Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[F:11][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:15](=[O:19])[C:16](=[O:17])[NH:12]2)=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(F)cc([N+](=O)[O-])c1N
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc(F)cc([N+](=O)[O-])c2[nH]c1=O
Temperature: 62.5 °C
Yield: 43.5 %

Procedure:
A mixture of 1,2-diamino4-fluoro-6-nitrobenzene (80 mg, 0.46 mmole) and oxalic acid dihydrate (70 mg, 0.56 mmole, used as received) in 4N HCl (4 mL) was refluxed at 120-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the supernatant was removed. The yellow solid was washed with cold water (2×2 mL), collected by filtration, and dried in vacuo for 2 h, affording 45 mg (42%) of crude 7-fluoro-5-nitro-1,4-dihydro-2,3-quinoxalinedione as a yellow powder. The crude product was taken up in 1N NaOH (1 mL) and filtered. The filtrate was acidified to pH=3, affording 35 mg (33%) of 7-fluoro-5-nitro-1,4-dihydro-2,3-quinoxalinedione; mp: 333-335° C. (dec.); IR (KBr, cm-1): 3427, 3328, 3104, 3072, 1716, 1545. 1H NMR (DMSO-d6): δ 12.418 (s, 1H), 11.149 (s, 1H), 7.819 (dd, J1 =2.4 Hz, J2 =9.0 Hz, 1H), 7.297 (dd, J1 =2.4 Hz, J2 =9.0 Hz, 1H); HRMS: calcd for C8H4FN3O4 (M+) m/z: 225.0185; found: 225.0188.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH2:29])[CH2:24]2)=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: Nc1cc2ccc(Br)cc2nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cc2ccc(Br)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a mixture of 3-amino-7-bromoquinoline-2-carboxylic acid (27.4 mg, 0.103 mmol), tert-butyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (31.4 mg, 0.107 mmol) and HATU (78.2 mg, 0.206 mmol), DMF (1.00 mL) was added, followed by DIPEA (83.6 mg, 0.647 mmol). The mixture was stirred at room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in DCM (2.0 mL); then TFA (1.0 mL) was added. The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to give the title compound as a yellow solid (10.1 mg, 22%). LCMS calc. for C20H22BrN6O (M+H)+: m/z=441.1. found 441.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH:32]1([C:35]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:36])[CH2:34][CH2:33]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8]([CH:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:11][C:12]([O:14]C)=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+]>CO.O>[C:1]([C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8]([CH:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:11][C:12]([OH:14])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CC(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C)c2[nH]ccc2c1C(CC(=O)O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of (±)-methyl 3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)propanoate (Example 145-C) (254 mg, 0.248 mmol) in MeOH (6 mL) was added 1N NaOH (1.439 mL, 1.439 mmol) and the resulting solution was stirred at rt. After stirring for 1.5 hrs additional 1N NaOH (1.439 mL, 1.439 mmol) was added to the mixture and the mixture was stirred at rt for 16 hrs. At this point, additional 1N NaOH (1.439 mL, 1.439 mmol) was added and the mixture was heated to 60° C. for 3.5 hrs. The reaction mixture was then cooled to rt, diluted with water and the aqueous layer (pH=10) was washed AcOEt (4×). The water layer was acidified with 1N HCl (pH=2-3) and then extracted with AcOEt. The organic layer was washed with water (2×). The combined organic layers were passed through a phase separator and concentrated to give crude product that was purified via preparative HPLC (HC-B) to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50-12.64 (m, 1H) 10.92 (br. s., 1H) 7.87-8.25 (m) 7.48 (d) 7.13 (t, J=2.78 Hz, 1H) 6.79 (s, 1H) 5.97 (dd, J=2.91, 1.89 Hz, 1H) 5.34 (dd, J=9.73, 4.67 Hz, 1H) 3.78 (s, 3H) 3.54-3.69 (m, 1H) 2.59-2.65 (m, 1H) 2.44 (s, 3H). HRMS calcd. for C21H18N4O3 (M+H)+ 375.1457. found 375.1458.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)Oc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
In a dry flask 5-amino-indazole-1-carboxylic acid t-butyl ester (1.4 g, 6.0 mmol) was dissolved in tetrahydrofuran (20 mL) and triethylamine (1.0 g, 9.9 mmol) were added and the reaction mixture cooled to 0° C. Phenyl chloroformate (1.0 g, 6.4 mmol) was added dropwise and the mixture was stirred an additional 15 minutes after the addition was complete. The reaction mixture was diluted with ethyl acetate, washed with water, and concentrated in vacuo. The crude material was purified by flash chromatography with 35% ethyl acetate in hexanes to give a white solid (1.9 g, 90%). 1H NMR (300 MHz, CDCl3), δ: 8.14 (d, J=10, 1H), 8.12 (s, 1H), 8.02 (bs, 1H), 7.40 (m, 3H), 7.24 (m, 4H), 1.73 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=[O:21])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:9]=1)([CH3:7])[CH3:6].CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>ClCCl>[CH3:26][N:27]([CH3:29])/[CH:28]=[N:20]/[S:17]([C:10]1[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3](=[O:21])[C:2]([F:1])([F:22])[F:23])[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=1)(=[O:19])=[O:18]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(S(N)(=O)=O)cc2c1OCC2
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)/C=N/S(=O)(=O)c1cc2c(c(C(C)(C)CC(=O)C(F)(F)F)c1)OCC2
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of 7-(4,4,4-trifluoro-1,1-dimethyl-3-oxobutyl)-2,3-dihydrobenzofuran-5-sulfonic acid amide (870 mg, 2.47 mmol) in 30 mL of dichloromethane was reacted with N,N-dimethylforamide dimethyl acetal (580 mg, 4.86 mmol). After 30 minutes, the mixture was concentrated in vacuo to dryness. The resulting solid was triturated with diethyl ether and collected to afford 950 mg of the title compound (94% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CC(C)=O.C(=O)=O.[C:13]([C:15]1(O)[CH2:21][CH:20]2[N:22]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:17]([CH2:18][CH2:19]2)[CH2:16]1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.N1C=CC=CC=1>[C:13]([C:15]1[CH2:16][CH:17]2[N:22]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:20]([CH2:19][CH2:18]2)[CH:21]=1)#[N:14]
Reactant: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: N#CC1=CC2CCC(C1)N2CC(F)(F)F
Temperature: 28 °C
Yield: 43.8 %

Procedure:
An oven-dried 100 ml 3-necked round bottom flask was fitted with a reflux condenser, thermometer and magnetic stirrer and the apparatus filled with a nitrogen atmosphere. Phosphorous oxychloride (8.89 g, 58 mmol) and pyridine (44 ml) were charged and the mixture then cooled to −10° C. in an acetone/Drikold™ bath. 3-Cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (6.17 g, 26.4 mmol—assumed) was added in one portion and the resulting exotherm raised the reaction mass temperature to 28° C. The mixture was then heated to 80° C. and held at this temperature overnight. The reaction mass was cooled to ambient (precipitation occurred) and added to a stirred mixture of saturated aqueous sodium carbonate (200 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous then extracted with ethyl acetate (2×200 ml). The combined organics were washed with brine (100 ml), dried (Na2SO4) and concentrated in vacuo to give 3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1 ]oct-2-ene (2.5 g, 35% yield).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[CH3:11][N+:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1>C1COCC1>[CH2:1]([CH:13]1[C:14]([CH3:19])=[C:15]([CH3:18])[CH:16]=[CH:17][N:12]1[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1cc[n+](C)cc1C
Agent: [I-]
Solvent: C1CCOC1
Product: CC1=C(C)C(Cc2ccccc2)N(C)C=C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3.02M of benzylmagnesium chloride (2M solution) in THF was added portionwise 300 g (20 g portions) of 1,3,4-trimethylpyridinium iodide. The reaction mixture was stirred at room temperature for 18 hrs. The THF was evaporated at reduced pressure, and the resulting residue was poured into iced saturated NH4Cl. The mixture was extracted with ether and the ether solution washed with additional saturated NH4Cl. The ether solution was dried over magnesium sulfate and evaporated to dryness at reduced pressure to afford 338 g of crude 2-benzyl-1,3,4-trimethyl-1,2-dihydropyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH2:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH2:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(N)c3ccccc3nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(N)c3ccccc3nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 25 mL rbf equipped with a nitrogen bubbler were charged 3,9-diaminoacridine (50 mg, 0.24 mmol) and anhydrous DCM (2 mL). To the resulting red suspension was added acetic anhydride (25 μL, 0.26 mmol) followed by triethylamine (37 μL, 0.26 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. LCMS showed incomplete reaction but only formation of expected product. Starting material was not really soluble in DCM. Pyridine (0.5 mL) was thus added and the mixture stirred overnight. LCMS still showed incomplete reaction. A further portion of acetic anhydride (25 μL, 0.26 nmol) was added and the reaction mixture was stirred at room temperature over three days. LCMS showed reaction completion.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[C:10]3[OH:26])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.[Pd]>[OH:26][C:10]1[C:9]2[C:14](=[N:15][CH:16]=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)[N:13]([CH3:17])[C:12](=[O:18])[C:11]=1[C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(C3=CCOCC3)cnc21
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(C3CCOCC3)cnc21
Temperature: 23 °C
Reaction time: 1.25 h

Procedure:
A mixture of 2-(6-(3,6-dihydro-2 H-pyran-4-yl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetic acid (71 mg, 198 μmol, Example 260)) and 1 N sodium hydroxide (988 μl, 988 μmol) in MeOH (5 mL) was treated with 10% Pd/C (5.3 mg, 49 μmol) under nitrogen atmosphere. The reaction vessel was degassed and backfilled with hydrogen (3×), and the mixture was stirred at 23° C. for 75 minutes under hydrogen atmosphere. The reaction mixture was filtered from the catalyst through a pad of Celite®, and the filter cake was washed with MeOH (50 mL). The combined filtrate was concentrated and acidified with concentrated HCl. The precipitated solid was collected by filtration, washed with water (10 mL), and dried in vacuo to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 362 (M+1). 1NMR (400 MHz, DMSO-d6) δ ppm: 10.49 (s, 1 H), 8.80 (d, J=2.0 Hz, 1 H), 8.26 (d, J=1.8 Hz, 1 H), 4.14 (d, J=5.3 Hz, 1 H), 3.98 (d, J=10.4 Hz, 2 H), 3.69 (s, 3 H), 3.42-3.52 (m, 2 H), 2.91-3.09 (m, 1 H), 1.65-1.88 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH3:10][N:11]1[C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CCCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:15]2[N:11]([CH3:10])[N:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Nc1ccc(Cl)cc1I
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Product: Cn1nccc1-c1cc(Cl)ccc1N
Temperature: 70 °C
Yield: 73.6 %

Procedure:
A 250-mL round-bottomed flask was charged with 4-chloro-2-iodoaniline (6.189 g, 24.42 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.62 g, 36.6 mmol), potassium carbonate (13.50 g, 98 mmol), and Pd(dppf) Cl2CH2Cl2 (0.997 g, 1.221 mmol). The flask was flushed with Ar, then 1,4-dioxane (61.0 mL) and water (20.35 mL) were added in sequence. A reflux condenser was attached, and the flask was heated to 70° C. for 4 h. After being cooled to room temperature, the mixture was diluted with water and EtOAc, which resulted in an emulsion (a small amount of brine was added to clear the emulsion). The layers were separated, and the aq. layer was extracted with EtOAc (twice). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was partially purified by chromatography on silica gel (30 to 80% EtOAc/Heptane). The partially purified product was taken up in a boiling mixture of heptane (100 mL) and EtOAc (5 mL) to give a murky solution. A 250 mL flask containing the solid was charged with heptane (100 mL). The mixture was cooled to room temperature after 3 h, then the solid was collected by filtration, washed with heptane (3×50 mL), and dried under a stream of N2 for 20 min to give 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)aniline (3.732 g, 17.97 mmol) as a light purple solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=7.50 (d, J=1.9 Hz, 1H), 7.16 (dd, J=2.6, 8.7 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 6.29 (d, J=1.8 Hz, 1H), 5.07 (s, 2H), 3.65 (s, 3H). m/z (ESI) 208.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH:12]1([C:7]([OH:11])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]2)=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Reaction time: 72 h
Yield: 74.1 %

Procedure:
Cyclohexylmandelic acid (885 mg, 3.78 mmol) was added to tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (957 mg, 3.44 mmol) and potassium carbonate (713 mg) in dimethyl formamide (10 mL) at RT with stirring. After 72 hours, the reaction was diluted with ethyl acetate and water. The organic extracts were washed with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in iso-hexane to afford the title compound (1.10 g, 75%).
Reaction SMILES: [C:1]1([C:11](=[CH2:15])[C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:13][C:12](=[O:14])[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[CH2:15])[CH3:22]
Reactant: C=C(C(=O)O)c1cccc2ccccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: C=C(C(=O)OCC)c1cccc2ccccc12
Yield: 94 %

Procedure:
1-Naphthylacrylic acid (9.5 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(a) to obtain the title compound (10.2 g, 94%) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=1)#[N:7]
Reactant: CNCCc1ccc(OCC(=O)OC)cc1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COC(=O)COc1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1f with 2j produced 3ak. MS found M+H=483. The oxalate salt of 3ak was recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[C:79](=[O:86])([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])[NH2:80]>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].O1CCOCC1>[C:82]([O:81][C:79](=[O:86])[NH:80][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1)([CH3:85])([CH3:84])[CH3:83]
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1c(-c2ccc(Br)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 110 °C

Procedure:
In a screw-capped vial are added 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (250 mg, 0.54 mmole), Pd(dba)2 (25 mg, 27 μmole), Xantphos (31 mg, 54 μmole), Cs2CO3 (704 mg, 2.16 mmoles), 1,4-dioxane (3.4 mL) and tert-butyl carbamate (316 mg, 2.7 mmoles). The flask is evacuated and filled with argon. The reaction mixture is heated at 110° C. for 4 hours. Water is added and pH adjusted to 10 with a few drops of 1N NaOH. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (100:0:0) to (95:5:0.5) to give {4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-carbamic acid tert-butyl ester melting at 194° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH:24]([NH:27][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)NC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 72.6 %

Procedure:
A solution of compound 119 (0.75 g, 2.926 mmol) in 1,2-dichloroethane (20 mL) was treated with AcOH (0.16 mL, 2.926 mmol), isopropyl amine (0.25 mL, 2.926 mmol), NaBH(OAc)3 (0.93 g, 4.390 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (3×50 mL). The combined ethyl acetate layer washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 139 (0.636 g, 73%) as a semi-solid. 1H NMR (DMSO-d6) δ 0.99 (d, 6H, J=6.0 Hz), 1.36-1.47 (m, 1H), 1.89-1.97 (m, 2H), 2.45-2.56 (m, 2H), 2.81-2.89 (m, 1H), 2.91-2.99 (m, 1H), 3.16 (brs, 1H), 6.14 (brs, 1H), 7.80 (s, 1H), 7.88 (dd, 1H, J=2.1, 9.0 Hz), 7.95 (d, 1H, J=9.0 Hz), 8.30 (d, 1H, J=2.1 Hz), 11.83 (brs, 1H); ESI-MS (m/z, %) 300 (MH+, 100), 241 (35).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O:25]1[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:26]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:25]1[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:32]=[C:33]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:34]=[CH:35][C:26]1=2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccc2c(c1)OCCCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCCO4)n2n1
Temperature: 110 °C
Yield: 26.1 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (49 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 9.5 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-55% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (20.8 mg, 26%). ESI-MS: m/z 459.2 (M+H)+.