Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33]([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>CN(C=O)C>[C:36]([O:35][C:33](=[O:34])[NH:40][CH2:41][CH2:42][C:43](=[O:44])[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (2.6 g, 16.8 mmol) was added to a stirred solution of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6 dione hydrochloride (2.0 g, 6.5 mmol) in DMF (100 mL). After stirring for 10 minutes, 1-hydrocybenztriazole (1.1 g, 7.8 mmol) and N—BOC-β-alanine (1.4 g, 7.1 mmol) were added. The reaction was initiated by addition of 1-[3-(dimethylamino0propyl]-3-ethylcarbodiimide hydrochloride (1.9 g, 9.7 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with H2O (40 mL) and CH2Cl2 (120 mL). The solid was collected to give (2-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-ethyl)-carbamic acid t-butyl ester (2.1 g, 73%) as a white solid: mp 203-205° C.; 1H NMR (DMSO-d6) δ 1.36 (s, 9H, 3CH3), 1.99-2.04 (m, 1H), 2.27-2.64 (m, 2H), 2.85-2.98 (m, 1H), 3.00-3.18 (m, 2H), 4.31 (d, J=5.3 Hz, 2H, CH2), 4.33-4.53 (dd, J=17.3 and 37.3 Hz, 2H, CH2), 5.10-5.17 (dd, J=4.8 and 13.1 Hz, 1H, CH), 6.79 (t, 1H, NH), 7.47-7.52 (m, 2H, Ar), 7.61-7.64 (m, 1H, Ar), 8.43 (t, J=5.3 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.54, 28.19, 31.17, 35.60, 36.67, 46.15, 51.55, 77.77, 121.60, 128.24, 130.56, 131.61, 134.56, 140.04, 155.43, 168.02, 170.43, 170.95, 172.80; Anal. calcd. for C22H28N4O6: C, 59.45; H, 6.35; N, 12.60. Found: C, 59.16; H, 6.31; N, 12.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH:14]1[CH2:32][CH:31]3[N:16]([C:17](=[O:37])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:15]1)=[N:8][C:7]([N:38]1[CH:42]=[CH:41][CH:40]=[N:39]1)=[CH:6]2.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:84][S:85]([CH:88]6[CH2:90][CH2:89]6)(=[O:87])=[O:86])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH:14]1[CH2:32][CH:31]3[N:16]([C:17](=[O:37])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:84][S:85]([CH:88]5[CH2:90][CH2:89]5)(=[O:87])=[O:86])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:15]1)=[N:8][C:7]([N:38]1[CH:42]=[CH:41][CH:40]=[N:39]1)=[CH:6]2
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)nc(-n3cccn3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)nc(-n3cccn3)cc2c1

Procedure:
The title compound was prepared from 18-[6-methoxy-3-(pyrazol-1-yl)isoquinolin-1-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (33) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=677 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:23]([C:29]([CH3:31])=O)[C:24](OCC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:24](=[O:25])[C:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:29]([CH3:31])[NH:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Product: Cc1[nH]n(C2CCN(Cc3ccccc3)CC2)c(=O)c1Cc1ccccc1
Yield: 60.2 %

Procedure:
A mixture of 1.52 g 1-benzyl-4-hydrazinopiperidine and 2.0 g of ethyl 2-benzylacetoacetate in 20 mL of xylenes was refluxed for 1 hour. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography (300 mL column). Elution with 0-5% MeOH in dichloromethane gave 1.61 g of product, 1-benzyl-4-(4-benzyl-5-methyl-1H-pyrazol-3(2H)-on-2-yl)-piperidine. ESI-MS 362.2 (M+H); HPLC A: 2.05 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:5])=[CH2:4].Cl[O-].[Na+].C([O-])(=O)C.[Na+].[Cl:14][C:15]1[C:24]([CH:25]=[N:26][OH:27])=[C:23]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>C(Cl)Cl>[Cl:14][C:15]1[C:24]([C:25]2[CH2:4][C:3]([O:2][CH3:1])([CH3:5])[O:27][N:26]=2)=[C:23]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Reactant: C=C(C)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)(OC)C2)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7.3 g (102 mmol) of 2-methoxy-1-propene, 28 ml of sodium hypochlorite solution (12.5% strength) and a spatula-tip of sodium acetate were added successively to 10.0 g (34 mmol) of methyl 2-chloro-3-(hydroxyiminomethyl)-4-methylsulfonylbenzoate in 200 ml of methylene chloride. The mixture was stirred at room temperature for 12 hours, the solvent was removed and the residue was taken up in ethyl acetate, washed with water, dried and concentrated. The residue was chromatographed over silica gel (eluent: cyclohexane:ethyl acetate=3:2). This gave 5.8 g (47% of theory) of methyl 2-chloro-3-(5-methoxy-5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of ethyl 3,3-bis(4-fluorophenyl)acrylate, prepared in the previous step, and palladium (10% weight on carbon, 2.68 g, 25.2 mmol) under a nitrogen atmosphere was added EtOH (100 mL). The nitrogen atmosphere was replaced by hydrogen from a double balloon and the reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was filtered through a pad of Celite and concentrated to give ethyl 3,3-bis(4-fluorophenyl)propanoate which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:11]=1[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.CCCCCCC.[Cu]>[Cl:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:11]=1[NH:12][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Nc1c(F)cc(F)cc1Cl
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Product: Cc1ccc(Nc2c(F)cc(F)cc2Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-iodotoluene (210 g, 0.96 mol), 2-chloro-4,6-difluoroaniline (204 g, 1.25 mol), copper powder (36 g, 0.57 mol), cuprous iodide (130 g, 0.68 mol), and potassium carbonate (118 g, 0.86 mol) in 500 ml of xylene is stirred vigorously and heated to reflux in a flask fitted with a Dean-Stark trap for 26 hours. After cooling to room temperature, the solids are filtered off, and the filter cake is washed with 100 ml of xylene. The solvents are evaporated under reduced pressure to give an oil which is dissolved in a mixture of 50 g of silica gel in 750 ml of heptane. The solids are filtered off and the solvents are evaporated under reduced pressure to give N-(2′-chloro-4′,6′-difluorophenyl)-4-methylaniline as an oil.
Reaction SMILES: [NH2:1][CH:2]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)[CH2:3][CH3:4].Cl[C:16]1[C:21]([Cl:22])=[C:20]([CH2:23][CH3:24])[N:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:22][C:21]1[C:16]([NH:1][CH:2]([CH:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6]2)[CH2:3][CH3:4])=[N:17][CH:18]=[N:19][C:20]=1[CH2:23][CH3:24]
Reactant: CCC(N)C1CCc2ccccc2N1
Reactant: CCc1ncnc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCc1ncnc(NC(CC)C2CCc3ccccc3N2)c1Cl
Temperature: 80 °C
Yield: 70.8 %

Procedure:
Example P-1:1.3 g of 2-(1-aminopropyl)-1,2,3,4-tetrahydro-quinoline, 1.4 g of 4,5-dichloro-6-ethylpyrimidine and 0.85 g of triethylamine in 60 ml of absolute isopropanol are placed in a sulfonation flask at room temperature. The internal temperature of the flask is increased to 80° C. and the reaction mixture is stirred under reflux for 12 hours. The solvent is then removed under a water-jet vacuum, the residue is taken up in a mixture of 200 ml of ethyl acetate and 70 ml of water andthe mixture is shaken well. The organic phase is removed and the aqueous phase is further extracted twice, each time with 100 ml of ethyl acetate. The organic phase is dried over Na2SO4 and the solvent is removed under a water-jet vacuum. The crude product which remains can thenbe further purified by flash chromatography on silica gel (eluant: ethyl acetate/n-hexane 1:3) to yield 1.6 g of 2-[1-(5-chloro-6-ethylpyrimidin-4-ylamino)propyl]-1,2,3,4-tetrahydro-quinoline in the form of a red oil (nD50 =1.5822).
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([C:8]2[C:9]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[N:10][C:11]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:12][CH:13]=2)=[N:5][N:4]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>ClCCl>[CH3:51][N:52]1[CH2:57][CH2:56][N:55]([CH2:2][C:3]2[O:7][C:6]([C:8]3[C:9]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])=[N:10][C:11]([NH:14][CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:12][CH:13]=3)=[N:5][N:4]=2)[CH2:54][CH2:53]1
Reactant: C[Si](C)(C)CCOc1nc(NCCc2ccncc2)ncc1-c1nnc(CO)o1
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2nnc(-c3cnc(NCCc4ccncc4)nc3OCC[Si](C)(C)C)o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 20 mL of dichloromethane, 5-(5-hydroxymethyl[1,3,4]oxadiazol-2-yl)-2-[2-(4-pyridyl)ethylamino]-4-(2-trimethylsilylethoxy)pyrimidine (0.76 g, 1.83 mmol) obtained in Step 2 was dissolved, then methanesulfonic anhydride (0.48 g, 2.75 mmol) and triethylamine (0.37 g, 3.66 mmol) were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, saturated aqueous sodium hydrogen carbonate solution was added and the reaction mixture was separated. Further, an aqueous layer was extracted with dichloromethane and those organic layers were combined. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), then 1-methylpiperazine (403 mg, 4.03 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction was confirmed by thin-layer chromatography, the mixture was treated as described above. The residue was purified by silica gel chromatography (chloroform/methanol) to give 5-[5-(4-methylpiperazinyl)methyl[1,3,4]oxadiazol-2-yl]-2-[2-(4-pyridyl)ethylamino]-4-(2-trimethylsilylethoxy)pyrimidine [Compound (IH) in which R2B is 2-(4-pyridyl)ethylamino and —X—Y—Z— is
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2/[CH:29]=[CH:30]/OCC)[O:25][CH2:24][C:23]2[N:18]3[C@@H:19]([CH3:35])[C:20](=[O:34])[NH:21][N:22]=2)([CH3:13])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C@H:19]1[C:20](=[O:34])[NH:21][N:22]=[C:23]2[N:18]1[C:17]1[CH:16]=[C:15]3[N:14]([C@@:10]4([CH3:13])[CH2:11][CH2:12][NH:8][CH2:9]4)[CH:30]=[CH:29][C:28]3=[CH:27][C:26]=1[O:25][CH2:24]2
Reactant: CCO/C=C/c1cc2c(cc1N[C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C(=O)NN=C2COc3cc4ccn([C@@]5(C)CCNC5)c4cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
To a solution of (S)-3-[(S)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.115 g, 0.273 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo and the residue was purified by prep-TLC (eluting with 15% MeOH in DCM) to give (S)-1-methyl-10-((S)-3-methyl-pyrrolidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one (0.020 g, 25%, SFC (Table 1, Method 53) Rt=1.81 min) as a white solid. 1H-NMR (400 MHz, methanol-d4) δ 7.41 (d, J=3.2 Hz, 1H), 7.25 (s, 1H), 7.22 (s, 1H), 6.49 (d, J=3.2 Hz, 1H), 5.11 (q J=6.8 Hz, 1H), 4.62-4.54 (d, J=13.6 Hz, 2H), 4.16-4.09 (m, 1H), 3.88-3.82 (m, 1H), 3.67-3.47 (m, 2H), 3.10-2.97 (m, 1H), 2.71-2.59 (m, 1H), 1.78 (s, 3H), 1.49 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 5) Rt=1.916 min; MS m/z: 340 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:26]([N:28]([CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:27].CN1C(=O)CCC1>CO>[CH:23]1([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:4]2[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:28]([CH2:36][CH3:37])[CH2:26][CH3:27])=[CH:34][CH:33]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CCN(CC)c1ccc(N)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCN(CC)c1ccc(Nc2cc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)cc1
Yield: 12.2 %

Procedure:
A microwave tube was charged with 1G (30 mg, 0.085 mmol), N1,N1-diethylbenzene-1,4-diamine (139 mg, 0.85 mmol), and NMP (1 mL). The mixture was irradiated in a microwave for three cycles of 15 min. (300W), 120° C. The crude reaction mixture was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min., 30 min. gradient, monitored at 220 nm) to afford 244A, (5 mg, 9.0% yield). HPLC: Rt=3.896 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=482.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][C:29]1[C:24]([Cl:23])=[N:25][CH:26]=[CH:27][C:28]=1[C:31]([F:34])([F:33])[F:32]
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Reactant: Oc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reaction time: 1 h

Procedure:
To a round bottom flask charged with 3-bromo-5-chlorophenol (5.20 g, 25.1 mmol) and potassium carbonate (3.46 g, 25.1 mmol) was added N-methylpyrrolidinone (25 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (5.00 g, 25.1 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 60 minutes, the reaction mixture was allowed to cool to room temperature at which point, water (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic fractions were washed with brine (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 330 gram column, eluting with 0-75% CH2Cl2 in hexanes to yield the title compound. 1H NMR (CDCl3) δ 8.53 (d, J=5.0 Hz, 1H), 7.62 (d, J=5.0 Hz, 1H), 7.29-7.27 (m, 1H), 6.87-6.84 (m, 1H), 6.76-6.73 (m, 1H). FIRMS (M+1)=385.8957.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:16])[C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[C:4]([C:17](=[O:19])[NH2:18])[CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:71]([CH:73]([CH2:81][CH2:82][CH2:83][CH3:84])[CH2:74][O:75][C:76](=[O:80])[CH2:77][CH2:78][SH:79])[CH3:72]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:71]([CH:73]([CH2:81][CH2:82][CH2:83][CH3:84])[CH2:74][O:75][C:76](=[O:80])[CH2:77][CH2:78][S:79][C:2]1[S:6][C:5]([NH:7][C:8](=[O:16])[C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[C:4]([C:17](=[O:19])[NH2:18])[CH:3]=1)[CH3:72]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sc(Br)cc1C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCSc1cc(C(N)=O)c(NC(=O)C(C)(C)OC(C)=O)s1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Intermediate 11 (1.4 g, 4 mmol) is dissolved in toluene (16 mL) and DIEA (1.4 mL, 8 mmol). Next, Pd2dba3 (110 mg, 0.12 mmol), Xantphos (139 mg, 0.24 mmol) and 3-Mercaptopropionic acid 2-ethylhexylester (1.14 mL, 5 mmol) are added, and the resulting solution is flushed with N2. Reaction mixture is stirred at 110° C. overnight. After evaporation, the crude is purified using column chromatography. The resulting product is obtained as an oil, which crystallised overnight. Obtained product is used as such.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[C:4]([I:9])[CH:3]=1
Reactant: BrCC1CC1
Reactant: Oc1ccc(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CC2)c(I)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 4-bromo-2-iodophenol (5.00 g, 16.7 mmol), bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate (6.54 g, 20.1 mmol) in 15 mL dimethylformamide was stirred at 50° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to the provide title compound (5.84 g, 99% yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](I)[CH3:24].O>CN(C)C=O>[CH2:23]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:20])[CH3:19])[CH3:24]
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 12.5 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl]phenyl]acetamide (U.S. Pat. No. 4,112,095) in 500 ml of dimethylformamide under argon, was added 2.47 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 4.1 ml of ethyl iodide was added. This mixture was stirred for 2.5 days, then poured into 1.5 liters of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a Waters Prep 500 silica gel column, eluting with dichloromethane:methanol (97:3). Fractions 8-13 were combined, evaporated in vacuo and the solid recrystallized from dichloromethane-hexane, giving 6.54 g of the desired product, mp 180°-185° C.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[C:22]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:38]3[C:33](=[C:34](O)[CH:35]=[CH:36][C:37]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:32][CH2:31][C:30]2=[O:46])=[CH:24][CH:23]=1>ClCCl>[C:22]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:38]3[C:33](=[C:34]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[CH:35]=[CH:36][C:37]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:32][CH2:31][C:30]2=[O:46])=[CH:24][CH:23]=1
Reactant: O=C1CCc2c(O)ccc(-c3ccccc3)c2N1Cc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCc2c(OS(=O)(=O)C(F)(F)F)ccc(-c3ccccc3)c2N1Cc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
Pyridine (1.12 ml) and trifluoromethanesulfonic anhydride (1.99 ml) were added with stirring at 0° C. to an anhydrous dichloromethane solution (40 ml) of 1-(biphenyl-4-ylmethyl)-5-hydroxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one (4.0 g), followed by stirring for 1 hour. The resulting mixture was concentrated under reduced pressure, water was added to the residue, and extraction with dichloromethane was performed. The extract was washed with water, an aqueous potassium hydrogensulfate solution and water in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 5.45 g (yield: quantitative) of 1-(biphenyl-4-ylmethyl)-8-phenyl-5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one as a white amorphous solid.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[I-:10].CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.[Na+].O>CN(C=O)C>[I:10][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH3:8])[CH:2]=1
Reactant: Cc1ccccc1O
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.8 %

Procedure:
To a solution of 10 g of o-cresol and 16.5 g (1.2 equiv) NaI in 250 ml of DMF was added 31 g (1.2 equiv) of chloramine-T hydrate. The dark green solution was stirred at rt for 1.5 h. The mixture, now a heterogeneous light brown, was poured into water, acidified, extracted with ethyl acetate, and the organic phase washed with water and bisulfite solution. The organic phase was dried over MgSO4. Concentration, trituration with hexane, and flash chromatography (silica gel, hexane, hexane/ethyl acetate (5:1)) provided 13.6 g (63%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.Br>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cccc(Cl)c2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(-c2cccc(Cl)c2)cc1
Yield: 76.9 %

Procedure:
A mixture of 3'-chloro-4-methoxybiphenyl (2.00 g), acetic acid (25 ml) and concentrated hydrobromic acid (25 ml) was heated at reflux for 6 hours. After cooling the reaction was added to water (200 ml) and the solution extracted with ether (300 ml). The ethereal solution was washed with saturated aqueous sodium hydrogencarbonate solution (2×150 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:hexane (1:1) then dichloromethane to give the sub-title compound as a white solid (1.44 g).