Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].I[CH2:12][CH2:13][CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH3:14])=[CH:4][N:3]=1
Reactant: CCCI
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)nc1
Reaction time: 18 h
Yield: 87 %

Procedure:
2-Bromo-5-hydroxypyridine (6 mmol) is dissolved in DMF (10 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min 1-iodopropane (1.1 eq.) is added and the reaction solution is stirred 18 hours. The reaction solution is pored into water and extracted with methyltert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-propoxy-pyridine is obtained as yellow oil in a yield of 87%; HPLC (method C): 1.93 min; LC-MS (method A): 1.78 min, 215.95 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Solvent: ClCCl
Product: O=C(CCc1ccccc1)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 69.8 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.12 g, 0.50 mmol), hydrocinnamoyl chloride (0.078 mL, 0.52 mmol) and poly-(4-vinylpyridine) (700 mg) in dichloromethane (10 mL) provided 0.13 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-yl-3-phenylpropanamide. MS (ESI) m/z 373; HPLC purity major: no impurities detected at 210-370 nm window; 99.5% at 252 nm (max. abs), RT=11.0 (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C25H28N2O+H+, 373.22744; found (ESI, [M+H]+), 373.2287.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:31]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:32]
Reactant: O=C(Cl)N1CCCC1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)N6CCCC6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of compound 7B (10.7 mg, 0.031 mmol), 1-pyrrolidinecarbonyl chloride (13 μL, 3.0 eq), triethylamine (26 μL, 6.0 eq) and dichloromethane (1 mL) was stirred at room temperature overnight. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12 mg, 87% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:10]([C:19]([OH:21])=O)[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:10]([C:19]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[O:21])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)O)c(-c3ccccc3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)NCc3ccc(OC)cc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To a stirred solution of 1-ethyl-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (18 mg) and 4-methoxybenzyl amine (10.3 mg) in DMF (1 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (28.6 mg) and N,N-dimethylaminopyridine (9.2 mg). The reaction mixture was stirred at room temperature for 18 hours and at 50° for 5 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with diluted HCl, water, saturated aqueous NaHCO3, water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crystalline residue was recrystallized from EtOAc and n-hexane to give 1-ethyl-N-(4-methoxybenzyl)-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (15.8 mg) as a colorless crystal.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:23]([O:25]CC)=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:23]([OH:25])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1-c1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)O)s2)ccn1
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a stirred solution of ethyl 2-[2-(acetylamino)pyridin-4-yl]-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylate (0.249 g, 0.620 mmol) in tetrahydrofuran (1.670 mL) and water (0.100 mL) was added lithium hydroxide, monohydrate (0.037 g, 0.891 mmol) and stirred for 18 h. The mixture was acidified to pH 6 with aqueous 1N HCl (1.20 mL, 1.20 mmol) and extracted with EtOAc (10.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (0.232 g) as a yellow solid and used without further purification. LC/MS (AA) ES+ 374, 376. 1H NMR (400 MHz, d6 DMSO) δ: 10.75 (br s, 1H), 8.69 (br s, 1H), 8.47-8.46 (m, 0.5H), 8.06-8.04 (m, 0.5H), 7.65-7.64 (m, 0.5H), 7.58-7.44 (m, 5H), 7.06-7.99 (m, 0.5H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](Cl)(C)=O>CO.CCOC(C)=O>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reaction time: 20 h

Procedure:
To a suspension of 3-methyl-2-nitro-benzoic acid (1.0 eq.) in MeOH (0.4 M) at 0° C. was added dropwise AcCl (3.0 eq.). The reaction mixture was stirred for 20 hr at reflux. The solvent was reduced in vacuo and the residue was dissolved in EtOAc and washed several times with sat. aq. NaHCO3 solution, brine and dried (Na2SO4). Evaporation of the solvent gave (A1) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ 7.86 (1H, d, J=7.5 Hz), 7.53-7.42 (2H, m), 3.89 (3H, s), 2.36 (3H, s). MS (ES) C9H9NO4 requires: 195. found: 218 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]([C:21]([OH:23])=O)=[N:9]1.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]([C:21]([Cl:27])=[O:23])=[N:9]1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccccc2Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccccc2Cl)n1

Procedure:
Part B: To a stirred solution of 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.37 g, 1.00 mmol) in dichloromethane (10 mL) is added oxalyl chloride (0.254 g, 2.00 mmol). The resulting mixture is concentrated in vacuo to give crude 1-(chlorophenyl)-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-carbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:13][CH2:21][CH3:22])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CCI
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a round bottom flask was placed 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (6.0 g, 23 mmol) in anhydrous DMF (22.8 mL). Potassium carbonate (6.3 g, 46 mmol) was then added followed by iodoethane (2.73 mL, 34.2 mmol). The resulting suspension was stirred at 60° C. for 2 h. The mixture was poured into 100 mL water and extracted with 200 mL of ethyl ether. The organic layers were separated, combined and washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated to 6.0 g of tan oil. LCMS calculated for C11H13BrClO2 (M+H)+: m/z=293.0; Found: 293.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-chlorophenyl)-3-phenylprop-2-en-1-one (1 g) in toluene (10 ml) magnesium oxide (0.41 g) and diethyl malonate (0.62 ml) were added. The slurry was stirred at rt for 2 h. The inorganics were removed by suction filtration and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue was recrystallised from diethyl ether/hexanes to provide diethyl 2-[3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]malonate (1.5 g) as colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)[N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1cc(OCCOCCOC)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCCOCCOC)nn1CC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1 g 5-[2-(2-Methoxy-ethoxy)-ethoxy]-2H-pyrazole-3-carboxylic acid ethyl ester in 10 ml of DMF and 154 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 5 min at room temperature, 966 mg of 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added. The reaction was stirred at room temperature for 2 h. Then 50 ml of water were added and the mixture was extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was used in the next reaction step without further purification. Yield: 1.2 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[N:3]=1
Reactant: CCCCN
Reactant: Nc1nc(N)nc(Cl)n1
Solvent: O
Product: CCCCNc1nc(N)nc(N)n1
Reaction time: 6 h
Yield: 96 %

Procedure:
A mixed solution of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3.5-triazine synthesized in Reference Example 1, 100 ml of water and 29.2 g (0.4 mol) of butylamine was warmed with stirring to the reflux temperature finally at which the reaction was allowed to proceed for 6 hours. After cooling the reaction mixture, the product was filtered off and further sufficiently washed with a large amount of water and then with toluene. the filtrate was dried at 70° C. for 6 hours under vacuum to obtain 17.5 g (yield: 96%) of the titled compound. Melting point: 167° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[CH:25]=[CH:26][O:22][CH:23]=5)[CH:28]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cccc(-c2ccoc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(-c3ccoc3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 79.6 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (48 mg, 0.17 mmol), 3-fur-3-ylbenzoic acid (32 mg, 0.17 mmol), HATU (65 mg, 0.17 mmol), HOBT (23 mg, 0.17 mmol) and DIPEA (88 μl) were stirred in DMF (1.5 ml) for 18 h at room temperature. The reaction was partitioned between ethyl acetate (100 ml) and hydrochloric acid (0.5M, 20 ml), the organic phase washed with aqueous sodium hydrogen carbonate (saturated) and dried (magnesium sulphate). The solvent was evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-fur-3-ylbenzamide (61 mg, 79%). NMR; δH [2H6]—DMSO 10.16,(1H, s), 8.35,(1H, t), 8.22,(1H, s), 7-89,(2H, d), 7.79,(2H, t), 7.69-7.65,(2H, m), 7.56,(1H, s), 7.45,(1H, t), 7.35,(2H, d), 7.19,(1H, d), 6.85,(1H, d), 6.49,(1H, m), 3.17,(2H, t), 2.18,(3H, s), 1.04,(1H, m), 0.42,(2H, m), 0.22,(2H, m). LCMS: retention time 3.75 min, MH+451.
Reaction SMILES: CNCC[C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1.[Br:11][C:12]1[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=1>>[Br:11][C:12]1[N:17]=[C:16]([C:18]([N:8]([CH3:10])[CH2:9][CH2:5][C:6]2[CH:5]=[CH:9][N:8]([CH3:10])[N:7]=2)=[O:20])[CH:15]=[CH:14][CH:13]=1
Reactant: CNCCc1cnn(C)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: CN(CCc1ccn(C)n1)C(=O)c1cccc(Br)n1

Procedure:
The title compound was prepared as described in Example 283, Step 1 using N-methyl-2-(1-methyl-1H-pyrazol-4-yl)ethanamine (125 mg, 0.90 mmol) and 6-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol) as starting materials.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH2:11]>>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:10][CH3:11])([CH3:9])[CH3:8]
Reactant: C=C
Reactant: CC(C)c1ccccc1
Product: CCC(C)(C)c1ccccc1

Procedure:
Particular preference is given to the reaction of toluene with ethene or propene to give propylbenzene or isobutylbenzene, the reaction of cumene with ethene to give tert-amylbenzene and the reaction of xylenes with butadiene to give 5-tolylpentenes, and the reaction of p-xylene with 1-butene or 2-butene to give 1-tolyl-2-methylbutane.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:20]([C:21](=[O:23])[CH3:22])=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:30])[CH:17]=3)[C:12]2=[O:31])=[CH:6][CH:5]=1.CO.[OH-].[Na+]>C1COCC1>[C:21]([C:20]1[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:17][C:16]([Cl:30])=[CH:15][CH:14]=2)(=[O:23])[CH3:22]
Reactant: COC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Reaction time: 12 h
Yield: 82.6 %

Procedure:
To a solution of 4-[(3-acetyl-6-chloro-1-oxo-4-phenyl-1H-isoquinolin-2-yl)methyl]benzoic acid methyl ester (1.5 g) in THF (15 ml) were added methanol (15 ml) and 8N-aqueous sodium hydroxide solution (0.8 ml) at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure, water and 10% hydrochloric acid were added to the residue. The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.2 g).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[O:8][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[CH3:20][N:21](C=O)C>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:9]2[O:8][C:7]([C:5]3[O:6][C:2]([C:20]#[N:21])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(-c2ccc(-c3ccc(Br)o3)o2)cc1
Reactant: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)o3)o2)cc1
Yield: 40 %

Procedure:
A mixture of 4 (740 mg, 2.35 mmol) and Cu(I)CN (423 mg, 4.7 mmol) in dry DMF (25 mL) was refluxed for 48 h. The reaction mixture was poured onto water/ammonia and extracted with methylene chloride. The extract was washed with water and brine, dried over Na2SO4, then passed on silica gel to give analytically pure product 5 in 40% yield, mp 194-195° C. 1H NMR (DMSO-d6); δ 7.17 (d, J=3.6 Hz, 1H), 7.21 (d, J=3.6 Hz, 1H), 7.43 (d, J=3.6 Hz, 1H), 7.76 (d, J=3.6 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H). 13C NMR (DMSO-d6); δ 152.3, 149.3, 144.3, 133.0, 132.9, 125.6, 124.3, 124.1, 118.7, 112.0, 111.8, 111.5, 110.0, 107.9. EIMS (m/z, rel.int.); 260 (M+, 100), 231 (15), 203 (25), 177 (25), 140 (10), 130 (55). Calcd for C16H8N2O2: C, 73.84; H, 3.09; N, 10.76. Found. C, 73.62; H, 3.18; N, 10.92.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7]/[C:8](=[N:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])/S(C(F)(F)F)(=O)=O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:42][CH:41]([OH:43])[CH2:40]2)=[CH:35][CH:34]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7]/[C:8](/[NH:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:40][CH:41]([OH:43])[CH2:42]2)=[CH:37][CH:38]=1)=[N:16]/[C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CC(O)C2)cc1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)S(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1ccc(N2CC(O)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
To a solution of {[(Z)-tert-butoxycarbonylimino]-trifluoromethanesulfonyl-methyl}-carbamic acid tert-butyl ester (13.62 g, 34.8 mM) and triethylamine (4.9 ml, 34.8 mM) in dry DCM (183 ml), 1-(4-aminophenyl)azetidin-3-ol (Method 37; 6.0 g, 36.5 mM) was added. The solution was stirred at room temperature under nitrogen for 48 hours. The reaction mixture was diluted with more DCM and washed with water (twice), saturated sodium bicarbonate solution (twice), water and saturated sodium chloride. The solution was then dried with anhydrous sodium sulphate, filtered and evaporated. The crude product was triturated with ether/isohexane (2:1), filtered washed with the same solvent and dried to give the title compound as a yellow solid (11.77 g, 83%). NMR 1.4 (s, 9H), 1.5 (s, 9H), 3.47 (t, 1H), 4.02 (t, 2H), 4.5 (m, 1H), 5.55 (d, 1H), 6.38 (d, 2H), 7.23 (d, 2H), 9.75 (s, 1H), 11.46 (m, 1H); m/z 407.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:7][CH3:8])=[N:5][CH3:6].Cl.[C:10](Cl)(=O)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:8][NH:7][C:4]1[N:5]([CH3:6])[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:2][N:3]=1
Reactant: CN=C(NC)NN
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Solvent: c1ccncc1
Product: CNc1nnc(-c2ccncc2)n1C
Temperature: 160 °C
Yield: 26.2 %

Procedure:
A mixture of 1000 mg (4.35 mmol) N-amino-N′, N″-dimethyl-guanidine hydriodide (Henry; Smith; J. Amer. Chem. Soc.; 73; 1951; 1858) and 774 mg (4.35 mmol) isonicotinoyl chloride hydrochloride in 3 ml of pyridine was heated with microwaves for 5 min at 160° C. K2CO3(sat) was added and the mixture was extracted 4 times with CHCl3. The organic phase was dried and concentrated. Recrystallization from ethanol, water and EtOAc gave 216 mg (26%) of a yellow white solid. 1H NMR (DMSO), d (ppm): 2.85 (d, 3 H) 3.45 (s, 3 H) 6.25 (d, 1 H) 7.65 (m, 2 H) 8.67 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:15](=[O:17])=[O:16].Cl>O1CCCC1>[CH3:12][C:7]1([CH3:13])[C:6]2[CH:14]=[C:2]([C:15]([OH:17])=[O:16])[CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC1(C)CCCCc2ccc(Br)cc21
Reactant: O=C=O
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCCCc2ccc(C(=O)O)cc21

Procedure:
The Grignard compound was prepared under an argon atmosphere from 4.00 g of 2-bromo-6,7,8,9-tetrahydro-9,9-dimethyl-5H-benzocycloheptene, as described in EP-A2-0315071, and 456 mg of Mg shavings in 20 ml of absolute tetrahydrofuran. After carrying out the metallation a vigorous CO2 stream was introduced at -10° C. The mixture was hydrolyzed with dil. HCl, extracted with ether and washed with a small amount of water. The acid was then purified by extraction in 1N NaOH, acidification to pH 1 (HCl) and re-extraction in ether. After washing with water, drying over Na2SO4 and evaporating there were obtained 2.64 g of 6,7,8,9-tetrahydro-9,9-dimethyl-5H-benzocycloheptene-2-carboxylic acid as colorless crystals of melting point 155°-156° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=1[S:37]([N:40]1[C:48]2[C:43](=[C:44]([OH:52])[CH:45]=[C:46](B(O)O)[CH:47]=2)[CH:42]=[CH:41]1)(=[O:39])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:46]1[CH:47]=[C:48]2[C:43]([CH:42]=[CH:41][N:40]2[S:37]([C:31]2[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:30]=2[F:29])(=[O:38])=[O:39])=[C:44]([OH:52])[CH:45]=1
Reactant: O=S(=O)(c1ccc(O)cc1F)n1ccc2c(O)cc(B(O)O)cc21
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)c4ccn(S(=O)(=O)c5ccc(O)cc5F)c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (28 mg, 0.06 mmol) were added (1-((2-fluoro-4-hydroxyphenyl)sulfonyl)-4-hydroxy-1H-indol-6-yl)boronic acid (22 mg, 0.06 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (5 mg, 0.01 mmol) and 63 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 8 mg (19% yield) as a white solid. Purity 99%.