Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20](O)=[O:21].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[C:27]2[CH3:33].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[C:27]2[CH3:33])=[O:21]
Reactant: Cc1n[nH]c2ccc(N)cc12
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(C)c3c2)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.1 %

Procedure:
The product of Example 21, Step 2 (200 mg, 0.63 mmol, 1.00 equiv), 5-amino-3-methylindazole (93 mg, 0.63 mmol, 1.0 equiv), and EDC (145 mg, 0.757 mmol, 1.20 equiv) were suspended in 1.75 mL DMF. Et3N (0.106 mL, 0.757 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 65 mg (23%) of the title compound as an off white solid. MS (ES+) m/e 447 [M+H]+
Reaction SMILES: [C:1]([O:4][CH:5](C(=O)C)[CH2:6][CH:7]1[C:9]([CH3:11])([CH3:10])[CH:8]1[CH:12]=[C:13]([Cl:15])[Cl:14])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.ClC1C=CC=[C:26]([C:30]([O:32]O)=[O:31])C=1.CSC>ClCCl>[C:30]([O:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C@H:7]1[C:9]([CH3:10])([CH3:11])[C@H:8]1[CH:12]=[C:13]([Cl:14])[Cl:15])(=[O:31])[CH3:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OC(CC1C(C=C(Cl)Cl)C1(C)C)C(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)OC(C[C@@H]1[C@H](C=C(Cl)Cl)C1(C)C)OC(C)=O
Temperature: 20 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
The contents of a 50-ml flask charged with 1-[2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropyl]-3-oxo-2-butyl acetate prepared as in Embodiment VI above (11.9 mmol, 100% (1R,cis) both spatial configurations around C--C(O)CH3 present), chloroform (10 ml) and 3-chloroperbenzoic acid (26 mmol) were stirred magnetically for five hours at 20° C. Then, another quantity of 3-chloroperbenzoic acid (6 mmol) was added and stirring was continued for 16 hours. The reaction mixture obtained was mixed with dimethyl sulphide (2 ml), keeping the temperature at 20° C., stirring was continued for 15 minutes, dichloromethane (30 ml) was added, the suspended material was filtered off, the filtrate was washed with two 20-ml portions of a saturated aqueous solution of sodium hydrogen carbonate and two 20-ml portions of a 10%w aqueous solution of sodium chloride. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated (2 kPa) from the dried liquid to leave a residue (2.3 g) containing the desired (100% (1R,cis), yield 63%). The nuclear magnetic resonance spectrum of this product showed the following absorptions (using a solution of this product in deuterochloroform and relative to a tetramethylsilane standard):
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:2][CH:3]=[CH2:4].C([Si]([O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)(C)C)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:5]1([CH2:1][CH2:2][CH:3]=[CH:4][C:21]2[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=2)[CH:9]=[CH:8][N:7]=[N:6]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Reactant: C=CCCn1ccnn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Oc1ccc(C=CCCn2ccnn2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3.00 g (24.4 mmol) 1-but-3-enyl-1H-[1,2,3]triazole, 6.79 g (20.3 mmol) tert-butyl-(4-iodo-phenoxy)-dimethyl-silane, 1.07 g (4.06 mmol) triphenylphosphine, 0.685 g (3.05 mmol) palladium(II)acetate and 56 ml triethylamine was heated to reflux for 24 h. The reaction mixture was cooled to r.t., evaporated, stirred with ice and adjusted to pH=1 by addition of conc. HCl. The organic material was collected with ethyl acetate/dichloromethane 1:2, the organic phase dried over sodium sulfate and evaporated. The residue was stirred with 20.3 ml 1M solution of tetrabutylammonium fluoride solution in THF at 28° C. for 3 h. After removal of THF, the residue was dissolved in dichloromethane, washed with water, evaporated and purified by chromatography on silica gel (ethyl acetate/n-heptane 5:1). The product containing fractions were collected, evaporated and stirred with little ethyl acetate/n-heptane 3:1 to yield 1.53 g (29%).
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][NH:32][CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:37](OC(OC)=O)(OC)=O.CCN(C(C)C)C(C)C>CN(C)C=O>[CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)OC(=O)OC
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a solution of 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 180 mg, 0.300 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (5 mL) were added dimethyl dicarbonate (176 mg, 1.31 mmol, 5.00 equiv) and DIEA (169 mg, 1.31 mmol, 5.00 equiv). The resulting solution was stirred overnight at 25° C. and then quenched with 20 mL of methanol. The resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC using the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (28% CH3CN up to 43% in 8 min, up to 100% in 3 min, down to 28% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 29.9 mg (19%) of the title compound as a white solid. m/z (ES+) 538 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.70 (m, 2H), 7.50-7.35 (m, 4H), 4.90 (m, 1H), 4.70 (s, 2H), 4.00 (m, 2H), 3.80 (m, 4H), 3.60 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.50 and 2.40 (2 singlets, amide rotamers, ArCH3, 3H), 2.16-2.00 (m, 6H), 1.86-1.64 (m, 4H).
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4][NH:3][CH2:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34]Cl)=[CH:27][CH:26]=1>CC(C)=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[C:12]([NH:13][C:14](=[O:15])[CH:5]3[CH2:4]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:29][CH:30]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: O=C1Nc2ccccc2N2CCNCC12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCN1CCN2c3ccccc3NC(=O)C2C1)c1ccc(F)cc1

Procedure:
A mixture of 1.3 g. of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 1.9 g. sodium iodide, 0.9 g. potassium carbonate, 2.6 g. of p-fluoro-γ-chloro butyrophenone and 50 ml. of acetone is refluxed for 20 hours under a nitrogen atmosphere. The reaction mixture is filtered and concentered. The residue is washed with ethyl acetate and filtered. The filtrate is acidified with hydrogen chloride and filtered to give 1.5 g. of solid product, m.p. 140°-180°. Recrystallization of the solid from ethanol-ether gives 0.85 g. of product, m.p. 145°-150°.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:17]=[C:18]2[C:33]([CH3:34])=[N:32][N:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:19]2=[N:20][C:21]=1[N:22]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.[C:48]([NH2:53])(=[O:52])[CH:49]([CH3:51])[CH3:50].N[C@@H]1CCCC[C@H]1N.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[CH:24]1([CH2:23][N:22]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:21]2[N:20]=[C:19]3[N:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:32]=[C:33]([CH3:34])[C:18]3=[CH:17][C:16]=2[CH2:15][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:47])([F:46])[F:1])[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=2)[C:8]2[N:13]=[CH:12][C:11]([NH:53][C:48](=[O:52])[CH:49]([CH3:51])[CH3:50])=[CH:10][N:9]=2)[CH2:26][CH2:25]1
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(Br)cn3)cc12
Reactant: CC(C)C(N)=O
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(NC(=O)C(C)C)cn3)cc12
Temperature: 80 °C
Reaction time: 72 h

Procedure:
5-(((3,5-Bis(trifluoromethyl)benzyl)(5-bromopyrimidin-2-yl)amino)methyl)-1-(tert-butyl)-N,N-bis(cyclopropylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-amine (150 mg, 0.207 mmol) and isobutyramide (0.018 g, 0.207 mmol) were dissolved in 1,4-dioxane (5 ml) in a sealed tube to which 1,2-transdiaminocyclohexane (0.007 g, 0.062 mmol), and CuI (0.007 g, 0.078 mmol) were added. The reaction mixture was de-gassed for 15 min with argon. K2CO3 (0.057 g, 0.414 mmol) was added to the reaction mixture and it was further degassed with argon for 15 min. The reaction mixture was then stirred at 80° C. for 3 days. Thereafter the reaction mixture was diluted with DCM-MeOH (3:1) mixture (10 ml), filtered through celite. The filtrate was concentrated under reduced pressure; purified by column chromatography using 60-120 silica gel and 25% EtOAc in petroleum ether as the eluent to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O.FC(F)(C1C=CC=CC=1)COCCCCCCN>>[F:1][C:2]([F:29])([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: Cc1cccc(C(F)(F)COCCCCCCN2C(=O)c3ccccc3C2=O)c1
Agent: NCCCCCCOCC(F)(F)c1ccccc1
Product: Cc1cccc(C(F)(F)COCCCCCCN)c1

Procedure:
Obtained from Intermediate 31 (4.0 g, 14.4 mmol) by the procedure described in Intermediate 9. {6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amine was obtained (1.93 g, 50%) as oil.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC(C2C=CC=CC=2)=C[C:30]=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:30][CH:26]=3)=[CH:13][C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)sc1NS(=O)(=O)c1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5-phenylthiophene-3-carboxylate and benzenesulphonyl chloride
Reaction SMILES: [CH:1]1([NH:7][S:8]([CH2:11][Br:12])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]([Cl:20])([S:18]Cl)[CH:15]([Cl:17])[Cl:16]>C(N(CC)CC)C>[CH:1]1([N:7]([S:18][C:14]([Cl:20])([Cl:13])[CH:15]([Cl:17])[Cl:16])[S:8]([CH2:11][Br:12])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(CBr)NC1CCCCC1
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(CBr)N(SC(Cl)(Cl)C(Cl)Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5.1 g (0.051 mol) sample of triethylamine was added dropwise to a cooled (20° C.) solution of 11 g (0.043 mol) N-cyclohexylbromomethanesulfonamide and 10.1 g (0.043 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride. After the addition was completed, the reaction was stirred at ambient temperature for 2 hours and then under reflux for 2 hours. The reaction mixture was then cooled, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the N-cyclohexyl-N-(1,1,2,2-tetrachloroethylthio)-bromomethanesulfonamide product, which after crystallization from dioxane melted at 38°-40° C. The elemental analysis for the product is tabulated in Table I under Compound No. 8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:20][CH:19]=3)[N:11]=2)[CH:3]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].CCCCCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[F:16][C:15]1[C:10]([NH:9][C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:7]=[CH:6][C:5]=2[OH:8])=[N:11][C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:20][CH:19]=2)=[N:13][CH:14]=1
Reactant: C=CC(=O)Cl
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cc(N)ccc3O)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)Nc1ccc(O)c(Nc2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 3.2 %

Procedure:
To a 25 mL 3-neck RBF previously equipped with a magnetic stirrer and CaCl2 guard tube was added 4-amino-2-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenol (0.075 g in 5 mL DCM) and it was cooled to −40° C. and acryloyl chloride (0.019 g in 3 mL DCM) was slowly added. The reaction was warmed to room temperature and stirred for 30 min. The reaction was monitored on TLC using hexane:ethyl acetate (7:3) as mobile phase. The reaction was complete after 30 min. The reaction mixture was poured in water (100 mL) and basified using sodium bicarbonate. The mixture was extracted with DCM (2×25 mL) and the combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated completely under reduced pressure at 40° C. Crude material was purified by preparative-HPLC to give 2.7 mg of N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)-4-hydroxyphenyl)acrylamide. 1H NMR: DMSO-d6 (400 MHz) 3.25 (s, 3H), 3.58 (s, 2H), 3.91 (s, 2H), 5.70 (d, 1H, J=10), 6.20 (d, 1H, J=16.8), 6.39 (dd, 1H, J=10.4, 17.2), 6.65 (d, 2H, J=8.8), 6.87 (d, 1H, J=8.8), 7.45 (m, 3H), 7.78 (s, 1H), 8.01 (s, 1H), 8.21 (s, 1H), 8.48 (s, 1H), 8.92 (s, 1H), 9.98 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](O)[C:15]([F:22])([F:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(=O)C(OC)=O.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N>CN(C1C=CN=CC=1)C.C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([F:22])([F:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(F)(F)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CN(C)c1ccncc1
Agent: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)(F)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of 2.25 g (6.7 mmol) of ethyl 3-(1-(t-butoxycarbonyl)-piperidin-4-yl)-3-hydroxy-2,2-difluoropropionate (from EXAMPLE 176, Step A) and 2.50 g (20.5 mmol) of 4-(N,N-dimethylamino)pyridine in 40 mL of CH2Cl2 at 0° C. was treated with 1.10 mL (12.0 mmol) of methyl chlorooxoacetate. The resulting mixture was warmed to rt, stirred for 1 h, then quenched with 100 mL of 0.5 N KHSO4. The quenched mixture was extracted with 250 mL of EtOAc; the extract was dried and concentrated. The crude oxalate ester, 3.70 mL (12.0 mmol) of tris(trimethylsilyl)silane and 500 mg (3.0 mmol) of 2,2′-azobisisobutyronitrile in 20 mL of toluene was heated at reflux under an Ar atmosphere for 1.5 h. The reaction mixture was cooled and concentrated. Flash chromatography on 75 g of silica gel using 10:1 v/v, then 4:1 v/v hexanes/ether as the eluants afforded 922 mg (43%) of the title compound as an oil: 1H NMR (500 MHz, CDCl3) δ 1.16-1.25 (m, 2H), 1.36 (t, J=7.0, 31), 1.46 (s, 9H), 1.74 (app d, J=15.0, 2H), 1.75-1.81 (m, 1H), 2.02 (dt, J=6.0, 18.0,22H), 2.68-2.73 (m, 2H), 4.05-4.09 (m, 2H), 4.33 (q, J=7.0, 2H).
Reaction SMILES: [Br:1][C:2]#[C:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C:10]1=[CH:9][C:8](=[O:24])[CH2:7][CH2:6]2.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C.C(OCC)(=O)C>[Br:1][C:2]#[C:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH:12]=[CH:11][C:10]1=[CH:9][C:8](=[O:24])[CH2:7][CH2:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CC#CBr)[C@@H]1CCC2=O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43CC#CBr)[C@@H]1CCC2=O
Yield: 45 %

Procedure:
A mixture of 313 mg of 10β-(3-bromo-2-propynyl)estr-4-ene-3,17-dione and 575 mg of chloranil in 21 ml of tert-butyl alcohol is heated at reflux for 2 hours. The mixture is diluted with ethyl acetate and filtered and the filtrate is washed with aqueous 1N sodium hydroxide, with brine and dried over sodium sulphate. The solvent is then evaporated and the residue chromatographed on silica gel using ethylacetate/n-hexane to give 140 mg of the title compound.
Reaction SMILES: C(O[CH2:5][C:6]([CH2:8][Si](C)(C)C)=[CH2:7])(=O)C.C(OC)(=O)/C=C\C(OC)=O.[C:23]([O:26][C:27](=[O:29])[CH3:28])(=[O:25])[CH3:24]>[Pd]>[CH2:5]=[C:6]1[CH2:8][CH:24]2[C:23](=[O:25])[O:26][C:27](=[O:29])[CH:28]2[CH2:7]1
Reactant: CC(=O)OC(C)=O
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: [Pd]
Agent: COC(=O)/C=C\C(=O)OC
Product: C=C1CC2C(=O)OC(=O)C2C1

Procedure:
Methods for the synthesis of suitable 3-azabicyclo[3.3.0]octane intermediates vary. For instance, Flynn et al., Tetrahedron 53(1): 1-20 (1996), provides two approaches to suitably functionalized 3-azabicyclo[3.3.0]octanes. Such reference is herein incorporated by reference with regard to such synthetic teaching. The first approach involves the palladium-catalyzed [3+2] cycloaddition reaction of 2-trimethylsilylmethyl-2-propen-1-yl acetate with dimethyl maleate. The resulting diester is saponified, treated with acetic anhydride, and pyrolyzed to give the fused cyclic anhydride, tetrahydro-5-methylene-1H-cyclopenta[c]furan-1,3(3aH)-dione. Treatment with ammonia followed by cyclization with acetyl chloride gives the imide, tetrahydro-5-methylene-1H-cyclopenta[c]pyrrole-1,3(2H,2aH)-dione. Reduction with lithium aluminum hydride and protection of the free amine with di-tert-butyl dicarbonate gives 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane. Subsequent transformations, using this methylene compound, are possible. For instance, ozonolysis of 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane will give 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-one. Alternately, treatment of 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane with borane, followed by aqueous basic hydrogen peroxide, will produce 7-(hydroxymethyl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane. Oxidation of this alcohol by any number of methods, known to those of skill in the art of organic synthesis, will generate 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid, a key intermediate for the synthesis of compounds of the present invention.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14][CH:15]([C:20]23OCC(C)(C[O:25]2)C[O:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:14][C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:20]([OH:25])=[O:21])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(NC(c1ccc(Br)cc1)c1nccs1)C12OCC(C)(CO1)CO2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of [(4-bromo-phenyl)-thiazol-2-yl-methyl]-[3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-amine (500 mg, 1.06 mmol) in THF (20 mL) and water (18 mL), was added 1N HCl (3.5 mL). The reaction mixture was stirred for 2 h. After checking the TLC for the disapperance of the starting material, Li(OH).H2O (280.2 mg, 6.3 eq.) was added and stirred at room temperature for 2 h. Then 1N HCl was added to adjust the pH 4-6, and the product was extracted with EtOAC and the organic layer dried over MgSO4. The solvent was evaporated to yield (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].S(=O)(=O)(O)O.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[O:14]=[C:3]1[C:2]2[N:1]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([F:15])[CH:17]=3)[O:20][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2oc(-c3cccc(F)c3)nc21
Reaction time: 0.08 h
Yield: 7.1 %

Procedure:
To a solution of 5.00 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 50 mL of nitrobenzene, 14.6 mL (120 mmol) of 3-fluorobenzoic acid chloride are added; after 5 min of stirring, 0.50 mL of concentrated sulfuric acid is then added with protection from light. After 24 h of reflux and complete cooling, 200 mL of ether are added to the reaction mixture. The precipitate formed is filtered, then redissolved in 200 mL of dichloromethane, to which 100 mL of a glacial sodium hydroxide solution are added. After 6 h of stirring at this temperature, the organic phase is extracted, washed several times with water and dried over calcium chloride. The solid obtained after evaporation of the solvent is purified on a medium-pressure column (support: silica; conditioning heptane; eluant: dichloromethane/heptane, 50/50). The yellow crystals so obtained are uncolored and recrystallized in a dichloromethane/heptane mixture (volume/volume) to produce 0.50 g of 4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([O:12][CH3:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17].OC1C2C=NC(S(C)(=O)=O)=NC=2N(C)C(=O)C=1C(NCC(OC(C)(C)C)=O)=O.N.CO>C1COCC1>[OH:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([O:12][CH3:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: COc1ncc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(C)c2n1
Agent: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cnc(S(C)(=O)=O)nc21
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2n1
Temperature: 0 °C

Procedure:
tert-Butyl 2-(5-hydroxy-2-methoxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate. To a mixture of tert-butyl 2-(5-hydroxy-8-methyl-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate (141 mg, 0.34 mmol) and THF (10 mL) was added ammonia, 2.0M methyl alcohol (3 mL, 5.1 mmol) at 0° C. under N2. The mixture was then stirred at 0° C. and warmed to room temperature overnight. LCMS showed no starting material was left and two peaks corresponding to the 7-amino and to the 7-OMe product (ca. 1:1). The white solid was filtered off and discarded. The filtrate was concentrated under reduced pressure to give the title compound. MS m/z: Calculated: 364.35. Observed: 365.