Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[NH:9]2)=[CH:4][CH:3]=1.I[C:27]1[CH:28]=[C:29]([CH3:35])[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[N:9]2[C:27]2[CH:28]=[C:29]([CH3:35])[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: COc1ncccc1-n1nc(C)c2c1C(=O)NC2c1ccc(Cl)cc1
Reactant: Cc1cc(I)cn(C)c1=O
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(C)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 23 using 4-(4-chlorophenyl)-1-(2-methoxypyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 71.4) and 5-iodo-1,3-dimethylpyridin-2(1H)-one (step 23.2) at 100° C. for 16 hr. Further purification by preparative achiral SFC (column Silica, gradient 22-27% in 6 min_total 11 min). tR: 4.34 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 476 [M+H]+ (LC-MS 2); Rf=0.51 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)(C)C.C(O[K])(C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:44])(=O)=O)=CC=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:44])([C:14](=[O:22])[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(F)(C(=O)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
4-(4-Fluoro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester in 0.5 mL of DMF was added to a solution at 0° C. containing 0.5 mL of tBuOH, (0.109 mg, 0.651 mmol) tBuOK and 2 mL of DMF. After 20 min stirring at 0° C., N-Fluorobenzenesulfonimide (0.246 g, 0.781 mmol) was added portionwise. The reaction was stirred at 0° C. during 45 min. and (0.55 g, 0.33 mmol) of tBuOK were added at 0° C. and 10 min later (0.123 g, 0.390 mmol) of N-Fluorobenzenesulfonimide. Each 0.5 h two more additions of (0.55 g, 0.33 mmol) tBuOK and (0.123 g, 0.390 mmol) N-Fluorobenzenesulfonimide were repited. 1 h later of the last addition the reaction was quenched with 4 mL of water and the DMF was removed under vacuum. The water was extracted with ethyl acetate and the combined organic phases were purified with column chromatography on silica using n-heptane-EtOAc (3:1). The product fractions were concentrated to give 0.122 g (0.375 mmol, 58% yield) of a yellow oil. MS (m/e): 326.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12](=O)[CH2:13][C:14](=O)[CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[C:4]([F:24])[CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[NH:27][N:26]=2)=[C:4]([F:24])[CH:3]=1
Reactant: CCOC(OCC)C(=O)CC(=O)c1cc(OC(C)C)c(Cl)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(OCC)c1cc(-c2cc(OC(C)C)c(Cl)cc2F)n[nH]1

Procedure:
The crude 1-(4-chloro-2-fluoro-5-isopropoxy-phenyl)-4,4-diethoxybutane-1,3-dione (Example H7) is initially introduced into 150 ml of dry ethanol. 2.90 g of hydrazine monohydrate are added dropwise at room temperature, while stirring. The mixture is then stirred for 4 hours, while heating under gentle reflux, and is subsequently cooled and the alcohol is removed on a rotary evaporator in vacuo. The residue obtained is partitioned between aqueous sodium bicarbonate solution and ethyl acetate. After extraction by shaking and separation of the phases, the organic phase is washed with water and then dried over sodium sulfate and concentrated. 17.5 g of a dark yellow oil are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[CH:17](OC)(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:17][N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nccc(-n2cnc3ccc(Br)cc32)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (750 mg, 2.68 mmol) in mixture of methanol (7 mL) and THF (30 mL) was added trimethyl orthoformate (8.81 ml, 80.32 mmol) and TsOH (0.04 ml, 0.27 mmol). The reaction mixture was stirred at 70° C. for 1 h. Then another portion of trimethyl orthoformate (4.4 ml, 40.16 mmol) was added. Stirring at 70° C. was continued for another 6 hr. The reaction mixture was allowed to cool down to RT then a saturated aqueous solution of NaHCO3 was added. The product was extracted into DCM (×3) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give the title compound; 1H NMR (500 MHz, DMSO) δ 7.08-7.24 (3H, m), 7.50 (1H, dd, J=8.51, 1.89 Hz), 7.71 (1H, d, J=8.51 Hz), 8.37 (1H, d, J=5.52 Hz), 8.83 (1H, d, J=1.73 Hz), 9.08 (1 H, s); LC-MS (Method B): m/z=+289.9, 291.8 (M+H)+. This compound, with LC-MS purity=70%, was used in the next step without further purification.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].C(=S)=S>Cl>[Cl:18][CH2:19][C:20]([C:8]1[CH:9]=[CH:10][C:5]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)C1(c2ccccc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)C1(c2ccc(C(=O)CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum trichloride (7.9 g, 0.060 mol) was added in portions to a mixture of methyl 1-phenylcyclopropanecarboxylate (3.5 g, 0.020 mol) and chloroacetyl chloride (2.0 mL, 0.026 mol) in carbon disulfide (40 mL, 0.7 mol) at 15-25° C. and then the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into conc. HCl (10 mL) in ice (100 g) and then extracted with ether. The ether extract was washed with brine, dried and concentrated. The product was purified by CombiFlash using hexane/EtOAc (max.EA 20%). The final product was analyzed by 1H NMR, which showed that the product was a mixture of para and meta substituted isomers with a ratio of 3:2.
Reaction SMILES: [CH3:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22](B(O)O)=[C:21]([CH3:29])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C)C=O.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].O>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:9][OH:10])[C:2]=2[CH3:1])=[C:21]([CH3:29])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Reactant: Cc1c(Br)cccc1CO
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(CO)c1C
Yield: 57.2 %

Procedure:
2-Methyl-3-bromo-phenylmethanol (201 mg, 1 mmol, prepared by a method disclosed in PCT patent application WO2010143733), (4-(benzyloxy)-2,6-dimethylphenyl) boronic acid 12b (300 mg, 1.20 mmol), 1 mL of 2M aqueous sodium carbonate solution, 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (33 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) were dissolved in 1 mL of N,N-dimethylformamide. The reaction mixture was reacted at 120° C. under microwave conditions for 1 hour. The resulting mixture was mixed with 10 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (4′-(benzyloxy)-2,2′,6′-trimethylbiphenyl-3-yl)methanol 12c (190 mg, yield 57.2%) as a red slime.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:33])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[S:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.OO.Cl([O-])=[O:37].[Na+]>C(#N)C.C(OCC)(=O)C>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:33])[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:27][C:28]([C:31]([OH:37])=[O:32])=[CH:29][CH:30]=2)=[CH:24][CH:25]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C=O)s2)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)O)s2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-(5-formyl-2-thienyl)phenyl]ethyl]-carbamate (180 mg) in acetonitrile (2 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1 ml) was added 30% hydrogen peroxide solution (30 μl) and 80% sodium chlorite (67 mg) below 10° C. The reaction mixture was stirred at 50° C. for 3 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 5-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2-thiophenecarboxylic acid (160 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:16].BrCCCCN1C2C(=CC=CC=2)CCC1=O.[C:33]([C:37]1[N:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:40]=[C:39]([C:49]([F:52])([F:51])[F:50])[N:38]=1)([CH3:36])([CH3:35])[CH3:34].CCN(CC)CC>CN(C)C=O.C(OCC)(=O)C>[C:33]([C:37]1[N:42]=[C:41]([N:43]2[CH2:44][CH2:45][N:46]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8][C:7]3=[O:16])[CH2:47][CH2:48]2)[CH:40]=[C:39]([C:49]([F:50])([F:51])[F:52])[N:38]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C1CCc2ccccc2N1CCCCCl
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Agent: O=C1CCc2ccccc2N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(N2CCN(CCCCN3C(=O)CCc4ccccc43)CC2)cc(C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(4-chlorobutyl)-3,4-dihydroquinolin-2(1H)-one and 1-(4-bromobutyl)-3,4-dihydroquinolin-2(1H)-one (0.30 g), 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)-pyrimidine (1.08 mmol, 0.31 g; prepared as in DE 19735410) and NEt3 (4.54 mmol, 0.46 g) in N,N-dimethylformamide (10 ml) was heated at 100° C. while stirring for 20 hours. The reaction mixture was allowed to cool, ethyl acetate was added, and the reaction mixture was washed twice with water. The combined organic phases were dried over Na2SO4, the desiccant was filtered off, and the organic phase was concentrated in vacuo. The resulting oily residue was purified by chromatography on silica gel (eluent: methyl tert-butyl ether:methanol 0-100%), resulting in 0.17 g of the title compound.
Reaction SMILES: [I:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:28](Cl)(Cl)=[O:29]>ClCCl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[C:28]2=[O:29])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(I)nn1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(I)nn2)C1=O
Reaction time: 8 h

Procedure:
385 mg tert. butyl [2-(6-iodo-pyridazin-3-ylamino)-ethyl]-carbamate are dissolved in 10 ml dichloromethane, combined with 360 μl N,N-diisopropyl-N-ethyl-amine and 560 μl of a 20% solution of phosgene in toluene are added dropwise thereto. After stirring overnight the mixture is diluted with ethyl acetate and washed with semisaturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is extracted from diethyl ether.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][N:8]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])(=[O:3])[NH2:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[C:1]([CH2:4][S:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:9][N:8]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])(=[O:3])[NH2:2]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)CSC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CSCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.06 g) and triethylamine (0.92 ml) in a mixture of tetrahydrofuran (40 ml) and N,N-dimethylformamide (5 ml) was added dropwise methanesulfonyl chloride (0.44 ml) under ice-cooling. The mixture was stirred at 2° C. for 1 hour and then allowed to stand at ambient temperature for 1 hour. To the reaction mixture was added ethyl acetate (50 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.70 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(O)C.O.[NH2:21][NH2:22]>C(OCC)C.CN(C)C1C=CN=CC=1>[NH:21]([C:14](=[O:16])[CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9]1)[NH2:22]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NN)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of ((3S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (5 g, 21.81 mmol) in diethyl ether (50 mL) was treated with N,N-dimethyl-4-pyridinamine (2.181 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide(HCl) (23.99 mmol), and ethanol (48.0 mmol) and was stirred at room temperature overnight. Analysis by LCMS indicated that all starting material had converted to the desired methyl ester. The reaction contents were diluted with ether (100 mL) and washed with saturated aq NaHSO4 solution, water, and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The resulting clear oil was dissolved in ethanol (25 mL), treated with hydrazine monohydrate (436 mmol), and was stirred overnight at 80° C. LCMS analysis indicated complete conversion of the intermediate. The reaction solution was concentrated to dryness in vacuo to afford the title compound as a clear oil (4.65 grams, 88% yield). No further purification was utilized. MS(ES)+ m/e 244.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:41][CH3:42])[C:25]([Cl:43])=[CH:24][N:23]=1>>[Cl:43][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:31][C:30]=2[O:41][CH3:42])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(N2CCOCC2)C3)ncc1Cl

Procedure:
The title compound was prepared from 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (50 mg, 0.2 mmol) and (2,5-dichloropyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (64 mg, 0.18 mmol) in an analogous manner to Example 946 to afford a white foam (95 mg, 88%). Mp: 122-4° C. LCMS (m/e) 595 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.28 (d, J=9 Hz, 1H), 8.10 (m, 2H), 7.58 (s, 1H), 7.40 (s, 1H), 6.91 (d, J=9 Hz, 1H), 3.94 (s, 6H), 3.75 (m, 7H), 3.22 (m, 5H), 2.90 (m, 2H), 2.70 (m, 2H), 2.60 (m, 2H), 2.40 (m, 2H), 2.11 (m, 2H), 1.79 (m, 2H), 1.37 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[F:20][C:21]([F:38])([F:37])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34](Cl)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.FC(F)(F)C1C=CC(C2C(C(O)=O)=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:34]([C:29]2[C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:37])[F:38])=[CH:23][CH:24]=3)=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:35])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Aminobenzoic acid ethyl ester (0.568 g) and triethylamine (0.570 g) were dissolved in methylene chloride (20 mL), and to this solution was dropwise added a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid chloride, which is prepared from 4′-trifluoromethylbiphenyl-2-carboxylic acid (1.00 g) in a similar manner to Example 1d), in methylene chloride under ice-cooling. The solution was stirred at room temperature for 2 hours, followed by addition of methylene chloride (100 mL). The reaction mixture was washed with 2N hydrochloric acid and saturated brine, dried over sodium sulfate and concentrated to give the title compound (1.43 g).
Reaction SMILES: [C:1]12[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][NH:2]2.[H-].[Na+].[CH:14]([P:16]([O:30][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35])([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:17])=[CH2:15]>CN(C)C=O>[O:11]=[C:8]1[C:9](=[O:10])[C:1]2[N:2]([CH2:15][CH2:14][P:16]([O:30][C:31]3[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=3)[C:34]([O:36][CH2:37][CH3:38])=[O:35])([O:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1=2
Reactant: O=c1c2c(c1=O)NCCCN2
Reactant: C=CP(=O)(Oc1cccc(C(=O)OCC)c1)Oc1cccc(C(=O)OCC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OP(=O)(CCN2CCCNc3c2c(=O)c3=O)Oc2cccc(C(=O)OCC)c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A suspension of 2.6-diaza-bicyclo[5.2.0]non-1(7)-ene-8,9-dione (2) (4 mmol, 608 mg) in N,N-dimethylformamide (60 mL) was treated under dry nitrogen and under stirring with 60% sodium hydride in oil (4.1 mmol, 164 mg). After 30 minutes at ambient temperature the yellow reaction mixture was cooled to 0° C. and a solution of diethyl 3,3′-[(vinylphosphoryl)bis(oxy)]dibenzoate (3) (4 mmol, 1.618 g) in N,N-dimethylformamide (30 mL) was added at once under vigorous stirring. The reaction mixture was then stirred at ambient temperature overnight, concentrated in vacuo and the residue partitioned between 5% aqueous ammonium chloride solution and ethyl acetate (2×60 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue (>1.5 g) was flash chromatographed on silica gel (60 g). Elution with 2% methanol in chloroform afforded 600 mg (27%) of the desired title compound as a white powder; mp 116-7° C. MS (ES+): m/e 557.2 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH2:14][OH:15])([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>O1CCCC1>[C:17]([C:16]1[C:9]2[CH2:10][C:11]([CH2:14][OH:15])([CH3:13])[O:12][C:8]=2[CH:7]=[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]=1[OH:4])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CO)O2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(CO)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 500 mg of 5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran in 7 ml of tetrahydrofuran was added dropwise to a suspension of 114 mg of lithium aluminum hydride in 3 ml of tetrahydrofuran. The mixture was heated under reflux for 2 hours and then cooled to room temperature. Ethyl acetate was added dropwise and then 10% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated, and the concentrate was purified by silica gel column chromatography eluting with n-hexane containing 20% ethyl acetate to give 320 mg of 4,6-di-t-butyl-5-hydroxy-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran as a white solid (yield 73%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: O=C(Cl)CCCCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCBr)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
Aniline 1 (12.69 g, 0.052 mol) was stirred in dichloromethane at 0° C. and 5-bromovaleryl chloride (8.9 mL, 0.052 mol) added followed by diisopropylethylamine (9 mL, 0.052 mol). The resulting white suspension was allowed to warm to room temperature and stirred for 3 h. The white solid was collected by filtration and recrystallised from ethyl acetate to give 2 as a white fluffy powder (10.22 g, 50%).