Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
4-bromo-1-chloro-2-(4-methoxybenzyl)benzene (226 g, 0.73 mol) was dissolved in methylene chloride (2240 mL) under a nitrogen protection and in a protection from light. To the resulting mixture was slowly added dropwise a solution of boron tribromide (357 g, 1.42 mol) in methylene chloride (1416 mL) at −78° C. After the completion of dropwise addition, the reaction mixture was warmed up to room temperature and reacted for 2 hr. TLC indicated the completion of reaction. To the reaction mixture was slowly added dropwise water in an ice-water bath. The methylene chloride phase was collected. The residual aqueous phase was extracted with methylene chloride (1 L) for two times. The organic phases were combined, washed with water for two times and with a saturated sodium chloride solution for one time, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 210 g of a product in a yield of 97%.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1.O>[C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([N:28]3[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]3)=[O:27])[CH2:11]2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(C(=O)O)CC2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
27 mg (0.05 mmol) of methyl 1-({3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)piperidine-4-carboxylate were initially charged in 0.8 ml each of THF and water, and 4 mg (0.15 mmol) of lithium hydroxide were added. The mixture was stirred at RT overnight. The reaction solution was concentrated under reduced pressure and acidified, and the precipitate was filtered off and dried. Yield: 16 mg (62% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12]Cl)=[O:9])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH:22][CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:18]=[CH:19][C:20]=1[F:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12][N:27]2[CH2:28][CH2:29][CH:24]([CH:23]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[NH:22][C:17]3[CH:18]=[CH:19][C:20]([F:21])=[C:15]([F:14])[CH:16]=3)[CH2:25][CH2:26]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(CCCCl)c1ccc(Cl)cc1
Reactant: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCNCC2)cc1
Product: O=S(CCCN1CCC(C(Nc2ccc(F)c(F)c2)c2ccc(F)cc2)CC1)c1ccc(Cl)cc1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 1-chloro-4-[(3-chloropropyl)sulfinyl]benzene and N-(3,4-difluorophenyl)-α-(4-fluorophenyl)-4-piperidinemethanamine.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC1C=NC(C2C=CC([O:42][CH2:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:51][C:52]([F:62])([F:61])[C:53]([F:60])([F:59])[O:54][C:55]([F:58])([F:57])[F:56])([F:50])[F:49])=CC=2)=NC=1)CCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:42][CH2:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:51][C:52]([F:61])([F:62])[C:53]([F:59])([F:60])[O:54][C:55]([F:57])([F:58])[F:56])([F:50])[F:49])=[C:18]([F:22])[CH:17]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2cccc(F)c2)nc1
Reactant: CCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)c(F)c2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyloxy-2-(3-fluorophenyl)pyrimidine (2.0 g, 6.3 mmol) with 3-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propoxy chloride (2.5 g, 7.0 mmol, Example 17). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (210-18° C. at 0.15 torr), to provide a yield of 3.2 g.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11](Br)[C:12]([O:14]C)=[O:13])=[C:6]([CH3:17])[CH:5]=1)(=[O:3])[CH3:2].C[O-].[Na+].Cl.O>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[C:6]([CH3:17])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(Br)Cc1ccc(C(C)=O)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(C=CC(=O)O)c(C)c1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 34.5 %

Procedure:
The obtained methyl 3-(4-acetyl-2-methylphenyl)-2-bromopropionate (2.79 g, 9.33 mmol) was dissolved in methanol (80 mL). The solution was cooled to 5° C. Sodium methoxide (1.51 g, 27.98 mmol) was added to the solution. The mixture was stirred at room temperature for 20 minutes, refluxed for 1 hour, cooled to room temperature, and acidized with 1N hydrochloric acid. Water (50 mL) was added to the mixture. The mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 657 mg of the desired compound as yellow crystalline product (yield 34%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:32])([F:31])[F:20])=[CH:23][CH:24]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1c2n(c3c(-c4ccc(C(F)(F)F)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (74 mg, 77%), MS (ISP) m/z=384.6 [(M+H)+], mp 252° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: Cl.[Cl:2]C1C=CC(NN)=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22](=O)[C:21]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:20]=3[NH:19]2)=[CH:14][CH:13]=1.N1C=CC(=O)N=1.P(Cl)(Cl)(Cl)=O>>[Cl:2][C:22]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[N:19]=[C:20]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]=12
Reactant: NNc1ccc(Cl)cc1
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCCCC2
Agent: Cl
Agent: O=C1C=CN=N1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-n2nc3c(c2Cl)CCCCC3)cc1

Procedure:
By substituting 2-carbethoxycycloheptanone [prepared by the method of G. Stork, et al., J. Am. Chem. Soc., 85, 207 (1963)] and p-chlorophenylhydrazine hydrochloride (available from Aldrich Chemical Company) in the procedure of Example 1(c), 2-(4-chlorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3(2H)-one (m.p. 224°-225°) was prepared. By reacting this pyrazolone with phosphorous oxychloride according to the procedure of Example 1(d), 3-chloro-2-(4-chlorophenyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole (m.p. 59°-61°) was obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18][C:13]=3[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[F:24][C:25]1[CH:26]=[C:27]([F:35])[C:28]2[CH2:29][C@H:30]3[O:34][C@H:31]3[C:32]=2[CH:33]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[F:35][C:27]1[CH:26]=[C:25]([F:24])[CH:33]=[C:32]2[C:28]=1[CH2:29][C@@H:30]([OH:34])[C@@H:31]2[N:12]1[C:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][C:14]=2[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:22])[F:23])[CH:5]=2)=[N:11]1
Reactant: Fc1cc(F)c2c(c1)[C@@H]1O[C@@H]1C2
Reactant: CC(=O)N1CCc2[nH]nc(-c3cccc(OC(F)(F)F)c3)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3cccc(OC(F)(F)F)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Temperature: 50 °C
Reaction time: 24 h
Yield: 23.3 %

Procedure:
A mixture of 1-[3-(3-trifluoromethoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (3e) (0.461 mmol), 0.44 g, 2.65 mmol), (1aS,6aR)-3,5-difluoro-6,6a-dihydro-1aH-1-oxa-cyclopropa[a]indene (6b) (0.077 g, 0.461 mmol) and K2CO3 (127 mg, 0.922 mmol) in 5 ml CH3CN was stirred at 50° C. for 24 h. Water was added, the mixture was extracted 3 times with CH2Cl2, the combined organic layers were dried over MgSO4, filtrated and the solution was evaporated to dryness. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 53 mg of 1-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-3-(3-trifluoromethoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (11a).
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH2:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[CH:43]=[O:44])[C:37]([OH:39])=O)[CH3:33].[CH2:45]([C:47]1[CH:62]=[C:61]([C:63](=[NH:66])[NH:64]O)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]>>[CH2:45]([C:47]1[CH:62]=[C:61]([C:63]2[N:66]=[C:37]([C:36]3[CH:40]=[CH:41][C:42]([CH:43]=[O:44])=[C:34]([CH2:32][CH3:33])[CH:35]=3)[O:39][N:64]=2)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCc1cc(C(=O)O)ccc1C=O
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)ccc1C=O
Yield: 49.8 %

Procedure:
The title compound (183 mg) is prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 3-ethyl-4-formyl-benzoic acid (140 mg, 0.786 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (256 mg, 0.786 mmol). LC-MS**: tR=0.72 min; [M+1]+=468.25; 1H NMR (D6-DMSO): δ 1.23 (t, J=7.8 Hz, 3H), 1.28 (t, J=7.3 Hz, 3H), 2.36 (s, 3H), 2.70-2.78 (m, 3H), 3.19 (q, J=7.3 Hz, 2H), 3.23-3.29 (m, 1H), 3.40-3.48 (m, 1H), 3.71-3.81 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.94-4.00 (m, 1H), 5.31 (d, J=5.3 Hz, 1H), 5.56 (t, J=5.5 Hz, 1H), 7.71 (t, J=5.8 Hz, 1H), 7.82 (s, 2H), 8.09 (d, J=8.0 Hz, 1H), 8.19-8.24 (m, 2H), 10.38 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])[S:9][CH:10]=1)=[O:5])[CH3:2].C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(SCCCC(=O)OCc2ccccc2)n1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1csc(SCCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (10.7 g) of (55-1) was dissolved in trifluoroacetic acid (30 mL), thioanisole (10.3 mL) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate as an eluent. The solvent was evaporated from the eluent to give the title compound (5.81 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:55]1[C:59](=[O:60])[C:58]2=[CH:61][CH:62]=[CH:63][CH:64]=[C:57]2[C:56]1=[O:65].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C@@H:9]1[CH2:33][O:34][N:55]1[C:56](=[O:65])[C:57]2=[CH:64][CH:63]=[CH:62][CH:61]=[C:58]2[C:59]1=[O:60])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To a solution of (2R,4S)-1-t-butoxycarbonyl-4-tritylthiopyrrolidine-2-methanol (2: 1.37 g: 2.88 mMol.) in tetrahydrofuran (8.6 ml) under ice cooling are added triphenylphosphin (892 mg: 3.40 mMol.), N-hydroxyphthalimide (705 mg: 4.32 mMol.) and azodicarboxylic acid diethyl ester (0.59 ml: 3.74 mMol.), and the mixture is stirred under ice cooling for 90 minutes. The reaction mixture is diluted with ethyl acetate (30 ml) and ice water (30 ml). The organic layer is taken, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give (2R,4S)-1-t-butoxycarbonyl-2-phtalimidooxymethyl-4-tritylthiopyrrolidine (3: 1.73 g). Yield: 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([OH:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([O:15][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1nc(O)nn1-c1ccc(Cl)c(Cl)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc(OCCN2CCCCC2)nn1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ol (0.41 mmol) was dissolved in methanol (150 mL) at room temperature. A solution of potassium carbonate in water (30 mL) was added dropwise until pH 9. After 15 min under stirring a solution of 1-(2 chloroethyl) piperidine hydrochloride (0.62 mmol) in water (100 mL) was added. The reaction was stirred at room temperature overnight. The methanol was evaporated and after extraction with CH2Cl2 the organic layer was dried over MgSO4 then evaporated and finally purified by chromatography in silica gel to give 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy]ethyl}piperidine (0.03 g, yield 20%) as a dark orange oil. H1NMR (300 MHz, CDCl3, 25° C.) δ: 7.53 (d, J=2.4 Hz, 1H); 7.48 (d, J=8.6 Hz, 1H); 7.23 (dd, J=2.4 Hz, 1H); 4.33 (t, J=5.9 Hz, 2H); 2.71 (t, J=5.9 Hz, 2H); 2.44 (t, J=4.9 Hz, 4H); 2.40 (s, 3H); 1.51 (q, J=5.5 Hz, 4H); 1.34 (m, 2H) ppm. EM (ES+) m/z=355 (100%) [M+H]+. C16H20Cl2N4O (355.26) calc. C, 54.09%; H, 5.67%; N, 15.77%. found C, 53.80%; H, 5.72%; N, 15.48%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C@@H:21]([CH2:55][CH2:56]O)[C:22]([NH:24][CH2:25][C@H:26]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]3[CH:48]=[N:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[C:42]([CH3:54])[CH:41]=1)=[N:32][CH:33]=[N:34]2)[CH3:27])=[O:23].C(Br)(Br)(Br)[Br:59]>C(Cl)Cl>[Br:59][CH2:56][CH2:55][C@H:21]([OH:20])[C:22]([NH:24][CH2:25][C@H:26]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]3[CH:48]=[N:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[C:42]([CH3:54])[CH:41]=1)=[N:32][CH:33]=[N:34]2)[CH3:27])=[O:23]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CNC(=O)[C@@H](O)CCO)c34)cc2C)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CNC(=O)[C@@H](O)CCBr)c34)cc2C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Triphenylphosphine (650 mg, 2.5 mmol) was added portion wise over 30 minutes to a solution of (2S)-2,4-dihydroxy-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide (856 mg, 1.65 mmol, obtained as described in Example 112) and carbon tetrabromide (658 mg, 2 mmol) in DCM (10 ml). The mixture was stirred overnight at room temperature. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2% to 5% 7N ammonia-methanol in DCM) to give the title compound (712 mg, 74%) as a solid; NMR Spectrum: (CDCl3) 1.53 (d, 3H), 2.07 (m, 1H), 2.28 (s, 3H), 2.38 (m, 1H), 2.52 (s, 3H), 3.51 (t, 2H), 3.80-3.65 (m, 2H), 4.34 (dd, 1H), 4.95 (m, 1H), 6.90 (m, 2H), 7.09 (d, 1H), 7.14 (dd, 1H), 7.28 (m, 1H), 7.50 (m, 3H), 7.63 (s, 1H), 8.23 (s, 1H), 8.44 (s, 1H); Mass spectrum: MH+ 580, 582.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=[N:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1ccnc2cc(-c3ccc(O)cc3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Yield: 55.9 %

Procedure:
A solution of 90 mg (0.32 mmol) of methyl 7-(4-hydroxyphenyl)-4-quinolinecarboxylate, 196 mg (0.64 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 178 mg (1.29 mmol) of K2CO3 in 2.5 mL DMF was stirred at ambient temperature for 60 hr. EtOAc was added and the mixture washed with three portions of H2O then brine. The solution was concentrated and the residue purified by silica gel chromatography (12 g of silica gel eluting with 0-50% EtOAc in hexanes over 45 minutes) to give 98 mg (56%) of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-quinolinecarboxylate as a clear glass. 1H NMR (400 MHz, CDCl3): δ 9.02 (d, J=4 Hz, 1H), 8.81 (d, J=9 Hz, 1H), 8.29 (s, 1H), 7.88-7.85 (m, 2H), 7.64 (d, J=8 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 7.35-7.32 (m, 1H), 6.91 (d, J=8 Hz, 2H), 4.79 (s, 2H), 4.05 (s, 3H), 3.34 (septet, J=7 Hz, 1H), 1.43 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)[N:19]2[CH2:23]CC[CH2:20]2)C2C=CC=CC=2N=N1.[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)(O)=[O:35].CNC.C(N(CC)CC)C>ClCCl>[CH3:20][N:19]([CH3:23])[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)=[O:35]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 3.5 g, 6.72 mmol) was added to a mixture of 5-carboxy-2-oxindole (1 g, 5.6 mmol), dimethylamine (5.6 mL of 2.0 M in THF, 11.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 3 hours, the reaction was diluted with more dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 480 mg (42%) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([OH:19])[C:11]=1[CH2:20][CH2:21][CH3:22].[Br:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[C:12]([O:19][CH2:27][CH2:26][CH2:25][Br:24])[C:11]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Yield: 98 %

Procedure:
A mixture of 6.0 g of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester, 19 ml of 1,3-dibromopropane and 2.0 g of anhydrous potassium carbonate in 175 ml of anhydrous acetone was stirred at reflux for 52 hours. The reaction mixture was concentrated in vacuo to give 8.1 g (98% yield) of 6-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]hexanoic acid methyl ester as an oil.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[NH2:8][C:9](=[NH:38])[CH2:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[O:28])[C:17]2=[O:35])=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl-].O[NH3+]>C(O)C>[NH2:38][C:9](=[N:8][OH:4])[CH2:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[O:28])[C:17]2=[O:35])=[CH:13][CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N=C(N)Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(Cc1ccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)cc1)=NO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
37 mg (0.07 mmol) of N-{2-[4-(2-amino-2-iminoethyl)benzyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-5-chloro-2-thiophenecarboxamide trifluoroacetate are suspended in 3 ml of ethanol, and 0.09 ml (0.65 mmol) of triethylamine and 22.7 mg (0.33 mmol) of hydroxylammonium chloride are added. The reaction mixture is stirred at room temperature for 5 h and then concentrated. The residue is stirred with water and filtered. This gives 21 mg (69% of theory) of the desired product as a solid.