Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][C:24]=1O.C[Si](OP(=O)=O)(C)C>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:17][C:24]3[CH:23]=[CH:22][C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:20][C:19]=3[N:18]=2)[CH:3]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: Cc1ccc(Cn2nc(C(=O)O)cc2C)cc1
Agent: C[Si](C)(C)OP(=O)=O
Product: Cc1ccc(Cn2nc(-c3nc4cc(-c5ccccc5)ccc4o3)cc2C)cc1
Temperature: 180 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
A flask containing 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid (Intermediate B, 5.0 g, 21.7 mmol), 3-aminobiphenyl-4-ol (4.0 g, 21.7 mmol) and trimethylsilyl polyphosphate (40 g) was heated at 180° C. for 30 min, and then the reaction mixture was poured into ice water (1 L). The mixture was stirred for 1 h and was extracted with dichloromethane (2 L). The layers were separated and the organic layer was washed with brine (2×1 L) and dried with sodium sulfate. The solvent was evaporated, and the residue was purified with an ISCO CombiFlash Companion using gradient elution from 100% hexane to 20% ethyl acetate in hexane to afford the title compound as a white solid (2.19 g, 27%): 1H NMR (300 MHz, CD2Cl2) 7.94 (d, 1H), 7.66 (m, 4H), 7.48 (t, 2H), 7.39 (m, 1H), 7.14 (dd, 4H), 6.82 (s, 1H), 5.37 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H); ES-MS m/z 380.2 (MH)+, HPLC RT (Method A) 4.25 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:27])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step D) (5.0 g, 11.3 mmol) in tetrahydrofuran (35 mL) was added dropwise isopropylamine (2.9 mL, 34.0 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was then warmed until all solids had dissolved and stirred an additional five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel, followed by trituration with ether/hexane to afford the title compound, a compound of the present invention, as a solid (4.6 g), melting at 195-196° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:22]=2)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(=O)CCC1=O.O>C(#N)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:22]=2)=[C:11]([Br:27])[C:10]([C:23]([F:26])([F:24])[F:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc3c(c2)CCCO3)n(Cc2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: FC(F)(F)c1nn(Cc2ccccc2)c(-c2ccc3c(c2)CCCO3)c1Br
Yield: 63 %

Procedure:
A solution 1-benzyl-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49c) (260 mg, 0.73 mmol) and N-bromosuccinimide (157 mg, 0.88 mmol) in acetonitrile (5 mL) was refluxed for 45 minutes. Water (5 mL) was added, and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organics layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 100/0 to 90/10) to provide the 1-benzyl-4-bromo-5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole (49d) (200 mg, 0.46 mmol, 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[Na].[CH3:21][C:22]1[C:23]([OH:28])=[N:24][CH:25]=[CH:26][N:27]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:28][C:23]2[C:22]([CH3:21])=[N:27][CH:26]=[CH:25][N:24]=2)[N:14]=1)=[O:8]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Reactant: Cc1nccnc1O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccnc1OCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 8 h

Procedure:
1-(3-fluorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (1.0 mmol) and excess of 3-methylpyrazin-2-ol sodium salt were dissolved in N,N-dimethylformamide (3 ml). The mixture was stirred overnight. Water (20 ml) was added and the product was extracted three times with dichloromethane. The organic was dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography using 0-70% gradient of saturated ammonia/MeOH and dichloromethane. 1H NMR (400 MHz, DMSO-d6): 10.73 (s, 1H), 7.48 (d, 1H), 7.36 (m, 1H), 7.15 (d, 1H), 7.06-7.12 (m, 3H), 6.96)m, 1H), 6.89 (s, 1H), 4.99 (s, 2H), 4.33 (d, 2H), 2.28 (s, 3H). MS (ES+): M/Z 374 (M+1).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[CH2:13][C:14]([CH3:16])=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][C:14](=[CH2:13])[CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1O
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1ccccc1C(=O)OC
Yield: 37 %

Procedure:
A mixture of 152 g of methyl salicylate, 99 g of 3-chloro-2-methylpropene, 151.8 g of potassium carbonate, and 500 ml of acetone was heated at reflux overnight. After cooling, the mixture was extracted with diethyl ether and ethyl acetate. The organic extracts were combined, washed twice with a 10% sodium chloride solution and water, dried over sodium sulfate, and concentrated in vacuo. The resulting liquid was vacuumed distilled. The fraction collected at 120°-121° C. and 1.5 torr provided 76.2 g of the desired subtitle intermediate. NMR, MS.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[C:21]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O

Procedure:
Approximately 1 mmol of 1-aminomethyl-3-phenyl-5,6-dihydroxy-3,4-dihydronaphthalene, from Example 2, was reacted with 1.2 mmol of acetic anhydride in the presence of 1.2 mmol of triethylamine in an excess of methylene chloride. The mixture was washed with 0.1N HCl, and dried. The product was precipitated by addition of ether, collected, and dried. mp 238° C. MS M/Z: 310. Anal. calc. for C19H19NO3.HBr C: 65.03; H, 5.72; N, 3.61; found: C, 73.46; H, 6.13; N, 4.49.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:26])=[CH:23][C:22]=4[O:37][CH3:38])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC1CN(C2CCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(C)C(=O)N2C
Yield: 58.6 %

Procedure:
A solution of 0.050 g (0.00018 mole) of (rac)-2-chloro-9-cyclobutyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-52), 0.047 g (0.00018 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.053 g (0.00028 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated and the residue diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25 n) to give 0.0535 g of (rac)-4-(9-cyclobutyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-52) as white powder. HRMS (ES+) m/z Calcd for C27H37N7O3+H [(M+H)+]: 508.3031. Found: 508.3031.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22](N)=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-:25].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([OH:25])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: Cc1ccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
A mixture of 100 parts of 4-[(4-methylphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxamide, 52.2 parts of potassium hydroxide and 638 parts of 1,2-ethanediol is stirred and refluxed for 25 hours. After cooling, 1200 parts of water are added and the whole is acidified with a concentrated hydrochloric acid solution. The acid aqueous phase is alkalized with a sodium hydroxide solution 60%: exothermic reaction. After cooling, the precipitated crude product is filtered off and dissolved in water. This solution is acidified with acetic acid (pH about 6.5) and the product is filtered off. It is crystallized from N,N-dimethylformamide, filtered off again, washed with 2-propanone and dried, yielding 4-[(4-methylphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylic acid; mp. 270° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[CH3:19][Si:20]([C:23]#[C:24][CH2:25]Br)([CH3:22])[CH3:21].CN1C(=O)N(C)CCC1>C1COCC1>[C:9]([O:13][C:14]([C:16]1([CH2:25][C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CC#C[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 14.0 ml (2.0 M in THF/n-heptane/ethylbenzene, 28 mmol) LDA in 100 ml THF was treated during 15 min at −78° C. with 2.84 g (20 mmol) cyclopropanecarboxylic acid tert-butyl ester in 20 ml THF. After 6 h at −78° C., a solution of 3-(trimethylsilyl) propargyl bromide and 29 ml DMPU in 40 ml THF was added during 20 min. Over night, the solution was naturally warmed to room temperature, poured on ice/aqueous saturated NH4Cl solution and extracted with ether (three times). The organic phases were washed with aqueous 10% KHSO4, water (5×), aqueous 10% NaCl and dried (Na2SO4) to give 5.59 g of the title compound as volatile dark brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:9]=[O:10])=[C:4]([CH3:18])[CH:3]=1.[H-].[Na+].[Br:21][CH2:22][CH2:23]Br>C1COCC1>[Br:21][CH2:22][CH2:23][O:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1C(C=O)c1ccc(F)cc1C
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=COCCBr)c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Fluoro-2-methylphenyl)-(2-methylphenyl)acetaldehyde (3.5 g, 0.0444 mol) was dissolved in dry THF (20 ml) and added dropwise to a suspension of sodium hydride (60% oil dispersion) (0.63 g, 0.0158 mol) in dry tetrahydrofuran (30 ml). The mixture was stirred at room temperature for 1 h and heated at reflux for 0.5 h. After cooling 1,2-dibromoethane (12.4 ml, 10 equiv.) was added, and the reaction mixture was allowed to stand at room temperature for 192 h. The reaction mixture was filtered and evaporated. The residue was pumped in vacuo, but still contained ca. 30% starting aldehyde, so the above procedure was repeated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([O:21]CC)=O)[N:3]=1.[OH-].[NH4+:25]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([NH2:25])=[O:21])[N:3]=1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Nc2cccc(C)c2C)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(N)=O)n2)c1C
Reaction time: 72 h

Procedure:
5.0 g of [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid, ethyl ester was added to 40 ml of concentrated ammonium hydroxide. Ethanol (40 ml) was then added and the reaction mixture was boiled to give a clear solution. This solution then stood at room temperature for three days. The precipitate thus formed was collected and recrystallized from ethanol giving 3.0 g of product, mp. 188°-191°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: COc1ccccc1N=C=O
Solvent: CO
Solvent: CC#N
Product: COc1ccccc1NC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.334 of 2-methoxyphenyl isocyanate according to the general procedure of Example 37 to give 0.9232 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-methoxy-phenyl)-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=595; mp 152.5-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:35]1[C:39]2([O:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:38][C@@H:37]([C:45]2[NH:46][CH:47]=[C:48]([C:50]3[CH:55]=[CH:54][C:53]([C:56]4[CH:61]=[CH:60][C:59]([C:62]5[N:63]=[C:64]([C@@H:67]6[CH2:71][CH2:70][CH2:69][N:68]6[C:72]([C@@H:74]([NH:78][C:79](=[O:82])[O:80][CH3:81])[CH:75]([CH3:77])[CH3:76])=[O:73])[NH:65][CH:66]=5)=[CH:58][CH:57]=4)=[CH:52][CH:51]=3)[N:49]=2)[NH:36]1>CN(C=O)C>[CH3:7][C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:8]([N:36]1[C@H:37]([C:45]2[NH:46][CH:47]=[C:48]([C:50]3[CH:51]=[CH:52][C:53]([C:56]4[CH:61]=[CH:60][C:59]([C:62]5[N:63]=[C:64]([C@@H:67]6[CH2:71][CH2:70][CH2:69][N:68]6[C:72](=[O:73])[C@@H:74]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH:75]([CH3:77])[CH3:76])[NH:65][CH:66]=5)=[CH:58][CH:57]=4)=[CH:54][CH:55]=3)[N:49]=2)[CH2:38][C:39]2([O:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:35]1)=[O:10]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)N[C@@H](C)C(=O)N1CC2(C[C@H]1c1nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)c[nH]1)OCCCO2
Reaction time: 0.05 h
Yield: 29 %

Procedure:
To a stirred solution of N-[(methyloxy)carbonyl]-L-alanine (22.5 mg, 0.153 mmol, prepared according to the procedure provided in WO2003055474) in DMF (2 mL) were added TEA (15.5 mg, 0.153 mmol) and HATU (58.2 mg, 0.153 mmol). After ˜3 min stirring, methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(3S)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (Example 19) (100 mg, 0.153 mmol) was introduced. After stirred for additional 2 hrs at rt, the reaction mixture was directly loaded to RP HPLC, eluting with 5 to 80% acetonitrile/water (0.2% NH3H2O (conc.)), to give methyl ((1S)-1-methyl-2-{(3S)-3-[4-(4′-{2-[(2S)-1-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-6,10-dioxa-2-azaspiro[4.5]dec-2-yl}-2-oxoethyl)carbamate (Example 5) as solid (36 mg, yield: 29%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.04-11.11 (m, 2H) 7.37-8.02 (m, 8H) 7.18-7.36 (m, 2H) 5.60 (br. s., 2H) 5.17-5.40 (m, 2H) 3.17-4.73 (m, 14H) 2.79-3.19 (m, 1H) 2.45-2.81 (m, 1H) 2.29-2.45 (m, 1H) 1.49-2.29 (m, 8H) 1.22-1.47 (m, 3H) 0.73-1.16 (m, 6H). HRMS: (M+H)+ calcd: 783.3830; found: 783.3832.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3Cl)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2Cl)[C@H](c2ccccc2)C1
Reactant: CN(C)CCN
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: CN(C)CCNc1ccccc1[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1c1ccccc1

Procedure:
The title compound, MS: m/e=564.3 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(2-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, N,N-dimethyl-ethylendiamine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH2:24]=[O:25].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:9])=[C:6]([CH:7]=1)[CH2:24][OH:25]
Reactant: C[C@@H](NC(=O)C(C)(C)C)c1ccc(Br)cc1
Reactant: C=O
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)C(C)(C)C)c1ccc(Br)cc1CO
Reaction time: 4 h
Yield: 66.9 %

Procedure:
In 10 ml of tetrahydrofuran is dissolved 2 g of N-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to this solution is dropwise added 14.3 ml of phenyllithium (1.48 M cyclohexane-diethyl ether solution), after which the temperature of the resulting mixture is elevated to −5° C. and the mixture is stirred at the same temperature for 4 hours. Subsequently, 1.06 g of paraformaldehyde is added thereto and the mixture is stirred at 5° C. for 1 hour, after which 6 ml of water is added to the reaction mixture and the organic layer is separated. The organic layer obtained is dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. The residue obtained is purified by silica gel chromatography (eluant; n-hexane:ethyl acetate=2:1) to obtain 1.48 g (yield: 66.9%) of 5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]-ethyl}benzyl alcohol.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25]([O:27]C)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].Cl>CO.O>[OH:24][CH:21]1[CH2:20][CH2:19][N:18]([C:16]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:29])[F:30])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:25]([OH:27])=[O:26])[CH2:13]2)=[O:17])[CH2:23][CH2:22]1
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
828 mg (1.92 mmol) of methyl 5-(4-(trifluoromethoxy)phenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylate were dissolved in 70 ml of methanol, 2159 mg (19.24 mmol) of potassium tert-butoxide were added and the mixture was stirred at 60° C. overnight. For work-up, the reaction solution was diluted with water and acidified with 1N hydrochloric acid (pH 1). The mixture was extracted with ethyl acetate. The combined organic phases were dried with sodium sulphate and concentrated under reduced pressure. Yield: 749 mg (94% of theory)
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[Br:19]Br>CO>[Br:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=[N:11][C:10]=1[NH2:13]
Reactant: BrBr
Reactant: Nc1ccc(-c2ccccc2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(-c2ccccc2)cc1Br
Reaction time: 16 h
Yield: 33.1 %

Procedure:
In a 150 mL round bottom flask was placed 6-phenylpyridazin-3-amine (2.5 g, 14.5 mmol), NaHCO3 (2.44 g, 29 mmol) and methanol (50 mL) then to this suspension was added Br2 (2.317 g, 14.5 mmol) drop wise over about 30 minutes at room temperature. The mixture was stirred for 16 h, then filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=2:1) to give 4-bromo-6-phenylpyridazin-3-amine (1.2 g, 33%) as a light orange solid. LC-MS: [M+H]+, 250.0, tR=1.487 min.
Reaction SMILES: [C:1]1([CH:11]=[N:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClN1C(=O)CCC1=O.[CH:22]([P:24]([CH3:28])(=[O:27])[O:25][CH3:26])=[CH2:23].C(N(CC)CC)C>>[C:1]1([C:11]2[CH2:23][CH:22]([P:24]([CH3:28])(=[O:27])[O:25][CH3:26])[O:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ON=Cc1cccc2ccccc12
Reactant: C=CP(C)(=O)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: COP(C)(=O)C1CC(c2cccc3ccccc23)=NO1
Yield: 96.8 %

Procedure:
39.1 g (0.25 mol) of naphthaldoxime, 36.7 g (0.275 mol) of N-chlorosuccinimide, 33 g (0.275 mol) of methyl vinyl(P-methyl)phosphinate and 38.2 ml (0.275 mol) of triethylamine are reacted as in Example 1 to give 70 g of oily product.