Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6](/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[F:21])[NH:17][N:16]=[C:15]3[CH3:22])/[C:9]#[N:10])=O)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH:30]([F:32])[F:31])=[CH:27][C:28]#[N:29].C(O)(=O)C>CC(O)C>[F:31][CH:30]([F:32])[C:26]1[NH:25][C:6]([C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[C:8]([C:9]#[N:10])[CH:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[F:21])[NH:17][N:16]=[C:15]3[CH3:22])[C:27]=1[C:28]#[N:29]
Reactant: Cc1n[nH]c2cc(F)c(/C=C(\C#N)C(=O)c3ccc(F)cc3)cc12
Reactant: N#CC=C(N)C(F)F
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(c4ccc(F)cc4)NC(C(F)F)=C3C#N)cc12
Reaction time: 6 h

Procedure:
A mixture of 200 mg (0.569 mmol) (2E)-2-(4-fluorobenzoyl)-3-(6-fluoro-3-methyl-1H-indazol-5-yl)-prop-2-enenitrile (Example 5A) and 69 mg (0.569 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Then, acetic acid (1.5 ml) was added, and stirring at reflux was continued for 6 h. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient, final mixture 80:20 v/v) to yield 36 mg (15% of th.) of the racemic title compound.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[Br:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH2:44])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[F:32].CC(N(C)C)=O>C1COCC1.O.C(OCC)(=O)C>[Br:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH:44][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Nc1cc2c(Nc3ccc(F)c(Br)c3)ncnc2cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Br)c3)ncnc2cn1)OCC
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
To a stirred mixture of CDI (8.44 g, 52.0 mmol) and dry THF (32 mL), at room temperature under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (10.2 g, 52.0 mmol) in THF (28 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 20 min (whence evolution of gases ceased). A solution of compound 159 (13.4 g, 40.0 mmol) in a mixture of dry THF (45 mL) and DMA (50 mL) was added and the reaction was stirred further at 40° C. The reaction was monitored by TLC (ethyl acetate) and found to be only ca. 70% complete after 1.5 hours. Thus, another batch of reagent was prepared by adding CDI (4.22 g, 26.0 mmol) in dry THF (16 mL) to 2-(diethoxyphosphoryl)acetic acid (5.10 g, 26.0 mmol) in dry THF (7 mL). This additional reagent was added to the reaction mixture before it was stirred further for 2 h at 40° C. and then poured into water (1,000 mL) and stirred with petroleum ether (1,500 mL) at room temperature for 16 h. The petroleum ether layer was then decanted. More petroleum ether (800 mL) was added and the mixture was stirred for 15 min. The solid was collected by filtration, washed with water (5×200 mL) and dried to give diethyl 2-(4-(3-bromo-4-fluorophenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (160) (20.1 g, 98%), m.p. 214-217° C. 1H NMR δ (CDCl3) 9.45 (s, 1H), 9.03 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.13 (dd, J=6.0, 2.6 Hz, 1H), 7.77 (s, 1H), 7.70-7.63 (m, 1H), 7.18 (dd, J=8.7, 8.2 Hz, 1H), 4.31-4.18 (m, 4H), 3.15 (d, J=21.0 Hz, 2H), 1.39 (t, J=7.1 Hz, 6H). Anal. Calcd for C19H20BrFN5O4P.0.2H2O: C, 44.24; H, 3.99; N, 13.58%. Found C, 44.00; H, 4.09; N, 13.42%.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(OO)(=[O:26])C.CC(O)C>C(O)=O.C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:26])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: CC(=O)OO
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: [Pd]
Solvent: CC(C)O
Solvent: O=CO
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 16 h

Procedure:
Thebaine (100 g, 0.321 mol) was dissolved in formic acid (100 g) and acetic acid (100 g); volume 253 ml. Solution 2: Peracetic acid (39% in acetic acid, 63.25 g, 0.325 mol) was diluted with acetic acid to give a solution of 85 ml volume. The two solutions were pumped through the continuous flow reactor in the ratio 6 ml/min solution 1 to 2 ml/min solution 2 at 20° C. (4 min residence time). An analytical control after the continuous reactor showed less than 4% Thebaine remaining. The continuous stream was added directly to the hydrogenation autoclave that was precharged with 2-propanol (60 g), formic acid (98-100%, 10 g) and 5% Pd/C (2.5 g) and held at 100° C. under H2 (40 bar). The hydrogenation was stirred for 16 h. After the hydrogenation, the catalyst was filtered off and the crude mixture was either basified with NaOH to obtain the low impurity Oxycodone base, or treated with HCl in 2-Propanol to give the Oxycodone HCl. The yields were 74% for the base and 73% for the HCl salt. The 14-hydroxy-codeinone content of the base was 27 ppm and of the HCl salt <10 ppm.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([CH2:14][O:15]CC1C=CC=CC=1)([OH:13])[CH2:4][O:5]CC1C=CC=CC=1.C(O)C>[Pd].C1(C)C=CC=CC=1>[F:1][C:2]([F:24])([F:23])[C:3]([OH:13])([CH2:14][OH:15])[CH2:4][OH:5]
Reactant: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: OCC(O)(CO)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
1,1,1-Trifluoro-3-[(benzyl)oxy]-2-{[(benzyl)oxy]methyl}-2-propanol (1.3 kg, 3.82 mol, 1.0 eq.) was placed in a 10 L flange flask equipped with a overhead stirrer, followed by ethanol (4.5 L). 10% palladium on carbon (27 g) was added under Argon atmosphere. The reaction was then subjected to hydrogenolysis at atmospheric pressure (6 balloons) and stirred overnight at 50° C. (the balloons were topped up repeatably during the day). 1H NMR showed completion of reaction had been reached after 1 week, required additional 10% palladium on carbon (4 g). The reaction mixture was filtered through a pad of celite and washed with ethanol (2.5 L). The filtrate was concentrated under reduced pressure to give an oil. This was placed under high vacuum overnight to obtain a solid material. Toluene (1.5 L) was added and the mixture heated until the solid dissolved (˜60° C.), 2 layers were observed. The mixture was stirred using a magnetic stirrer and cooled using an ice-water bath, where a solid precipitated. The solid was broken up and stirred for a further 30 minutes, then isolated by filtration. The solid was washed with toluene (250 ml) and petroleum ether (250 ml). The solid was dried under high vacuum overnight to yield desired product (465 g).
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH3:21][O:19][C:18](=[O:20])[CH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (556 μL, 8.93 mmol) was added dropwise to a cooled (0° C.) mixture of commercially available 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid (2.09 g, 8.12 mmol) and K2CO3 (2.81 g, 20.3 mmol) in 20 mL of DMF. The reaction mixture was permitted to warm to rt and stir overnight. The reaction mixture was diluted with ether and washed four times with water, then once with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 40% ethyl acetate/hexanes) provided tert-butyl 4-(3-methoxy-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17])(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1.Cl>C1COCC1.CCOC(C)=O>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[C:14]([F:23])=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:38]=[CH:37][N:36]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 20 °C
Yield: 70.7 %

Procedure:
In a 1000 mL flask was placed methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (9.64 g, 27.9 mmol) and THF (200 mL) was added. The flask was placed in an ice/water bath and LiHMDS (90 mL, 90 mmol) was added. 2-Chloro-4-methylpyrimidine (4.5 g, 35.0 mmol) in THF (60 mL) was added dropwise via addition funnel. After the addition was complete, the reaction was allowed to warm to 20° C. over 1 h. The THF volume was reduced to half under reduced pressure and then treated with 6 N HCl. EtOAc was added and the layers were separated. The aqueous layer was extracted twice with EtOAc and the combined organic layer was washed once with brine, dried over NaSO4, and concentrated. The residue was triturated with EtOAc/ether to afford 8.71 g (71%) of the title compound of Step D. MS (ESI): 442 [M+H]+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=1.Cl.O1CCCC1>O>[F:14][C:12]([F:13])([F:15])[CH:11]([C:8]1[S:7][C:6]([CH:2]=[O:1])=[N:10][CH:9]=1)[OH:16]
Reactant: OC(c1cnc(C2OCCO2)s1)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ncc(C(O)C(F)(F)F)s1
Yield: 79.8 %

Procedure:
A mixture of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]-2,2,2-trifluoroethanol (2.56 g), 1M hydrochloric acid (10 mL) and tetrahydrofuran (10 mL) was stirred with heating under reflux for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.69 g, yield 80%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). melting point 64-66° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:19][C@H:20]1CC[CH2:22][N:21]1[CH3:25].BrC1C=C2C(=CC=1)NC=C2C[C@H]1CCCN1C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:19][CH2:20][N:21]([CH3:22])[CH3:25]
Reactant: CN1CCC[C@@H]1Cc1cn(C(=O)c2ccccc2)c2ccc(Br)cc12
Agent: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(Br)cc12

Procedure:
(R)-5-Bromo-3-[(N-methylpyrrolidin-2-yl)methyl]-1-benzoylindole: (76%), from (R)-5-Bromo-3-[(N-methylpyrrolidin-2-yl)methyl]-1H-indole (Example 3d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[C:17]=1[F:33])[CH2:13][O:14][CH3:15])(=[O:11])=[O:10].C([O-])(=O)C.[Na+].[Br:39]Br.[OH-].[Na+]>C(O)(=O)C>[Br:39][C:26]1[S:25][C:24]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:23][C:22]=1[C:18]1[C:17]([F:33])=[C:16]([N:12]([CH2:13][O:14][CH3:15])[S:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])(=[O:10])=[O:11])[CH:21]=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: COCN(c1cccc(-c2csc(C3CCOCC3)n2)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCN(c1cccc(-c2nc(C3CCOCC3)sc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Yield: 77.7 %

Procedure:
2,5-difluoro-N-{2-fluoro-3-[2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide (1.4 g, 2.808 mmol) was dissolved in acetic acid (28 mL), sodium acetate (461 mg, 5.616 mmol, 2 eq) was added and the mixture was stirred until complete dissolution. Bromine (0.2 mL, 3.9 mmol, 1.4 eq) was then added dropwise over 45 min and stirred at r.t. overnight. The reaction mixture was then added dropwise to a cooled 1 N solution of sodium hydroxide (300 mL) and the mixture was extracted with ethyl acetate. The organic phase was washed with 0.5 N sodium hydroxide, 5% NaHSO3 and brine, dried over Na2SO4 and evaporated to dryness, affording 1.26 g (78%) of the title product as colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>CC(O)C>[C:29]([O:28][C:27](=[O:33])[NH:26][CH:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:25][CH2:24]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.80 mmol) in 2-propanol (50 mL) was added cis-tert-butyl 4-aminocyclohexylcarbamate (425 mg, 1.98 mmol) followed by triethylamine (200 mg, 1.98 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was suspended in dichloromethane (50 mL), washed with water (3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 550 mg, 67.1%).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH3:6][S:7][CH2:8][C:9]([O:11]CC)=O.[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[N:15].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C(N(CC)CC)C>ClCCl.C(O)(=O)C>[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:21](=[C:8]([S:7][CH3:6])[C:9](=[O:11])[N:20]=2)[CH:22]=1)#[N:15]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=O)CSC
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CSC1=c2cc(C#N)ccc2=NC1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
Sulphuryl chloride (3.4 ml , 5.71 g, 42.4 mmol) was added via syringe to a stirred solution of ethyl 2-(methylthio)acetate (5.4 ml, 5.63 g, 42.0 mmol) in dry dichloromethane (30 ml) cooled to −78° C., under a nitrogen atmosphere. After stirring for 15 min, a solution of 4-cyanoaniline (5.0 g, 42.3 mmol) and 1,8-bis(dimethylamino) naphthalene (9.0 g, 42.0 mmol) in dry dichloromethane (50 ml) was added maintaining the temperature at −78° C. Stirring was continued for 3 hours at −78° C., and then triethylamine (5.9 ml , 4.28 g, 42.3 mmol) was added at −78° C., and then the mixture was allowed to warm to room temperature. Stirring was continued under a nitrogen atmosphere for 3 days. Glacial acetic acid (5.0 ml, 5.25 g, 87.3 ml) was then added and the mixture was stirred for 1 hour. The reaction mixture was washed with 8%aq. NaHCO3 (50 ml) and water (2×100 ml), dried (Na2CO3), and concentrated in vacuo. Silica gel chromatography, eluting with 1:2 ethyl acetate/i-hexane, gave 5-cyano-3-methylthio-2-oxoindole as a yellow solid (2.8 g, 13.7 mmol, 32%); δH CDCl3 8.95 (1H, br s), 7.67 (1H, s). 7.60 (1H, d), 7.01 (1H, d), 4.30 (1H, s), 2.08 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C([O-])(O)=O.[Na+]>>[Cl:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(-c3ccc(F)cc3)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1

Procedure:
A solution of 4-(4-fluorophenyl)-7-methylquinoline (3.09 g, 12.2 mmol) in phosphorus oxychloride (8 mL, 85.8 mmol) was stirred 30 min. at 90° C. The mixture was poured slowly into an aqueous saturated solution of NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane/hexanes, 1:70:29) gave the title compound. MS (+ESI): 271 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38][C:37]=1OS(C(F)(F)F)(=O)=O.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:37]4[N:38]=[CH:39][C:40]5[C:45]([C:36]=4[F:35])=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Oc1ncc2ccccc2c1F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4ncc5ccccc5c4F)c3)cn2)CC1
Temperature: 105 °C

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (39.0 mg, 0.0831 mmol), trifluoromethanesulfonic acid 4-fluoroisoquinolin-3-yl ester (25.1 mg, 0.0850 mmol), and PS-PPh3-Pd (0.10 mmol/g loading; 55 mg, 0.0055 mmol; Argonaut) in 1,4-dioxane (1.3 mL, 16 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (53.1 mg, 0.163 mmol) in H2O (0.36 mL, 20 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The resin was filtered off and washed with DCM. The combined filtrate and washings were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC [20×20 cm plate, 500 μm layer of silica gel, eluting with 3.5% MeOH in DCM (3×)]. Material from the main band was collected and dried in vacuo overnight giving the title compound as a yellow glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.14 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.18 (dd, J=0.8, 8.2 Hz, 1H), 8.06 (dt, J=8.0, 0.8 Hz, 1H), 8.01 (dd, J=2.6, 2.6 Hz, 1H), 7.84 (ddd, J=1.2, 7.2, 8.2 Hz, 1H), 7.75 (d, J=0.6 Hz, 1H), 7.72 (ddd, J=1.0, 7.0, 8.2 Hz, 1H), 7.64 (d, J=0.6 Hz, 1H), 5.90 (brs, 2H), 4.40-4.15 (m, 3H), 2.91 (brt, J=10.6 Hz, 2H), 2.18 (brdd, J=2.2, 12.4 Hz, 2H), 1.97 (dq, J=4.4, 12.2 Hz, 2H), 1.48 (s, 9H). MS(ES+): m/z=489.16 (100) [MH+], 433.16 (4) [MH+-isobutene]. HPLC: tR=3.05 min (polar—5 min, ZQ3), 2.71 min (polar—5 min, ZQ2).
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:7]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Reactant: Fc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2CCCCC2)N1Cc1cc(F)ccc1Cl

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC(CN(CC2C=CC([N+]([O-])=O)=CC=2)C2C=CC=CC=2)=CC=1)([O-])=O>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)c2ccon2)cc1
Agent: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Product: Nc1ccc(CN(Cc2ccc(N)cc2)c2ccon2)cc1
Yield: 79 %

Procedure:
The title compound was prepared using the methods from Example 1B substituting the product from Example 33A for the product from Example 1A to provide the title compound (0.32 g, 79% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]2=[N:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:32]([F:35])([F:34])[F:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C.CN(C)C=O>[OH:23][C:22]1([C:32]([F:35])([F:34])[F:33])[C:12]2[C:13](=[N:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[CH:11]=2)[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C1c2ccccc2-c2ncc(OCCN3CCCC3=O)cc21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1CCCN1CCOc1cnc2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Temperature: 0 °C
Yield: 68 %

Procedure:
3-[2-(2-Oxo-pyrrolidin-1-yl)-ethoxy]-indeno[1,2-b]pyridin-5-one (0.0376 g) and potassium carbonate (0.001 g) were mixed with dimethylformamide (1.0 ml), and the mixture was stirred at 0° C. To this mixture was added trimethyl(trifluoromethyl)silane (0.035 ml), and the mixture was stirred at 0° C. for 1 hr. Trimethyl(trifluoromethyl)silane (0.018 ml) was further added, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added acetic acid (0.010 ml), then a 1M solution (0.12 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added ethyl acetate (20 ml), and the mixture was placed in a separatory funnel. The organic layer was washed 3 times with water (10 ml) and once with saturated brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (silica gel, eluent: n-hexane/ethyl acetate=7/3) to give the title compound (0.0389 g, 68%).