Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:25]=[CH:26][C:27]=1[CH3:28].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:22]([Cl:21])[CH:23]=2)[N:30]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: Cc1ccc(NNC(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1Cl
Yield: 26.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-(3-chloro-4-methylphenyl)hydrazinecarboxylate (Intermediate-87, 0.450 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.180 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.[C:17]([OH:21])(=O)[CH:18]=O.O.[NH2:23][NH2:24]>O.C(O)(=O)C>[N:7]1[CH:8]=[CH:9][C:4]([C:1]2[CH:2]=[CH:18][C:17](=[O:21])[NH:23][N:24]=2)=[CH:5][CH:6]=1
Reactant: NN
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccncc2)n[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64 %

Procedure:
99.5 g 4-Acetylpyridine is added to a cold (10° C.) solution of 222.4 potassium carbonate and 76.3 glyoxylic acid monohydrate in 1 L of water and the solution stirred at room temperature for 2.5 h. After cooling to 0° C., 325 ml of acetic acid are added followed by 58.8 ml hydrazine hydrate, and the resulting solution stirred under reflux for 1.5 h. The solution is then cooled to 0° C., the pH adjusted to 7 with solid K2CO3, the precipitate collected and washed with water and i-PrOH to give 89.27 g (64%) of 6-Pyridin-4-yl-2H-pyridazin-3-one.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].Br[CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C(OCC)C>CN(C)C=O.O>[S:19]1[CH:20]=[CH:21][C:17]([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[CH2:10][O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8])=[CH:18]1
Reactant: OCC#CCO
Reactant: BrCc1cccc(-c2ccsc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: OCC#CCOCc1cccc(-c2ccsc2)c1
Yield: 79.7 %

Procedure:
Under a nitrogen atmosphere, 0.47 g of 60% oily sodium hydride was suspended in 10 ml of dimethylformamide, and a dimethylformamide solution (10 ml) of 1.0 g of 2-butyn-1,4-diol was added dropwise with stirring and ice cooling. After the mixture was stirred for 10 minutes, a dimethylformamide solution (5 ml) of 0.59 g of 3-(3-bromomethylphenyl)thiophene was added. The mixture was stirred at room temperature for 1 hour and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=3/1] to give 0.48 g of 4-[3-(3-thienyl)benzyloxy]-2-butyn-1-ol as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][CH:29]3[CH2:31][CH2:30]3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CC1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCC4CC4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and cyclopropanecarbaldehyde. MS (ESI) m/z 433.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].C(OC)=O.[S:8](=[O:11])([OH:10])[O-:9].[Na+:12].[OH-].[Na+].[CH2:15]1[CH2:20][CH2:19]C[CH2:17][CH2:16]1>O>[CH:2]1([CH:1]=[O:3])[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1.[S:8](=[O:9])([OH:11])[O-:10].[Na+:12]
Reactant: C1CCCCC1
Reactant: CC=O
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC=O
Product: O=CC1CCCCC1

Procedure:
A solution of cyclohexane with 1000 ppm acetaldehyde and 500 ppm methyl formate impurities was prepared and a partitioning run was carried out in a 500 mL separatory funnel, reacting this mixture with aqueous sodium bisulfite as the reducing agent and aqueous sodium hydroxide as the base. The cyclohexane-aldehyde solution was prepared by mixing 1000 g cyclohexane, 1.0 g acetaldehyde, and 0.5 g methyl formate in a large flask. After mixing, a portion was decanted into a labeled vial for analysis. Sodium bisulfite solution was prepared by mixing 9.66 g water and 2.16 g Na2S2O5 in a flask with shaking until complete dissolution had occurred. Sodium hydroxide solution was drawn from 0.2 N sodium hydroxide laboratory stock solution.
Reaction SMILES: [Br:1]Br.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>[N+](C1C=CC=CC=1)([O-])=O.C1(C)C=CC=CC=1>[Br:1][C:16]1[CH:17]=[N:18][C:19]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([C:8]1[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=1)[CH:20]=2
Reactant: BrBr
Reactant: Fc1ccc(-c2ccc3cccnc3c2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: Fc1ccc(-c2ccc3cc(Br)cnc3c2)cc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 57.8 %

Procedure:
A solution of bromine (0.9 mL, 17.6 mmol) in nitrobenzene (2.5 mL) was added dropwise over 15 minutes to a thick slurry of 7-(4-fluorophenyl)quinoline hydrochloride (3.80 g, 14.6 mmol) in nitrobenzene (7.5 mL) at 140° C. (oil bath temperature). The resulting mixture was stirred at 140° C. for 6 hours, allowed to cool to ca. 80° C., diluted with toluene (30 mL) and then cooled to room temperature. The orange solid was collected under suction and washed with toluene followed by diethyl ether. The solid was suspended in water (100 mL), the mixture basified with aqueous sodium carbonate and extracted with dichloromethane (2×50 mL). The combined extracts were dried (MgSO4) and evaporated to give a yellow solid. This was purified by flash chromatography, eluting with 2:1 dichloromethane/isohexane, dichloromethane then 5% ethyl acetate/dichloromethane, to afford 3-bromo-7-(4-fluorophenyl)quinoline as an off-white solid (2.55 g, 58%). 1H NMR (500 MHz, CDCl3) δ 8.93 (1H, d, J 2.2 Hz), 8.33 (1H, d, J 2.1 Hz), 8.24 (1H, s), 7.82-7.78 (2H, m), 7.71-7.69 (2H, m), 7.20 (2H, t, J 8.6 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH3:25]O>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:25])=[O:18])=[CH:16][C:3]1=2
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Reflux 8 gm. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid in 600 cc. of methanol containing 1 cc. of sulfuric acid for 19 hours. Cool and separate the solids by filtration to obtain the title product. (m.p. 130°-131° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C)C=O>[CH2:7]([O:18][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([Cl:11])=[C:13]([O:21][CH3:22])[CH:14]=1)[CH:8]=[CH2:9]
Reactant: COc1cc(C(=O)O)ccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
Potassium carbonate (4.44 g, 32.156 mmol) and allyl bromide (2.78 ml, 32.156 mmol) were added to a stirred solution of 4-chloro-3-methoxybenzoic acid (3 g, 16.078 mmol) in N,N-dimethylformamide (30 ml) and allowed to stir at room temperature for 18 hours. The reaction mixture was partitioned between diethyl ether (200 ml) and water (150 ml), the organic phase extracted and further washed with water (150 ml), dried over sodium sulfate and concentrated in vacuo to afford the title compound as an orange oil in 98% yield, 3.57 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Solvent: O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 58 mg, 52%). mp 171–173° C. 1H NMR (300 MHz, DMSO-d6) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.51 (m, 1H), 7.65 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.81 (m, 1H) 8.05 (s, 1H), 8.12 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 434 (M+H)+, 451 (M+NH4)+. Anal. calc. for C21H21F2N3O3S.0.25 H2O: C, 58.19; H, 4.88; N, 9.69. Found: C, 57.69; H, 5.01; N, 9.18.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([C:23]([N:1]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:24])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C1COCCOCCOCCN1
Product: O=C(N1CCOCCOCCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [O:1]=[C:2]([CH2:6]C)[C:3]([O-:5])=[O:4].[NH2:8][C@H:9]([C:14]([O-:16])=[O:15])[CH2:10][C:11]([O-])=[O:12]>>[O:12]=[CH:6][CH:2]([OH:1])[C:3]([O-:5])=[O:4].[CH3:11][CH2:10][C@H:9]([NH3+:8])[C:14]([O-:16])=[O:15]
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Reactant: CCC(=O)C(=O)[O-]
Product: CC[C@H]([NH3+])C(=O)[O-]
Product: O=CC(O)C(=O)[O-]

Procedure:
reacting the 2-ketobutyrate, L-aspartate and transaminase enzyme under conditions appropriate to produce oxolactate and L-2-aminobutyrate;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14]C(OCC2C=CC=CC=2)=O)[C@@H:10]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28]2)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@@H:10]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28]2)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reaction time: 20.5 h
Yield: 12.7 %

Procedure:
In a dry 500-mL Paar flask charged with palladium (10 wt % Pd, dry basis, on carbon, 31 mg) was added methanol (10 mL) and (3S,4R)-4-benzyloxycarbonylamino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (150 mg, 2.08 mmol). The reaction mixture was hydrogenated at 45 psi for 20.5 hours with vigorous shaking. The reaction mixture was filtered through a plug of celite. The plug was washed with 20 mL of ethanol and the combined filtrates were concentrated in vacuo to give a colorless oil (111 mg, 98%). 1H NMR (300 MHz, CDCl3), δ: 8.75 (bs, 2H), 7.09 (m, 2H), 6.97 (m, 2H), 4.30 (m, !H), 4.01 (m, 2H), 3.70 (m, 2H), 3.25 (m, 1H), 3.10 (m, 1H), 2.75 (m, 1H), 2.48 (m, 4H), 1.82 (m, 5H), 1.42 (s, 9H), 1.21 (m, 2H). MS (ESI), m+/z: (M+H)+=420.3.
Reaction SMILES: [C:1]1([N:10]=[C:11]=[O:12])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[CH2:13]([CH:15]([NH:18][OH:19])[CH2:16][CH3:17])[CH3:14]>ClCCl>[C:1]1([NH:10][C:11]([N:18]([OH:19])[CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:12])[CH:2]=[CH:3][C:4]([NH:7][C:8]([N:18]([CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[OH:19])=[O:9])=[CH:5][CH:6]=1
Reactant: CCC(CC)NO
Reactant: O=C=Nc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CCC(CC)N(O)C(=O)Nc1ccc(NC(=O)N(O)C(CC)CC)cc1
Yield: 62.8 %

Procedure:
The same general procedure as reported in Example 13 was followed. 1,4-Phenylene diisocyanate (3.2 g, 20 mmol), N-(1-ethylpropyl)hydroxylamine (4.3 g, 42 mmol), and dichloromethane (200 ml) were combined. The product formed as a precipitate. Purification by recrystallization from N,N-dimethylformamide.backslash.water yielded 4.6 g of the desired product as a white powder: MP: 202.0° C. (decomp); 1H NMR (300 MHz, DMSO): δ 9.13 (s, 2H), 8.72 (s, 2H), 7.44 (s, 4H), 3.96-3.87 (septet, J=4.7 Hz, 2H), 1.60-1.33 (m, 8H), 0.84 (t, J=7.3 Hz, 12 H); 13C NMR (75 MHz, DMSO): δ 157.9, 134.0, 119.3, 59.6, 24.6, 11.1; IR (KBr): 3401, 3134, 2964, 2923, 2873, 1634, 1541, 1462, 1412, 1269, 1218, 1159, 1103, 1060, 833, 755, 736 cm-1 ; MS (FAB): m/e 367.2331 (367.2345 calc'd for C18H31N4O4, M+H); Anal. calc'd for C18H30N4O4 : C, 59.00; H, 8.25; N, 15.29. Found: C, 58.72; H, 8.34; N, 15.28.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)[CH2:3][OH:4].I[CH3:14]>C1COCC1>[I:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:2]([NH2:1])[CH2:3][O:4][CH3:14])=[CH:11][CH:10]=1
Reactant: CI
Reactant: NC(CO)Cc1ccc(I)cc1
Solvent: C1CCOC1
Product: COCC(N)Cc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 12.0 g (43.3 mmol) 2-amino-3-(4-iodophenyl)-propan-1-ol (I41) and 350 mL THF is cooled down to 0° C. 3.81 g (95 mmol) NAH (60% in min. oil) are carefully added and the mixture is stirred at 0° C. for 30 min. 3.25 mL (52.0 mmol) iodomethane are added and cooling is removed. The reaction mixture is stirred at r.t. for 1 h. The mixture is poured onto water and extracted with EtOAc (2×). The combined organic layers are washed with brine, dried with Na2SO4 and the solvent is removed in vacuo. The compound is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][NH:7][C@H:8]([C:15]([OH:17])=[O:16])[CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13])([O-])=O.[H][H]>[Ni]>[NH2:1][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][NH:7][C@H:8]([C:15]([OH:17])=[O:16])[CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CSC[C@H](NCc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: [H][H]
Agent: [Ni]
Product: Nc1ccccc1CN[C@@H](CSCC(=O)O)C(=O)O

Procedure:
N-(2-amino-benzyl)-S-carboxymethyl-cysteine was prepared in analogy to Example 1 (b) by reducing N-(2-nitro-benzyl)-S-carboxymethyl-cysteine with hydrogen in the presence of Raney nickel and double the quantity of soda. Melting point: 214° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])(C)(C)C.CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[C:15]([O:14][CH2:13][C:12]#[C:11][CH2:10][CH2:9][CH2:8][C:7]([OH:6])=[O:22])(=[O:17])[CH3:16]
Reactant: CC(C)=O
Reactant: CC(=O)OCC#CCCCCO[Si](C)(C)C(C)(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(=O)OCC#CCCCC(=O)O
Reaction time: 1 h

Procedure:
A solution of crude (28) in acetone (100 mL) was treated with Jones Reagent (18.0 mL, 41.4 mmol, 2.3 M) and cooled with an ice bath. After 1 hour at room temperature, 10 mL isopropyl alcohol was added and the mixture stirred for 15 minutes. The mixture still had a brown color so another 10 mL isopropyl alcohol was added. After another 15 minutes, the color had not changed so the mixture was filtered through celite and the filtrate evaporated in vacuo. The residue was partitioned between 100 mL ether and 100 mL saturated ammonium chloride solution. The aqueous layer was extracted with 100 mL ether and the combined ether solution washed with brine and then dried (MgSO4), filtered and evaporated to leave a yellow oil (6.333 g) that was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(=O)(N(C)C)N(C)C.[CH2-]C(C)=O.Br[CH2:35][CH2:36][C@H:37](O)[CH2:38][OH:39].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:35][CH2:36][C@@H:37]([CH2:38][OH:39])[O:18][C:16]2=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H](O)CCBr
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [CH2-]C(C)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1O[C@H](CO)CC[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of tetrahydrofuran was dissolved 1.01 g (10 millimoles) of diisopropyl amine, and 6.5 ml of 14.5% solution of n-butyl lithium in hexane was added to the solution to form lithium diisopropylamine. The solution was cooled to -20° C. and a solution of 1.21 g (5 millimoles) of 4-benzyloxyphenylacetic acid in 5 ml of tetrahydrofuran was added dropwise into the solution. Then 3 ml of hexamethyl phosphorictriamide was added to the mixture, and reaction was carried out at a temperature maintained at -5° to 0° C. with stirring for 30 minutes. The obtained di-anion solution was cooled to -30° C., and 2.3 g (9.6 millimoles) of (S)-4-bromo-1,2-butanediol acetonide was added dropwise into the solution. After the dropwise addition, the mixture was stirred for 2 hours at a temperature controlled to 10° to 20° C. Then, water was added to the mixture, tetrahydrofuran was removed by distillation, and the residue was neutralized with dilute hydrochloric acid. The reaction product was extracted from the solution with chloroform, and the extract was washed with water and dried over magnesium sulfate. The solvent was removed under a reduced pressure. The obtained product was purified by the silica gel column chromatography to obtain purified (2R,5S)-2-(4-benzyloxyphenyl)-5-hydroxymethyl-δ-valerolactone.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C@H:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH2:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)=O)=[CH:7][CH:6]=2)[CH2:2]1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C@H:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH2:12]/[C:13](/[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)=[N:30]\[OH:31])=[CH:7][CH:6]=2)[CH2:2]1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-3-(4-(azetidin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=386.0 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cnc2ccccc2n1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc2ccccc2n1

Procedure:
To a stirring solution of 2-methylquinoxaline (20.0 g, 155 mmol) and benzoyl peroxide (3 g, 12 mmol) in carbon tetrachloride (800 mL) was added 1,3-dibromo-5,5-dimethyl hydantoin (22 g, 77 mmol). The resulting mixture was irradiated with a spotlight (200 watt) for 1.5 hours. The mixture was cooled, filtered, and concentrated to afford crude product which was purified by HPLC (4:1 hexane/EtOAc) to yield 14.0 g (40%) of monobromomethyl product as a grey solid: 1H NMR (CDCl3): δ9.00 (s, 1H, ArH), 8.10 (m, 2H, ArH), 7.80 (m, 2H, ArH), 4.72 (s, 2H, BrCH2 --Ar); and 15.0 g (35%) of dibromomethyl product as a white solid: 1H NMR (CDCl3): δ9.39 (s, 1H, ArH), 8.15 (m, 2H, ArH), 7.90 (m, 2H, ArH), 6.76 (s, 1H, Br2CH--Ar).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C@:14]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:46])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:54][C:55]([O:57][CH3:58])=[O:56].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C>[CH2:1]([N:8]([CH2:54][C:55]([O:57][CH3:58])=[O:56])[CH2:9][CH2:10][NH:11][C:12]([C@:14]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:15]1[C@@H:16]1[C@@:29]([CH3:32])([CH2:30][CH2:31]2)[C@@:28]2([CH3:33])[C@@H:19]([C@:20]3([CH3:46])[C@@H:25]([CH2:26][CH2:27]2)[C:24]([CH3:35])([CH3:34])[C:23]([C:36]2[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=2)=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)OC)Cc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(benzylamino)ethylcarbamoyl)-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)benzoate (50 mg, 0.071 mmol), methyl 2-bromoacetate (32.5 mg, 0.213 mmol) and potassium carbonate (29.4 mg, 0.213 mmol) in dioxane (1 mL) and acetonitrile (1 mL) was heated up at 78° C. for 3 hours. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×4 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a white solid (45 mg, 82%). LCMS: m/e 777.48 (M+H)+, 3.12 min (method 1).