Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].CCN(C(C)C)C(C)C>ClC1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[C:18]([C:19]([O:21][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[CH:3]=2)=[O:20])=[CH:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=1
Reactant: O=C1C=C(Br)C2CCC1C2
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C

Procedure:
A mixture of 27 g of a 6.2% solution of 4-bromobicyclo[3.2.1]oct-3-en-2-one in chlorobenzene, 110 mg of ZnCl2, 2.34 g of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid and 1.2 g of Hünig's base is stirred at room temperature under a nitrogen atmosphere until a dark-brown solution is formed. With stirring, the reaction mixture is then maintained under moderate reflux for 19 hours in an oil bath. The mixture is then divided into 2 portions. To one portion there are added a further 1.12 g of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid, 0.06 g of ZnCl2 and 0.6 g of Hünig's base. With stirring, the reaction mixture is then maintained under moderate reflux for 12 hours in an oil bath. The solution is then washed twice with 0.1M hydrochloric acid (20 ml each time) and twice with water (20 ml each time). After drying the organic solution using magnesium sulfate and concentrating in vacuo, 3.9 g of 4-(2-methoxyethoxymethyl-6-trifluoromethyl-pyridin-3-ylcarbonyloxy)-bicyclo[3.2.1]oct-3-en-2-one are obtained in the form of a brown oil.
Reaction SMILES: [F-].[Cs+].[Br:3][C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1.[F:11][C:12]([Si](C)(C)C)([F:14])[F:13]>COCCOC>[Br:3][C:4]1[S:8][C:7]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)s1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC(c1ccc(Br)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
CsF (400 mg, 2.6 mmol) was added to a solution of 5-bromothiophene-2-carboxaldehyde (5.0 g, 26.17 mmol) in dry 1,2-dimethoxyethane (20 mL), followed by trifluoromethyl trimethylsilane (4.6 mL, 31.4 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 3 h, quenched with 1.5N HCl, and stirred for an additional 30 min. The crude product was extracted with CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleum ether) to get 1-(5-bromothiophen-2-yl)-2,2,2-trifluoroethanol (4 g, yield 59%). 1H NMR (400 MHz, CDCl3) δ 7.01 (m, 1H), 6.95 (m, 1H), 5.23-5.18 (q, J=5.9 Hz, 1H), 3.07 (br s, 1H). MS (ESI) m/z: Calculated for C6H4BrF3OS: 261.91. found: 260.7 (M−1)−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([NH2:26])([C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)[CH3:19]>>[CH3:17][C:18]([NH:26][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)[CH3:19]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: Cc1cc(C(C)(C)N)on1
Product: Cc1cc(C(C)(C)NC(=O)c2cccc(-c3cccc(Cl)c3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-(3-methyl-isoxazol-5-yl)-ethylamine as starting materials, MS (EI): 356.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:15][C:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18].CSC.B.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(Br)c(NC(=O)C(C)(C)C)c1[N+](=O)[O-]
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Br)c(NCC(C)(C)C)c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
3.76 g (10.47 mmol) of methyl 4-bromo-3-[(2,2-dimethylpropanoyl)amino]-2-nitro-benzoate were suspended in toluene and admixed with 6 ml (11.26 mmol) of borane-dimethyl sulfide (2M in toluene). The mixture was left with stirring under reflux for 15 h and then cooled. Thereafter, 50 ml of saturated NaHCO3 solution were added, stirring was carried out again at RT for 30 min, and then the organic phase was separated off, dried over MgSO4 and concentrated. The product was then subjected to chromatographic separation (silica gel, heptane/ethyl acetate 4:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)=[CH:9][CH:8]=1)=[O:5].[OH-].[Na+].Cl>C(O)C.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(NC(=O)COC)cc3)cs2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCC(=O)Nc1ccc(-c2csc(Cn3cc(C(=O)O)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution (4 mL) of the compound (250 mg, 0.62 mmol) obtained in Example 36c in ethanol was added 2N aqueous sodium hydroxide solution (1.6 mL, 3.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (110 mg, 49%) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([Cl:30])=[C:22]([Cl:31])[CH:21]=4)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=3)=[CH:7][CH:6]=2)[CH2:2]1.C(N(CC)CC)C.[N:39]([CH3:42])=[C:40]=[O:41]>CN(C=O)C>[Cl:31][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH:3]4[CH2:4][N:1]([C:40]([NH:39][CH3:42])=[O:41])[CH2:2]4)=[CH:6][CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[Cl:30]
Reactant: CN=C=O
Reactant: FC(F)(F)c1cc(C2(C(F)(F)F)CC(c3ccc(C4CNC4)cc3)=NO2)cc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)N1CC(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(C(F)(F)F)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(4-(azetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0.05 mmol) was dissolved in DMF (1 mL); triethylamine (0.20 mmol) was added, followed by a solution isocyanatomethane. The resulting solution was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the crude product purified by preparative HPLC to give 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-N-methylazetidine-1-carboxamide (11.2 mg) MH+ 540.1; retention time 6.14 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].BrC[CH2:27][CH2:28][O:29][CH2:30][CH2:31]CBr>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: BrCCCOCCCBr
Product: CCOCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21

Procedure:
Using ((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester and 2-bromomethyl-ethyl ether, the title product was prepared in the same manner as described for example 1a (83%). Pink, viscous oil. MS: m/e=397(M+H+).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:30][C:31]1([CH2:39]Br)[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33][CH2:32]1>CN(C=O)C>[CH:3]1([C:9]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=3[N:11]3[C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH2:39][C:31]2([CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33][CH2:32]2)[CH2:30]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Reactant: CC1(C)OCC(CBr)(CBr)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
NaH (5 eq, 60% dispersion in mineral oil) was added to a degassed solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in published International patent application WO2006/046030) in DMF (0.2 M) and the solution was allowed to stir for 20 min at RT. The mixture was then placed in an oil bath preheated at 70° C., a degassed solution of 5,5-bis(bromomethyl)-2,2-dimethyl-1,3-dioxane (1.5 eq) in dry DMF (0.4M) was added and the mixture was stirred for 1 h; additional electrophile (1.5 eq) was added and stirring was continued for 3 h at 70° C. The reaction was quenched with sat. aq. NH4Cl, acidified with 1N HCl and extracted with Et2O; the organic layer was washed with H2O and brine, dried over Na2SO4 and the solvent was removed in vacuo. The crude was purified by FC (PE/EtOAc) to afford the title compound (50%) and recovered starting material (44%). (ES+) m/z 490 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([O:12][CH2:13][CH:14]=[CH:15]B1OC(C)(C)C(C)(C)O1)(=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC1CCCO1.O.C([O-])(O)=O.[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:7]=[C:6](/[CH:15]=[CH:14]/[CH2:13][O:12][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(=O)OCC=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC1CCCO1
Solvent: O
Product: COC/C=C/c1ccnc(Cl)n1
Temperature: 125 °C
Yield: 95.5 %

Procedure:
A microwave vessel was charged with 2,4-dichloropyrimidine (500 mg, 3.36 mmol), 3-acetoxy-1-propenylboronic acid pinacol ester (997 mg, 5.03 mmol) and solid potassium phosphate tribasic (2.14 g, 10.1 mmol), which were then suspended in 2-methyltetrahydrofuran (4 ml) and water (1 ml). The vessel was deoxygenated three times, then Palladium(II) acetate (37.7 mg, 0.17 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (138 mg, 0.34 mmol) were introduced and the dark mixture was heated under microwave irradiation at 125° C. for 15 min. The reaction mixture was diluted with saturated aqueous NaHCO3 (80 ml) and extracted with EtOAc (2×75 ml). The combined organic layers were dried over MgSO4 and concentrated. The crude orange oil was purified by flash column chromatography (SiO2: 100% Hex to 100% EtOAc), which afforded 2-chloro-4-[(1E)-3-methoxyprop-1-en-1-yl]pyrimidine (623 mg, 3.21 mmol, 96% yield) as an orange-red solid. MS ESI: [M+H]+ m/z 185.1.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:12]([Mg]Cl)[CH:13]([CH3:15])[CH3:14].S(=O)(=O)(O)O>O1CCCC1.O>[CH3:12][CH:13]([CH3:15])/[CH:14]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(C)C[Mg]Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)/C=C/c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
4-Carboxybenzaldehyde (1.0 g, 6.66 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to 0° C. To the mixture was added isobutylmagnesium chloride (16 mL, 32 mmol, 2.0 M solution in THF). The reaction mixture was warmed to room temperature and stirred for 2 hours. The solution was acidified with 50% sulfuric acid in water and the THF was removed under vacuum. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give the desired compound (950 mg) as grey powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:24])=[CH:18]/[C:19](OCC)=[O:20])=[CH:13][CH:12]=1.CC(C[AlH]CC(C)C)C>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[CH3:24])=[CH:18]/[CH2:19][OH:20])=[CH:15][CH:16]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2c(OC)cccc2OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1cccc(OC)c1-c1ccc(/C(C)=C/CO)cc1

Procedure:
(E)-Ethyl 3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enoate (0.90 g, 2.76 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52 b to give (E)-3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol as a colourless solid; 0.82 g (100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][CH:10]([CH3:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:12].O>C(Cl)Cl>[CH3:9][CH:10]([CH3:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[N:12]=[CH:7]/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CC(C)C(N)c1ccccc1
Reactant: O=Cc1ccccn1
Solvent: O
Solvent: ClCCl
Product: CC(C)C(/N=C/c1ccccn1)c1ccccc1

Procedure:
In air, 2-pyridinecarboxaldehyde (0.185 g, 0.164 mL, 1.72 mmol, 1.00 equiv) was added to a solution of 2-methyl-1-phenylpropan-1-amine (0.257 g, 1.72 mmol, 1.00 equiv) in CH2Cl2 (8 mL). After heating at reflux for 2 h with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure and dried under high vacuum to give ligand (L-1), (E)-2-Methyl-1-phenyl-N-(pyridin-2-ylmethylene)propan-1-amine, as a yellow oil (0.379 g, 92% yield).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O1CCCC1.[CH2:11]([O:13][C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[C:25](=[CH:26][CH2:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][C@H:22]1[OH:35])[CH3:12].[NH4+].[Cl-]>C(OCC)C>[CH2:11]([O:13][C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[C:25](=[CH:26][CH2:27][C:28]([OH:34])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][C@H:22]1[OH:35])[CH3:12]
Reactant: CCCCCC(=O)CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(O)(CC=C1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC)CCCC

Procedure:
1.6 g. Butyl lithium, dissolved in 60 ml. tetrahydrofuran, is added dropwise to 3.7 g. 9β-hydroxy-15-oxo-12-prostenoic acid ethyl ester, dissolved in 150 ml. dry diethyl ether, with the exclusion of moisture, under argon and with stirring at -15°. The mixture is stirred for another hour, allowed to warm to 0° and mixed dropwise, with ice cooling, with 300 ml. saturated aqueous NH4Cl solution. The organic phase is separated, washed with water and dried over Na2SO4. The solvent is removed to obtain as residue 9β,15-dihydroxy-15-butyl-12-prostenoic acid ethyl ester.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1>>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:23]3[CH:24]=[CH:19][CH:20]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:22]=3)[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: FC(F)(F)Oc1cccc(I)c1
Product: O=C1CCN(c2cccc(OC(F)(F)F)c2)CCN1CCCN1CCCCC1

Procedure:
The title compound was prepared from 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (Example 33B) and 1-iodo-3-trifluoromethoxy-benzene in analogy to example 33. MS: 400.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[C:4]([C:15]([Cl:18])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].ClCCl.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>>[Cl:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([F:19])[C:2]([N:1]([S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])[S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(Cl)c(C(=O)OCc2ccccc2)c1F)S(=O)(=O)CCC
Temperature: 0 °C
Yield: 72.7 %

Procedure:
Benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 15.37 mmol) was dissolved in dry dichloromethane (270 mL) Triethylamine (5.36 mL, 2.5 eq.) was added, and the mixture was chilled to 0° C. Propane-1-sulfonyl chloride (3.63 mL, 32.3 mmol, 2.1 eq.) was then added via syringe, and a precipitate resulted. Once the addition was complete, the mixture was allowed to warm to room temperature, and the starting material was consumed as determined by TLC (3:1 hexane:ethyl acetate). The mixture was then diluted with dichloromethane (200 mL), washed with 2M aqueous HCl (2×100 mL), saturated Na2HCO3 solution, dried over sodium sulfate and concentrated. The resulting residue was purified on a 65 Biotage chromatography system (40% ethyl acetate/hexane) to produce benzyl 6-chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (5.5 g, 72%) as an oil that slowly solidified upon standing. NMR (CDCl3, 400 MHz) δ 7.28-7.45 (m, 7H), 5.42 (s, 2H), 3.58-3.66 (m, 2H), 3.43-3.52 (m, 2H), 1.08 (t, 6H, J=8).
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([OH:23])=[O:22])=[O:15])([OH:3])=[O:2]>C(O)CC>[CH2:1]([O:22][C:21]([C@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:24])[N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:1]([O:3][CH2:9][CH2:10][CH3:11])=[O:2])=[O:23])[CH2:4][CH3:8]
Reactant: O=C(O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Solvent: CCCO
Product: CCCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.2 %

Procedure:
A mixture of 170 mg (0.5 mmol) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid and 54 mg Amberlite® IR120 in 10 ml propanol were stirred at room temperature for 48 hours. After filtration the solvent was distilled off, the residue was taken up in dichloromethane and extracted with 2% aqueous sodium bicarbonate. The organic extract was dried with sodium sulfate and the solvent was distilled off to yield 65 mg (31%) (R)-1-{6-oxo-6-[(R)-2-propoxycarbonyl-pyrrolidin-1-yl]-hexanoyl}-pyrrolidine-2-carboxylic acid propyl ester as alight yellow oil, MS m/e (%): 424 (M+, 3), 268 (100), 156 (21), 70 (69).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[F:25])=[O:16])=[CH:10][CH:9]=2)=[CH:6][C:5]([B:26]2[O:30]C(C)(C)C(C)(C)[O:27]2)=[CH:4][N:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([B:26]([OH:27])[OH:30])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[F:25])=[O:16])=[CH:10][CH:9]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3cc(B4OC(C)(C)C(C)(C)O4)cnc3N)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3cc(B(O)O)cnc3N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 1-(4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea (AGN-227971, 108 mg, 0.234 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added aq HCl (3N, 2 mL) and the reaction was first stirred at room temperature for two hours. Additional conc. HCl (0.5 mL) was dropwise added to the reaction and the mixture was stirred at 50° C. for further four hours. The reaction was then poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was isolated, washed with brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated to lesser amount, and the solid crashed-out was filtered. This solid was further purified by a reversed phase chromatography (from WATER-CH3CN 9:1 to CH3CN) to give (6-amino-5-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)pyridin-3-yl)boronic acid as a grey solid in amount of 7 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH2:16][CH2:15][CH2:14][S:13]1(=[O:18])=[O:17]>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:16][CH2:15][CH2:14][S:13]([OH:18])(=[O:17])=[O:12])=[CH:11][CH:10]=1
Reactant: O=S1(=O)CCCO1
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(NCCCS(=O)(=O)O)cc1
Yield: 70.9 %

Procedure:
Methyl 4-aminobenzoate (1.34 g, 8.87 mmol) and [1,2]oxathiolane 2,2-dioxide (1.02 g, 8.36 mmol) were heated at 100–110° C for 1 h. The cooled residue was washed with 1N HCl and water and air-dried to give 4-(3-sulfo-propylamino)-benzoic acid methyl ester (1.62 g, yield: 71%). 1H NMR (DMSO-d6) δ 7.70 (d, J=8.7 Hz, 2H), 6.65 (d, J=8.7 Hz, 2H), 5.88 (br, s, NH+SO3H), 3.19 (t, J=7.0 Hz, 2H), 2.63 (t, J=7.3 Hz, 2H), 1.87 (quint, J=7.0 Hz, 2H). LC/MS (ESI) 256.22 (M+H)+, tR=2.21 min (10–90% MeOH in H2O with 10 mM NH4OAc in a 4-min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14]I>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:14])=[C:4]([O:9][C:10]([F:11])([F:13])[F:12])[CH:3]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1S
Reactant: CI
Product: CSc1ccc(Br)cc1OC(F)(F)F
Reaction time: 8 h
Yield: 85 %

Procedure:
4-Bromo-1-methylthio-2-trifluoromethoxybenzene was prepared from 4-bromo-2-trifluoromethoxybenzenethiol and methyl iodide by following Method C. The reaction was conducted at room temperature overnight. The crude residue was chromatographed in 20% EtOAc/Hexanes to afford 4-bromo-1-methylthio-2-trifluoromethoxybenzene (85% yield).
Reaction SMILES: [N:1]([CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:7]=2[N:6]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:5]1=[O:27])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.O.[Cl-].[Na+].O>[NH2:1][CH:4]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:7]=2[N:6]([CH2:22][C:23]([F:26])([F:24])[F:25])[C:5]1=[O:27]
Reactant: [N-]=[N+]=NC1N=C(c2ccccc2)c2cccc(Cl)c2N(CC(F)(F)F)C1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NC1N=C(c2ccccc2)c2cccc(Cl)c2N(CC(F)(F)F)C1=O
Yield: 51.9 %

Procedure:
A solution of 3-azido-9-chloro-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.320 g, 0.812 mmol) and triphenylphosphine (0.426 g, 1.62 mmol) in tetrahydrofuran (13 mL) and water (1.5 mL) was stirred at room temperature for 48 h. Workup with ethyl acetate and saturated sodium bicarbonate, followed by saturated brine and drying over sodium sulfate gave the product. The crude product was purified by chromatography (silica gel, 0–5% methanol in methylene chloride gradient elution), giving the title compound (0.155 g). 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J=8 Hz, 2H), 7.49 (tt, J=2,7 Hz, 1H), 7.42 (t, J=8 Hz, 2H), 7.32 (t, J=8 Hz, 1H), 7.26 (d, J=7 Hz, 1H), 5, 22 (m, 1H), 4.56 (s, 1H), 4.30 (m, 1H), 2.15 (br s, 2H).