3:26])[C:23](=[O:24])[C:22]2[CH:31]=[C:18]([O:17][C:16]3[C:15]([CH3:36])=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])=[CH:34][C:33]=3[CH3:35])[CH:19]=[CH:20][C:21]=2[OH:32])[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cc(NC(=O)COCc2ccccc2)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)CO)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Reaction time: 2 h

Procedure:
To a solution of 5-[4-(2-benzyloxy-acetylamino)-2,6-dimethyl-phenoxy]-N-cyclobutyl-2-hydroxy-N-methyl-benzamide (50 mg) in EtOAc (2.0 mL) was added catalyst 10% Pd/C (10 mg). The reaction mixture was hydrogenated under 50 psi at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated to give the title compound of Step B and Example 9 (40 mg) as a white solid. MS (APCI−) Calc.: 398.2, Found: 397.2 (M−1).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.N[C@@H:31]1[CH2:36][CH2:35][C:34]2[C:37]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[CH:38][CH:39]=[C:40]([C:41](=[O:43])[NH2:42])[C:33]=2[O:32]1>CN(C)C=O>[C:41]([C:40]1[C:33]2[O:32][CH2:31][C@@H:36]([NH:20][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:17][CH:16]=3)[CH2:35][C:34]=2[C:37]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[CH:38][CH:39]=1)(=[O:43])[NH2:42]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(c2ccc(C(N)=O)c3c2CC[C@@H](N)O3)CC1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(N)=O)c3c2C[C@H](NC(=O)c2ccc(C(=O)c4ccccc4)cc2)CO3)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
4-Benzoylbenzoic acid (95 mg, 0.42 mmol) and 1,1′-carbonyldiimidazole (71 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 75° C. for 1 h. The reaction mixture was cooled to room temperature and a solution of (S)-2-amino-8-carbamoyl-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (120 mg, 0.40 mmol) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was stirred at room temperature for 4 days and the solvent was evaporated in vacuo giving 290 mg of a crude product. Purification by preparative TLC on silica using chloroform/ethanol (saturated with ammonia) (15:1) as the eluent afforded 75 mg (38% yield) of the title compound: mp 259° C. (dec); EIMS (70 eV) m/z (relative intensity) 498 (38, M+); [α]21D−3° (c 0.1, chloroform).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:12][C:11]1[C:4]2[N:3]=[C:2]([O:27][C:20]3[C:21]([CH3:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=3[Cl:18])[N:6]([CH3:7])[C:5]=2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(C)c12
Reactant: Cc1cc(Cl)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 100 °C
Yield: 63.7 %

Procedure:
A solution of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (5.5 g, 20.2 mmol), 2,4-dichloro-6-methylphenol (10 g, 56.5 mmol) and potassium carbonate (8.4 g, 60.8 mmol) in N,N-dimethylformamide (55 mL) was heated at 100° C. for 9 h. To the mixture was added 2,4-dichloro-6-methylphenol (5 g, 28.3 mmol) and potassium carbonate (4.2 g, 30.4 mmol) and heated at 100° C. for 16 h. Additional 2,4-dichloro-6-methylphenol (5 g, 28.3 mmol) and potassium carbonate (4.2 g, 30.4 mmol) were added and heated at 100° C. for 9 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH silica gel eluting with a 12.5% ethyl acetate/n-hexane. The resulting solids were recrystallized from a 10% ethyl acetate/n-hexane to give 5.3 g (64%) of the title compound as a colorless crystal.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[O:12])[CH2:7][CH2:6]1.O.[OH-].[Na+]>C1COCC1.ClCCl>[O:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[C:11]([N:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]2[CH2:2][O:18]2)[CH2:6][CH2:7]1)=[O:12]
Reactant: O=C([C@H]1CCCO1)N1CCN(C[C@H](O)CCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C([C@H]1CCCO1)N1CCN(C[C@H]2CO2)CC1
Reaction time: 1 h

Procedure:
To a cold solution of (S)-1-chloro-3-(4-[(R)-tetrahydro-2-furoyl]-1-piperazinyl)-2-propanol (2.4 g, 8.67 mmol) in THF (25 mL) in an ice bath was added water (7 mL), and then sodium hydroxide (0.416 g, 10.41 mmol) as solid pellets. The mixture was stirred vigorously at the same temperature for 1 h, and diluted with dichloromethane (200 mL). The mixture was washed with 1M sodium hydroxide and brine solution, then dried and concentrated, to provide the title intermediate.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH3:40])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2([OH:30])[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C@H:9]([CH3:40])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2([OH:30])[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](N)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((tert-butoxycarbonyl)amino)propanoate in EtOAc (3 mL) was added HCl (4 M in EtOAc, 3 mL) in drops at 0° C. The resulting mixture was warmed to rt after 30 min and stirred for 2 h. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (20 mL×3). The organic layer was washed with H2O (10 mL×4) and then dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was then purified via Prep-TLC (CH2Cl2: MeOH=10:1) to afford the (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-aminopropanoate (8 mg, 43% yield) as a white solid. LRMS (M+H+) m/z 458.5. 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.17 (d, J=9.6 Hz, 1H), 5.02 (m, 1H), 3.54 (m, 1H), 2.43-2.48 (m, 1H), 1.08-2.15 (m, 24H), 0.88 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2].N([O-])=[O:14].[Na+].NC(N)=O>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:14])=[CH:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1ccc(N)cc1Cl
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(C)c1ccc(O)cc1Cl
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
4-tert-Butyl-3-chloroaniline (690 mg, 3.8 mmol) was dissolved in 12 M sulfuric acid (30 ml) and then heated at 90° C. To the clear solution was added 5 ml of aqueous solution of sodium nitrite (776 mg, 11.3 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 15 minutes. Urea was added to the mixture until excess sodium nitrite was destroyed (by checking starch-iodine test paper). A small amount of cupric sulfate was added to the mixture and then the mixture was stirred at 90° C. for 30 minutes. The resulting organic layer was extracted with ethyl acetate washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=¼ to furnish 0.44 g (64% yield) of the title compound as a brown oil.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][CH2:23][S:24][CH3:25])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH2:26].[OH:27]O>C(O)(=O)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][CH2:23][S:24]([CH3:25])(=[O:27])=[O:26])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: OO
Reactant: CSCCC(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Reactant: O
Solvent: CC(=O)O
Product: CS(=O)(=O)CCC(CC(=O)O)NC(=O)CCCCc1ccc(C=NN)cc1
Reaction time: 48 h

Procedure:
(±)-3-[[5-[4-(Aminoiminomethyl)phenyl]-1oxopentyl]amino]-5-(methylthio)pentanoic acid (2.5 g) was added to water (15 ml) and acetic acid (5 ml) and 30% H2O2 (10 ml) . The oxidation was allowed to proceed for 48 hours after which the reaction mixture was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.51 (m, 4H), 1.56 (m, 2H), 2.0 (m, 2H), 2.10 (s, 3H), 2.90 (m, 4H), 2.71 (m, 2H), 4.10 (m, 1H), 7.35 (m, 9H), 7.7 (bd, 1H, J=7.9 Hz), 9.10 (bs, 2H), 9.25 (bs, 2H); MS (FAB) m/e 398.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([CH3:19])=[CH:21][CH:22]=1)=[O:3]
Reactant: Cc1ccc(CO)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: Cc1ccc(COC(=O)N2[C@H](C)CNC[C@@H]2C)cc1
Product: Cl

Procedure:
4-Methylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 4-methylbenzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a white solid (0.2614 g, 87% overall); λmax (diffuse reflectance)/cm−1 2749, 2656, 2541, 1697, 1594, 1518, 1330, and 1112; δH (400 MHz, DMSO-d6) 10.05 (1H, br), 9.32 (1H, br), 7.26 (2H, d, J 8.0 Hz), 7.18 (2H, d, J 8.0 Hz), 5.07 (2H, s), 4.30 (2H, m), 3.14 (2H, d, J 12.8 Hz), 3.05 (2H, m), 2.30 (3H, s), and 1.30 (6H, d, J 7.2 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:7]2[CH:13]=[N:12][CH:11]=[C:8]2[S:9][CH:10]=1.C(N(CC)CC)C.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>CN(C=O)C>[NH2:22][S:21]([N:4]([CH2:5][C:6]1[N:7]2[CH:13]=[N:12][CH:11]=[C:8]2[S:9][CH:10]=1)[CH2:3][CH2:2][OH:1])(=[O:24])=[O:23]
Reactant: NS(=O)(=O)Cl
Reactant: OCCNCc1csc2cncn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)N(CCO)Cc1csc2cncn12
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A 410 mg potion of 3-[N-(2-hydroxyethyl)amino]methyl imidazo[5,1-b]thiazole was dissolved in 6 ml of DMF, and 1.40 ml of triethylamine and 491 mg of sulfamoyl chloride were added thereto at -30° C., followed by stirring at -30 to -20° C. for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in water, adjusted to pH 7.5 with an aqueous sodium hydrogencarbonate solution, and then purified by Diaion HP-20 Resin and Cephadex LH-20, whereby 59 mg of 3-[N-aminosulfonyl-N-(2-hydroxyethyl)amino]methylimidazo[5,1-b]thiazole was obtained from the first half of the fraction of Cephadex LH-20.