Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[OH-].[Na+].Br[O-].[Na+].CNC.[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])([CH3:13])[CH3:12]>O.C(Cl)Cl>[Br:1][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:15]=1[OH:20]
Reactant: BrBr
Reactant: CC(C)c1ccccc1O
Agent: CNC
Agent: [Na+]
Agent: [O-]Br
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cccc(Br)c1O
Reaction time: 0.17 h

Procedure:
198.1 ml (3.85 mol) of bromine were added dropwise at -5° to 0° C. to a solution of 470 g of sodium hydroxide in 2 l of water. The mixture was stirred at this temperature for a further 10 min, The resulting sodium hypobromite solution was added dropwise at -5° to 0° C. to a solution of 464 g of a 40% strength aqueous dimethylamine solution (4.11 mol) in 50 ml of water. The mixture was stirred for a further 30 min, then the organic phase was separated off and the aqueous phase was extracted twice using 750 ml portions of methylene chloride, The combined organic phases were briefly dried over magnesium sulfate and filtered, The filtrate was added dropwise at -10° C. to a solution of 500 g (3.67 mol) of ortho-isopropylphenol in 900 ml of methylene chloride. After addition of about 2/3 of the filtrate, a solid formed and the reaction mixture became viscous and difficult to stir. 500 ml of methylene chloride were added at -10° C. and the mixture was stirred for a further hour. The solid was filtered off with suction, washed with a little cold methylene chloride, suspended in 1.5 1 of 2N sulfuric acid and stirred at room temperature until all the solid had changed to an oil. The organic phase was separated off and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with sodium chloride solution and dried, and the solvent was removed in vacuo. The residue was distilled through a 30 cm Vigreux column in a water Jet vacuum.
Reaction SMILES: [CH3:1][OH:2].[C:3]1([N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(N(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41](Cl)(=[O:44])[CH:42]=[CH2:43]>C1C=CC=CC=1>[CH3:1][O:2][C:41](=[O:44])[CH:42]=[CH2:43].[C:16]1([N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CC(=O)Cl
Reactant: CO
Agent: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C=CC(=O)OC

Procedure:
(Procedure 1): Triphenylamine methyl alcohol as a triphenylamine derivative and an acrylic acid chloride were dissolved in benzene, and then the resultant benzene solution was stirred at 0° C. for five hours so as to cause the triphenylamine methyl alcohol to react with the acrylic acid chloride. After the reaction, the benzene solution was evaporated under reduced pressure so as to obtain a triphenylamine methyl acrylate monomer as a crude crystal. Next, the crude crystal was recrystallized by benzene for purification. The reaction scheme of the triphenylamine methyl alcohol and the acrylic acid chloride is shown in Scheme 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:8]=3[N:7]([CH2:17][CH2:18][O:19][CH2:20][CH2:21]O)[C:6]=2[CH:23]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]1>C(OCC)C.CC(C)=O.C(OCC)(=O)C.CCCCCCC.C(N(CC)CC)C>[CH2:44]([O:43][C:41]([C@@H:37]1[CH2:38][CH2:39][CH2:40][N:35]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][N:7]2[C:6]3[CH:23]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:8]2=3)[CH2:36]1)=[O:42])[CH3:45]
Reactant: OCCOCCN1c2cc(Cl)ccc2CCc2ccc(Cl)cc21
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3cc(Cl)ccc3CCc3ccc(Cl)cc32)C1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a mixture of the above alcohol (1.3 g, 3.7 mmol), triethylamine (1.3 ml) and dry diethyl ether (75 ml) was added dropwise a solution of methanesulfonyl chloride (0.63 g, 5.5 mmol) in dry diethyl ether (25 ml). Stirring was continued for 1 h at room temperature. The reaction mixture was washed with water and dried over potassium carbonate. The solvent was evaporated in vacuo to give an oily residue which was dissolved in acetone (30 ml). To this solution was added potassium carbonate (1.0 g, 7.4 mmol) and ethyl (R)-3-piperidinecarboxylate (1.2 g, 7.4 mmol) and the suspension was heated at reflux temperature for 16 h. Another portion of ethyl (R)-3-piperidinecarboxylate (0.5 g) was added and the mixture was heated at reflux temperature for 24 h. This cooled reaction mixture was filtered and from the filtrate the solvent was evaporated in vacuo. This afforded an oil which was submitted to column chromatography on silica gel (100 g) using a mixture of ethyl acetate and n-heptane (1:1) as eluent. Collecting the proper fractions gave 1.5 g of (R)-N-(2-(2-(3,7-dichloro-10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.18 (SiO2 ; ethyl acetate/n-heptane=1:1 ).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([CH2:13][CH2:14][CH2:15][CH:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].O>C1C=CC=CC=1.CN(C)C=O.CCOCC>[C:10]([C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([CH2:13][CH2:14][CH2:15][CH:16]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])(=[O:12])[CH3:11]
Reactant: CCCCCC(CCCC(C(C)=O)c1ccccc1)OCc1ccccc1
Reactant: CCOC(=O)CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (0.8 g., 0.033 mole) is suspended in a mixture of benzene (50 ml.) and dimethylformamide (50 ml.) and 3-phenyl-7-benzyloxy-2-dodecanone (12.1 g., 0.033 mole) is added dropwise. The resulting mixture is heated on the steam bath for one hour and then cooled to room temperature. Ethyl 7-bromoheptanoate (8.8 g., 0.037 mole) is added dropwise and the mixture is heated on the steam bath for 24 hours. The reaction mixture is cooled, poured into water (200 ml.) and the oily product taken up into ether and dried over sodium sulfate. The solvent is distilled in vacuo to leave 14 g. of ethyl 8-acetyl-8-phenyl-12-benzyloxyheptadecanoate as a yellow oil which is used in Step G without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[F:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CO.COCCOC>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][S:12][C:7]3[NH:8][C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[CH:3][NH:4][C:5]=4[N:6]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: Cc1c[nH]c2nc(SCc3ccc(C(=O)c4ccc(F)cc4)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
In methanol (25 ml) was suspended 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.82 g) followed by addition of 1N-sodium hydroxide (10.5 ml) for dissolution. Then, under ice-cooling, a solution of 4-(4-fluorobenzoyl)benzyl bromide (3.51 g) in DME (10 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours and the resulting crystalline precipitate was collected by filtration and rinsed with water. The crystals were further rinsed with 50% ethanol/water, methanol and ether serially, dried, and recrystallized from DME (1,2-dimethoxyethane) to provide the title compound (2.71 g). 1H-NMR (DMSO-d6) δ: 2.24(3H,s), 4.51(2H,s), 6.65(1H,s), 7.37(2H,t,J=8.8Hz), 7.64(2H,d,J=8.8Hz), 7.70(2H,d,J=8.8Hz), 7.81(2H,dd,J=5.6,8.8Hz), 11.43(1H,s), 11.97(1H,s).
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:8][CH2:9][P:10]([CH2:15][N:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:14])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:36][C:37]([CH2:39]Br)=[CH2:38]>>[C:24]1([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][CH:15]([P:10]([CH:9]([N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:39][C:37]([Br:36])=[CH2:38])(=[O:14])[O:11][CH2:12][CH3:13])[CH2:39][C:37]([Br:36])=[CH2:38])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)CN=C(c1ccccc1)c1ccccc1
Reactant: C=C(Br)CBr
Product: C=C(Br)CC(N=C(c1ccccc1)c1ccccc1)P(=O)(OCC)C(CC(=C)Br)N=C(c1ccccc1)c1ccccc1
Yield: 71 %

Procedure:
Analogously to Example 6, the bis-alkylated phosphinates 9 were prepared in a yield of 71% from the protected phosphinate 3 and 2,3-dibromopropene.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:28][C:27]=1[O:40][CH3:41].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:28][C:27]=1[O:40][CH3:41])=[O:24]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)c1cc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
In DMF (10 ml), EDC HCl (1.43 g, 7.45 mmol) was added to indole-2-carboxylic acid (1.00 g, 6.21 mmol), tert-butyl 4-amino-3-methoxyphenylacetate (1.47 g, 6.21 mmol), HOBt (0.42 g, 3.10 mmol), and DMAP (0.38 g, 3.10 mmol). The resulting mixture was stirred at 60° C. for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane:ethyl acetate (1:1, v/v) eluate fractions, tert-butyl (4-((2-indolylcarbonyl)amino)-3-methoxyphenyl)acetate (1.31 g, 55%) was obtained as a brown solid.
Reaction SMILES: [C@H:1]12[CH2:25][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19](N(OC)C)=[O:20])[CH:16]=[C:17]([Br:18])[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2.Cl.[CH2:27]1COCC1>>[C@H:1]12[CH2:25][C@H:4]([N:5]([C:7]([C:9]3[N:13]4[CH:14]=[C:15]([C:19](=[O:20])[CH3:27])[CH:16]=[C:17]([Br:18])[C:12]4=[N:11][CH:10]=3)=[O:8])[CH2:6]1)[CH2:3][O:2]2
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1cc(Br)c2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)n2c1
Agent: Cl
Product: CC(=O)c1cc(Br)c2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)n2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-8-bromo-N-methoxy-N-methylimidazo[1,2-a]pyridine-6-carboxamide (286 mg) in THF (10 mL) was added dropwise 1M methylmagnesium bromide THF solution (2.1 mL) under ice-cooling. The reaction mixture was stirred at 0° C. for 20 min, 1N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[CH:7][C:8]([NH:12]C(OC(C)(C)C)=O)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
To a stirred sloution of 4-[7-chloro-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-quinolinyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (2 g, 4.33 mmol) in CH2Cl2 (30 mL) was added TFA (4 mL) at rt. The reaction mixture was kept at reflux for 4 h, then cooled to rt. After removal of the solvent and excess TFA, the mixture was diluted with CH2Cl2, and treated with NaOH (10%) to pH 12. The mixture was extracted with CH2Cl2, washed with brine, and dried over Na2SO4. Concentration in vacuo afforded the product as a free base (1.13 g, 98%). LC-MS: 262 (M++1). 1H NMR (DMSO-d6): 62.90 (s, 8H), 6.20 (s, 1H), 6.4 (s, 2H) 7.08 (d, 1H), 7.35 (s, 1H), 7.68 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[Br:21][C:22]1[CH:23]=[C:24]([NH2:34])[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([NH:34][C:2]2[C:11]3[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:3]=2[CH3:20])[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:26][CH:27]=1
Reactant: Nc1cc(Br)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(F)ccc(F)c2c1Cl
Product: Cc1c(-c2ccccn2)nc2c(F)ccc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1

Procedure:
Prepared according to the acid catalyzed Procedure K, Method 2 using 4-chloro-5,8-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (300 mg, 1.03 mmol) and 5-bromo-2-morpholinopyridin-3-amine to give N-(5-bromo-2-morpholinopyridin-3-yl)-5,8-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=512.0 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([OH:12])[CH:6]=1)C.[NH2:14][NH2:15]>>[OH:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH3:11])[C:4]([NH:14][NH2:15])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Product: Cc1ccc(C(=O)NN)cc1O
Temperature: 150 °C

Procedure:
A suspension of ethyl 3-hydroxy-4-methylbenzoate (14.42 g, 80 mmol) (from Example 2 supra) in anhydrous hydrazine (30 mL, 956 mmol) (Aldrich) was heated at reflux (150° C. bath temperature) for 2.0 hours. After cooling to room temperature, mixture was concentrated under reduced pressure (high vacuum) to give crude 3-hydroxy-4-methyl-benzoic acid hydrazide as an off-white solid. (Yield 13.26 g, 100%).
Reaction SMILES: [F:1][C:2]([F:33])([C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:3][CH2:4]/[C:5](=[CH:19]/[C:20]([O-:22])=[O:21])/[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7].[S:34]([O-:37])([OH:36])=[O:35].[Na+:38].O.C(O)C>C(OCC)(=O)C>[F:1][C:2]([F:33])([C:23]([F:31])([F:32])[C:24]([F:29])([F:30])[C:25]([F:28])([F:27])[F:26])[CH2:3][CH2:4][C:5]([S:34]([OH:37])(=[O:36])=[O:35])([CH2:19][C:20]([O-:22])=[O:21])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7].[Na+:38]
Reactant: O=S([O-])O
Reactant: CCCCCCCCCCOC(=O)/C(=C\C(=O)[O-])CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(CC(=O)[O-])S(=O)(=O)O
Yield: 22.9 %

Procedure:
Monodecyl mono(3,3,4,4,5,5,6,6,6-nonafluorohexyl)maleate (48.0 g, 90 mmol), sodium hydrogensulfite (10.4 g, 99 mmol) and water/ethanol (50 mL, 1/1 (v/v)) were mixed and refluxed for 5 hours with heating. Then, the reaction mixture was added with ethyl acetate, and the organic phase was washed with a saturated sodium chloride aqueous solution. The organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was recrystallized from acetonitrile to obtain the target compound (12.5 g, yield: 22%) as colorless transparent solid.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:10]1=[O:23].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:55][C:56]1[CH:61]=[C:60]([Cl:62])[CH:59]=[CH:58][C:57]=1[CH2:63][NH2:64]>ClCCl>[Cl:55][C:56]1[CH:61]=[C:60]([Cl:62])[CH:59]=[CH:58][C:57]=1[CH2:63][NH:64][C:14]([CH:13]1[CH2:12][N:11]([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:10](=[O:23])[N:9]1[CH3:8])=[O:16]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CN1C(=O)N(c2ncccn2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(c2ncccn2)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.5 %

Procedure:
A mixture of 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylic acid TFA salt (168 mg, 0.5 mmol), 1-hydroxybenzotriazole hydrate (101 mg, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol) and N-ethyl morpholine (0.316 ml, 2.5 mmol) in dichloromethane (8 ml) was stirred at room temperature for 10 minutes. A solution of [1-(2,4-dichlorophenyl)methyl]amine (0.067 ml, 0.5 mmol) in dichloromethane (2 ml) was added and the reaction stirred at room temp for 4 hours. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate, The organic phase was separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-[(2,4-dichlorophenyl)methyl]-3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxamide (20 mg, 10.5% yield). LC/MS [M+H]+=380, retention time=2.22 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])[CH2:9][C:10]([N:25]([O:26][CH3:27])[CH3:24])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CC(c1ccc(Br)cc1)c1ccccc1C(F)(F)F
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 74, step 4, from 3-(4-bromo-phenyl)-3-(2-trifluoromethyl-phenyl)-propionic acid and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a brown viscous oil, MS (ESI+): m/z=416.2 ([M+H]+, 1Br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([N:21]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31](=[O:33])[CH3:32])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CCCN[C@H]2CC[C@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Reaction time: 1 h

Procedure:
A mixture of trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-phenyl-propyl)-amine (0.4 g, 1.0 mmol), pyridine (4 ml) and acetic anhydride (2 ml) was stirred at 0° for 1 h. Evaporation of the solvents and crystallization of the residue with hexane, gave trans-N-[4-(4-benzyloxy-phenyl)-cyclohexyl]-N-(3-phenyl-propyl)-acetamide (0.26 g, 59%) as white crystals. Mp. 80.0-81.5°, MS: m/e=441 (M+).
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=1.[Br:23]Br.CC(C)=O.CCCCCC>O.C(Cl)(Cl)Cl>[Br:23][C:17]1[N:18]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])[NH:15][C:16]=1[C:19]([F:21])([F:22])[F:20]
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)cc2Cl)[nH]1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1[nH]c(-c2ccc(Cl)cc2Cl)nc1Br

Procedure:
Sodium bicarbonate is made into a paste by adding a few drops of water to 1.5 g (9.4 mol). The 2-(2,4-dichlorophenyl)-5-trifluoromethylimidazole is dissolved in 100 ml chloroform and added to the flask containing the paste. 1.5 g of bromine is added and stirred. TLC on alumina using 50:50 acetone-hexane clearly differentiates starting material from product. Additional bromine is added until starting material is no longer present (0.1 g). Water is added and the organic phase removed. The layer is washed with sodium bisulfite, brine and dried over sodium sulfate. The organic phase is stripped and the residue taken up in 1:1 ether hexane and filtered through silica gel.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH3:18]>ClCCCl>[Cl:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:17][CH3:18])=[CH:11][C:12]([CH:13]=[O:14])=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=1
Reactant: COc1cc(C=O)ccc1OCCCl
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCl
Temperature: -10 °C
Yield: 40 %

Procedure:
Fuming nitric acid (10 mL) is added dropwise to a −40° C. suspension of 5.00 g (23.36 mmol) of 4-(2-chloroethoxy)-3-methoxybenzaldehyde (Milbank, J. B. J., et. al., J. Med. Chem., 42(4), 649-658, 1999) in 23 mL of 1,2-dichloroethane. The reaction mixture is slowly allowed to warm to −10° C. The mixture is poured onto 300 mL of ice water and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the pale yellow solid is collected by filtration to provide 2.43 g (40%) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde, mp 148-150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:59]=[CH:58][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][C@@H:45]3[F:57])=[N:26]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH:41][C:14]([C:10]5[C:9](=[O:17])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH:13]=[CH:12][N:11]=5)=[O:16])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[CH2:46][C@@H:45]3[F:57])=[N:26]2)=[CH:58][CH:59]=1
Reactant: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3F)c3c(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1

Procedure:
Prepared from 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (60 mg, 0.26 mmol, prepared according to the procedure for Example 125, Step E) and ±(3S*,4S*)-tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (50 mg, 0.086 mmol, obtained from Example 146, Step A) according to the procedure described for Example 145, Step B. Yield: 42 mg (58%).