Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]>>[CH:28]1([O:27][C:25](=[O:26])[NH:1][C:2]2[C:3]([C:7]3[NH:23][C:10]4=[CH:11][C:12]5[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=5[CH:17]=[C:9]4[N:8]=3)=[N:4][NH:5][CH:6]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OC4CCCC4)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid cyclopentyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and cyclopentyl chloroformate (126 μl, 0.97 mmol). The title compound was obtained as yellow powder (116 mg, 34%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[O-]CC.[Na+].[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18]>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:22]([OH:23])=[C:16]([CH3:15])[C:17](=[O:18])[NH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Br)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)n(-c2cccc(Br)c2)[nH]c1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
To a suspension of 1-(3-bromophenyl)hydrazine hydrochloride (1.0 g, 4.47 mmol) in ethanol (8.9 mL) was added dropwise 2.0 M sodium ethoxide in ethanol (0.77 mL, 9.84 mmol, 2.2 eq.). Diethyl 2-methylmalonate (0.85 mL, 4.92 mmol, 1.1 eq.) was then added. The reaction mixture was stirred at 90° C. for 16 hours and then quenched with 2 N aqueous hydrochloric acid (50 mL). The reaction was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure. Purification using MPLC (Biotage) eluted with 3:1 v/v ethyl acetate-hexane gave the desired product as a white solid (125 mg, 0.46 mmol, 10.4% yield). MS LC-MS (ES MH+=269/271); TLC (Rf=0.10, 50% ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([CH:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].IC[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29]>>[F:32][C:27]([F:33])([C:28]([F:29])([F:30])[F:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:15][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FC(F)(F)C(F)(F)CCCCCCI
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Product: C=CCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5 and the 1-iodo-7,7,8,8,8-pentafluorooctane prepared in Example 4, the same procedure as shown in Example 5 was repeated to give ethyl 2-(7,7,8,8,8-pentafluorooctyl)-9-decenoate.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]([CH2:15][OH:16])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]([CH2:15][O:16][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1c2ccccc2C=Cc2cc(Br)ccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2c3ccccc3C=Cc3cc(Br)ccc32)cc1
Yield: 88.9 %

Procedure:
To a solution of 2-bromo-5-hydroxymethyl-dibenzo [a,d]cycloheptene (6.1 g) in dry dichloromethane (60 ml) was added p-toluenesulphonyl chloride (4.9 g). pyridine (4 g) and 4-dimethylamino pyridine (100 mg). The reaction mixture was refluxed for 14 h, cooled, washed with water (2×50 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue. was purified by flash silica chromatography using 10% ethyl acetate in hexane as eluent to give the title compound as a colourless oil (8.2 g). δ (360 MHz, CDCl3) 2.46 (3H, s, CH3), 4.12 (1H, dd J=6.2 and 3.5 Hz, CH--CH2 --O), 4.24-4.32 (2H, m, CH--CH2 --O), 6.50 (1H, d, J=11.9 Hz, CHA =CHB), 6.73 (1H, d, J=11.9 Hz, CHA =CHB), 7.10-7.40 (11H, m, ArH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[CH3:16][N+:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13].[CH3:16][N+:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCCCCCCCCCC(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCCCCCCCCCC(=O)[O-]

Procedure:
Tetramethylammonium 11-aminoundecanoate was synthesized by titration of a methanolic suspension of 11-aminoundecanoic acid (4.04 grams (g) in approximately 4 ml methanol, Aldrich) with methanolic tetramethylammonium hydroxide (8.4 ml, Aldrich), evaporation of the solvent under reduced pressure, and recrystallization from tetrahydrofuran (about 50 ml, Aldrich).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.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.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:21])[CH:27]=3)[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)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: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1cc(-c2cccc(N)c2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 44.9 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (70 mg, 0.21 mmol), 3-aminophenylboronic acid (66 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.021 mmol), in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (0.3 mL) was heated in a sealed vial at 10° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate, followed by trituration with 50% ethyl acetate in hexane afforded 32 mg (45%) of 3-(2-pyridyl)-5-(3-cyano-5-(3-aminophenyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ−8.82 (d, 1H), 8.57 (s, 2H), 8.40 (s, 1H), 8.22 (d, 1H), 8.08 (t, 1H), 7.66 (m, 1H), 7.20 (t, 1H), 7.00 (m, 2H), 6.69 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([OH:10])[CH2:7][S:8][CH:9]=1)=[O:4].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:10])=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CSCC1O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cscc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
1.6 parts of 3-hydroxy-dihydrothiophene-4-carboxylic acid methyl ester are introduced into 15 parts by volume of carbon tetrachloride and the mixture is cooled to 0° C. 1.78 parts of N-bromosuccinimide are added in portions over 30 minutes and the mixture is kept for one hour at 0° C. The end product is isolated from the reaction mixture analogously to Example 5c. 1.2 parts (76% of theory) of 3-hydroxythiophene-4-carboxylic acid methyl ester of melting point 40°-43° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1C=CC=CC=1.Cl>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:10])=[O:9]
Reactant: NC1CCCCC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(NC1CCCCC1)c1ccccc1Br
Reaction time: 3 h

Procedure:
To a 20 mL vial were added a stirbar, 2-bromobenzene-1-sulfonyl chloride (1.053 g, 4.12 mmol), cyclohexylamine (431 mg, 4.34 mmol) and dry pyridine (5 mL). The mixture was stirred for 3 hours before adding it to a separatory funnel containing 1 N HCl and EtOAc. The layers were mixed thoroughly and then separated. The organic layer was then washed with water followed by sat. NaHCO3, dried over MgSO4, filtered and evaporated to dryness to give the title compound. MS (ESI): mass calcd. for C12H16NO2SBr 317.01, m/z found 318.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.14 (dd, J=7.9, 1.7, 1H), 7.71 (dd, J=7.9, 1.2, 1H), 7.49-7.42 (m, 1H), 7.42-7.35 (m, 1H), 5.05 (d, J=7.7, 1H), 3.19-3.04 (m, 1H), 1.79-1.66 (m, 2H), 1.66-1.57 (m, 2H), 1.52-1.44 (m, 1H), 1.28-1.04 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:27]=[C:28]([C:36](Cl)=[O:37])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:27]=[C:28]([C:36]([N:10]([CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:37])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)#[N:25]
Reactant: C=CCC(CNC)c1ccc(F)cc1
Reactant: N#Cc1cc(C(=O)Cl)c2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(CN(C)C(=O)c1cc(C#N)cc2ccccc12)c1ccc(F)cc1
Yield: 80.5 %

Procedure:
[2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (1.0 g, 5.2 mmol) was dissolved in CH2Cl2 and stirred at 0° C. during addition of DIPEA (1.5 g, 11.4 mmol) and 3-cyano-1-naphthoyl chloride (Method 11; 1.1 g, 5.17 mmol). The mixture was stirred with cooling for a short while and then stirred at room temperature for 2 h. The mixture was washed twice with water, once with an aqueous solution of KHSO4, and then with brine. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (methanol-CH2Cl2, 5:95). There was obtained 1.55 g (80%) of 3-cyano-N-[2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-1-naphthamide as an oil. 1H NMR (400 MHz, CDCl3): 2.1-4.9 (cm, 8H), 5.0-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.4-8.0 (cm, 9H), 8.2 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([CH:13]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][N:14]3C(OCC3C=CC=CC=3)=O)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>CO.[Pd]>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:13]([C:10]2[NH:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]=3[N:11]=2)[NH:14]1
Reactant: NC(=O)c1cccc2[nH]c(C3Cc4ccccc4CN3C(=O)OCc3ccccc3)nc12
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(C3Cc4ccccc4CN3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl 3-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2-(1H)-carboxylate (400 mg, 0.938 mmol) in methanol (20 ml) was added 10% Pd/C (40 mg) and the reaction mixture was degassed and stirred under H2 at 1 atmosphere pressure for 2 h at RT. The reaction mixture was filtered and the filtrate was concentrated and the crude was product further triturated with ether to afford 2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-benzo[d]imidazole-4-carboxamide. MS (ES+): m/z 293.1 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][O:16][C@@H:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:14]1.C(N(CC)CC)C>C(#N)C>[NH2:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH2:14]2)[N:7]=1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: O=C([C@H]1CNCCO1)N1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc(N2CCO[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.8 %

Procedure:
2-Chloro-5-nitropyrimidin-4-amine (106 mg, 0.612 mmol) was added to a solution of (R)-morpholin-2-yl(pyrrolidin-1-yl)methanone hydrochloride (0.15 g, 0.68 mmol) and triethylamine (0.28 mL, 2.04 mmol) in acetonitrile (10 mL) at room temperature. The reaction mixture was heated at 80° C. for 1 h, then was cooled to room temperature and stirred for 12 h. The solvent was removed under reduced pressure and the resulting crude material was triturated with diethyl ether to afford (R)-(4-(4-amino-5-nitropyrimidin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone (0.11 g). MS (ES+APCI) (M+H) 323.1; LCMS retention time: 3.518 min (Method S1).
Reaction SMILES: [CH:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][C@H:9]3[CH2:14][NH:15][CH2:16][CH2:17][N:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2]>O1CCCC1.[Pd]>[CH2:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][C@H:9]3[CH2:14][NH:15][CH2:16][CH2:17][N:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1cccc2c1OCC[C@H]1CNCCN21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cccc2c1OCC[C@H]1CNCCN21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 237A (60.8 mg, 0.264 mmol) in tetrahydrofuran (20 mL) was added to 5% Pd—C (wet, 18.24 mg, 0.171 mmol). The solution was stirred under H2 (30 psi) for 16 hours at ambient temperature. The solution was then filtered through a nylon membrane and concentrated. Purification via HPLC (ammonium acetate method) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.72-6.92 (m, 3H), 4.27-4.42 (m, 1H), 4.04-4.16 (m, 1H), 2.69-3.15 (m, 7H), 2.43-2.59 (m, 2H), 1.76-2.03 (m, 2H), 1.08 (t, J=7.54 Hz, 3H); MS (ESI+) m/z 233 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[C:3]=1[F:17].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:3]1[C:4]([F:16])=[CH:5][C:6]2[CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:9]3[C:10]=2[C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: O=C1NCCn2c1cc1cc(F)c(F)c(Br)c12
Reactant: OB(O)c1ccc(F)cc1
Product: O=C1NCCn2c1cc1cc(F)c(F)c(-c3ccc(F)cc3)c12

Procedure:
The title compound, off-white solid (69 mg, 87%), MS (ISP) m/z=317.0 [(M+H)+], mp 286.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-7,8-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (75.3 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][CH:28]([CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[C:29]#[N:30].C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:34]=[N:33][N:32]([CH2:31][CH:28]([CH3:27])[C:29]#[N:30])[CH:36]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC(C#N)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C#N)Cn1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2 (1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 2-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (7.5 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (2.9 mg). LCMS (M+H)+: m/z=472.3.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:32]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CCOC(C)=O>C1COCC1.O.Cl[Pd]Cl>[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]([C:9]2[CH:10]=[CH:11][C:12]3[C:17]4=[C:16]5[C:5](=[CH:4][CH:3]=[CH:2][C:15]5=[CH:14][CH:13]=3)[CH:6]=[CH:7][C:8]=24)[CH:30]=[C:31]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:32]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(B(O)O)c1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Reaction time: 24 h
Yield: 122.5 %

Procedure:
0.122 g (5 mol %) of PdCl2 (dppf) was added to 0.686 g (2.44 mmol) of 1-bromopyrene in a darkroom, and dissolved with 12 ml of THF/H2O. 1.0 g (2.19 mmol) of 3,5-bis-tert-butyldimethylsilyloxymethyl Phenylboronic acid dissolved in 12 ml of THF/H2O was added, 3.66 ml (3 eq) of 2N NaOHaq was injected, the reaction was initiated in a 65° C. oil bath with light shielding, and the mixture was agitated for 24 hours. Strong fluorescence was continued with the naked eye by TLC (Hex:EtOAc=5:1). This was extracted with EtOAc, and the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure to obtain 1.5203 g of a mixture of the target product and hydrolysates.
Reaction SMILES: NCCCN.O.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[N:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[OH:25])([O-])=O>C1(C)C(C)=CC=CC=1.[Cu].II.CC(O)=O>[OH:25][C:19]1[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[N:17]1[N:16]=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:7]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: [Cu]
Agent: II
Agent: NCCCN
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
11.6 g of 1,3-diaminopropane (0.16 mol) and 2 g of copper-II-acetate (0.01 mol) are placed into 50 ml of water and the whole is heated, with the exclusion of air and with stirring, to 85°-90° C. A solution of 10 g of 2-nitro-2'-hydroxy-5'-methyl-azobenzene (0.04 mol) in 100 ml of xylene heated to 60° C. is then added, and after 20 hours the reaction mixture is cooled to room temperature. The aqueous phase is separated, and the organic phase is extracted with aqueous hydrochloric acid, and then washed with water until neutral. The xylene is distilled off to leave 7.7 g of crude product. Analysis of the crude product by means of LC (liquid chromatography) gives 86% of theory of 2-(2'-hydroxy-5'-methylphenyl)-benzotriazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[C:27]([Cl:33])[CH:26]=4)=[CH:23][NH:22][N:21]=3)[CH:19]=2)=[O:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:34]1(=[O:39])[O:38][CH2:37][CH2:36][CH2:35]1.C[Al](C)C>CS(C)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][OH:39])=[C:27]([Cl:33])[CH:26]=4)=[CH:23][NH:22][N:21]=3)[CH:19]=2)=[O:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Reactant: O=C1CCCO1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCCO)NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzyl amine 11 (0.05 mmol) in DMSO (1 mL) was mixed with a solution of 4-butyrolactone (0.05 mmol) in CH2Cl2 (1 mL) under N2. To the mixture was added AlMe3 (0.25 mmol) and stirred for 10 min at room temperature and then 6 h at 45° C. The crude product was purified from preparatory HPLC to give II-8 as a yellow oil.
Reaction SMILES: [I:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:9]#[N:10])[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>[Ag-]=O.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[C:4]([C:3]=1[O:11][CH3:12])[C:9]#[N:10]
Reactant: COc1c(I)c[nH]c(=O)c1C#N
Reactant: COc1ccc(CCl)cc1
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ncc(I)c(OC)c2C#N)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a mixture of 5-iodo-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (3.00 g), silver(I) oxide (2.77 g) and toluene (80 mL) was added 4-methoxybenzyl chloride (2.21 g) at room temperature, and the mixture was stirred 110° C. for 5 hr. To the reaction mixture was added 4-methoxybenzyl chloride (2.21 g), and the mixture was stirred at 110° C. for 16 hr. The reaction mixture was cooled to room temperature, the insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether, and the precipitate was collected by filtration to give the title compound (3.32 g).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:17]([OH:19])=O)[NH:15][N:16]=2)=[C:8]([CH3:20])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].FC1C=CC(C2C(CO[C:35]3[CH:36]=[C:37]([C:40](O)=O)[NH:38][N:39]=3)=C(C)ON=2)=CC=1>>[N:39]1([NH:38][C:17]([C:14]2[NH:15][N:16]=[C:12]([O:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:20])[CH:13]=2)=[O:19])[CH2:40][CH2:37][CH2:36][CH2:35]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)[nH]n1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)O)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN2CCCC2)[nH]n1
Yield: 48 %

Procedure:
As described for example 10b, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid (140 mg, 0.5 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid, was converted, to the title compound (83 mg, 48%), which was obtained as a white solid. MS: m/e=348.3 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:38](I)([CH3:40])[CH3:39]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH:38]([CH3:40])[CH3:39])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CC(C)I
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(C(C)C)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and isopropyl iodide (0.30 mL) as starting materials, 5-benzyloxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.68 g) was obtained.