Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1>ClC(Cl)C.C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8]2)[CH3:21])=[CH:16][CH:15]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(c1ccc(Br)cc1)N1CCOC(c2ccccc2)C1

Procedure:
The above compound could be made the following way: 1 eq. of 2-Phenylmorpholine (Array) in dichloroethane could be combined with 1.2 eq. 4′-Bromoacetophenone (Aldrich) and stirred overnight at room temperature. 1.5 eq. borane-pyridine complex could be added and the reaction stirred for several hours. The reaction mixture could be diluted with methylene chloride and washed with water and brine. The organics could be dried over sodium sulfate and purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5](NC1C=CC=C(C2CCN(CCNC)CC2)C=1)=[O:6].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH:36]=2)=[CH:31][C:30]=1[N+:48]([O-:50])=[O:49]>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH:36]=2)=[CH:31][C:30]=1[N+:48]([O-:50])=[O:49])=[O:6]
Reactant: CNCCN1CCC(c2cccc(NC(=O)c3ccccc3OC)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c([N+](=O)[O-])c2)CC1
Product: COc1ccccc1C(=O)Nc1ccc(C2=CCNCC2)cc1[N+](=O)[O-]
Yield: 71 %

Procedure:
The title compound 202 (1.04 g, 2.22 mmol, 71%) was prepared following the procedures described for the synthesis of 192 (scheme 33, Example 36, steps 5 and 6) using 201 (1.00 g, 3.13 mmol) in place of 190. LRMS (ESI): calc. 353.1, found 411.3 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([N+:21]([O-])=O)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)(=O)C.Cl.O.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH2:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.9 %

Procedure:
To a solution of 7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (14.70 g, 42.36 mmol) in glacial acetic acid (180 mL), add a solution of tin(II) chloride (25.0 g, 129.21 mmol) and tin(II) chloride dihydrate (19.5 g, 84.72 mmol) as a solution in 10% HCl (71 mL). Stir the resulting solution at room temperature for 24 h. TLC indicates an incomplete reaction. Add more tin(II) chloride dihydrate (49.3 g, 213.95 mmol) followed by 6M HCl (20 mL) and stir the reaction 24 h more at room temperature. TLC now shows complete reaction. Pour the reaction into a vigorously stirring solution of NaOH (135.4 g) in water (250 mL) with ice (500 mL) and EtOAc (600 mL). Stir the suspension vigorously for 10 min (pH=5) then add more NaOH (72 g) as a solution in water (100 mL). The suspension clears up on vigorous stifling for 1 h. Partition the layers (pH aq=9-10) and extract the aqueous with more EtOAc (2×600 mL). Dry the combined organics (K2CO3 and Na2SO4) and concentrate in vacuo. Dissolve the residue in methylene chloride and filter to remove residual inorganics. Remove the solvent in vacuo to give 13.38 g of 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as an oil.
Reaction SMILES: ClCCCCC1N(C2CCCCC2)N=NN=1.BrCC1C=CC(C(OCC)=O)=CC=1.[NH:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31]1>>[NH:32]1[C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:38]=2[N:30]=[CH:31]1
Reactant: c1cnc2nc[nH]c2c1
Agent: CCOC(=O)c1ccc(CBr)cc1
Agent: ClCCCCc1nnnn1C1CCCCC1
Product: c1cc2[nH]cnc2cn1

Procedure:
Utilizing the procedure described in Example 1(a) employing 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in lieu of ethyl 4-bromomethylbenzoate and imidazo[4,5-b]pyridine in lieu of . imidazo[4,5-c]pyridine yielded an impure mixture of isomers. The mixture was purified by column chromatography (silica gel, 5% ethanol in chloroform) to yield a less polar isomer which was recrystallized from diethyl ether-chloroform to yield 3-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butyl]-3H-imidazo [4,5-b]pyridine as a colorless crystalline solid, having a melting point of 94°-95° C. and the following physical characteristics:
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.O.C(N(CC)CC)C>[O:1]=[C:2]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:36][CH:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]([OH:47])=[O:46])=[O:21])=[CH:22][CH:23]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (30 mg, 0.1 mmol) was dissolved in DMF (0.5 ml) and 18 mg (0.1 mmol) of carbonyldiimidazol (90% pure) was added and the mixture stirred for 4 h. Phenylalanine (33 mg, 0.2 mmol) was dissolved in of H2O (0.5 ml) together with triethylamine (0.05 ml) and added to the activated acid. This reaction mixture was heated at 75° C. for 2 h. After cooling it was made acidic and diluted 5×with H2O. The precipitate was filtered and washed with H2O and dried under vacuum. FlashTube chromatography using EtOAc/MeOH(7:3) yielded a small amount of 2-[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoylamino]-3-phenyl-propionic acid. The material contained approx. 10% of starting material. 1H NMR (400 MHz, DMSO-d6) δ 8.7 (1H, s), 8.31 (2H, d), 8.21 (1H, d), 7.82 (2H, d), 7.70 (1H, d), 7.62 (1H, t), 7.50 (1H, t), 7.2-7.3(4H, m), 7.17 (1H, t), 4.50 (1H, m), 3.1-3.2 (2H,m).
Reaction SMILES: C(N1CC(O)CC1=O)C.N1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1.[CH2:25]([N:27]1[CH2:31][CH:30]([O:32][C:33](=O)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][C:28]1=[O:41])[CH3:26]>C(OCC)(=O)C.O>[CH2:25]([N:27]1[CH2:31][CH:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][C:28]1=[O:41])[CH3:26]
Reactant: CCN1CC(OC(=O)c2ccccc2)CC1=O
Agent: CCN1CC(O)CC1=O
Solvent: c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Product: CCN1CC(OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Three g. 1-ethyl-4-hydroxypyrrolidin-2-one are dissolved in 30 ml. anhydrous pyridine and 2.7 ml. benzoyl chloride are added thereto. The reaction mixture is stirred overnight at ambient temperature, then it is poured into water containing 20 ml. concentrated sulphuric acid and extracted with ethyl acetate. The organic phases are collected, washed with a saturated aqueous solution of ammonium sulphate, evaporated to dryness and separated by chromatography to give 4.8 g. 1-ethyl-4-benzoyloxypyrrolidin-2-one; m.p. 53°-54° C.; Rf=0.27 (silica gel; eluant ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]#[N:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[NH4+].[Cl-]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)nc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3ccc(-c4nnn[nH]4)cc3nc2-c2ccc(F)cc2)cc1

Procedure:
A solution of 2,3-bis(4-fluorophenyl)quinoxaline-6-carbonitrile (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), NaN3 (500 mg, 7.69 mmol, 17.59 equiv), and NH4Cl (116 mg, 2.19 mmol, 5.00 equiv) was stirred for 4 h at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 7×50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated in vacuo, washed with dichloromethane, resulting in 34 mg (20%) of 2,3-bis(4-fluorophenyl)-6-(1H-tetrazol-5-yl)quinoxaline as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Example 6 was prepared from diphenylacetyl chloride and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 1H, J=8.0 Hz), 7.71–7.63 (m, 3H), 7.42–7.23 (m, 10H), 6.89 (d, 1H, J=7.6 Hz), 4.96 (s, 1H), 3.41 (dd, 2H, J=5.6, 7.6 Hz), 3.00 (d, 2H, J=11.6 Hz), 2.60 (m, 1H), 2.47 (t, 2H, J=6.4 Hz), 2.45 (m, 1H), 2.06–2.01 (m, 2H), 1.89–1.64 (m, 6H), 1.13 (d, 6H, J=6.8 Hz); ESMS m/e: 499.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH3:17])=[CH:12]2)=[O:5].[Br:23]N1C(=O)CCC1=O.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>ClCCl.C(OCC)(=O)C>[Br:23][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:2]=2[Cl:1])=[C:16]2[C:11]=1[CH:12]=[C:13]([CH3:17])[CH:14]=[N:15]2
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)ccc(Br)c2c1
Yield: 17.5 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-3-methylquinoline (250 mg), N-bromosuccinimide (175 mg) and 2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile) (23.3 mg) in dichloromethane was refluxed for 2 hours. After cooling, the mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane) to give 5-bromo-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (54.2 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[CH:22][CH:21]=1>CC(=O)CC.C(=O)([O-])[O-].[K+].[K+]>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:27][C:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=4[N:30]=3)=[CH:22][CH:21]=2)[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: Oc1ccc(-n2nc3ccccc3n2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Oc1cc(OCc2ccc(-c3nc4ccccc4o3)cc2)ccc1-n1nc2ccccc2n1
Temperature: 0 °C

Procedure:
2-(p-Tolyl)benzoxazole was reacted with N-bromosuccinimide in the presence of benzoyl peroxide by the standard procedure to produce the known compound, 2-(4-bromomethylphenyl)benzoxazole (A). 2-(2,4-Dihydroxyphenyl)benzotriazole (B) (0.1 mole) and 2-(4-bromomethylphenyl)benzoxazole (A) (0.1 mole) was stirred in a mixture of 2-butanone (300 ml.) and potassium carbonate (100 g.). After refluxing 16 hr., the mixture was poured onto 1000 g. ice/water. Filtration, washing with water and recrystallization from methyl cellosolve/isopropyl alcohol gave the tan, crystalline product I.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
The process of claim 1, wherein benzene and benzoic acid are reacted to give benzophenone.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]>>[Cl:3][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Yield: 97.8 %

Procedure:
Phosphorus oxychloride (25 ml, 0.27 mol) was added to 4-hydroxy-3-nitropyridine (7.0 g, 50.0 mmol), followed by reaction at 80° to 90° C. for 1.5 hours. Phosphorus oxychloride was removed by distillation. About 100 g of ice was added to the residue, and 28% aqueous ammonia was added dropwise thereto to adjust the pH to 7. Then, 100 ml of water was added thereto, and the aqueous mixture was extracted three times with 200 ml of dichloromethane. The resulting dichloromethane layer was dried, and then dichloromethane was removed by distillation under reduced pressure to obtain 7.75 g of a yellow liquid (yield: 97.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][C:10](=[O:12])[CH3:11])[CH:8]=1
Reactant: Cc1ccc(F)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(F)ccc1C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
5-Fluoro-2-methylaniline (10.0 g, 79.9 mmol, 1 equiv) was dissolved In toluene (50 mL) and placed in a cool water bath. Acetic anhydride (11.3 mL, 120 mmol, 1.5 equiv) was added slowly. After 15 minutes, a white precipitate had formed. The solid was collected by filtration and washed with toluene several times, affording 10.93 g (82%) of the title compound as a white crystalline solid. MS (ES+) m/e 213 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1.O>O1CCOCC1.C(=O)([O-])O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:40])([F:39])[F:27])=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(Br)cc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 78.8 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{[(4-bromobenzyl)oxy]methyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.0 g) synthesized in Example 152-1 and 4-(trifluoromethyl)phenylboric acid (621 mg) were dissolved in dioxane (10 mL) and sodium hydrogen carbonate aqueous solution (2 mol/L, 5 mL), tetrakis(triphenylphosphine)palladium (162 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (900 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([PH:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C[Si](C)(C)Cl.[C:22]([O:26][C:27]([NH:29][CH:30]1[O:33][C:31]1([CH3:34])[CH3:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1.ClCCl.[Cl-].[Zn+2].[Cl-]>[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([OH:33])([CH3:34])[CH2:32][P:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[O:6][CH2:7][CH3:8])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCC[PH](=O)OCC
Reactant: CC(C)(C)OC(=O)NC1OC1(C)C
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCP(=O)(CC(C)(O)CNC(=O)OC(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 15.0 g of ethyl n-butylphosphinate in anhydrous tetrahydrofuran containing 11.11 g of triethylamine is treated under an inert gas with an anhydrous tetrahydrofuran solution of 11.95 g of trimethylchlorosilane. A white precipitate forms immediately and the resulting suspension is stirred for 24 hours at room temperature under an inert gas. The reaction mixture is then filtered under an inert gas and the filtrate concentrated in vacuo to afford a cloudy oil which is then treated with 3.76 g of 3-(N-tert.-butoxycarbonylamino)-2-methyl-2,3-epoxypropane and 1 g of anhydrous zinc chloride. An exothermic reaction results. After the exotherm has subsided the clear solution is heated slowly to 70° and stirred at this temperature for 4 hours, after which time chromatographic analysis indicates the reaction to be complete. The reaction mixture is cooled to room temperature, diluted with dichloromethane and washed with water. Drying of the solvent and removal in vacuo affords an oil. The excess starting material is removed by Kugelrohr-distillation in high vacuum and the pale yellow residue chromatographed on silica-gel to give ethyl 3 -(N-tert.-butoxycarbonylamino)-2-hydroxy-2-methyl-propyl-(n-butyl)phosphinate as a colourless oil; 1H-NMR (CDCl3): δ (ppm)=5.17+4.68 (1H, Exch. D2O, NH), 4.07 (2H, m, CH2OP), 3.18 (2H, m, CH2N), 1.93-1.22 (24H, m, becomes 23H on D2O exchange), 0.92 (3H, t,CH3). 31P-NMR (CDCl3); 59.6, 59.3.
Reaction SMILES: [CH:1]1([C:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12](Br)=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:29](=[O:32])([O-])[O-].[Cs+].[Cs+]>C(O)C(F)(F)F>[CH:1]1([C:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:32][CH2:29][C:15]([F:18])([F:17])[F:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F)C1CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: OCC(F)(F)F
Product: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Temperature: 80 °C
Yield: 153.9 %

Procedure:
A mixture of 0.050 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide and 0.050 g cesium carbonate in 0.5 ml trifluoroethanol was heated to 80° C. for 20 min. The reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine evaporated and the crystalline residue was triturated under heptane to yield 0.040 g of the title compound as off white powder. MS (M−H) at 496.4 and 498.4.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C:38](C1C=C(B(O)O)C=CC=1)#[N:39]>>[NH2:37][C:9]1[C:8]([C:5]2[CH:6]=[C:7]([CH:2]=[CH:3][CH:4]=2)[C:38]#[N:39])=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:33])([F:35])[F:34])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cccc(C#N)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3-cyanophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=522, obsd.=522).
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[C@@H:20]5[O:29][C@@H:21]53)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(=CC(=O)C=C3)C=C4)CC2)C)OC1>>[O:29]1[C@H:20]2[C:19](=[O:30])[CH:18]=[C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]2)[CH:15]=[CH:16]3
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 60.2 %

Procedure:
The procedure of Example 26 was repeated except that 0,426 g (1.0 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one was used in lieu of 0.410 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one to give 0.205 g of 1α,2α-epoxy-3-oxopregna-4,6-diene-20-carbaldehyde (yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Yield: 105.8 %

Procedure:
A solution of Example A1 (20.00 g, 79 mmol) in MeOH (40 mL) was hydrogenated in presence of Raney Nickel (2.00 g, 34.1 mmol) at 40 psi for 3 h. The catalyst was removed via filtration, rinsed with MeOH and the filtrate concentrated to dryness to afford 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine (18.52 g, 105%) as a brown solid. MS (ESI) m/z: 222.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C[O:18][C:19](=[O:23])[CH:20](Cl)[CH3:21].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:20]([CH3:21])[C:19]([OH:23])=[O:18])=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)Cl
Reactant: Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 127.5 parts of 4-(2',4'-dichlorophenoxy)-phenol and 69.2 parts of 2-chloropropionic acid methyl ester in 650 parts of xylene, 100 parts of 50% sodium hydroxide solution are added dropwise at about 110° C. and 500 mbar while simultaneously distilling off the azeotropic mixture of water and methanol. The addition being complete, stirring is continued for 15 minutes at 110° C. Work-up is as described in Example 1. 163.3 Parts of 2-[4'-(2",4"-dichlorophenoxy)-phenoxy]propionic acid are obtained. The content of pure final product is 99.8%, corresponding to 99.6% of theory. The residual amount of 4-(2',4'-dichlorphenoxy)-phenol is 0.15%.