Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:16]([O:18][CH3:19])=[O:17]>C(O)C.[OH-].[Pd+2].[OH-]>[C@H:1]12[N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1=CC[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1CC[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
(1S,5R)-8-tert-butyl 2-methyl 8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate (5.45 g) was dissolved in ethanol (200 mL), Palladium hydroxide (20% wt, 2.73 g) was added. After vacuum degassed, the reaction mixture was hydrogenated under hydrogen balloon overnight. After filter through a pad of celite, washed with ethanol, the filtrate was concentrated to give 5.49 g of crude product. The crude was brought to next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([O:16]C(C)(C)C)=[O:15]>C(Cl)Cl>[Cl:8][C:9]1[C:10]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
Trifluoroacetic acid (1.04 mL, 14 mmol) was added to a mixture of tert-butyl 5-chloro-4-(3,4-dichlorophenylthio)-2-fluorobenzoate (571 mg, 1.40 mmol) in DCM (10 mL) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated to dryness to give the title compound as a white solid (492 mg, 100%). No further purification.
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([CH3:34])=[N:9][C:10]2[CH2:11][CH2:12][N:13]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:14][C:15]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[C:3]([O:5][CH3:6])=[O:4].C(O[C:39]([CH3:42])([CH3:41])[CH3:40])(=O)C>C(Cl)Cl>[C:39]([O:1][CH:2]([C:7]1[C:8]([CH3:34])=[N:9][C:10]2[CH2:11][CH2:12][N:13]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:14][C:15]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.5 %

Procedure:
To a solution of benzyl 3-(1-hydroxy-2-methoxy-2-oxoethyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 11) (0.10 g, 0.217 mmol) in CH2Cl2 (3 ml) was added tert-butyl acetate (2.05 ml, 15.2 mmol) followed by HClO4 (0.056 ml, 0.651 mmol). The flask was sealed and stirred at room temperature for 2.5 h. The reaction was quenched with sat'd aq NaHCO3 (gas evolution). The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (Biotage; 0%-30% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give benzyl 3-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (82.4 mg, 72% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.01-7.78 (m, 9H), 5.13 (s, 2H), 4.97 (s, 1H), 4.29-4.32 (m, 1H), 4.05-4.10 (m, 1H), 3.78-3.81 (m, 2H), 3.71 (s, 3H), 3.06 (bs, 2H), 2.64 (s, 3H), 2.45 (s, 3H) 0.99 (s, 9H). LCMS (M+H) calcd for C31H37N2O5: 517.27. found: 517.4.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[O:9]1[C:13]2([CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[C:19](OCC)=[O:20])[O:12][CH2:11][CH2:10]1>C1COCC1>[C:1]([CH2:2][C:19]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]21[O:9][CH2:10][CH2:11][O:12]2)=[O:20])#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)C1CCCCC12OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC12OCCO2
Yield: 47.9 %

Procedure:
To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 mL) was added ethyleneglycol (10.1 g) and p-toluenesulfonic acid (2.8 g) at room temperature and the mixture was heated under reflux with Dean-Stark apparatus for five hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-BuLi (160 mmol) at −78° C. Further, ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyano-2-(1,4-dioxa-spiro[4,5]decan-6-yl)ethan-2-one (14.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2-(1,4-dioxa-spiro[4,5]-decan-6-yl)ethan-2-one (1.2 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.3 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:47]=[O:48])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:6]=1[CH2:7][CH2:8][CH3:9].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([CH:47]=[O:48])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1c(Br)cc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: CCCc1c(Br)cc(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 52 %

Procedure:
This compound was prepared using the same procedure as in Example 1.10 g of 4-bromo-5-n-propyl-1-[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]-2-pyrrolaldehyde (0.015 moles) and 19 mL of 4N HCl (0.075 moles) yield 3.5 g of product. Formula: C22H20BrN5O (m.w. 450.34). Yield 52%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[CH3:39][Si:40]([CH3:59])([CH3:58])[C:41]#[C:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:48]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:42]#[C:41][Si:40]([CH3:39])([CH3:59])[CH3:58])=[CH:10][CH:9]=2)[C:5]([C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:26][CH2:27]4)[CH:20]=[N:19][CH:18]=2)=[N:6]1
Reactant: CC1(C)OB(c2ccccc2C#C[Si](C)(C)C)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccccc5C#C[Si](C)(C)C)cc34)n2)C1
Temperature: 160 °C
Yield: 59.6 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (159 mg, 0.272 mmol), trimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethynyl)silane (123 mg, 0.408 mmol), PdCl2(Amphos) (19.26 mg, 0.027 mmol), and potassium carbonate (408 μL, 0.816 mmol) in dioxane (2720 μL) was heated in the microwave for 10 min at 160° C. The crude was purified via automated flash chromatography (silica gel) with 100% hexanes to 20% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(2-((trimethylsilyl)ethynyl)phenyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (110 mg, 0.162 mmol, 59.7% yield) as a yellowish oil. MS (ESI, pos. ion) m/z: 678.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH2:43][NH2:44].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>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]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:44][CH2:43][C:42]5[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=5[Cl:40])[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Reactant: NCc1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccccc5Cl)c4)nn(COCC[Si](C)(C)C)c3n2)CC1

Procedure:
To a stirred solution of {4-[3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 39 supra) (300 mg, 0.486 mmol), 2-chlorobenzylamine (83 mg, 0.583 mmol), DavePhos (38 mg) and t-BuONa (56 mg, 0.58 mmol) in 1,4-dioxane (5 mL), Pd2(dba)3 (28 mg, 0.48 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100° C. for 4 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:EtOAc, 3:1, v/v) to give {4-[3-[3-(2-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 110 mg, 33%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][N:70]=[C:69]([N:73]3[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]3)[CH:68]=2)[C:56]=1[CH3:80].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][N:70]=[C:69]([N:73]5[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]5)[CH:68]=4)[C:56]=3[CH3:80])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccnc(N3CCN(C)CC3)c2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccnc(N3CCN(C)CC3)c2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.041 mmol), 2,5-dimorpholinopyridin-3-amine (0.082 g, 0.31 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)quinoline (0.10 g, 0.26 mmol) and Pd2dba3 (0.009 g, 0.010 mmol) and sodium tert-butoxide (0.072 g, 0.75 mmol) in toluene (2.6 mL) at 100° C. for 1.6 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25 (1H, d, J=5.5 Hz), 7.80 (1H, d, J=6.3 Hz), 7.62-7.67 (1H, m), 7.55 (1H, d, J=2.5 Hz), 7.49 (1H, ddd, J=13.2, 9.2, 2.6 Hz), 6.93 (1H, s), 6.81 (1H, dd, J=5.0, 1.1 Hz), 6.44 (1H, d, J=2.7 Hz), 3.79-3.61 (8H, m), 3.48-3.56 (4H, m), 3.14 (2H, br. s.), 2.99 (4H, d, J=2.2 Hz), 2.83 (2H, br. s.), 2.36-2.44 (4H, m), 2.22 (3H, s), 1.99 (3H, s). Mass Spectrum (ESI) m/e=617.3 (M+1).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[S:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[S:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.[Na+:2]
Reactant: COC(=O)c1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
360 μl of a 1N aqueous solution of sodium hydroxide were added to a solution of 34 mg of methyl 4-[3-(4-chlorophenyl)-1-(imidazol-1-ylmethyl)propylthio]benzoate (prepared as described in Example 31) in 360 μl of methanol, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then treated and purified by the same method as described in Example 8, to give 21 mg of the title compound as a colorless powder.
Reaction SMILES: [Si]([O:8][C:9]([C@:11]12[CH2:55][CH2:54][C@@H:53]([C:56]([CH3:58])=[CH2:57])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:52])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH2:51][C:35]4([CH2:38][C:37]([C:45]([O:47][CH:48]([CH3:50])[CH3:49])=[O:46])([C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:36]4)[CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.Cl>[CH:48]([O:47][C:45]([C:37]1([C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:38][C:35]2([CH:34]=[C:33]([C:20]3[C:21]([CH3:32])([CH3:31])[C@H:22]4[C@:17]([CH3:52])([CH2:18][CH:19]=3)[C@@H:16]3[C@:25]([CH3:30])([C@@:26]5([CH3:29])[C@H:13]([CH2:14][CH2:15]3)[C@H:12]3[C@H:53]([C:56]([CH3:58])=[CH2:57])[CH2:54][CH2:55][C@:11]3([C:9]([OH:10])=[O:8])[CH2:28][CH2:27]5)[CH2:24][CH2:23]4)[CH2:51]2)[CH2:36]1)=[O:46])([CH3:50])[CH3:49]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((tert-butyldimethylsilyl)oxy)carbonyl)-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)spiro[3.3]hept-5-ene-2,2-dicarboxylate (0.026 g, 0.021 mmol (based on 65% purity)) in THF (2 mL) was added TBAF (75% in water) (10.81 mg, 0.031 mmol). The mixture was stirred at rt for 30 minutes, then was diluted with 15 mL of 1N HCl and was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(6,6-bis(isopropoxycarbonyl)spiro[3.3]hept-1-en-2-yl)-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]chrysene-3a-carboxylic acid (0.024 g, 0.021 mmol (based on 60% purity), 100% yield). The material was used in the next step with no additional purification. LCMS: m/e 701.5 (M−H)−, 3.35 min (method 3). 1H NMR (400 MHz, chloroform-d) δ=10.58 (br. s., 1H), 5.87 (s, 1H), 5.52 (d, J=4.8 Hz, 1H), 5.13-5.02 (m, 2H), 4.75 (s, 1H), 4.62 (br. s., 1H), 3.07-2.97 (m, 1H), 2.70 (s, 4H), 2.63-2.55 (m, 2H), 1.70 (s, 3H), 2.54-0.77 (m, 49H). The material was used in the next step with no additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][NH2:30])[N:24]=1.O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:12]([CH3:13])=[N:30][N:29]([C:25]3[N:24]=[C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)[CH:28]=[CH:27][N:26]=3)[C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C(SCc1ccc(Cl)cc1)C(C)=O
Reactant: NNc1nccc(-c2ccccn2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
To a solution of 3-(4-chloro-benzylsulfanyl)-pentane-2,4-dione (1.15 g, 4.48 mmol) in ethanol (60 mL) was added (4-pyridin-2-yl-pyrimidin-2-yl)-hydrazine (0.838 g, 4.48 mmol) and p-toluenesulfonic acid monohydrate (ca. 20 mgs). The solution was heated to reflux and stirred for 5 hours. The reaction mixture was allowed to cool to room temperature, and water (200 mL) was added. The precipitate that formed was isolated by filtration and recrystallized from aqueous methanol to provide 1.36 g (74%) of the product as white needles: 1H NMR (CDCl3) δ 8.94-8.92 (m, 1H), 8.75-8.73 (m, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.28-8.26 (m, 1H), 7.91 (t, J=7.9 Hz, 1H), 7.46-7.43 (m, 1H), 7.20 (d, J=8.0 Hz, 2H), 6.89 (d, J=8.0 Hz, 2H), 3.66 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H) ppm. 13C NMR (CDCl3) δ 164.6, 160.5, 157.4, 155.2, 153.5, 149.8, 147.3, 137.6, 137.2, 133.1, 130.6, 128.7, 126.1, 122.2, 114.7, 111.3, 40.1, 14.2, 12.6 ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=2)=[CH:7][C:6]=1[F:8]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: COc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1OC

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 3,4-dimethoxyphenyboronic acid (step 1) to give 1,2-difluoro-4-(3,4-dimethoxypheny)-5-[4(methylsulfonyl)phenyl]benzene as a colorless solid: mp 140.0-141.0° C.; NMR (CDCl3) δ 3.04 (s, 3H), 3.61 (s, 3H), 3.86 (S, 3H), 6.48 (d, J=2 Hz, 1H), 6.65 (dd, J=2, 8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 7.17-7.29 (m, 2H), 7.31 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H); MS (FAB) m/z 411 (M+Li)+; HRMS calc'd for M+ 404.0894, found 404.0893. Anal. Calc'd for C21H18F2O4S (0.24 H2O): C, 61.70; H, 4.51. Found: C, 61.69; H, 4.56.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[OH:15])=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][O:22][C:23](=O)[O:24]N2C(=O)CCC2=O)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][O:22][C:23]([N:12]2[CH2:13][CH2:14][C@H:9]([CH2:8][NH:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C@H:10]([OH:15])[CH2:11]2)=[O:24])=[CH:19][CH:18]=1
Reactant: OC1CNCCC1CNc1ccncc1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(COC(=O)N2CC[C@H](CNc3ccncc3)[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of the 4-(pyridin-4-ylaminomethyl)-piperidin-3-ol from Step 2 above (0.076 g, 0.367 mmol) in DMF (1.5 mL) was treated with carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-methyl-benzyl ester (0.097 g, 0.37 mmol) (INTERMEDIATE 1A) and the resulting reaction mixture stirred at rt for 5 min. The mixture was then partitioned between dilute sodium carbonate solution and EtOAc. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a crude product. Purification by flash column chromatography (DCM to 80/20/2 DCM MeOH NH4OH) afforded the cis 3-hydroxy-4-(pyridin-4-ylaminomethyl)-piperidine-1-carboxylic acid 4-methyl-benzyl ester compound. M.S (M+1): 356.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]2[C:5]([CH:6]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:38]=[O:39])C>C1COCC1>[Si:13]([O:12][CH:6]1[CH2:7][CH2:8][NH:9][C:10]2[N:11]=[C:2]([CH:38]=[O:39])[CH:3]=[CH:4][C:5]1=2)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](OC1CCNc2nc(Br)ccc21)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCNc2nc(C=O)ccc21)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 7-bromo-4-((tert-butyldiphenylsilyl)oxy)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 72, 400 mg, 0.856 mmol) in THF (6 ml) at −78° C. was treated with n-BuLi (1.6 M in hexane, 1.34 ml, 2.14 mmol). The reaction mixture was stirred 15 min at −78° C. and then, the solution was warmed up to −20° C. and stirred at this temperature for 30 min. The mixture was then cooled to −78° C., treated with DMF (0.66 mL, 8.6 mmol), stirred at −78° C. for 15 min and then warmed up to −20° C. and stirred at −20° C. for 30 min. The reaction was quenched with water and extracted with DCM (3×). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (heptanes/EtOAc) to give the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.66-9.71 (m, 1H), 7.63-7.69 (m, 2H), 7.43-7.56 (m, 6H), 7.35-7.42 (m, 2H), 7.21 (br. s., 1H), 7.01 (d, 1H), 6.88 (d, 1H), 4.80-4.85 (m, 1H), 3.43-3.52 (m, 1H), 3.23-3.31 (m, 1H), 1.77-1.87 (m, 1H), 1.56-1.67 (m, 1H), 1.00 (s, 9H).