Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([C:18]#[N:19])(=[O:17])[O:14][CH2:15][CH3:16].Cl.C(=O)([O-])O.[Na+]>CC(O)=O.O>[NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:6])[NH:19][C:18]([C:13]([O:14][CH2:15][CH3:16])=[O:17])=[N:1]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C#N
Agent: COC(=O)c1ccc(Br)cc1N
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc2cc(Br)ccc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 115.7 %

Procedure:
Methyl 2-amino-4-bromobenzoate was prepared from the corresponding acid by Fischer esterification. A mixture of methyl 2-amino-4-bromobenzoate (1.1 g, 4.8 mmol) and ethyl carbonocyanidate (0.95 g, 9.66 mmol) in HOAc (4 mL) was treated with a s12 N HCl (0.4 mL) and the resulting mixture was stirred at 70° C. for 3 h. After cooling to rt, water was added followed by addition of aq sodium hydrogen carbonate to pH ˜5. The precipitated solid was filtered and washed thoroughly with water and diethyl ether to afford ethyl 7-bromo-4-oxo-3,4-dihydroquinazoline-2-carboxylate (825 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.06-8.09 (m, 2H), 7.81 (d, J=8.4 Hz, 1H), 4.38 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H); LC-MS (ESI) m/z 296 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[NH:6]C(=O)C)C>Cl>[N:17]1[C:18]2[C:13](=[CH:12][C:11]([CH2:10][CH:5]([C:4]([OH:21])=[O:3])[NH2:6])=[CH:20][CH:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(Cc1ccc2ncccc2c1)NC(C)=O
Agent: Cl
Product: NC(Cc1ccc2ncccc2c1)C(=O)O
Reaction time: 20 h

Procedure:
N-Acetyl β-(6-quinolinyl)-D,L-alanine ethyl ester (728 mg, 2.55 mmol) was heated at reflux in 6N HCl (20 mL). After 20 h, the reaction mixture was concentrated to dryness and the residue was dried in vacuo to provide the title compound, which was used directly in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:18])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:19]S([O-])=O.[Na+].[Na+].CCOC(C)=O.C(Cl)Cl>C(O)(C)(C)C.O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:18])=[CH:15][N:16]=2)[C:11](=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)c2cc(Br)cnc21
Temperature: 50 °C

Procedure:
A mixture of 6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (2.16 g, 6.90 mmol) and NaH2PO4 (2.38 g, 17.2 mmol) in t-butanol and water (1:1 mixture, 300 mL) is heated to 50° C. and NaMnO4 (11.4 g, 32.2 mmol) solution (aq.) is added. The mixture is heated for 2 hrs. The reaction mixture is cooled and solid Na2SO3 is added until the purple color disappears. 50 mL of EtOAc and 50 mL of water are added and the mixture is filtered through diatomaceous earth to remove the black solid. The aqueous layer of the filtrate is separated and extracted with 2×100 mL of EtOAc. The organic layers are combined dried with MgSO4 and concentrated to give the crude product. The product is dissolved into CH2Cl2 and purified via silica chromatography to give 1.09 g 6-bromo-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:14])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4]
Reactant: CC(C)CBr
Reactant: CC=CCC1Cc2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC=CCC1Cc2ccc(OCC(C)C)cc2C1=O
Yield: 93 %

Procedure:
A solution of 4.74 g of (RS)-2-(2-buten-1-yl)-6-hydroxy-1-indanone, 5.18 ml of isobutyl bromide and 5.98 g of potassium carbonate in 40 ml of N,N-dimethylformamide was heated to 60° for 48 hours. After cooling, the solution was poured into 100 ml of water and extracted twice with 70 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. 5.2 g (93%) of (RS)-2-(2-buten-1-yl)-6-isobutoxy-1-indanone were obtained as a red-brown oil which was used directly in the next reaction.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:9][NH:10][C:11](=[O:22])[C@H:12]([NH:14]C(OC(C)(C)C)=O)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(O)(C(F)(F)F)=O>ClCCl>[NH2:14][C@@H:12]([C:11]([NH:10][CH2:9][C@@H:8]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[CH3:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of benzyl [(1S)-1-benzyl-2-({(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl}amino)ethyl]carbamate (1.43 g, 3.14 mmol) from preparation 1 in dichloromethane (30 mL) and methanol (2 mL) was added TFA (20 ml) at 0° C. The reaction mixture was stirred for 5 hours and then concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and loaded onto a 20 g SCX2 cartridge (pre-wetted with methanol). The cartridge was eluted with methanol to remove non-basic impurities and then eluted with 3M NH3 in methanol. Fractions containing the title compound were combined and concentrated under reduced pressure to afford the title compound as a white solid in 90% yield, 1.01 g. 1H NMR (400 MHz, MeOH-d4) : 1.21 (d, 3H), 2.70 (dd, 1H), 2.78-2.84 (m, 1H), 3.17 (dd, 1H), 3.31-3.44 (m, 3H), 3.88-4.01 (m, 2H), 4.98 (s, 2H), 7.11-7.34 (m, 10H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[CH2:41][O:40][C:13]2([CH2:36][CH2:35][C@@:34]3([CH3:37])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@:33]3([OH:38])[CH2:32][CH2:31][C@@:30]3([CH3:39])[C@H:19]4[CH2:20][CH2:21]/[C:22]/3=[C:23](/[O:28][CH3:29])\[C:24](OC)=[O:25])[CH2:14]2)[O:12]1.O>C1(C)C=CC=CC=1>[CH2:41]1[CH2:11][O:12][C:13]2([CH2:36][CH2:35][C@@:34]3([CH3:37])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@:33]3([OH:38])[CH2:32][CH2:31][C@@:30]3([CH3:39])[C@H:19]4[CH2:20][CH2:21]/[C:22]/3=[C:23](/[O:28][CH3:29])\[CH2:24][OH:25])[CH2:14]2)[O:40]1
Reactant: COC(=O)/C(OC)=C1\CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CO/C(CO)=C1/CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Under nitrogen a 1M solution of diisobutylaluminium hydride in toluene (0.1 ml) was added to a stirred solution of methyl (20Z)-3,3-ethylenedioxy-9α-hydroxy-20-methoxypregna-5,17(20)-dien-21-oate (112 mg, prepared according to Example 19) in dry toluene (8 ml) at -20° C. The reaction mixture was stirred at -20° C. for 30 minutes. To complete the reaction the same quantity of diisobutylaluminium hydride solution was added and stirring was continued at -20° C. for 5 minutes. Next, water (2 ml) was added and the mixture was stirred at 0° C. for 1 hour. The heterogeneous mixture was filtered, then the filtrate was concentrated under reduced pressure to afford 66 mg of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].CC1C=CC(C(C)C)=CC=1.C[O-].[Na+]>>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccc(C(C)C)cc1
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C
Yield: 33.1 %

Procedure:
2-(2-Hydroxy-3-diethylaminomethyl-5-methylphenyl)-2H-benzotriazole (21.0 g, 0.067 mol), 2-hydroxy-4-n-octyloxybenzophenone (22.0 g, 0.067 mol), and p-cymene (80 g) are charged to a reaction flask. The mixture is heated to dissolve, and sodium methoxide (1.0 g, 25% in methanol) is added as catalyst. The solution is heated with agitation under a nitrogen flow at reflux (176°-178° C.) for 24 hours. After cooling to room temperature, the solution is filtered, and the black filtered solid (~1 g) is discarded. The product is then precipitated with methanol. The yellow solid (12.5 g) obtained is vacuum filtered, and identified using thin layer chromatography, with toluene:acetone (1:1) as the mobile phase. To remove the yellow color, the solid product is dissolved in hot toluene, and silica gel is introduced. The silica gel is gravity filtered hot. The toluene is removed by vacuum distillation, yielding 8.2 g of the title compound as an off-white solid, m.p. 124°-126° C. H NMR shows proton resonances at 0.73 ppm, triplet, 3 protons, (terminal --CH3 in --OC8H17); 1.06-1.24 ppm, complex, 8 protons, (inner 4X-CH2 in --OC8H17); 1.32 ppm, quintet, 2 protons, (--CH2 beta to Ar--O); 1.71 ppm, quintet, 2 protons, (--CH2 gamma to Ar--O); 2.32 ppm, singlet, 3 protons (--CCH3); 4.03 ppm, triplet, 2 protons, (--CH2 alpha to Ar-0); 4.24 ppm, singlet, 2 protons, (Ar--CH2 --Ar); 6.48 ppm, doublet, 1 proton, (C8H17OCCH--); 6.82 ppm, 1 proton, (CH3CCHC--CH2 --Ar); 7.40-7.64 ppm, complex, 6 protons, (Ar--COCCHCH3 --, C8H17OCCHCH--,--NCCHC2H2 --); 7.68 ppm, doublet, 2 protons, (AR--COCCHC3H3CH), 7.95 ppm, complex, 2 protons, (--NCCHC2H2CH); 8.05 ppm, 1 proton, (CH3CCHCNCOH); 11.46 and 12.80 ppm, two singlets, two protons, (exchangeable --OH protons).
Reaction SMILES: [SH:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=2)=[N:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][S:1][C:2]2[O:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:8]=3)=[N:4][N:3]=2)=[CH:28][C:27]=1[C:34]([F:35])([F:37])[F:36]
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: O=C(CCc1ccccc1)Nc1cc(-c2nnc(S)o2)ccn1
Product: COc1ccc(CSc2nnc(-c3ccnc(NC(=O)CCc4ccccc4)c3)o2)cc1C(F)(F)F
Yield: 39 %

Procedure:
In the same manner as in Example 1 and using N-[4-(5-mercapto-1,3,4-oxadiazol-2-yl)-2-pyridyl]-3-phenylpropionamide instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 39%) was obtained as colorless crystals.
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][C:6]=1[NH2:12])C.[OH-].[Na+].Cl.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:51]([C:58]1[S:62][C:61]([CH2:63][NH2:64])=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C(O)C.[Cl-].[Na+].O>[NH2:12][C:6]1[N:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=1[C:4]([NH:64][CH2:63][C:61]1[S:62][C:58]([O:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[CH:59][CH:60]=1)=[O:13]
Reactant: CCOC(=O)c1ccc(N)nc1N
Reactant: NCc1ccc(Oc2ccccc2)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 2,6-diamino-nicotinic acid ethyl ester described in Preparation Example A-14 (18 mg, 0.1 mmol) in ethanol (10 mL) was added 1N sodium hydroxide aqueous solution (5 mL), and the solution was stirred for 1 hour 10 minutes under reflux. After cooling the reaction solution, the solution was neutralized with 1N hydrochloric acid and concentrated. The resulting crude product was suspended in N,N-dimethylformamide (3 mL), triethylamine (0.02 mL, 0.15 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (65 mg, 0.15 mmol) and C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation Example 26 (30 mg, 0.15 mmol) were added thereto, followed by stirring at room temperature for 19 hours 40 minutes. After the reaction was completed, reaction solution was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate then concentrated, the obtained residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (8.7 mg, 0.025mol, 25%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:29])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH2:30](O)[CH2:31][CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1CCc1ccc([N+](=O)[O-])cc1
Reactant: OCCCCO
Product: O=C1c2ccccc2C(OCCCCO)(c2ccc(Cl)cc2)N1CCc1ccc([N+](=O)[O-])cc1
Yield: 46.4 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (562 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (306 mg, 63%). 1H NMR (300 MHz, CDCl3): 8.11-8.08 (m, 2H, O2N—C—CH), 7.91-7.88 (m, 1H, C(O)═C═CH), 7.55-7.53 (m, 2H, Ar—H), 7.30-7.14 (m, 7H, Ar—H), 3.66 (m, 2H, N—CH2), 3.45 (t, J=8.1 Hz, 2H, HO—CH2), 3.16-3.11 and 3.03-2.99 (m, 2H, OCH2), 3.00-2.89 and 2.73-2.66 (m, 2H, NCH2CH2), 1.75-1.63 (m, 5H, CH2 and OH). 13C NMR (75 MHz, CDCl3): 168.23, 147.02, 146.62, 145.32, 137.69, 134.84, 132.74, 131.98, 129.99, 129.48, 128.74, 127.87, 123.65, 123.51, 123.10, 94.54, 62.79, 62.43, 40.51, 34.21, 29.60, 26.07. HPLC: Rt=3.45 min. calc. for C26H25ClN2O5: C, 64.93; H, 5.24; N, 5.82. Found: C, 64.82; H, 5.18; N, 5.68.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11](Br)[C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2].CC1C=C(C)N=C(C)C=1.C1(C)C(C)=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 140 °C

Procedure:
A mixture of 0.605 g. (0.0010 mole) of [1α,3β,7ξ,24R]-7-bromo-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.6 ml. of s-collidine and 18 ml. of xylene was heated at reflux (140° C.) for 0.5 hr and cooled. The mixture was diluted with 30 ml. of toluene. This solution was washed with 10% aqueous sulfuric acid, and saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on 0.06-0.20 mm silica gel to yield [1α,3β,24R]-24-fluorocholesta-5,7-dien-1,3,25-triol 1,3-diacetate, [α]D23 -21° (c 0.5, CHCl3).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[OH:12][CH2:13][CH:14]1[CH2:18][O:17][C:16](=[S:19])[NH:15]1.N1C=CC=CC=1>C1COCC1>[S:19]=[C:16]1[NH:15][CH:14]([CH2:13][O:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=2)[CH2:18][O:17]1
Reactant: C=Cc1ccc(C(=O)Cl)cc1
Reactant: OCC1COC(=S)N1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=Cc1ccc(C(=O)OCC2COC(=S)N2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
A solution of 4-vinylbenzoyl chloride (21.0 g, 126 mmol) in dry THF (50 mL) was added to a solution of 4-hydroxymethyl-1,3-oxazolidine-2-thione (14.0 g, 105 mmol) in dry THF (250 mL) and pyridine (10.2 mL, 126 mmol) at 0° C. After 12 hours of stirring at room temperature, pyridine hydrochloride was filtered off, and the solvent was evaporated out in vacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate/acetone (1/1=v/v), followed by recrystallization from a mixed solvent [n-hexane/ethyl acetate (3/1=v/v)] to afford 4-vinylbenzoic acid 2-thioxo-oxazolidin-4-ylmethyl ester as a colorless solid. Yield 73% (24.1 g, 91.5 mmol). 1H NMR (DMSO-d6): δ=4.25–4.77 (5H, >CH—, —CH2—O(CO)—, and —(SC)O—CH2—), 5.45 (d, J=10.8 Hz, 1H, —CH═CH2), 6.03 (d, J=17.8 Hz, 1H, —CH═CH2), 6.84 (dd, J=11.3 and 17.7 Hz, 1H, —CH═CH2), 7.64 (d, J=8.1 Hz, 2H, —C6H4—), 8.01 (d. J=8.1 Hz, 2H, —C6H4—), 10.3 (broad s, 1H, —NH—) ppm. 13C NMR (DMSO-d6): δ=55.0 (CO—CH2—CH<), 65.1 (>CH—), 71.8 (—CH2—O(CO)—), 117.7 (—CH═CH2), 126.5, 128.6, 130.1 (—C6H4—), 136.0 (—CH═CH2), 142.2 (—C6H4—), 165.6 (—O(CO)—C6H4—), 189.3 (>C═S) ppm. IR (KBr): 3185, 1712 (—OCOPh), 1504 (C═S), 1280, 1180, 1110, 971 cm−1.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O[CH2:21][C@@H:22]([CH3:54])[C@H:23]([NH:34][C:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:24]([O:26]CC1C=CC=CC=1)=[O:25]>C1COCC1>[CH3:21][C@@H:22]1[CH2:54][O:26][C:24](=[O:25])[C@H:23]1[NH:34][C:35]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:46]2[C:47]1=[CH:42][CH:43]=[CH:44][CH:45]=2
Reactant: C[C@H](CO)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1COC(=O)[C@H]1NC1(c2ccccc2)c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
The relative stereochemical assignments of the DIBAL-reduction products were made based on NOE studies conducted on lactone derivatives prepared from each isomer by employing the following protocol: LiHMDS (50 μL of 1.0 M/THF, 0.05 mmol) was added to a cooled (ice-water) THF (2.0 mL) solution of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (62.7 mg, 0.135 mmol), and the reaction mixture was stirred at similar temperature for ˜2 hr. The volatile component was removed in vacuo and the residue was partitioned between CH2Cl2 (30 mL), water (20 mL) and saturated aqueous NH4Cl solution (1 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo, and the resulting crude material was submitted to a Biotage purification (40 g silica gel; 10-15% EtOAc/hexanes) to afford (3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one as a colorless film of solid (28.1 mg). (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was elaborated similarly to (3S,4R)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one. (3S,4S)-lactone isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.83 (d, J=7.5, 2H), 7.46-7.17 (m, 11H), 4.14 (app t, J=8.3, 1H), 3.60 (d, J=5.8, NH), 3.45 (app t, J=9.2, 1H), ˜2.47 (m, 1H, partially overlapped with solvent signal), 2.16 (m, 1H), 0.27 (d, J=6.6, 3H). LC (Cond. 1): RT=1.98 min; LC/MS: Anal. Calcd. for [M+Na]+ C24H21NNaO2: 378.15. found 378.42. (3S,4R)-lactone isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.89 (d, J=7.6, 1H), 7.85 (d, J=7.3, 1H), 7.46-7.20 (m, 11H), 3.95 (dd, J=9.1, 4.8, 1H), 3.76 (d, J=8.8, 1H), 2.96 (d, J=3.0, NH), 2.92 (dd, J=6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, J=7.0, 3H). LC (Cond. 1): RT=2.03 min; LC/MS: Anal. Calcd. for [M+Na]+ C24H21NNaO2: 378.15. found 378.49.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([C:19]([O:21]C(C)(C)C)=O)[CH:17]=[CH:18][C:12]=2[NH:11][C@H:10]([CH2:26][OH:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH2:39][NH:40][CH3:41].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([C:19]([N:40]([CH3:41])[CH2:39][C:31]3[N:30]([CH3:29])[C:38]4[C:33]([CH:32]=3)=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:21])[CH:17]=[CH:18][C:12]=2[NH:11][C@H:10]([CH2:26][OH:27])[C:9]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C(=O)[C@@H](CO)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(Cc1ccccc1)C(=O)[C@@H](CO)N2
Yield: 82.9 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-4-benzyl-2-hydroxymethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.39 g, 1.0 mmole), 1-methyl-2-(methylaminomethyl)indole (0.18 g, 1.1 mmole), Et3N (0.31 mL, 2.2 mmole), HOBt.H2O (0.15 g, 1.1 mmole), and EDC.HCl (0.21 g, 1.1 mmole), the title compound (0.40 g, 83%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 1-3% MeOH/CHCl3): MS (ES) m/e 483.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][NH2:20])=[C:15]([CH3:23])[CH:14]=1)[CH3:9].Cl[C:25]1[C:30]([Cl:31])=[C:29]([CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1>C1(C)C=CC=CC=1>[Cl:31][C:30]1[C:25]([NH:20][CH2:19][CH2:18][O:17][C:16]2[CH:21]=[CH:22][C:13]([CH2:12][CH2:11][O:10][CH2:8][CH3:9])=[CH:14][C:15]=2[CH3:23])=[N:26][C:27]([CH3:33])=[N:28][C:29]=1[CH3:32]
Reactant: Cc1nc(C)c(Cl)c(Cl)n1
Reactant: CCOCCc1ccc(OCCN)c(C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOCCc1ccc(OCCNc2nc(C)nc(C)c2Cl)c(C)c1
Reaction time: 5 h
Yield: 55.8 %

Procedure:
1.0 g of triethylamine and 2.2 g of 2-[4-(2-ethoxyethyl)-2-methylphenoxy]ethylamine were added to 1.8 g of 4,5-dichloro-2,6-dimethylpyrimidine dissolved in 50 ml of toluene. The mixture was heated under reflux, whilst stirring, for 5 hours. At the end of this time, the reaction product was washed with water and dried over anhydrous sodium sulfate. Toluene was then removed by distillation under reduced pressure, and the oily product obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and etyl acetate) to isolate the product. The crystals obtained were recrystallized from hexane, to give 2.0 g of the title compound as colorless granular crystals melting at 61°-63° C.