Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)=[C:6]([O:19]C)[CH:5]=1)[CH3:2].C([O-])(=O)/C=C/C([O-])=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)=[C:6]([OH:19])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2nc3cnccc3[nH]2)c(OC)c1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CCOc1ccc(-c2nc3cnccc3[nH]2)c(O)c1

Procedure:
2-(4-Ethoxy-2-methoxyphenyl)imidazo(4,5-c)pyridine, fumarate, m.p. 213°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15]S(C1C=CC(C)=CC=1)(=O)=O.[CH2:26]([O:28][C:29](=[O:43])[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][C:35]=1[CH2:41][OH:42])([CH3:32])[CH3:31])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:26]([O:28][C:29](=[O:43])[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:36][C:35]=1[CH2:41][OH:42])([CH3:32])[CH3:31])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1CO
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CO
Temperature: 80 °C
Yield: 19.6 %

Procedure:
To a 25 mL round bottom flask under a nitrogen atmosphere were charged 0.77 g (2.17 mmol) of toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester, and 0.5 g (1.97 mmol) of 2-(4-hydroxy-2-hydroxymethylphenoxy)-2-methylpropionic acid ethyl ester dissolved in 10 mL of absolute ethanol. Next, 0.54 g (3.94 mmol) of potassium carbonate (325 mesh) was added and the reaction was heated to 80° C. for 12 h. The volatiles were removed in vacuo and the crude residue was dissolved in 75 mL EtOAc and washed twice with brine, dried over Na2SO4, and removed in vacuo to give a crude oil. This crude residue was purified using radial chromatography with a 2 mm normal phase silica gel plate, eluting with a step gradient of 5:95 EtOAc:Hex to 35:65 EtOAc:Hex to give a colorless oil (0.17 g, 20%). MS (ES) m/e 452 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:23]C(C)([O-])C.[Na+].IC>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCOCC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CCOCC1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
To a 20 mL vial containing 2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (0.0907 g, 0.279 mmol) was added DMSO (0.5 mL); placed in a dry ice-acetone bath and then added sodium tert-butoxide (0.030 g, 0.307 mmol) followed by DMSO (0.5 mL) and iodomethane (0.019 ml, 0.307 mmol). The dry ice-acetone bath was removed and the mixture was allowed to warm up to room temperature and stirred for 16 h. The reaction was diluted with 10 mL of water and vigorously stirred at room temperature. Collected rust/orange solids by vacuum filtration, washed with additional water and dried under high vacuum affording 2-chloro-6a-methyl-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (46.0 mg, 48.4% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (d, J=0.76 Hz, 3 H) 2.48-2.72 (m, 2 H) 3.17-3.34 (m, 1 H) 3.41-3.77 (m, 5 H) 3.94-4.19 (m, 6 H) 4.61 (tt, J=12.38, 4.29 Hz, 1H) 7.98-8.14 (m, 1 H). MS [M+H] found 339.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([F:17])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CC(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:12]=[C:11]([F:10])[CH:16]=[C:15]([F:17])[CH:14]=2)=[C:3]([F:9])[CH:4]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(-c2cc(F)cc(F)c2)c(F)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
4-Bromo-3-fluorophenol (T-1) (50.0 g), 3,5-difluorophenylboronic acid (45.5 g), potassium carbonate (72.4 g), Pd(Ph3P)2Cl2 (5.52 g) and 2-propanol (500 ml) were put in a reaction vessel and heated to reflux for 5 hours under an atmosphere of nitrogen. After the reaction solution had been cooled to 25° C., it was poured into water (500 ml) and mixed with it. Toluene (500 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from a mixed solvent of heptane/Solmix A-11 and dried, giving 4-hydroxy-2,3′,5′-trifluoro-1,1′-biphenyl (T-2) (43.4 g). The yield based on the compound (T-1) was 74%.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[CH3:27]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)cc1C
Yield: 34.1 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (3.95 g, 15 mmol), 4-amino-3-methylphenol (2.46 g, 20 mmol) and 1,4-dioxan (15 ml) were warmed briefly to reflux, then the solid filtered off and washed with ethyl acetate. Conversion to free base and recrystallisation from ethanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (1.79 g, 34%), m.p. 252°-253°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([C:7]([CH2:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:14](Br)(Br)([Br:16])[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:4]([CH:5]=[C:14]([Br:16])[Br:15])[C:3]=1[CH2:12][CH3:13]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1ccc(Cl)c(CC)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(Cl)c(CC)c1C=C(Br)Br

Procedure:
1-Chloro-3-(2,2-dibromo-vinyl)-2,4-diethyl-benzene was prepared from 3-chloro-2,6-diethyl-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.14 (3H, t, CH3), 1.17 (3H, t, CH3), 2.56 (2H, qd, CH2), 2.72 (2H, q, CH2), 7.03 (1H, d, ArH), 7.29 (1H, d, ArH), 7.44 (1H, s, CH═CBr2).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12]C)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2>Br>[Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2
Reactant: COc1ccc2nc(C)ccc2c1Br
Agent: Br
Product: Cc1ccc2c(Br)c(O)ccc2n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 122.2 %

Procedure:
A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol) in 48% HBr (135 mL) was heated to reflux for 7 h then cooled to 5° C. in 1 hour to give a brown and thick slurry. The slurry was stirred at 0–5° C. for 1 hour then filtered, washed with EtOAc (2×50 mL) and dried in a vacuum oven to give 34.9 g (92%) of the hydrobromide of the title compound as a brown solid. 1H NMR (DMSO) δ8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64 (s, 3H). A slurry of the hydrobromide salt of 5-bromo-2-methyl-6-quinolinol (3.4 g, 10.5 mmol) and Amberlyst A-21 ion-exchange resin (1.7 g, pre-washed with MeOH then dried in oven) in MeOH (35 mL) was stirred at room temperature for 3 h. The mixture was then filtered and concentrated in vacuo to give 2.5 g (100%) of a yellow solid. Rf=0.36 (1:1) EtOAc:heptane; 1H NMR (DMSO) δ 8.26 (d, J=8.4 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.47 (t, J=9.1 Hz, 2H), 2.66 (s, 3H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1cccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(F)(F)c1cccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (230 mg) in THF (dry) (20 mL) and MeOH (20 mL). The mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated. The residue was crystallized from EtOAc/hexane to give the title compound (79.4 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]=[O:13])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>CC(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:15])=[O:13])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1cc(C=O)c2ccc(F)cc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1cc(C(=O)O)c2ccc(F)cc21
Temperature: 25 °C
Yield: 70.1 %

Procedure:
In acetone (200 ml) was dissolved 6-fluoro-1-methylindole-3-carbaldehyde (3.10 g, 17.5 mmol). To the resulting solution was added potassium permanganate (0.2M aqueous solution, 175 ml, 35.0 mmol) in portions under stirring at room temperature. After stirring at room temperature for 10 hours, the reaction mixture was filtered through Celite. After the filtrate was distilled under reduced pressure under reduced pressure, the residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give 6-fluoro-1-methylindole-3-carboxylic acid (2.37 g, 70%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:37]([F:40])([F:39])[F:38])=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C@@H:14]([CH2:15][O:16]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:13][CH2:12][C:11]1=[O:36])[C:5]#[N:6]>O1CCOCC1.Cl.O>[OH:16][CH2:15][C@H:14]1[CH2:13][CH2:12][C:11](=[O:36])[N:10]1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([C:37]([F:40])([F:38])[F:39])[C:2]=1[CH3:1]
Reactant: Cc1c(N2C(=O)CC[C@@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)ccc(C#N)c1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(N2C(=O)CC[C@@H]2CO)ccc(C#N)c1C(F)(F)F
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a solution of (R)-3-methyl-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3h) (0.48 g, 0.93 mmol) in 1,4-dioxane (15 mL), 2M HCl in 1,4-dioxane (5 mL) was added at 0° C. and stirred for 4 h. After completion of reaction (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were washed with water (2×30 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound was purified by column chromatography to provide the alcohol 3i (0.22 g, 79%) as a white solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:11]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:10]1)=[O:8].C(O)(=[O:37])C.OO.[OH2:41]>ClCCl.[Zn]>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:11]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:10]1)=[O:8])(=[O:37])=[O:41]
Reactant: O
Reactant: CSCCCNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Reactant: CC(=O)O
Agent: OO
Agent: [Zn]
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCCS(C)(=O)=O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methylsulfanyl-propyl)-amide (119.2 mg, 0.23 mmol) and dichloromethane (2 mL) was added to a solution of refluxing acetic acid (5 mL, 79.4 mmol) and 30% hydrogen peroxide (2 mL) for 5 min. The reaction mixture was cooled to room temperature and stored in the freezer overnight. The mixture was diluted with water and dichloromethane, the organic layer was separated and solvent removed under reduced pressure. The resulting oil was carried directly to the next step by adding acetic acid (5 mL, 79.4 mmol) and zinc dust (0.85 g, 13 mmol). After stirring at room temperature for 3 h, an additional amount of zinc dust (0.85 g, 13 mmol) was added and stirred for an additional 3 h at room temperature. Reaction worked up by filtration through celite, washing with dichloromethane (50 mL). The filtrate was washed with water (2×) and the organic layer was separated, dried with MgSO4, filtered and the solvent evaporated under reduced pressure to yield crude oil. Purification by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-methanesulfonyl-propyl)-amide (36.5 mg, 28.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H33Cl2N3O3S+H [(M+H)+]: 550.1693. found: 550.1692.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([CH:24]3[CH2:25][CH2:26][N:27]([CH:39]4[CH2:40][CH2:41][O:36][CH2:37][CH2:38]4)[CH2:28][CH2:29]3)=[O:23])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: O=C1CCOCC1
Reactant: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)cc1
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(C3CCOCC3)CC2)CC1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound 4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide was prepared from 4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide using tetrahydro-4H-pyran-4-one instead of acetone and was obtained as a white foam. MS m/e: 612.2 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)[CH3:36]>O1CCOCC1.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[CH:39]=[N:38][N:37]([CH2:35][CH3:36])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)cn1
Temperature: 100 °C

Procedure:
A mixture of bis(triphenylphosphine)palladium chloride (14.01 mg, 0.020 mmol), tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol), and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177 mg, 0.798 mmol) in dioxane (4 mL) and saturated aqueous NaHCO3 (1 mL) was heated to 100° C. in a Biotage Initiator microwave for 1 hour. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-25% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a white solid (87 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (t, J=7.3 Hz, 3H), 1.75-1.77 (m, 1H), 2.10-2.11 (m, 1H), 3.61-3.63 (m, 1H), 3.85-3.86 (m, 1H), 3.93-3.94 (m, 1H), 3.96-3.98 (m, 2H), 4.18 (q, J=7.32, 2H), 4.47-4.48 (m, 1H), 7.04-7.05 (m, 1H), 7.89-7.91 (m, 2H), 8.30 (s, 1H), 8.37 (s, 1H), 8.88 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H21FN6O2, 361. found, 361.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Br[CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].BrC(C(Br)C)C>C(#N)C.O>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([N:19]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: BrCCCCBr
Agent: CC(Br)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2N2CCCC2)CC1
Reaction time: 72 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 0.50 g), 1,4-dibromobutane (0.21 ml) and potassium carbonate (0.30 g) are refluxed in 4 ml of acetonitrile for 1 week. After 1 week, additional dibromobutane (0.21 ml) is added and refluxing is continued for 3 days. The reaction mixture is poured into water, extracted with methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography eluting with ethyl acetate/hexane (10/90) to ethyl acetate/hexane (25/75). The appropriate fractions are pooled and concentrated to give the title compound, NMR (300 MHz, CDCl3) 7.78, 6.98, 6.78, 3.52, 3.20-3.10, 1.87 and 1.44 δ.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[N:23]=[C:22]([CH2:24][C:25]#[N:26])[CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9]([C:18]3[N:23]=[C:22]([CH2:24][C:25]#[N:26])[CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1
Reactant: N#CCc1cccc(Br)n1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)n3)cc21

Procedure:
Prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and (6-bromo-2-pyridyl)acetonitrile (J. Org. Chem. 1988, 53, 786-790). An off-white solid, mp 210-212.5° C. 1H NMR (DMSO-d6) δ1.68 (s, 6H), 4.27 (s, 2H), 7.00 (d, 1H, J=8.3 Hz), 7.34 (d, 1H, J=7.1 Hz), 7.89-7.96 (m, 2H), 8.00-8.05 (m, 2H), 10.42 (s, 1H). MS (ESI) [M−H]−=292. Anal. calcd. for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C, 68.49; H, 5,19; N, 13.74.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2/[CH:11]=[C:12]2\[C:13]([CH2:17][OH:18])([CH2:15][OH:16])[CH2:14]\2)=[C:4]([NH:19][CH:20]2[CH2:22][CH2:21]2)[N:3]=1.C1(N)CC1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2/[CH:11]=[C:12]2/[C:13]([CH2:17][OH:18])([CH2:15][OH:16])[CH2:14]/2)=[C:4]([NH:19][CH:20]2[CH2:22][CH2:21]2)[N:3]=1
Reactant: Nc1nc(NC2CC2)c2ncn(/C=C3/CC3(CO)CO)c2n1
Agent: NC1CC1
Product: Nc1nc(NC2CC2)c2ncn(/C=C3\CC3(CO)CO)c2n1
Yield: 86 %

Procedure:
The procedure described for the Z-isomer 1h in Example 21 was followed with the E-isomer 2b and cyclopropylamine (0.70 mL, 5 mmol, 50° C., 20 h) to give compound 2h (130 mg, 86%).
Reaction SMILES: [PH4+].[CH:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=O.[CH2:15]1[O:19][CH2:18][CH2:17][CH2:16]1>>[O:19]1[C:18]2[CH:2]=[C:4](/[C:14](/[CH3:13])=[CH:2]/[C:4]3[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=3)[CH:5]=[CH:16][C:17]=2[CH2:8][CH2:7][CH2:6][CH2:15]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [PH4+]
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)OCCCC3)cc1

Procedure:
4.9 g of 2,3,4,5-tetrahydro-α-methyl-1-benzoxepine-8-methanol were dissolved in 50 ml of acetonitrile and treated with 13 g of triphenylphosphine hydrobromide. The reaction mixture was stirred at 40° C. for 24 hours. Thereafter, the majority of the solvent was removed under reduced pressure and the residue was partitioned between hexane and ethanol/water (8:2). The heavy phase was evaporated and dried, whereby 11.96 g of white phosphonium salt were obtained. 6.29 g of Phosphonium salt were dissolved in 13 ml of butylene oxide, treated with 2.6 g of ethyl 4-formylbenzoate and heated to reflux for 18 hours. Thereafter, the majority of the solvent was removed under reduced pressure and the residue was partitioned between hexane and ethanol/water (8:2). The light phase was dried over magnesium sulfate and evaporated. Chromatography on silica gel (petroleum ether/ethyl acetate (97:3)) and recrystallization from hexane yielded 1.4 g of ethyl p-[(E)-2-(2,3,4,5-tetrahydro-1-benzoxepin-8-yl)propenyl]benzoate, m.p. 71°-72° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:13])[CH3:14])[C:6]=2[N:7]=1
Reactant: Cc1nn(C(C)C)c2nc(Br)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reaction time: 12 h
Yield: 27.5 %

Procedure:
A solution of 6-bromo-1-isopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.3 g, 1.01 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.306 g, 2.01 mmol) in DMSO (4 mL) and was stirred at room temperature for 15 min. Then PyBOP (0.78 g, 1.51 mmol) was added to it and stirring was continued for 12 h. After completion of the reaction, reaction mass was poured into ice to obtain solid, which was filtered and washed with acetonitrile followed by ether to provide 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.12 g, 27.5%).