Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:48])([Cl:47])[C:3]([O:6][C:7]([N:9]1[C@H:14]2[C:15]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[CH:20][CH:19]=3)[CH2:17][C@@H:10]1[CH2:11][N:12]([C:40]([O:42]C(C)(C)C)=O)[CH2:13]2)=[O:8])([CH3:5])[CH3:4].Cl.O1CCOC[CH2:51]1.CCN(C(C)C)C(C)C.C(Cl)(=O)C>CN(C1C=CN=CC=1)C.CO.C1COCC1.C(Cl)Cl>[Cl:47][C:2]([Cl:48])([Cl:1])[C:3]([O:6][C:7]([N:9]1[C@H:14]2[C:15]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:23]=3)[CH2:17][C@@H:10]1[CH2:11][N:12]([C:40](=[O:42])[CH3:51])[CH2:13]2)=[O:8])([CH3:4])[CH3:5]
Reactant: C1COCCO1
Reactant: CCOC(=O)C1=C(c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc(OCCO)cc2)C[C@@H]2CN(C(C)=O)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl

Procedure:
As for compound S1, from H7 (5.80 g, 7.73 mmol), CH2Cl2 (60 mL), 4M HCl/dioxane (60 mL), THF (50 mL), DMAP (47 mg, 0.384 mmol), DIPEA (5.29 mL, 31.7 mmol), acetyl chloride (0.604 mL, 8.08 mmol), and MeOH (5 mL). Purification of the residue by FC (EtOAc/heptane 1:1→EtOAc MeOH/EtOAc 1:9) led to the title compound (3.07 g, 69%). Rf=0.20 (EtOAc). LC-MS: Rt=4.80; ES+: 576.93.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32].C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:16])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccn1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccn1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 77.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (165 mg, 0.56 mmol, 1.0 eq), L-isoleucine pyridin-2-ylmethylamide (246 mg, 1.11 mmol) and dichloromethane (2 mL), was treated with triethylamine (475 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (721 uL, 2.0 eq), to provide 214 mg (77%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] pyridin-2-ylmethylamide.
Reaction SMILES: [C:1]1([NH:7][C:8](=S)[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:14][C:15]([CH2:17][C:18](=O)[CH3:19])=[O:16]>O1CCCC1>[NH:7]([C:8]1[C:17]([C:15](=[O:16])[CH3:14])=[C:18]([CH3:19])[NH:10][N:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=S)Nc1ccccc1
Reactant: CC(=O)CC(=O)CCl
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1c(Nc2ccccc2)n[nH]c1C
Reaction time: 12 h

Procedure:
50 g of 4-phenylthiosemicarbazide is suspended in 300 ml of tetrahydrofuran and 0.5 ml of concentrated HCl is added. Then 40.4 g of 3-chloroacetyl acetone is allowed to run in all at once and the whole is cooled with an ice-bath. After 12 hours' stirring, the precipitate formed is suction filtered, washed with acetone and then boiled in a water/acetone mixture (1:1). This hot solution is filtered off from the sulfur and neutralized with aqueous ammonia solution. The product is then suction filtered and recrystallized from acetone; m.p. 246°-247° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCCC1.O>[N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
D-hPro-OH (5.0 g, 38.7 mmol) was dissolved in tetrahydrofuran (100 mL) and water (30 mL). The pH of the solution was adjusted to 9.5 with 2N sodium hydroxide and benzyl chloroformate (5.5 mL, 38.7 mmol) was added dropwise and the pH maintained at 9.5 with 2N sodium hydroxide. The reaction was stirred for an additional 1 hour at room temperature. The organic solvent was evaporated in vacuo, diethyl ether (100 mL) and water (50 mL) was added to the residue. The aqueous layer separated, the pH of the solution was adjusted to 2.8 with 3N hydrochloric acid and ethyl acetate (150 mL) was added. The organic layer was separated and dried (MgSO4); the filtrate was concentrated in vacuo to give 9.6 g (95%) of a clear oil.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[S:19][C:20]([CH2:24][C:25]([O:27][CH2:28]C)=[O:26])=[C:21]([CH3:23])[N:22]=1>N1C=CC=CC=1>[CH3:28][O:27][C:25]([CH2:24][C:20]1[S:19][C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[N:22][C:21]=1[CH3:23])=[O:26]
Reactant: CCOC(=O)Cc1sc(N)nc1C
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: COC(=O)Cc1sc(N=C2SC[C@@H]3Cc4ccccc4CN23)nc1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (10 g) is added to a solution of ethyl (2-amino-4-methylthiazol-5-yl)acetate (5.5 g) in pyridine (150 cc). After 48 hours at a temperature of the order of 20° C., the solution is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 60° C. The residue is dissolved in a mixture of methylene chloride (200 cc) and N sodium hydroxide solution (100 cc). The organic phase is washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. The residue is crystallised by dissolving it in boiling ethanol (120 cc) and cooling to 0° C. The resulting crystals are filtered off, washed with ethanol (30 cc) and diethyl ether (20 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(5-methoxycarbonylmethyl-4-methylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (8.1 g), as a white solid, m.p.=66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:25]([F:28])([F:27])[F:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:25]([F:28])([F:27])[F:26])([OH:16])[C:4]=2[CH:3]=1
Reactant: Cc1cc(Cl)cc2c1-c1ccccc1C2=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc2c1-c1ccccc1C2(O)C(F)(F)F

Procedure:
Under anhydrous calcium chloride drying conditions, 2-chloro-4-methyl-fluoren-9-one (18.627 g), potassium carbonate (3.372 g) and dimethylformamide (100 ml) were mixed, trimethyl(trifluoromethyl)silane (16 ml) was added dropwise over 25 min at room temperature with stirring, and the mixture was further stirred at room temperature for 14 min. To this mixture, a 1M solution (122 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added dropwise over 6 min. To the reaction mixture was added aqueous ammonium chloride (400 ml), and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed once with water (100 ml), once with saturated aqueous sodium hydrogen carbonate and 3 times with water, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (200 ml), activated carbon (1.5 g) was added, and the mixture was stirred at room temperature for 10 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (24.689 g). The obtained residue was directly used for the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]=[N:10][C:11]#N)[N:3]=1.[CH2:13](N)[CH2:14]C>O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]=[N:10][CH2:11][CH2:13][CH3:14])[N:3]=1
Reactant: CCCN
Reactant: N#CN=CNc1cccc(O)n1
Solvent: O
Product: CCCN=CNc1cccc(O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g (14 mmol) of N-(2-hydroxy-6-pyridyl)-N'-cyanoformamidine are added in portions at room temperature over a period of 20 minutes to a stirred solution of 8.3 ml (99 mmol) of n-propylamine in 8 ml of water The reaction mixture is stirred for 2 hours at room temperature It is then extracted three times with chloroform The combined organic phases are dried over MgSO4 and concentrated by evaporation. The resulting crude product is chromatographed on silica gel with methylene chloride and then crystallised from ether/n-hexane. N-(2-pyridon-6-yl)-N'-propylformamidine and N-(2-hydroxy-6-pyridyl)-N'-propylformamidine having a melting point of 178°-179° are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[C:19]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([OH:21])=[O:20]>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][C:19]([OH:21])=[O:20])=[CH:25][CH:26]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCC(=O)O)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-(2-carboxyethyl)phenylboronic acid according to Method C (Example 178). Yield: 1.4 g (100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[CH2:12][C@@H:13]3[C:18]([CH3:20])([CH3:19])[C@:17]([CH3:21])([C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH2:15][N:14]3[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCCC1>[CH2:22]([N:14]1[CH2:15][CH2:16][C@:17]2([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:13]1[CH2:12][C:11]1[C:6]([CH2:4][OH:3])=[CH:7][CH:8]=[CH:9][C:10]=12)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cccc2c1C[C@H]1N(Cc3ccccc3)CC[C@]2(C)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)[C@H]2Cc3c(CO)cccc3[C@]1(C)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid ethyl ester (0.96 g) in tetrahydrofuran (2 mL) is added dropwise to LiAlH4 (1.6 mL, 2.4 mol/L in tetrahydrofuran) in tetrahydrofuran (1.5 mL). The reaction mixture is stirred at ambient temperature for 90 min. Then, water (4 mL) is added carefully and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (MgSO4). The solvent is removed under reduced pressure to give the product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1>>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])[CH:7]=2)[C:2]([C:40]2[C:35]([O:34][CH3:33])=[N:36][CH:37]=[CH:38][CH:39]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and 2-methoxy-3-pyridineboronic acid were used as the coupling partners. The final compound was purified via column chromatography (RediSep Gold 12 g silica gel column, gradient elution 0-10% MeOH:DCM) to afford 4-fluoro-1-(2-methoxypyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.00 (br. s., 1H), 8.73 (d, J=1.3 Hz, 1H), 8.51 (d, J=1.3 Hz, 1H), 8.39 (dd, J=1.9, 4.9 Hz, 1H), 8.01 (dd, J=1.7, 8.9 Hz, 1H), 7.87-7.76 (m, 2H), 7.31 (d, J=4.6 Hz, 1H), 7.22 (dd, J=5.0, 7.2 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 3.77 (s, 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[C@@H:8]1([CH2:15][OH:16])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14].COC1C=CC(C=O)=CC=1>O.C(O)C.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OCC)(=O)C.C(Cl)Cl>[C@H:9]12[CH2:13][O:14][C:15](=[O:16])[C@H:8]1[CH2:12][CH2:11][CH2:10]2
Reactant: OC[C@@H]1CCC[C@@H]1CO
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C1OC[C@@H]2CCC[C@H]12
Yield: 92.9 %

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. Cis-1,2-cydopentane dimethanol (10.0 grams) is added to the glycine solution with stirring until dissolution occurs, followed by the addition of β-NAD+ (Sigma, 2 grams) and flavin mononucleotide (Sigma, 30 grams). To the resulting dear orange solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent 1:1 ethyl acetate-methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (1R,5S)-(+)-7-oxabicyclo[3.3.0]octan-6-one (9 grams) as an orange oil. The product may be further purified by distillation at reduced pressure to yield a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Yield: 77 %

Procedure:
The required starting material, 4-iodo-3-nitrobenzoic acid, can be prepared as described in Tetrahedron, 61, 2005, 10113-10121, or by any other suitable method. The conversion of 4-iodo-3-nitrobenzoic acid to its methyl ester using sulfuric acid and methanol is described in U.S. 2007/0135485 A1 (section [0255], page 30). The method involves reacting a methanolic solution of 4-iodo-3-nitrobenzoic acid with sulfuric acid, neutralizing the acid with sodium bicarbonate, removal of methanol, diluting with water and extracting with diethyl ether, to obtain an oily product, which was subjected to chromatography to get 4-iodo-3-nitro benzoic methyl ester as a solid in 77% yield. Diethyl ether is not a suitable solvent on an industrial scale because of its high inflammability. Also column chromatography for purification in large scale is not desirable. Hence, we have modified the reported procedure. We have found that methyl tert-butyl ether (MTBE) is a better solvent for extraction which gives the product as a solid directly without any need for chromatographic purification (98.5% HPLC) and in high yield (85%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]12(O)[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.B(F)(F)F.CCOCC>CCCCC>[C:21]12([C:8]3[C:9]([OH:20])=[CH:10][C:11]4[CH2:12][CH2:13][C@@H:14]5[C@@H:5]([C:6]=4[CH:7]=3)[CH2:4][CH2:3][C@@:2]3([CH3:1])[C@H:15]5[CH2:16][CH2:17][C:18]3=[O:19])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: FB(F)F
Solvent: CCCCC
Solvent: CCOCC
Product: C[C@]12CC[C@@H]3c4cc(C56CC7CC(CC(C7)C5)C6)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
Estrone [3-hydroxyestra-1,3,5(10)-trien-17-one, 270 mg, 1 mmol) and 1-adamantanol (170 mg, 1 mmol) were added to anhydrous n-pentane (6 mL) and the stirred mixture was cooled with an ice bath. Boron trifluoride etherate (BF3.EtOEt, 0.4 mL) was added over a 10 minute period. After an additional 15 minutes, the ice bath was removed and stirring was continued for an additional 45 minutes at room temperature. During the 45 minute period, solids present in the reaction mixture were dissolved and a yellow oil formed. Crushed ice was then added while shaking and swirling the reaction flask and a pink solid was formed. The filtered, crude pink product was washed with water until the filtrate had a neutral pH, and then the solid was dried in a vacuum oven at 50° C. The crude pink powder (0.4 g) was purified by flash chromatography (silica gel eluted with 20% ethyl acetate in hexanes) to get the pure product (0.31 g, 76.7%). The product was recrystallized from a mixture of chloroform and isopropyl alcohol and characterized as follows: (i) melting point=322-324° C. (see, e.g., Lunn, W. H. W.; Farkas, E., Adamantyl Carbonium Ion as a Dehydrogenating Agent: Its Reactions with Estrone, Tetrahedron 1969, 24, 6773-76, citing melting point as 295-296° C.); (ii) 1H NMR (CDCl3, 300 MHZ) δ0.94 (s, 3H, C18—CH3), 2.8 (m, 2H, C6CH2), 4.7 (s, 1H, C3—OH), 6.4 (5, 1H, C4—H), 7.12 (5, 1H, C1—H); (iii) 13C NMR CDCl3, 300 MHZ) δ3.76, 21.47, 25.93, 26.41, 28.63, 28.95 (3×C), 31.56, 35.81, 36.56, 36.98 (3×C), 38.42, 40.69 (3×C), 44.25, 47.99, 50.35, 116.87, 124.11, 131.59, 134.00, 135.02, 152.44, 221.43. (Chemical Abstracts Registry Number [21003-01-0].)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:16])[NH:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.IC.[C:19](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3](=[O:16])[N:4]([CH3:19])[CH:5]=[C:6]([C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1c[nH]c(=O)c(Br)c1)N1CCOCC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cc(C(=O)N2CCOCC2)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-(morpholine-4-carbonyl)pyridin-2(1H)-one (430 mg, 1.498 mmol), iodomethane (0.112 mL, 1.797 mmol), and potassium carbonate (207 mg, 1.498 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 30-70% ACN in H2O (containing 10 mM NH4HCO3) to give the title compound.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30])=O)C1C=CC=CC=1>C(O)(=O)C.C(OCC)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30]
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (3.0 g) and hydrobromic add (45% in acetic acid, 6.2 ml) was stirred for 1 h at room temperature under an atmosphere of nitrogen. The mixture was then diluted with cold anhydrous diethyl ether (40 ml) and it was stirred at 0° C. for 45 min. The white precipitate was collected by filtration, washed with cold diethyl ether (4×30 ml) and then dissolved in a mixture of water (30 ml) and aqueous sodium hydroxide (2M, 15 ml). The basic aqueous phase was extracted with ethyl acetate (3×70 ml) and the combined organic layers were washed with brine (30 ml), dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel using 94:6, dichloromethane:methanol as the eluant, to afford the title compound (1.6 g). Mp 133°-136° C. 1H NMR (360 MHz, CDCl3) δ 1.02-1.40 (4H, m), 1.47-1.56 (1H, m), 1.61-1.74 (3H, m), 1.84-1.91 (1H, m), 1.96-2.06 (1H, m), 2.17 (2H, brs), 2.70-2.80 (1H, m), 3.39 (3H, s), 4.29 (1H, s), 7.20-7.27 (2H, m), 7.44-7.54 (2H, m).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18](Cl)=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:27][C:28]([NH2:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O-:32].[Na+]>CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([O:32][CH3:31])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:27][C:28]([NH2:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: COc1ccc(N2CCN(CC(N)=O)[C@@H](Cc3ccccc3)C2)c2ccc(Cl)nc12
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(N3CCN(CC(N)=O)[C@@H](Cc4ccccc4)C3)ccc(OC)c2n1
Reaction time: 18 h
Yield: 54.7 %

Procedure:
A stirred solution of (S)-2-(2-benzyl-4-(2-chloro-8-methoxyquinolin-5-yl)piperazin-1-yl)acetamide (40 mg, 0.1 mmol) in MeOH (1.2 mL) was treated with sodium methoxide (1.0 mL, 4.4 mmol) as a 25% solution in MeOH. The reaction mixture was allowed to stir for 18 h, then evaporated and purified by silica gel chromatography eluting with EtOAc to afford product as a yellow solid (23 mg, 55%). 1H NMR (MeOH-d4) 8.24-8.40 (br s, 1H), 7.10-7.24 (m, 5H), 7.03 (d, J=8.2, 1H), 6.94 (d, J=8.4, 1H), 6.82-6.88 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 3.42-3.56 (m, 1H), 2.94-3.27 (m, 8H), 2.64-2.85 (m, 2H). LC/MS 2.34 min, [M+1]+ 421.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-])=O)=[C:13]([CH:16]=1)[CH:14]=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1>C1(C)C=CC=CC=1.[Pd]>[NH2:17][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: O=Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: c1ccsc1
Product: Nc1ccc(C(=O)c2ccccc2)cc1C=O

Procedure:
A mixture of 5-benzoyl-2-nitrobenzaldehyde (0.01 mol) in toluene was hydrogenated at room temperature and normal pressure with 5% Pd/C (2 g) as a catalyst in the presence of 4% thiophene solution (2 mL). After uptake of H2 gas (3 equiv.), the catalyst was filtered off and the filtrate was evaporated (water bath at 50° C.). The residue was dissolved in diethyl ether (10 mL) and crystallized out at room temperature. The crystals were filtered off, washed with a small amount of diethyl ether and diisopropyl ether, then dried (vacuum, 40° C.) to yield the title compound as a solid.