Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[C:2]21[CH2:21][C:10]1[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=1[CH2:8][CH2:7][CH2:6]2)[N:15]([C:18](=[O:20])[CH3:19])[N:14]=[CH:13]3.C(O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+]>C1(C)C=CC=CC=1>[C:18]([N:15]1[C:16]2[C:12](=[CH:11][C:10]3[CH2:21][C:2](=[O:1])[CH2:6][CH2:7][CH2:8][C:9]=3[CH:17]=2)[CH:13]=[N:14]1)(=[O:20])[CH3:19]
Reactant: CC(=O)n1ncc2cc3c(cc21)CCCC1(C3)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: Cc1ccccc1
Product: CC(=O)n1ncc2cc3c(cc21)CCCC(=O)C3
Temperature: 142 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
1-Acetyl-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (79) (30 g, 124 mmol) was added to a round bottom flask, equipped with a Dean Stark trap and condenser. Ethane-1,2-diol (27.6 mL, 495 mmol), pTSA (2.36 g, 12.38 mmol) and toluene (300 mL) were added and the resulting mixture was heated to about 142° C. for about 90 min. After cooling to rt, the mixture was concentrated and sonicated with water (˜50 mL). The resulting solids were collected by filtration and taken into MeOH (200 mL) and water (200 mL). Potassium hydroxide (13.9 g, 248 mmol) was added and the mixture was stirred at rt for about 30 min. The mixture was extracted with DCM (300 mL), washed with brine (200 mL), dried over MgSO4 and concentrated to afford 5,7,8,9-tetrahydro-M-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (81), (28.3 g, 93%); LC/MS, method 1, Rt=1.20 min, MS m/z 245 (M+H)+1H NMR (400 MHz, DMSO) δ 12.79 (bs, 1H), 7.93-7.87 (m, 1H), 7.44 (s, 1H), 7.22 (s, 1H), 3.97-3.76 (m, 4H), 3.06 (s, 2H), 2.91-2.81 (m, 2H), 1.91-1.81 (m, 2H), 1.70-1.59 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:18])[C:8]([C:12]3[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:18])[C:8]([C:12]3[CH:16]=[C:15]([NH:17][C:21](=[O:22])[CH2:20][C:19]([O:25][CH2:26][CH3:27])=[O:24])[NH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2ccc(F)cc2nc1-c1cc(N)[nH]n1
Reactant: CCOC(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Nc1cc(-c2nc3cc(F)ccc3nc2C)n[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(7-fluoro-3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine (45.7 g, 188 mmol) in pyridine (750 mL) was added ethyl hydrogen malonate (5.35 mL, 62.5 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.0 g, 282 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 3 h, and then concentrated in vacuo. The residue was triturated with water, ethanol and acetone subsequently to give ethyl 3-{[3-(7-fluoro-3-methylquinoxalin-2-yl)-1H-pyrazol-5-yl]amino}-3-oxopropanoate. MS (APCI): m/z 358 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([OH:26])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[S:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:29]3[CH2:30][CH2:31][S:27][CH2:28]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Product: O=C(c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
120 mg (0.31 mmol) of the compound of Example 36A is reacted analogously to the synthesis of the compound of Example 3 with 30 mg (0.34 mmol) of thiazolidine. 86 mg (60% of theory) of the title compound is obtained.
Reaction SMILES: [CH:1]12[N:7]([C:8](=[O:39])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=3)=[C:15]4[C@H:29]([CH3:38])[CH2:30][N:31]3[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]3)([CH3:11])[CH3:10])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[BH4-].[Na+]>>[CH:4]12[N:7]([C:8](=[O:39])[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16]([C:21]3[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([CH3:27])[CH:26]=3)=[C:15]4[C@H:29]([CH3:38])[CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]3)([CH3:11])[CH3:10])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN2CCC(=O)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN2CCC(O)CC2)c1
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of (S)-1-{2-[5-[2-(7-aza-bicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-piperidin-4-one (15 mg in 0.10 mL dry methanol) at 0° C. was added a solution of sodium borohydride (1 mg in 0.15 mL methanol) and the mixture stirred at low temperature. After 4 hours, the solvent was removed in vacuo and the residue purified by flash chromatography on silica gel (methylene chloride:methanol, 9:1) to give the title compound (14 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(C#CC2CC2)ccc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(CCC2CC2)ccc1Cl
Reaction time: 14 h
Yield: 93.3 %

Procedure:
To a solution of 2-chloro-5-(cyclopropylethynyl)benzoic acid (200 mg) in ethyl acetate (20 mL) was added 10% palladium on carbon (40 mg), and the mixture was stirred under hydrogen atmosphere (0.2 MPa) for 14 hours, then was filtered off on celite, and the mother liquor was concentrated in vacuo. The residue was purified on silica gel column chromatography to obtain the titled compound (190 mg) as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)=[O:9]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:18]=[CH:17][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CN1CCN(C(=O)c2ccc(C=O)cc2)CC1

Procedure:
Prepared from N-methylpiperazine and 4-formylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:16](F)=[N:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[CH3:7])=[O:5].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)=[N:32]1>O>[Cl:1][C:2]1[C:16]([O:47][C:44]2[CH:45]=[C:46]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][N:38]=[C:37]3[NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=2)=[N:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[CH3:7])=[O:5]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CN(C)CCN(C)C(=O)c1ccnc(F)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCN(C)C(=O)c1ccnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
3-Chloro-N-[2-(dimethylamino)ethyl]-2-fluoro-N-methylisonicotinamide (116 mg, 0.45 mmol) and potassium tert-butoxide (70 mg, 0.62 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (650 mg, 0.25 mmol), and stirred under a nitrogen atmosphere at 80° C. for 2 hours. The reaction solution was cooled to room temperature, water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate to chloroform:methanol=1:3 to 100:2) to obtain the entitled compound (101 mg, yield: 84%) as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][O:28][C:29]1[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1>C(#N)C.C(O)(=O)C>[Cl:1][C:2]1[C:3]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: COc1ccccc1N
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccccc1Nc1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12
Temperature: 180 °C
Yield: 27 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (30 mg) was dissolved in o-anisidine (0.75 ml) and heated in a microwave oven (180° C., 20 min). The resulting mixture was diluted with acetonitrile (1 ml) and acetic acid (0.5 ml) and subjected to semi-preparative HPLC-C18. The fractions containing product (it co-elutes with o-anisidine) were pooled and evaporated in vacuo. The residue was dissolved in EtOAc (20 ml) and washed with 1% aqueous NaHCO3 (10 ml). The organic phase was treated with activated carbon and MgSO4, filtered and evaporated in vacuo. The oily residue was triturated with n-heptane (1 ml) and a few drops of EtOAc, which caused the product to crystallize. It was collected by filtration and washed with EtOAc to give the pure product as a white powder (10 mg, 27%). A second crop (2.9 mg) crystallized from the combined mother liquor and washing liquids.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Reactant: C1CNCCN1
Product: Nc1cc(N2CCNCC2)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) was reacted with piperazine following the procedure described in Example 163 to afford 4-amino-N-(1H-indazol-6-yl)-5-nitro-2-piperazin-1-ylbenzamide. The product thus obtained was treated with BOC anhydride as in Example 163 to obtain 4-[5-amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([CH:15]=1)[O:10][CH2:11][C:12](Cl)=[O:13].[OH:27][CH2:28][CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([CH:15]=1)[O:10][CH2:11][C:12]([O:27][CH2:28][CH2:29][P:30](=[O:37])([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])=[O:13]
Reactant: O=C(Cl)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCOP(=O)(CCO)OCC
Product: CCOP(=O)(CCOC(=O)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
by using 5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy-acetyl chloride and diethyl 2-hydroxyethylphosphonate there is obtained diethyl 2-[[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy]acetoxy]-ethylphosphonate, 1H-NMR (CDCl3, 400 MHz) 7.96 ppm (d, 1H), 7.80 ppm (d, 1H), 7.59 ppm (q, 1H), 7.21 ppm (d, 1H), 6.71 ppm (d, 1H), 6.52 ppm (q, 1H), 4.78 ppm (s, 2H), 4.45 ppm (m, 2H), 4.12 ppm (m, 4H), 2.17 ppm (m, 2H), 1.33 ppm (tt, 6H);
Reaction SMILES: [CH2:1]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:11]=[N:10][C:9]=1[C:20]([O:22]C)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CCO>[CH2:1]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:11]=[N:10][C:9]=1[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nnn(-c2ccccc2F)c1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nnn(-c2ccccc2F)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 5-benzyl-1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate obtained in Step 1 as described above was dissolved in EtOH and NaOH (8.10 ml; 5 M; 40.48 mmol; 5 eq.) was added, the mixture was stirred overnight at room temperature. Water (30 mL) was added and the aqueous phase was washed with Et2O (2×30 mL). The aqueous layer was acidified to pH 2 with HCl 5 N and extracted with EtOAc (2×50 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a yellow oil. It was taken up in petroleum ether and it was sonicated. The suspension was filtered off, affording Intermediate 24 as a beige solid. 1H-NMR (DMSO-d6, 300 MHz) δ 13.43 (br s, 1H), 7.74-7.69 (m, 1H), 7.64-7.58 (m, 1H), 7.53-7.42 (m, 2H), 7.22-7.17 (m, 3H), 6.83-6.72 (m, 2H), 4.38 (s, 2H). LC/MS (Method B): 298.2 (M+H)+. HPLC (Method A) Rt 3.60 min (Purity: 92.7%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[O:26][C:27]=1[CH3:28]>>[CH2:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[O:26][C:27]=1[CH3:28])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:20])[CH2:17][CH:18]=[CH2:19]
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Reactant: C=CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: C=CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3OC)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-but-3-enyloxy-3-(1H-indol-5-yl)-propionic acid methyl ester (preparation 9) was reacted with 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole to give rac-2-but-3-enyloxy-3-{1-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as light brown oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:3]=1[C:21]#[N:22].[CH3:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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>[CH:16]1([C:4]2[C:3]([C:21]#[N:22])=[C:2]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:23])[CH:29]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=3)[N:5]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(C#N)c(C3CCCC3)nc3ccc(C(F)(F)F)cc23)ccn1
Temperature: 90 °C
Yield: 14.9 %

Procedure:
A suspension of 4-bromo-2-cyclopentyl-6-trifluoromethyl-quinoline-3-carbonitrile (130 mg, 352 μmol), 2-methylpyridine-4-boronic acid pinacol ester (92.6 mg, 423 μmol), cesium carbonate (103 mg, 317 μmol) and tetrakis(triphenylphosphine)palladium (0) (40.7 mg, 35.2 μmol) in DMF (5.2 ml) was heated to 90° C. for 16 h. The reaction mixture was poured on water and extracted with EtOAc. The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining solid was purified by column chromatography (silica gel, n-heptane/EtOAc 4:1) to afford the title compound (20 mg, 15%) as off-white solid. MS (ESI): 382.6 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:3]=1.[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]>CCOC(C)=O>[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]3)[CH:3]=2)=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Reactant: N#CC1(c2cc(Br)ccn2)CCC1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.3, but using 1-(4-bromo-pyridin-2-yl)-cyclobutanecarbonitrile (Step 19.3) and (4-methyl-thiazol-2-yl)carbamic acid tert-butyl ester (Step 18.4). The reaction mixture is stirred for 3 h at 100° C. Title compound: ESI-MS: 371.1 [M+H]+; tR=4.86 min (System 1); TLC: Rf=0.66 (Hex/EtOAc, 1:1).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([C:20]3[C:25]([F:26])=[CH:24][N:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:21]=3)[CH3:19])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.O.[OH-].[Li+]>CO.C1COCC1>[F:26][C:25]1[C:20]([N:18]([CH3:19])[CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[N:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=[CH:7]3)=[N:21][C:22]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:23][CH:24]=1
Reactant: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(-c4ccc(OC)cc4)ncc3F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ncc(F)c(N(C)CCCOc3ccc4c(ccn4CC(=O)O)c3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of methyl(5-{3-[[5-fluoro-2-(4-methoxyphenyl)-4-pyrimidinyl](methyl)amino]propoxy}-1H-indol-1-yl)acetate (Example 86, 0.1 g, 0.20 mmol) in methanol (2 mL), THF (2.00 mL), and water (1.00 mL) was added lithium hydroxide (0.05 g, 1.99 mmol). The mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was taken up in water and washed with ether. The aqueous layer was acidified to pH 3.5 and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give the title compound (0.092 g, 100%). 1H NMR (300 MHz, CD3OD) δ 8.20-8.17 (m, 2H), 8.03-8.01 (m, 1H), 7.18-6.78 (m, 6H), 6.33-6.30 (m, 1H), 4.74 (s, 2H), 4.11 (t, 2H), 3.94 (t, 2H), 3.83 (s, 3H), 3.36-3.34 (m, 3H), 2.26-2.20 (m, 2H). LC/MS m/z 465.2 (M+H)+, RT 2.51 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:6][CH:7]=1.O.NN>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)cn1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(Br)cn1
Temperature: 70 °C
Yield: 97.9 %

Procedure:
A mixture of 2-((5-bromopyridin-2-yl)methyl)isoindoline-1,3-dione from Step 1 of Example 265 (630 mg, 1.987 mmol) and hydrazine monohydrate (0.484 mL, 9.93 mmol) was heated to 70° C. for 1.5 hr. A thick suspension formed. after cooling to rt, the reaction mixture was diluted with 20 ml of EtOH, filtered and the filter cake was washed with EtOH. The filtrate was concentrated to ⅓ volume and was refiltered. Concentration of that filtrate afforded (5-bromopyridin-2-yl)methanamine (364 mg, 1.946 mmol, 98% yield) as a colorless semisolid. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=2.2 Hz, 1H), 7.99 (dd, J=8.4, 2.4 Hz, 1H), 7.45 (dd, J=8.4, 0.4 Hz, 1H), 3.77 (s, 2H). MS (ES+) m/z: 187.12, 189.07 (M+H); LC retention time: 0.298 min (analytical HPLC Method O).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([CH3:37])[C:15]2[O:20][C:19]([CH2:22][CH2:23]OS(C3C=CC(C)=CC=3)(=O)=O)([CH3:21])[CH2:18][CH2:17][C:16]=2[C:35]=1[CH3:36].C1(C)C=CC=CC=1>O>[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([CH3:37])[C:15]2[O:20][C:19]([CH2:22][CH2:23][N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]3)([CH3:21])[CH2:18][CH2:17][C:16]=2[C:35]=1[CH3:36]
Reactant: OCCN1CCNCC1
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCOS(=O)(=O)c1ccc(C)cc1)O2
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCN(CCO)CC1)O2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution composed of 20 g of N-(2-hydroxyethyl)piperazine, 5 g of 3,4-dihydro-6-methoxy-2-[2-(p-toluenesulfonyloxy)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran and 100 ml of toluene was refluxed for 8 hours in a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. Low-boiling substances were distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 3.66 g of 1-[2-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)ethyl]-4-(2-hydroxyethyl)piperazine [Compound (35)] having the following physical characteristics.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)(=O)C>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1cnoc1-c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1cnoc1-c1ccccc1
Yield: 92.9 %

Procedure:
A mixture of ethyl (E)-3-(5-phenyl-4-isoxazolyl)propenoate (4.89 g), 2N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 3 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give (E)-3-(5-phenyl-4-isoxazolyl)propenoic acid (4.02 g, yield 93%). The crystals were recrystallized from acetone-hexane. melting point: 197–199° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:53][CH2:52][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[CH:51]=[C:43]3[C:42]2=[O:54])=[N:28][CH:29]=[CH:30][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:53][CH2:52][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[CH:51]=[C:43]3[C:42]2=[O:54])=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: Cn1cc(Br)cc(Nc2ccc(S(C)(=O)=O)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(S(C)(=O)=O)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 57.9 %

Procedure:
A sealed tube was charged with 117d (100 mg, 0.28 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (115 mg, 0.3 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), K3PO4 (126 mg, 0.6 mmol), and NaOAc (60 mg, 0.6 mmol) in MeCN (8 mL) and H2O (1 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel flash column eluting with DCM:MeOH (20:1) to afford 117e (100 mg, 40%). MS: [M+H]+ 617.