Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[C:22]2[C:21]([S:23][CH3:24])=[C:20]([CH2:25][C:26]([O:28]CC3C=CC=CC=3)=[O:27])[CH:19]=[C:18]([CH3:36])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C>[CH2:3]([N:10]1[C:22]2[C:21]([S:23][CH3:24])=[C:20]([CH2:25][C:26]([OH:28])=[O:27])[CH:19]=[C:18]([CH3:36])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CSc1c(CC(=O)OCc2ccccc2)cc(C)c2c3ccccc3n(Cc3ccccc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1c(CC(=O)O)cc(C)c2c3ccccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
50 ml of ethanol and 50 ml of a 2N aqueous solution of sodium hydroxide was added to 1.16 g of benzyl (9-benzyl-4-methyl-1-methylthiocarbazol-2-yl)acetate, as obtained in Example 13a). The reaction mixture was stirred for 2 hours at room temperature, after which time it was acidified by adding a 1N aqueous solution of hydrochloric acid and then concentrated by evaporation under reduced pressure. Ethyl acetate was added to the residue thus obtained. The aqueous layer was extracted with ethyl acetate and the organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 20 g of silica gel with a 1:1 v/v mixture of hexane and ethyl acetate as the eluent, and then recrystallized from ethyl acetate and hexane, to yield 0.90 g of the title compound, melting at 219°-220° C.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH:10]1([C:13]([O:15]CC)=O)[CH2:12][CH2:11]1>CCOCC>[CH:10]1([C:13]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[OH:15])[CH2:11][CH2:12]1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CC1
Agent: [Mg]
Solvent: CCOCC
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CC1
Temperature: 25 °C

Procedure:
Magnesium metal (98.2 g) was stirred with 100 ml of anhydrous ether under nitrogen for 1 hr. 4-Fluorobromobenzene (700 g) was dissolved in 1750 ml of anhydrous ether. A 20 ml aliquot of the solution was added to the magnesium metal to initiate reaction. Once reflux had begun, the 4-fluorobromobenzene solution was added at such a rate as to maintain a gentle reflux. After the addition was complete, the mixture was heated under reflux for 1 hr. Ethyl cylopropylcarboxylate (180.6 g) was dissolved in 500 ml of anhydrous ether. After the Grignard solution had been cooled to ambient temperature, the solution was added dropwise such that a gentle reflux was maintained. After complete addition of the ester, the mixture was heated under reflux for 45 mins and cooled to ambient temperature. The reaction mixture was quenched with 500 ml of saturated aqueous ammonium chloride and 2 l of ice water. The ether layer was separated and the aqueous layer was extracted twice with ether. The ether extracts were combined and washed with water and saturated brine. The ethereal mixture was dried over sodium sulfate, filtered and the solvent removed under vacuum to provide a quantitative yield or cyclopropyl-bis-(4-fluorophenyl)methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].[C:28](Cl)(=[O:30])[CH3:29].N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:28](=[O:30])[CH3:29])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (100 mg, 0.249 mmol) (intermediate 1) was treated with acetyl chloride (22 mg, 0.299 mmol) in THF (10 ml) containing pyridine (23 mg, 0.299 mmol) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 30 min. THF was evaporated and the residue was washed with saturated sodium bicarbonate solution and water. The solid obtained was purified by silica gel column chromatography using 30% acetone-chloroform as eluent to obtain 25 mg of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 252° C.
Reaction SMILES: [C:1]([N:6]=[C:7](OCC)[CH2:8][CH2:9][CH2:10][CH3:11])(OCC)=[O:2].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>>[CH2:8]([C:7]1[NH:6][C:1](=[O:2])[N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([F:25])([F:26])[F:15])[N:24]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=NC(=O)OCC)OCC
Reactant: NNc1ccccc1C(F)(F)F
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Yield: 66 %

Procedure:
Ethyl-N-carbethoxyvalerimidate (from Example 4, Step B) was reacted with 2-(trifluoromethyl)phenylhydrazine according to the procedure of Example 4, Step C. Flash chromatography of the crude product on silica gel (gradient elution with 0.5-2% MeOH in CH2Cl2) gave a 66% yield of the title compound as white crystals, mp 124°-126° C.; homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 286 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Br)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[S:6].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][NH2:19]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[S:6])[NH:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:20])[CH3:14]
Reactant: CN(C)CCCN
Reactant: CC1(C)CN1P(=S)(Br)N1CC1(C)C
Solvent: C1CCOC1
Product: CN(C)CCCNP(=S)(N1CC1(C)C)N1CC1(C)C
Temperature: 25 °C
Yield: 35 %

Procedure:
In a similar manner 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)thiophosphinic bromide and about 170ml of THF are treated by dropwise addition with 0.02 moles of 3-dimethylaminopropyl amine in 25 millimeters of THF stirred for several hours at ambient temperature, filtered, concentrated by rotary evaporation, and vacuum distilled to produce about 35% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N-(3-dimethylaminopropyl)thiophosphinic amide.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].Cl>O.CN(C=O)C>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=c1c2cc(Cl)ccc2oc2c(Cl)c(O)ccc12
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc2c(=O)c3cc(Cl)ccc3oc2c1Cl
Reaction time: 4 h
Yield: 53.9 %

Procedure:
A mixture of 4,7-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), potassium carbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) was stirred at 60°-65° C. for 4 hours. After cooling the mixture, sodium hydroxide (4 g) and water (100 ml) were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from DMF gave 1.3 g of 4,7-dichloro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 262°-263° C. This compound gave a mass spectrum having a molecular ion peak at m/e 338.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([OH:6])=[O:5].N#N.[CH3:20][C:21](=[CH2:23])[CH3:22].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)C>[NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([O:6][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:5]
Reactant: C=C(C)C
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N#N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Yield: 78 %

Procedure:
10 g (42 mol) of (2S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken for 3 days, in an autoclave and under 20 atm. N2 pressure, in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4. Excess isobutylene was blown off, and 150 ml of diethyl ether and 150 ml of a saturated solution of NaHCO3 were added to the remaining solution. The phases were separated and the aqueous phase was extracted 2 times with 100 ml of diethyl ether on each occasion. The combined organic phases were washed with 2×100 ml of H2O and dried over Na2SO4. After the solvent had been removed in vacuo, 9.58 g (78%) of (1.6) were obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=CC1(c2ccc(Br)cc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccc(Br)cc2)CCCC1

Procedure:
To a stirred solution of 1-(4-bromophenyl)-cyclopentanecarbaldehyde (225) (51.0 g, 201.47 mmol) in methanol (400 mL), was added NaBH4 (15.31 g, 402.94 mmol) portion-wise at 0° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)=O>CCOCC>[C:1]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Oc1ccccc1)c1cc(O)c(O)c(O)c1

Procedure:
A reaction mixture was prepared containing 15 g. of anhydrous gallic acid, 8 g. of phenol, 4 ml. of phosphorous oxychloride and 200 ml. of anhydrous ether in a round-bottom flask. The mixture was heated to refluxing temperature for about 18 hours. The ether solvent was removed by evaporation. Water was added to the resulting residue and the pH of the aqueous layer adjusted to about 5 by the addition of dilute aqueous sodium hydroxide. Phenyl gallate, being insoluble at pH=5, separated and was extracted with ether. The ether extracts were separated and dried and the ether removed therefrom by evaporation. Recrystallization of the residue yielded phenyl gallate melting at about 190°-191° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[CH3:13]O>OS(O)(=O)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ncccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ncccc12
Yield: 90 %

Procedure:
To a solution of 1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (V) (0.39 g, 2.4 mmol) in dry MeOH (10 mL) was added concentrated H2SO4 (4 drops) and refluxed for 6 h under nitrogen. The solution was cooled and the solvent was evaporated under vacuum. The residue was partitioned between DCM and saturated NaHCO3 solution. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified on a flash silica gel column (100% DCM→100:3 DCM:MeOH) to produce methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VI) as a white solid (382 mg, 2.16 mmol, 90% yield). 1H NMR (CDCl3) δ ppm 4.08 (s, 3 H), 7.38 (m, 1 H), 8.63 (dd, J=8.10, 1.51 Hz, 1 H), 8.72 (dd, J=4.62, 1.41 Hz, 1H); ESIMS Found for C8H7N3O2 m/z 178.2 (M+H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C.[N:15]1[CH:20]=[CH:19][C:18](=[O:21])[CH:17]([C:22]([NH2:24])=[O:23])[CH:16]=1.C(O[CH:29]1[O:51][C@@H:50]([CH2:52][O:53][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:40]([O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]1[O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:32]([O:31][C@H:30]1[C@@H:40]([O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:50]([CH2:52][O:53][C:54](=[O:61])[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[O:51][C@@H:29]1[N:15]1[CH:20]=[CH:19][C:18](=[O:21])[C:17]([C:22]([NH2:24])=[O:23])=[CH:16]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: NC(=O)C1C=NC=CC1=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1cn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)ccc1=O
Reaction time: 2 h
Yield: 8.6 %

Procedure:
To a mixture of hexamethyldisilazane (50 mL, 239.77 mmol) and chlorotrimethylsilane (1.0 mL, 21.43 mmol) was added pyridine-4-one-3-carboxamide (1.38 g, 10.0 mmol) (Prepared by the procedure reported: W. C. J. Ross, J. Chem. Soc., C, 1816, (1966); W. Herz and D. R. K. Murty, J. Org. Chem., 26, 122, 1961). The mixture was refluxed with stirring for 2 h and then evaporated to dryness under vacuum and further dried under high vacuum for 2 h at 60° C. The dry gummy residue was suspended in freshly distilled 1.2-dichlorethane (50 mL) and to this suspension was added 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose (5.06 g, 10.0 mmol) and freshly distilled SnCl4 (1.0 mL, 8.52 mmol). The reaction mixture was refluxed for 1.5 h, cooled and diluted with CH2Cl2 (100 mL) and sat. aqueous NaHCO3 (25 mL). The mixture was filtered through celite and the bed was washed with CH2Cl2 (20 mL). The organic phase was separated, washed with water until the washings are neutral, dried over anhydrous sodium sulfate. The organic extract was evaporated to dryness to give a gummy residue. The residue was purified by flash chromatography over silica gel using CH2Cl2→EtOAc as the eluent. Pure fractions were pooled and concentrated to provide 0.50 g (9%) of 33 as white foam: 1H NMR (CDCl3): δ 4.94 (m, 3H, C4′H and C5′H), 6.12 (m, 1H), 6.20 (m, 1H), 6.32 (d, 1H) and 7.20-8.30 (m, 20H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN1CCOCC1

Procedure:
The title compound was prepared from N-(t-butoxycarbonyl)D-prolinal and morpholine according to the general method of Example 200; MS (ES+), m/e 271 [M+H]+.
Reaction SMILES: [SH2:1].Cl[CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8]>CO>[SH:1][CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8]
Reactant: S
Reactant: CO[Si](CCCCl)(OC)OC
Solvent: CO
Product: CO[Si](CCCS)(OC)OC
Temperature: 70 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
267.6 g of a methanol solution of 22% sodium hydrogensulfide anhydride (1.05 mol) was put into an autoclave with an internal volume of 1 liter, and the air was replaced by nitrogen. 0.3 mol of hydrogen sulfide was then blown in and the system was pressurized to 0.9 kgf/cm2 to oversaturate hydrogen sulfide. After heating the system up to 70° C., 198.7 g (1.0 mole) of 3-chloropropyltrimethoxy silane was dripped for 3 hours, and, during the dripping, 0.05 mol of hydrogen sulfide was blown into the system so that the pressure in the system was kept at 2.5 kgf/cm2. After the dripping, the temperature was raised to 100° C. and the system was aged for 1 hour, followed by cooling. By-product salts produced in the reaction were filtered away. The composition was analyzed by means of gas chromatography. 3-mercaptopropyltrimethoxy silane was obtained with a yield of 94.1%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>O1CCCC1CO.[C].[Pd]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C#Cc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Agent: [Pd]
Solvent: OCC1CCCO1
Product: CC(=O)Nc1ccc(CCc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Yield: 82.1 %

Procedure:
tert-Butyl 2-({4-[(4-acetamidophenyl)ethynyl]phenyl}acetyl)hydrazinecarboxylate (29 mg, 0.071 mmol) was dissolved in a mixture of tetrahydrofuran-methanol (1:1) and hydrogenated using a continuous hydrogenation reactor (trade name: H-CUBE, manufactured by ThalesNano) equipped with a 10%-palladium carbon cartridge. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=97:3) to give tert-butyl 2-({4-[(4-acetamidophenyl)ethyl]phenyl}acetyl)hydrazinecarboxylate (24 mg, yield 82%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:14][CH2:13][C@@H:12]([C@@H:11]2[C@:17]3([CH3:25])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:21]([C:20]=4[CH2:19][CH2:18]3)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]5([CH3:27])[CH3:26])=[CH:9][CH2:10]2)[CH3:16])[CH2:31][CH2:30]1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCN(C)CC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with 1-methylpiperazin and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(4-methylpiperazin-1-yl)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH3:28])[CH2:9]1)=O)(C)(C)C.[F:29][C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH2:39])[CH:33]=[C:34]([F:36])[CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([CH2:37][CH2:38][NH:39][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]4[CH3:28])[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cc(F)cc(F)c1
Product: C[C@@H]1CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 111 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 425. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.72 (s, 1H), 8.36 (t, 2H), 7.97 (d, 1H), 7.73 (d, 1H), 7.69 (d, 1H), 7.01 (d, 2H), 6.72 (s, 1H), 4.43 (d, 1H), 4.05 (m, 3H), 3.55 (m, 6H), 3.39 (m, 1H), 3.06 (t, 2H), 1.77 (d, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]C)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:26][CH:25]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 61.1 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.262 g, 1.19 mmol) the acid chloride was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.242 g, 2.39 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-octylbenzamide (0.220 g, 69% yield). 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 2H), δ 7.37 (t, 1H), δ 7.17 (d, 2H), 63.56 (q, 2H), δ 3.44 (t, 2H), δ 2.59 (t, 2H), δ 1.58 (m, 2H), δ 1.27 (m, 10H), 60.86 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.4, 147.3, 131.7, 128.8, 127.4, 50.9, 39.7, 36.1, 32.1, 31.5, 29.7, 29.5, 29.5, 22.9, 14.3 ppm; HRMS (ESI) calcd for C17H28N4O (M+) 302.2107. found 302.2104.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[N:28]2[CH:29]=[C:30]([CH2:33][O:34]S(C)(=O)=O)[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+].[F:45][CH:46]([F:49])[CH2:47]O>>[F:45][CH:46]([F:49])[CH2:47][O:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]2[N:28]([C:24]([C:22]([NH:21][C:3]3[CH:4]=[C:5]([C:8]4[N:12]=[C:11]([CH:13]5[CH2:16][N:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]5)[O:10][N:9]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[O:23])=[CH:25][N:26]=2)[CH:29]=1
Reactant: OCC(F)F
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(COS(C)(=O)=O)cn45)c3)no2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(COCC(F)F)cn45)c3)no2)C1

Procedure:
Methyl 3-(3-(4-methyl-3-(6-(((methylsulfonyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (133) (15.0 mg, 0.028 mmol) and K2CO3 (8.3 mg, 0.06 mmol) in 2,2-difluoroethanol (0.5 mL) was heated at 120° C. for 5 minutes. The reaction mixture was purified by preparative HPLC to afford methyl 3-(3-(3-(6-((2,2-difluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F95). MS m/z 527.1 (M+1)+.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17]Br.N(OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:17][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1N
Reactant: BrBr
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-amino-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonitrile and 3 ml of bromine in 50 ml of chloroform was added 1.7 g of isoamyl nitrite. The reaction mixture was stirred at room temperature for approximately 10 minutes and then refluxed for approximately one hour. The solution was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel employing toluene as the eluent. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 0.8 g of 5-bromo-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbonitrile after crystallization from 3A alcohol. mp=101°-102° C.