Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Br:16])[C:5]2[O:10][CH2:9][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:4]1[C:5]2[O:10][CH2:9][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)[CH:3]=1
Reactant: CC(C)(C)N1COc2c(Br)cc(Br)cc2C1
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)N1COc2c(Br)cc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2C1
Temperature: 72 °C
Yield: 20.1 %

Procedure:
A mixture of 6,8-dibromo-3-(tert-butyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (Intermediate 6) (2.4 g, 6.92 mmol), (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (1.628 g, 7.27 mmol), and potassium carbonate (1.434 g, 10.4 mmol) in 2-propanol (40 mL) and water (8 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (336 mg, 0.29 mmol) was added and the resulting mixture heated at 72° C. for 3 h then the cooled reaction mixture concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give a solid that was re-crystallized from ethyl acetate to give 8-bromo-3-(tert-butyl)-6-(4-chloro-3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.625 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9](O)[C:8]1=[O:15])=[O:5])[CH3:2].P(Br)(Br)([Br:18])=O.[OH-].[NH4+]>C(Cl)(Cl)Cl.ClCCl>[Br:18][C:9]1[C:8](=[O:15])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]([CH3:13])=[CH:11][N:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)Cn1c(C)cnc(O)c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A slurry of 1-(ethoxycarbonylmethyl)-3-hydroxy-6-methylpyrazinone (4.24 g, 20 mmol), as prepared in the preceding step, and phosphorous oxybromide (6.3 g, 22 mmol) in chloroform (15 mL) was stirred at 50° C. under nitrogen for 2 hours, then allowed to cool to room temperature overnight. The reaction mixture was diluted with dichloromethane and ice-water, basified with ammonium hydroxide, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, treated with activated carbon, filtered and concentrated. The solid was collected, washed with 15% ethyl acetate in hexane, and dried under high vacuum to give the title compound as an orange colored solid (5.1 g, 93%). 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 4.77 (s, 2H), 4.26 (q, 2 H, J=7.1 Hz), 2.24 (s, 3H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][CH:20]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B([C:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:45]([OH:47])=[O:46])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)(O)O>>[C:1]1([C@H:7]([O:9][C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[CH:21][C:22]([C:36]3[CH:41]=[CH:40][C:39]([C:42]4([C:45]([OH:47])=[O:46])[CH2:44][CH2:43]4)=[CH:38][CH:37]=3)=[CH:23][CH:24]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccc(B(O)O)cc2)CC1
Reactant: C[C@@H](OC(=O)Nc1cnccc1-c1ccc(OS(=O)(=O)C(F)(F)F)cc1)c1ccccc1
Product: C[C@@H](OC(=O)Nc1cnccc1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: trifluoro-methanesulfonic acid 4-[3-((R)-1-phenyl-ethoxycarbonylamino)-pyridin-4-yl]-phenyl ester and 1-(4-boronophenyl)cyclopropanecarboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH:16]=[C:15]([Cl:18])[CH:14]=[CH:13][C:12]=2[C:11](=[O:19])[C:10]2=[CH:20][CH:21]=[CH:22][N:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]N1C(=O)CCC1=O.[Al]>C1COCC1>[CH2:1]([N:8]1[C:17]2[CH:16]=[C:15]([Cl:18])[CH:14]=[CH:13][C:12]=2[C:11](=[O:19])[C:10]2=[CH:20][CH:21]=[C:22]([Cl:23])[N:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2cccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: [Al]
Solvent: C1CCOC1
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2c(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
5-Benzyl-7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (4.5 g) was taken up in 50 ml of THF and a catalytic amount of dibenzoyl eroxide was added. N-chlorosuccinimide (1.95 g) was added portionwise over a period of 10 min. The flask was covered with aluminum foil and the mixture stirred at room temperature overnight under N2. The reaction mixture was concentrated and the residue taken up in chloroform and extracted with H2O and brine. The organic layer was then dried (MgSO4), charcoaled, filtered and concentrated to a green semisolid. This was purified by HPLC (silica, dichloromethane) to give a light green powder which was recrystallized from ethanol to yield 2.3 g of green crystals, mp 134°-136°.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=O)[CH2:3]1.[CH2:14]([NH2:17])[C:15]#[CH:16]>>[CH3:1][C:2]1([CH3:13])[CH2:3][C:4]2[N:17]=[CH:14][CH:15]=[CH:16][C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]1=2
Reactant: C#CCN
Reactant: CC1(C)CC(=O)Cc2ccccc21
Product: CC1(C)Cc2ncccc2-c2ccccc21
Yield: 49 %

Procedure:
The title compound is prepared from 4,4-dimethyl-3,4-dihydro-1H-naphthalen-2-one and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 49% of theory; LC (method 1): tR=2.40 min; Mass spectrum (ESI+): m/z=210 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[C:19]([O:20][CH:21]([F:23])[F:22])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[C:3]=1Br.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[C:19]([O:20][CH:21]([F:23])[F:22])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1Br)C(c1ccccc1)Oc1cccc(OC(F)F)c1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc2c(c1)C(c1ccccc1)Oc1cccc(OC(F)F)c1-2
Yield: 79 %

Procedure:
A solution of Example 4 (1.19 g), triethylamine (2.8 mL) and 10% Pd/C (120 mg) in ethyl acetate (100 mL) was shaken under 1.5 atms. hydrogen for 15 minutes. The mixture was filtered and concentrated under reduced pressure. The residue was taken up in toluene (50 mL), washed with aqueous KHCO3, dried (Na2SO4), filtered and concentrated. The resulting material was purified on silica eluting with 25% hexane −75% CH2Cl2 to provide the titled compound (0.763 g, 80%). 1H NMR (300 MHz, CDCl3) δ 3.75 (br s, 2H), 5.95 (s, 1H), 6.14 (d, J=3 Hz, 1H), 6.50 (t, J=75 Hz, 1H, CHF2) 6.71 (dd, J=9 Hz, 3 Hz, 1H), 6.77 (dd, J=9 Hz, 1Hz, 1H), 6.87 (dd, J=9 Hz, 1Hz, 1H), 7.05 (t, J=8 Hz, H), 7.30-7.40 (m, 5H), 8.12 (d, J=9 Hz, 1H). MS (APCI) m/e 340 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)\[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH:16]1(/[C:7](/[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)C2CCCCC2)cc1
Yield: 70.6 %

Procedure:
As described in Example 99, (2E,4Z)-5-cyclohexyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester (5.2 g) was saponified in a refluxing mixture of methanol (20 mL) and 2N NaOH (20 mL). After 2.5 hours the crude product was isolated in the usual way crystallized from 2-propanol-hexane to give 3.5 g of (2E,4Z)-5-cyclohexyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid, mp 185°-186° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:38]([O:40][CH3:41])=[O:39].CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:38](=[O:39])[O:40][CH3:41])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.3 %

Procedure:
To a solution of compound 339 (220 mg, 0.433 mmol) and methyl chloroformate (50.2 μl, 0.65 mmol) in THF (4 ml) was added DIPEA (227 μl, 1.30 mmol) and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, the residue was triturated with MeOH and the solid suspension was collected by filtration and purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 25 g column) to afford compound 340 (123.1 mg, 0.218 mmol, 50.2% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (s, 1H), 8.56-8.50 (m, 2H), 8.33 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.2 Hz, 1H), 7.20 (dd, J=8.8, 1.2 Hz, 1H), 6.65 (d, J=5.6 Hz, 1H), 6.56 (d, J=2.8 Hz, 1H), 4.54 (s, 2H), 3.64 (s, 2H), 3.44 (s, 3H), 3.22 (s, 2H), 2.59-2.51 (m, 1H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 566.4 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:4]=2[C:5]2[C:9]([CH3:10])=[N:8][O:7][C:6]=2[C:11]2([N:14]=1)[CH2:13][CH2:12]2.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:17]1[CH:16]=[CH:15][C:4]2[C:5]3[C:9]([CH3:10])=[N:8][O:7][C:6]=3[C:11]3([CH2:13][CH2:12]3)[N:14]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[C:3]=2[CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1noc2c1-c1ccc(Cl)cc1C(Cl)=NC21CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1noc2c1-c1ccc(Cl)cc1C(c1ccc(F)cc1)=NC21CC1
Temperature: 82 °C

Procedure:
To a solution of 6,8-dichloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane] (61.9 mg, 0.211 mmol) in toluene (22 mL) was added 4-fluorophenylboronic acid (37 mg, 0.264 mmol) and Pd(Ph3P)4 (11.22 mg, 9.71 μmol). The reaction was evacuated and purged with N2 (g) (3×), followed by addition of aqueous Na2CO3 (211 μl, 0.422 mmol, 2 M). The reaction was heated to 82° C. for 15 min at which time LC-MS analysis indicated complete conversion to desired product. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude product was purified on Biotage system (5% EtOAc:95% Hexanes to 10% EtOAc:90% Hexanes). The product 8-chloro-6-(4-fluorophenyl)-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane] (62 mg, 0.176 mmol, 83% yield) was obtained as a white crystals. LC/MS m/z 353 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.77 (m, 1H), 7.75-7.71 (m, 1H), 7.45-7.38 (m, 2H), 7.19-7.26 (m, 3H), 2.52 (s, 3H), 1.29 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[C:6]2=[O:18].[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:15][CH2:16][CH2:17]1)[CH:6]2[OH:18]
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(c(C)c1C)NCC1(CCC1)C2O
Reaction time: 2 h

Procedure:
To a cold solution of 6′-methoxy-7′,8′-dimethyl-1′H-spiro[cyclobutane-1,3′-quinolin]-4′(2′H)-one (2 g) in a mixture of 13 mL of THF and 5 mL of CH3OH cooled in ice bath, was added NaBH4 (2.4 g). After 2 hours, the mixture was quenched with ice, evaporated to dryness to give 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol as a crude mixture (11 g). NaBH4 (3 g) was added in portions to a mixture of trifluoroacetic acid and acetic acid (25 mL, v/v:1/1) cooled in ice bath, and to this mixture was added the above obtained mixture of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-4′-ol dissolved in 10 mL of THF. After 15 min, the mixture was quenched with ice, extracted with dichloromethane, and washed with brine. The organic phase was then washed with NaOH (2 M) and brine, dried, evaporated to dryness and passed through a silica column (Hexane: EtOAc; 10:1) to give 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (1.3 g) as a liquid with slightly yellow color. 1H-NMR (300 MHz, CDCl3) δ=6.44071 (s, 1H), 3.74 (s, 3H), 3.59-3.24 (s, 1H), 3.18 (s, 2H), 2.75 (s, 2H), 2.13 (s, 3H), 2.03 (s, 3H), 2.01-1.73 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=149.88, 136.21, 123.51, 131.91, 118.09, 110.83, 56.51, 51.91, 40.82, 36.09, 30.84, 15.25, 13.07, and 12.03 ppm.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pt]=O>[CH2:8]([C:9]1[NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=1[C:16]=23)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCc2c(C#Cc3ccccc3)[nH]c3cccc1c23
Agent: O=[Pt]
Solvent: CO
Product: O=C1NCCc2c(CCc3ccccc3)[nH]c3cccc1c23
Temperature: 24 °C
Reaction time: 20 h

Procedure:
2-Phenylethynyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (Compound 17) (37 mg, 0.13 mmol) and platinum oxide (1.5 mg, 0.05 mmol) were suspended in 2 mL MeOH under an argon atmosphere. The flask was flushed with hydrogen gas and the resulting mixture stirred at 24° C. under 1 atmosphere of hydrogen for 20 h. The catalyst was filtered off and the resulting solution concentrated, leaving a pale-yellow crystalline solid. Purification by radial chromatography (5% MeOH in CHCl3) followed by recrystallization (MeOH/CHCl3/hexanes) yielded 2-phenethyl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 14 mg (37%), as a pale-yellow solid. mp 207-208° C.; 1H NMR (300 MHz, d6-DMSO) δ2.60 (m, 2H), 2.95 (m, 4H), 3.26 (m, 2H), 7.17 (m, 6H), 7.46 (dd, 1H, J=7.8, 0.6 Hz), 7.61 (dd, 1H, J=7.5, 0.6 Hz), 7.90 (br t, 1H), 11.16 (br s, 1H); MS (FAB, MH+) 291; Anal. (C19H18N2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[CH:30]=[C:31](I)[S:32][C:25]=34)=[CH:19][CH:18]=2)[C:9]([C:11]2([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][C:38]#[CH:39])[CH3:35]>>[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][C:38]#[C:39][C:31]1[S:32][C:25]2[C:26](=[N:27][CH:28]=[CH:29][C:24]=2[O:23][C:20]2[CH:21]=[CH:22][C:17]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]([C:11]3([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]3)=[O:10])=[CH:18][CH:19]=2)[CH:30]=1)[CH3:35]
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)cc2)CC1
Reactant: C#CCN(CC)CC
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3)c2s1
Yield: 27.4 %

Procedure:
Prepared from N-(4-fluorophenyl)-N-(4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)cyclopropane-1,1-dicarboxamide (155 mg, 0.24 mmol) and N,N-diethylprop-2-yn-1-amine (24 mg, 0.21 mmol) according to the procedure for Example 6, Step B. The crude product was purified on a Horizon reverse phase using Biotage 12M C18 column. The crude was loaded to the samplet with EtOAc and dried under vacuum. Product eluted at 55-75% acetonitrile and was obtained as a white powder (32 mg, 24%). 1H NMR (CDCl3, 400 MHz) δ 9.58 (s, 1H), 8.94 (s, 1H), 8.46 (d, J=5 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.54 (s, 1H), 7.47 (m, 2H), 7.14 (d, J=9.0 Hz, 2H), 7.03 (t, J=8.6 Hz, 2H), 6.55 (d, J=5 Hz, 1H), 3.70 (s, 2H), 2.65 (q, J=7, 14 Hz, 4H), 1.71 (m, 4H), 1.13 (t, J=7.4 Hz, 6H) (350 mg, 31%). LRMS (ESI pos) m/e 557 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1>CN(C=O)C>[CH3:21][C:22]1[CH:23]=[N:24][N:25]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[CH:26]=1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)c1
Temperature: 110 °C
Yield: 70.2 %

Procedure:
To a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K2CO3 (496 mg, 3.59 mmol) in DMF (3 mL) was added 4-methyl-1H-pyrazole (196 mg, 2.391 mmol) in one portion. Then the mixture stirred under N2 was heated to 110° C. and reacted for 15 h. LCMS analysis showed the starting material disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give crude material which was purified by silica column chromatography (PE/EA=10/1 to 5/1) to afford pure product 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole (500 mg, 1.678 mmol, 70.2% yield): 1H NMR (400 MHz, CD3OD): δ 8.83 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 2.18 (s, 3H). ES-LCMS: m/z 272.2 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[H-].[Na+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>CN(C=O)C.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:3])=[O:18])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: Clc1ncccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ncccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.5 g, 2.0 mmol) in anhydrous DMF (10 mL) were added NaH (0.240 g, 6.0 mmol, 60% in mineral oil) and 2-chloro-pyrimidine (0.275 g, 2.4 mmol) at 0° C. After stirring at room temperature for 16 hours, the reaction mixture was cooled to 0° C., diluted with water (20 mL) and acidified to pH 2 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the organic extract washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and aqueous LiOH (1N, 5 mL) was added at 0° C. After stirring at room temperature for 1 hour, the mixture was acidified to pH 3 using dilute hydrochloric acid and concentrated. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=10:1:trace) to give the product (0.132 g, 22.0%). mp 118-120° C. 1HNMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.65 (d, J=4.68 Hz, 2H), 7.22-7.45 (m, 2H), 7.11 (s, 1H), 5.53 (dd, J=9.51, 1.90 Hz, 1H), 3.10 (dd, J=15.66, 2.49 Hz, 1H), 2.31 (s, 3H), 2.15 (dd, J=15.52, 9.66 Hz, 1H). MS (ESI) m/z=301 [M+H]+.
Reaction SMILES: N[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.C(ON=O)CC(C)C.[ClH:22]>C(#N)C.O>[CH3:13][O:12][C:10]([C:3]1[C:2]([Cl:22])=[N:7][C:6]([Cl:8])=[C:5]([Cl:9])[N:4]=1)=[O:11]
Reactant: Cl
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(Cl)c(Cl)nc1Cl
Temperature: 65 °C
Yield: 42 %

Procedure:
Methyl 3-amino-5,6-dichloro-2-pyrazinecarboxylate (2.6 g, 11.8 mmol), CuCl2 (2.37 g, 17.6 mmol) and iso-amylnitrite (2.07 g, 17.7 mmol) were combined in 100 mL of acetonitrile and heated at 65° C. for 18 h. The solution was cooled, acidified with 2N HCl (50 mL), diluted with water (100 mL), and extracted with DCM (3×30 mL). The combined extracts were dried, concentrated and the residue was purified by flash chromatography (eluent: 10 to 50% EtOAc+0.1% triethylamine in hexane) to afford 56a (1.21 g, 42% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9](=O)([O:17]C1C=CC([N+]([O-])=O)=CC=1)[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>C1COCC1>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:9]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.5 g of 4-piperidinylmethanol were dissolved in 170 ml of THF. 25.8 g of 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate and 15.9 ml of N,N-diisopropylethylamine were successively added thereto. The mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The residue was taken up in 400 ml of ethyl acetate and washed once with 300 ml of 0.5 N HCl and twice with 250 ml of 1 N NaOH each time. The organic phase was dried with MgSO4, the solvent was removed in vacuo, and the residue was purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30](=[O:35])N(OC)C)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([C:10]2[S:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:35])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cccc2scnc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2sc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)nc12
Yield: 60 %

Procedure:
To a solution of 4-methoxybenzothiazole (413 mg, 2.5 mmol) in THF (10 ml) at −75° C. was added dropwise n-BuLi (2.5M in Hex, 1.1 ml) such that the temperature did not exceed −70° C. The brown solution was stirred at this temperature for 15 min before the dropwise addition of a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (680 mg, 2.5 mmol) in THF (2 ml). The temperature was also kept below −70° C. The brown solution was then gradually allowed to reach RT (over 3 h). The mixture was poured on water and extracted with EtOAc. Organic extracts were washed with brine and dried over MgSO4 and concentrated. Chromatography on SiO2 (hex/EtOAc 2:1) gave 565 mg (60%) of a yellowish solid.