Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29]C)=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:26][O:25][C:24]1[C:3](=[O:2])[C:4]([CH3:31])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:22](=[O:29])[C:23]=1[O:27][CH3:28]
Reactant: COc1c(C)c(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-phenylbenzoic acid (340 mg, 0.7819 mmol) was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (1.10 g, 2.0072 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (234 mg, 0.5969 mmol, 76%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1.CO.C([O-])=O.[NH4+]>C1COCC1.C(Cl)Cl.[Pd]>[O:19]1[CH2:18][CH2:17][N:16]([C:4]2[C:5]3[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=3)[N:7]=[CH:2][CH:3]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1cn2nc(Cl)cc(N3CCOCC3)c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2nccc(N3CCOCC3)c2n1

Procedure:
Compound 5b (8.6 g, 28 mmol) was suspended in THF (100 mL)/MeOH (50 mL). The reaction mixture was purged with argon, and 10% Pd/C (1.5 g, 1.4 mmol) was added followed by solid ammonium formate (8.7 g, 140 mmol). The reaction mixture was stirred under reflux for 1 h, during which time some of the ammonium formate sublimed onto the reflux condenser. The solid was rinsed back into the reaction flask with dry MeOH. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to obtain a solid, which was dissolved in DCM (200 mL), and washed with water (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give compound 5c as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.34 (s, 1H), 8.04 (d, J=5.6 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.98-4.07 (m, 4H), 3.88-3.96 (m, 4H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: F[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:22]=[N+:23]=[N-:24].[Na+]>CCOC(C)=O>[N:22]([C:6]1[CH:7]=[CH:2][C:3]([N+:14]([O-:16])=[O:15])=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=1)=[N+:23]=[N-:24]
Reactant: O=[N+]([O-])c1c(F)cccc1N1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 1-(fluoro-2-nitro-phenyl)-piperidine (389 mg, 1.73 mmol, as prepared in the previous step) in 5, mL of DMF was added sodium azide (169 mg, 2.60 mmol) and the resultant mixture heated to 50° C. for 14 h, and then 80° C. for 6 h. The reaction was diluted with EtOAc (100 mL), washed with water (2×50 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative TLC (50% EtOAc-hexane) afforded 316 mg (74%) of the title compound as a tan solid. Mass spectrum (ESI, m/z): Calcd. for C11H13N5O2, 248.1 (M+H), found 247.9.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: COc1ccccc1CCCCO
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1CCCCOCCCCCCBr
Yield: 58.8 %

Procedure:
NaH (46% dispersion in oil; 1.36 g) was added portionwise to a solution of 2-methoxybenzenebutanol (5.0 g) and 1,6-dibromohexane (13.8 g) in THF (50 ml). The suspension was refluxed for 20 h and was treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (2×50 ml) and the dried extract was evaporated to leave a yellow oil. The oil was purified on a column of silica (Merck 9385, 600 ml) [A] to give the title compound as a colourless oil (5.6 g). T.l.c. [B] Rf 0.2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32]>>[CH:31]([C:30]1[N:27]=[C:26]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)[O:28][N:29]=1)([CH3:33])[CH3:32]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Product: CC(C)c1noc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=469 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:27])[NH2:26])[CH:7]=[CH:8][CH:9]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:2]([F:28])([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([O:24][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:27])[NH2:26])[CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Reaction time: 0.05 h
Yield: 82.5 %

Procedure:
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (115 mg, 0.28 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (65 mg, 0.41 mM) was added and the resultant mixture stirred at room temperature for 23 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 112 mg (83%) of the {9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.5-7.0 (m, 9H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3488, 3141, 1763, 1674, 1501, 1444, 1269, 1215, 1178, 1102, 772, and 714. MS (FD) m/e 472.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:7]([O:21][CH3:22])[CH:6]=1)([OH:4])[CH3:3].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl.C(N(CC)CC)C>[CH3:3][C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:23](=[O:25])[CH3:24])=[C:7]([O:21][CH3:22])[CH:6]=1)([OH:4])[CH3:1]
Reactant: COc1cc(C(C)(C)O)ccc1NS(=O)(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)(C)O)ccc1N(C(C)=O)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-1-(4-phenylsulfonylamino-3-methoxyphenyl)-ethanol (2.65 g; prepared in Reference Example 38.) in methylene chloride (15 ml), acetic anhydride (3.05 ml) and triethylamine (4.60 ml) were added. The mixture was stirred overnight at room temperature. The solvent was distilled off. The residue was purified on silica gel column chromatography (hexane:AcOEt=3:4) to give the title compound (2.33 g) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC.O>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>[F:15][C:14]([F:17])([F:16])[CH:13]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:12]=[CH:11]/[C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH:27]=[CH2:28])[CH:10]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)O
Yield: 55.1 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (600 mg, 1.23 mmol) in dry toluene (10 mL) was added tributyl(vinyl)stannane (470 mg, 1.48 mmol) and the mixture was degassed with argon for 15 min Pd(PPh3)4 (72 mg, 0.06 mmol) was added and the reaction mixture was refluxed for 2 h. The reaction mixture was brought to ambient temperature, water was added and the mixture extracted with EtOAc. The organic layer was washed with 2N HCl and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica eluting with 30% EtOAc in petroleum ether to afford the title compound as brown solid (295 mg, 55%): 1H NMR (300 MHz, DMSO-d6) δ 13.05 (bs, 1H), 7.91 (s, 2H), 7.81-7.75 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.48 (dd, J=17.4, 10.8 Hz, 1H), 7.03 (dd, J=15.9, 8.7 Hz, 1H), 6.84 (d, J=15.6 Hz, 1H), 5.88 (d, J=16.5 Hz, 1H), 5.39 (d, J=12.3 Hz, 1H), 4.89-4.82 (m, 1H); ESIMS m/z 432.18 ([M−H]−); IR (thinfilm) 3418, 1689, 1114, 747 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:26](O)[CH3:27].OS(O)(=O)=O.CCCCCC>CO.C(OC(=O)C)C>[CH2:26]([O:24][C:23](=[O:25])[CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=1)[CH3:27]
Reactant: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(-c2ccc(Cl)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoic acid (300 g, 840 mmol) and ethanol (3 L) were placed in a flask. Concentrated H2SO4 (2.4 mL, 86.4 meq.) was added with stirring. The reaction was then heated to reflux. After approximately 30 minutes, the suspension dissolved. The reaction was monitored by TLC (silica gel; hexane:ethylacetate:methanol;70:20:10). After refluxing for 9 hours, all starting material was gone and 2 liters of ethanol was removed by distillation. The remaining solution was cooled with stirring to 0° C. and seeded with known ethyl-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoate. The resulting suspension was stirred at 0° C. for 30 minutes and then filtered, washed with cold ethanol (100 mL) and vacuum dried (room temperature, ca. 5 mm Hg) to give ethyl-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoate (275.0 g, 85% yield) as a clean white powder (mp=80-81° C.). An additional 27.9 g of ethyl-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoate was obtained as a tan powder after reducing the volume of the mother liquor to approximately 100 mL and seeding with known ethyl-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OC2C3C(=CC=CC=3)N(C3C=CC(Cl)=CC=3)N=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[C:34]([OH:48])=[N:35][N:36]2[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47].CCN(P1(N(CC2C=CC=CC=2)CCCN1C)=NC(C)(C)C)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C(OC(N1CCC(OS(C)(=O)=O)CC1)=O)(C)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:48][C:34]2[C:33]3[C:37](=[CH:38][CH:39]=[CH:40][C:32]=3[F:31])[N:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccc(Cl)cc3)c3ccccc23)CC1
Reactant: Oc1nn(-c2ccccc2F)c2cccc(F)c12
Agent: C=Cc1ccc(C=C)cc1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C=Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccccc3F)c3cccc(F)c23)CC1
Yield: 51 %

Procedure:
4-[4-Fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 46) was prepared as described above for Intermediate 42 using Intermediate 45 (300 mg, 1.218 mmol), PS-BEMP resin (1.108 g) and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 2) (374 mg, 1.34 mmol) in DMF (10 ml) to afford 265 mg (51%) of Intermediate 46 as a yellow oil. MS (M+1)=430.2.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][N:6]=[CH:5][N:4]=1)[NH2:2].[C:19](OCC)(OCC)(OCC)[CH3:20]>>[CH3:19][C:20]1[N:4]2[CH:5]=[N:6][CH:7]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:3]2=[N:1][N:2]=1
Reactant: NNc1ncncc1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2c(-c3cccc(C(F)(F)F)c3)cncn12
Reaction time: 0.17 h

Procedure:
A mixture of 1.0 g. of 4-hydrazino-5-(3-trifluoromethylphenyl)pyrimidine and 10-12 ml. of triethyl orthoacetate is stirred at room temperature. Complete solution is effected in about 10 minutes and stirring is continued for an additional 30-40 minutes until a new precipitate begins to form. This precipitate is collected in 3 crops over a 4 hour period to yield 0.85 g. (77%) of product. The product is recrystallized from chloroform-hexane to give the title compound, m.p. 157°-159° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[C:12]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:7]2=[C:6]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[N:5]=1)#N.[C:35]([O-])(O)=[O:36].[Na+].CC(=O)[O:42]CC.C(Cl)Cl>Cl.CO>[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:12]1[C:7]2[N:8]([C:4]([CH2:3][C:1]([O:36][CH3:35])=[O:42])=[N:5][C:6]=2[C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccc(-c2nc(CC#N)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1nc(-c2ccc(C(=O)OC)cc2)c2c(NCc3ccc(OC)cc3OC)nccn12
Yield: 86 %

Procedure:
To a solution of methyl 4-(3-(cyanomethyl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (12 g, 26.2 mmol) in HCl/MeOH (150 mL) was stirred at RT for 2 hrs. After the reaction was completed, the mixture was neutralized with aq NaHCO3 and extracted with EA and water. The organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with PE:EA:DCM=2:1:1 to give methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-methoxy-2-oxoethyl)imidazo[1,5-a]pyrazin-1-yl)benzoate (11 g, yield 86%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.C(Cl)Cl.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[C:14]1([S:11]([N:7]2[C:8]3[C:4](=[C:3]([CH2:20][N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:2]([OH:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCNCC3)c(O)ccc21
Reaction time: 4 h
Yield: 53 %

Procedure:
tert-Butyl 4-{[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate, (10 mg, 0.018 mmol, Intermediate 64) was dissolved in DCM/TFA 50/50 (1 mL) and left in RT for 4 hours after which time the solvent was removed at reduced pressure and the residue was purified on a preparative HPLC, Method A, to yield 5.5 mg (53%) of the target compound as a colourless oil. MS (ESI+) for C19H21N3O3S m/z 372 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].C([O:13][C:14](=O)[CH:15]([CH3:19])[C:16](=O)[CH3:17])C>CCO.CC(O)=O>[OH:13][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:16]([CH3:17])[C:15]=1[CH3:19]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N#Cc1ccnc(NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn(-c2cc(C#N)ccn2)c(O)c1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile (134 mg, 1 mmol, PREPARATION 2) and 2-methyl-3-oxo-butyric acid ethyl ester (158 mg, 1.1 mmol) in EtOH (5 mL) and AcOH (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (CH2Cl2) to afford the title compound (100 mg, 47%) as an orange solid. [M+H] Calc'd for C11H10N4O, 215. Found, 215.
Reaction SMILES: CN(OC)[C:3](=[O:16])[CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([CH:6]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH2:5][CH2:4][C:3]([CH2:4][CH2:5][CH:6]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)CCCc1c[nH]c2ccccc12
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCC(Cc1ccccc1)c1c[nH]c2ccccc12)CCC(Cc1ccccc1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a solution of 147 mg (0.60 mmol) of amide 139 in 4.0 mL of THF at -78° C. was added 1.31 mL (1.31 mmol) of benzylmagnesium chloride (1.0M in Et2O) and the reaction mixture was allowed to warm to room temperature and stir for 3 h. The reaction was quenched with 5% KHSO4 and extracted into ether. The combined ethereal layers were washed with brine and dried over MgSO4. Flash chromatography (elution with 25% ether in hexane) gave 108 mg of the ketone 140. 1H NMR consistent with structure.
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:24]([CH3:25])=[N:23][C:16]3[N:17]=[C:18]([NH:21][CH3:22])[N:19]=[CH:20][C:15]=3[CH:14]=2)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])C.Cl.[F:30][C:31]([F:39])([F:38])[C:32]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33]1.CN1CCCC1>C1COCC1.CCOC(C)=O>[F:27][C:8]1[CH:9]=[C:10]([CH3:26])[C:11]([C:13]2[C:24]([CH3:25])=[N:23][C:16]3[N:17]=[C:18]([NH:21][CH3:22])[N:19]=[CH:20][C:15]=3[CH:14]=2)=[CH:12][C:7]=1[NH:6][C:5]([NH:37][CH2:36][CH2:35][C:32]1([C:31]([F:39])([F:38])[F:30])[CH2:34][CH2:33]1)=[O:4]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)nc3nc2C)c(C)cc1F
Reactant: NCCC1(C(F)(F)F)CC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC4(C(F)(F)F)CC4)c(F)cc3C)c(C)nc2n1
Temperature: 65 °C
Yield: 41.8 %

Procedure:
Treat a mixture of prop-1-en-2-yl(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (1.09 g, 2.86 mmol) and 2-(1-(trifluoromethyl)cyclopropyl)ethanamine hydrochloride (0.542 g, 2.86 mmol) in THF (30 mL) with 1-methylpyrrolidine (1.52 mL, 14.3 mmol) and heat at 65° C. for 4 h. Cool the mixture to RT, dilute with EtOAc, wash with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (MeOH/EtOAc). Treat the resulting material with acetonitrile, cool to −20° C. for 2 h, collect the solids via filtration, rinse with acetonittrile (−20° C.) and dry to afford the title compound as a pale yellow solid (570 mg, 42% yield). MS (m/z): 477.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (226 mg) and 1-(2-bromoethoxy)-4-nitrobenzene (500 mg) in N,N-dimethylformaldehyde (5 mL) was added potassium carbonate (281 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (20 ml). The extract was washed successively with 0.5M aqueous hydrochloric acid solution, 1M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-(2-(4-nitrophenoxy)ethoxy)benzaldehyde (560 mg).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][OH:27])[CH:20]=[CH:19]3)=[N:12][CH:13]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1>O1CCOCC1.CO>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][CH2:26][OH:27])[CH:20]=[CH:19]4)=[N:12][CH:13]=2)=[CH:31][CH:30]=1
Reactant: OCCn1ccc2cc(C#Cc3ccc(Br)cn3)ccc21
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Temperature: 110 °C

Procedure:
Under an N2 atmosphere 56 mL 2 M Na2CO3 solution and 1.29 g (1.1 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 19.0 g (55.7 mmol) 2-[5-(5-bromo-pyridin-2-ylethynyl)-indol-1-yl]-ethanol and 11.55 g (72.4 mmol) 4-chlorophenyl-boric acid in 320 mL 1,4-dioxane and 80 mL MeOH and the reaction mixture is heated to 110° C. for 16 h. The mixture is evaporated down i. vac., the residue is combined with 300 mL water and the suspension is stirred vigorously. The precipitate is filtered off and washed with 200 mL water. The precipitate is suspended three times, each time with 600 mL PE/DCM (5:1), suction filtered and finally dried in the air until a constant weight is obtained.