Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8](OCC)=[O:9])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC.C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1
Reactant: CCOC(=O)[C@@H]1CCCN(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN1CCC[C@@H](CO)C1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
A solution of (R)-ethyl 1-methylpiperidine-3-carboxylate (5.69 g, 33 mmol) in ether (20 ml) was added dropwise to a stirred solution of lithium aluminum hydride (36.6 ml of a 1M solution in THF, 36.6 mmol) in ether (85 ml) cooled to maintain a reaction temperature of 20° C. The mixture was stirred for 1.5 hours at ambient temperature and then water (1.4 ml), 15% aqueous sodium hydroxide solution (1.4 ml) and then water (4.3 ml) were added. The insolubles were removed by filtration and the volatiles removed from the filtrate by evaporation to give (R)-(1-methylpiperidin-3-yl)methanol (4.02 g, 94%) as a colourless oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26]C)=[O:25])[CH:18]=2)[C:13]2[N:28]=[CH:29][CH:30]=[CH:31][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.O1CCOCC1>[CH2:3]([C:10]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:18]=2)[C:13]2[N:28]=[CH:29][CH:30]=[CH:31][C:12]=2[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)Cc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
1N aqueous solution of sodium hydroxide (2 ml) was added to a solution of 2-benzyl-4-(3-methoxycarbonylmethylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (213 mg) in methanol (4 ml) and 1,4-dioxane (2 ml). After stirred at room temperature for 1 hour, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to give 2-benzyl-4-(3-carboxymethylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (163 mg) as powder.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9](OC(=O)N(C)C)[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](OC(OC)=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)N(C)C)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Yield: 44.2 %

Procedure:
The procedure of Example 17 was repeated except that 44.6 mg (0.0798 mmole) of 7α-(N,N-dimethylcarbamoyloxy)-20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-en-3β-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate to give 16.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate. In addition, 16.0 mg of 7α-(N,N-dimethylcarbamolyoxy)-20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-en-3β-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was 69% based on consumed 7α-(N,N-dimethylcarbamoyloxy)-20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-en-3β-yl acetate. The 1H-NMR spectrum of the product 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate obtained in Example 17.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[C:17](OC)=[O:18])=[N:9]1.O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH3:7][N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][OH:18])=[N:9]1
Reactant: COC(=O)c1cccc2nn(C)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cn1cc2c(CO)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a suspension of lithium aluminum hydride (14.27 g, 421 mmol) in tetrahydrofuran (315 mL) was added a solution of methyl 2-methyl-2H-indazole-4-carboxylate (40.0 g, 210 mmol) in tetrahydrofuran (106 mL) under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with diethyl ether at 0° C., water (15 mL), 10% aqueous sodium hydroxide solution (15 mL) and water (30 mL) were added and the mixture was stirred until gas generation stopped. The resulting precipitate was collected by filtration, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was triturated with ethyl acetate and hexane to give the title compound (30.7 g, yield 90%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].[NH:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31].C([BH3-])#N.[Na+]>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:35][CH2:34][CH2:33][C@H:29]4[C:30]([OH:32])=[O:31])[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCc1c(CN2CCC[C@H]2C(=O)O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (80 mg, 0.212 mmol) and L-proline (48.9 mg, 0.425 mmol) in Ethanol (10 mL) was stirred at room temperature for 15 min, then sodium cyanoborohydride (40.1 mg, 0.637 mmol) was added. The mixture was stirred at room temperature for 2 h. After concentration, the residue was partitioned between ethyl acetate and aqueous diluted HCl, washed with saturated brine. The organic phase was evaporated in vacuo. The residue was purified by mass Directed AutoPrep to afford 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-L-proline (E81) (26 mg) as a TFA salt.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:20]([NH:22][CH3:23])[CH3:21].CC(C)([O-])C.[Na+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH2:20]([N:22]([CH3:23])[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Reactant: CCNC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CCN(C)c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Yield: 82 %

Procedure:
A solution of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.915 mmol), N-ethyl-N-methylamine (0.258 ml, 3.00 mmol), X-phos (26.1 mg, 0.0546 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.6 mg, 0.00187 mmol) and sodium tert-butoxide (131 mg, 1.37 mmol) in dioxane (6 ml) was stirred under an argon atmosphere for 2 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (230 mg, 82.1%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[F:1][C:2]1[CH:7]=[C:6]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: c1cn[nH]c1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (4.88 g, 10 mmol), pyrazole (0.681 g, 10 mmol), Cu2O (0.143 g, 1 mmol), salicylaldoxime (0.549 g, 4 mmol), and Cs2CO3 (6.52 g, 20 mmol) in CH3CN (100 mL) was refluxed for 5 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/THF (1/2) and recrystallized from EtOH/H2O to give the title compound (1.90 g, 44% yield) as a pale yellow powder: mp 214-216° C.; 1H NMR (300 MHz, CDCl3) δ ppm 3.92 (3H, s), 6.44 (1H, t, J=9.0 Hz), 6.53 (1H, dd, J=1.9, 2.3 Hz), 7.30 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.34 (1H, d, J=1.9 Hz), 7.37-7.48 (5H, m), 7.61 (1H, dd, J=2.3, 12.4 Hz), 7.76 (1H, d, J=1.9 Hz), 7.79 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=2.3 Hz), 7.92 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 429 [M+H]+. Anal. Calcd for C23H17FN6O2: C, 64.48; H, 4.00; N, 19.62. Found: C, 64.41; H, 4.00; N, 19.54.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])(C)[CH3:9]>C(Cl)Cl>[C:11]([SiH:8]([CH3:9])[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN([SiH](C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
10 g (0.1 mol) of 1-methylpiperazine and 11.1 g (0.11 mol) of triethylamineare dissolved in 500 ml of methylene chloride and then the reaction mixtureis cooled to 0° C. A solution of 16.6 g (0.11 mol) of t-butyldimethylsilyl chloride in 20 ml of methylene chloride is slowly added to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture is passed through a silica gel column and the solvent is stripped off under reduced pressure. The residue is distilled under reduced pressure (115° C. to 120° C./0.5 mmHg) to afford 18.4 g of a colorless liquid compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1.CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CCOC(C)=O>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](O[C@H]1OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 95 °C

Procedure:
(3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)octahydropyrano[3,4-c]pyrrole (example 2: 646 mg, 1.35 mmol) was combined with 1,3-cyclopentanedione (200 mg, 2.03 mmol) and PTSA (26 mg, 0.135 mmol). Toluene (15 mL) was added to the reagents and the vessel was heated to 95° C. for 1 hr. The reaction was diluted with EtOAc and washed twice with 2N NaOH. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted with a 1 to 5% linear gradient of (10% NH4OH-methanol)/DCM which furnished the title compound. 1H-NMR (CD3OD): δ 1.38 (d, 3H, J=7.0 Hz), 2.20-2.44 (m, 4H), 2.55-2.84 (m, 3H), 2.80-3.24 (m, 2H), 3.34-3.80 (m, 3H), 4.24-4.34 (m, 1H), 4.42 (dd, 1H, J=2.5, 8.0 Hz), 4.78-4.92 (m, 1H), 5.09 (q, 1H, J=7.0 Hz), 6.96-7.02 (m, 2H), 7.20 (dd, 2H, J=6.05, 8.5 Hz), 7.39 (s, 2H), 7.76 (s, 1H) ppm. MS: (MH)+558.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH:8]1[CH2:13][CH:12]([C:14](OCC)=[O:15])[S:11][C:10]2[S:19][CH:20]=[CH:21][C:9]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.CCOCC>[OH:15][CH2:14][CH:12]1[S:11][C:10]2[S:19][CH:20]=[CH:21][C:9]=2[CH:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:13]1
Reactant: CCOC(=O)C1CC(OCOCCOC)c2ccsc2S1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOC1CC(CO)Sc2sccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
Compound 6 (23.5 g, 0.07 tool) was dissolved in tetrahydrofuran (50 ml). The solution was added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (3.3 g, 0.0875 mol) in anhydrous ether (100 ml) with cooling in ice. The mixture was stirred at ambient temperature for 15 hrs. The reaction was then cooled in ice and decomposed by carefully adding dropwise water (3.5 ml), 20% sodium hydroxide (2.6 ml) and water (12.3 ml). The mixture was diluted with ether (100 ml) and filtered. The solids were washed with ether. The combined ether solutions were washed with saturated sodium chloride, dried, filtered and concentrated in vacuo to yield 20.3 g 7 (50%) as a pale yellow oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>O1CCOCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 50 °C
Yield: 99 %

Procedure:
In a 3 L, 3-necked, round-bottomed flask was placed ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (139.4 g, 287 mmol) in dioxane (1.8 L). The mixture was added 2N lithium hydroxide (0.431 L, 861 mmol) and heated to 45-55° C. for 3 h. The mixture was concentrated in vacuo. The residue was added MTBE/water and acidified with concentrated HCl (until pH3) while keeping the temperature under 20° C. with an ice bath. The aqueous layer was separated and extracted with MTBE. The combined organic layers were washed several times with water until pH3 at the end of the washes. Acetonitrile and water were added to the MTBE solution and the mixture was concentrated in vacuo to give the title compound (130 g) without further purification. LCMS m/z=458.4.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][CH:18]=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[C:21]([CH2:24][N+]1C=CC=CC=1)(=O)[NH2:22].CNC>CO>[O:19]=[C:18]1[CH:17]=[C:16]([C:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=23)[CH:24]=[CH:21][NH:22]1
Reactant: NC(=O)C[n+]1ccccc1
Reactant: O=CC=Cc1c(-c2ccccc2)nn2ccccc12
Agent: CNC
Agent: [Cl-]
Solvent: CO
Product: O=c1cc(-c2c(-c3ccccc3)nn3ccccc23)cc[nH]1
Temperature: 200 °C
Yield: 24.8 %

Procedure:
A mixture of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylaldehyde (cis and trans mixture) (1.15 g) and 1-carbamoylmethylpyridinium chloride (0.80 g), 50% aqueous dimethylamine (0.44 g) and methanol (10 ml) was refluxed for 3 hours. The reaction mixture was evaporated in vacuo and the residue was heated for 10 minutes at 200° C. The resulting mixture was chromatographed on silica gel (80 g) with a mixture of chloroform and methanol (100:1). The fractions containing the object compound were combined and evaporated in vacuo and recrystallized from ethanol to give 3-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.33 g).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:40]=[CH:39][S:38][CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:40]=[CH:39][S:38][CH:37]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccsc1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccsc1
Reaction time: 2 h
Yield: 85 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)thiophene-3-sulfonamide (20 mg, 0.035 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 14 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)thiophene-3-sulfonamide (percentage yield: 85%), was obtained.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]1=[O:26].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:34]([NH:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:4]1=[O:26])(=[O:36])[CH3:35]
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C)c(C)c2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCN2C(=O)N(NC(C)=O)CC2c2ccc(C)c(C)c2)cc1
Reaction time: 0.75 h
Yield: 77.7 %

Procedure:
A solution of compound 1-amino-3-[2-(4-methoxy-phenyl)ethyl]-4-(3,4-dimethylphenyl)-2-imidazolidinone hydrochloride (300 mg, 0.80 mmol) in dichloromethane (3.0 mL) is cooled in an ice bath and triethylamine (0.26 mL, 1.8 mmol) is added, followed by dropwise addition of acetyl chloride (0.068 mL, 0.96 mmol). The reaction is stirred in the cold for 45 minutes and washed with 0.1 N aqueous HCl, H2O, 10% aqueous NaHCO3, and brine. The organic phase is dried (Na2SO4) and concentrated under reduced pressure. The residue is purified over silica (2.5% methanol/dichloromethane) to afford 237 mg (78% yield) of the desired compound. 1H NMR (CDCl3) δ 9.18 (s, 1H), 7.12 (m, 3H), 7.07 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz), 4.41 (t, J=8.4 Hz, 1H), 3.91 (t, J=8.4 Hz, 1H), 3.81 (s, 3H), 3.71 (m, 1H), 3.59 (t, J=8.1 Hz, 1H), 2.94 (m, 1H), 2.80 (m, 1H), 2.67 (m, 1H), 2.29 (s, 6H), 2.09 (s, 3H). MS 382 (MH+). Anal. Calcd. For C22H27N3O3¼H2O: C, 68.46, H, 7.18; N, 10.89. Found: C, 68.72, H, 6.97; N, 10.85.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[N:11]=[C:10]([C:12](Cl)=[O:13])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1.Cl>>[Cl:5][C:6]1[N:11]=[C:10]([C:12](=[O:13])[C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=2[Cl:22])[CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cccc(Cl)c1
Reactant: O=C(Cl)c1cccc(Cl)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cccc(Cl)n1)c1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
40.9 g AlCl3 is added in portions to a mixture of 26.4 g 6-chloro-2-pyridinecarboxylic acid chloride and 112 g 1,3-dichlorobenzene. The mixture is slowly heated until 130°-40° C. After standing overnight, it is added to a mixture of diluted HCl and crushed ice, basified and extracted with ethyl ether. The ethereal extracts are washed with water, dried and solvent evaporated (water pump). The residual deep green oil is crystallised from ethanol:water in the presence of decolorizing carbon. Yield: 10 g title compound, m.p. 103°-4° C.; UV (ethanol): λmax. 281 nm; ε: 14,500; Cl 37.02 (37.12).
Reaction SMILES: [NH2:1][C:2]([O:4][C@@H:5]([C@@H:48]([CH3:53])/[CH:49]=[CH:50]\[CH:51]=[CH2:52])[C@@H:6]([CH3:47])[C@H:7]([O:39][Si](C(C)(C)C)(C)C)[C@@H:8]([CH3:38])[CH2:9]/[C:10](/[CH3:37])=[CH:11]\[C@H:12]([CH3:36])[C@@H:13]([O:28][Si](C(C)(C)C)(C)C)[C@@H:14]([CH3:27])/[CH:15]=[CH:16]\[C:17]([N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])=[O:3].Cl.C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]([O:4][C@@H:5]([C@@H:48]([CH3:53])/[CH:49]=[CH:50]\[CH:51]=[CH2:52])[C@@H:6]([CH3:47])[C@H:7]([OH:39])[C@@H:8]([CH3:38])[CH2:9]/[C:10](/[CH3:37])=[CH:11]\[CH:12]([CH3:36])[CH:13]([OH:28])[CH:14]([CH3:27])/[CH:15]=[CH:16]\[C:17]([N:19]([CH3:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=[O:3]
Reactant: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)N(C)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C/C(C)=C\C(C)C(O)C(C)/C=C\C(=O)N(C)c1ccccc1
Temperature: 23 °C
Reaction time: 36 h
Yield: 31.5 %

Procedure:
To a solution of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N,4,6,8,10,12,14-heptamethyl-N-phenyl-2,7,15,17-octadecatetraenamide (70 mg, 0.091 mmol, 1 eq) in MeOH (10 mL) is added a MeOH solution of HCl (15.5 mL, 15 mL MeOH+0.5 mL 12N HCl). The resulting solution is stirred at 23° C. (36 hours). The pH is adjusted to 8 by the addition of solid NaHCO3 at 0° C. The solution was dried in vacuo, the residue was dissolved in CH2Cl2 (10 mL) and filter through Celite. HPLC purification provided the desired compound (15.5 mg, 32%) as a white solid: [α]25D=+225.7380 (c 0.25, CH2Cl2); HRMS ESI m/z 541.3588 (M+H+, C32H50O5N2 requires 541.3641).