Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:23][C:24]1[N:25]=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2.C(N(CC)CC)C.ClCCl>C(O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:25]2[C:24](=[O:23])[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)=[CH:26]2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Oc1cc2ccccc2cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-n2cc3ccccc3cc2=O)cc1)C(=O)O
Reaction time: 48 h

Procedure:
The mixture of 98 mg of (2S)-2-[(t-butoxycarbonyl)amino]-3-[4-(dihydroxyboranyl)phenyl]propionic acid, 46 mg of 3-hydroxyisoquinoline, 43 mg of copper acetate (II), 175 μl of triethylamine and 10 ml of dichloromethane was stirred for two days and diluted with ethanol. After Celite filtration, the filtering solvent was concentrated and the obtained residue was diluted with ethyl acetate. After extraction by an aqueous solution of 1N sodium hydroxide, the water phase was acidified by hydrochloric acid. The organic phase was extracted with ethyl acetate. The residue was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate to remove the solvent. The obtained residue was split by HPLC to obtain the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(C(=O)O)c(N)c1
Agent: [BH4-]
Solvent: C1CCOC1
Product: COc1ccc(CO)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-methoxybenzoic acid (15.0 g, 89.8 mmol) in THF (300 mL) was added borohydride in THF (450 mL, 450 mmol) at 0° C., and the reaction mixture was stirred at RT overnight. LCMS showed the reaction was completed. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (500 mL×3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound. MS (ES+) C8H11NO2 requires: 153. Found: 154 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([OH:24])=O.O.[NH2:39][NH2:40]>CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([NH:39][NH2:40])=[O:24]
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) was added to a solution of 3-(2-chloro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid from above (40 mg, 0.09 mmol) in DMSO (1 mL), and stirred overnight at 60° C. Hydrazine hydrate (13 mg, 0.27 mmol) was added, and the reaction solution was stirred for an additional 4 h at 60° C. The reaction solution was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 70% EtOAc in hexanes to afford the desired product (17 mg, 41%). LC-MS (M+H=483, obsd.=438).
Reaction SMILES: C(OC(=O)[N:10]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:14]([N:24]([C:26](=[O:44])[C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)([CH3:29])[CH3:28])[CH3:25])=[CH:13][N:12]=1)C1C=CC=CC=1>CO.CN(C)C=O.[Pd]>[CH2:45]([NH:10][C:11]1[N:12]=[CH:13][C:14]([N:24]([CH3:25])[C:26](=[O:44])[C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:31]=2)([CH3:29])[CH3:28])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH:16]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Cc1ccccc1-c1cc(N(Cc2ccccc2)C(=O)OCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc(NCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 973 mg (1.35 mmol) benzyl-(5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-carbamic acid benzyl ester in 13 ml methanol and 1 ml N,N-dimethylformamide was added 40 mg 10% palladium on activated charcoal and the mixture was hydrogenated (room temperature, 1 bar) for 1 h. Filtration of the catalyst and evaporation of the filtrate afforded 795 mg (quantitative) of the title compound as a yellow oil. MS m/e (%): 586 (M+H+, 100).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][O:7][C:5]1=[O:6])(=O)[CH3:2].[OH-].[Na+].O.[CH:13]1(C=O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH:2]1([CH:1]=[C:4]2[CH2:9][CH2:8][O:7][C:5]2=[O:6])[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)C1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCCC1=CC1CCCCC1
Temperature: 25 °C
Yield: 21 %

Procedure:
A solution of 2-acetyl-γ-butyrolactone (15.4 g) in toluene (100 mL) was treated portionwise with sodium hydroxide (4.8 g) during 10 min and then refluxed with a Dean & Stark moisture receiver until the formation of water had stopped (about 1 h). After that the reaction mixture was treated dropwise with cyclohexanecarbaldehyde (15.0 g) during 1 h. Upon completion of the addition, the mixture was refluxed for 4 h, then cooled to room temperature and washed with water. After drying over magnesium sulfate, the obtained organic phase was filtered, concentrated on a rotary evaporator and distilled in vacuum to give 4.54 g (21%) of the title compound.
Reaction SMILES: [C:1]([N:4]([C:12]1[N:13]=[C:14]([C:18]2[CH:19]=[N:20][C:21]([NH:28][C:29]3[CH:37]=[CH:36][C:32]4[N:33]=[CH:34][S:35][C:31]=4[CH:30]=3)=[CH:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[O:15][C:16]=1[CH3:17])C(=O)OC(C)(C)C)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:35]1[C:31]2[CH:30]=[C:29]([NH:28][C:21]3[N:20]=[CH:19][C:18]([C:14]4[O:15][C:16]([CH3:17])=[C:12]([NH:4][C:1](=[O:3])[CH3:2])[N:13]=4)=[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])[CH:22]=3)[CH:37]=[CH:36][C:32]=2[N:33]=[CH:34]1
Reactant: CC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl acetyl(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)carbamate (35) (30 mg, 0.057 mmol) in DCM (5 mL) was treated with TFA (0.230 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated and azeotroped with chloroform three times to obtain gummy solid. The crude material obtained was purified by prep HPLC to furnish N-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)acetamide. 1H NMR: 400 MHz, CD3OD: δ 1.33 (d, J=6.40 Hz, 6H), 2.16 (s, 3H), 2.35 (s, 3H), 3.73-3.79 (m, 1H), 6.14 (s, 1H), 7.52 (dd, J=2.40, 8.80 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.38 (d, J=2.00 Hz, 1H), 8.49 (s, 1H), 9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min; retention time: 1.823 min; LCMS (ES-API), m/z 423.2 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.484 min; Purity: 95.1%.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.NC(N)=[S:13].[CH2:15]([O:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24](Br)[C:23]=2[N:22]=[CH:21][C:20]=1[CH3:30])[CH:16]=[CH2:17].[OH-].[Na+]>O.C(O)C>[CH2:15]([O:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([S:13][C:2]3[NH:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[C:23]=2[N:22]=[CH:21][C:20]=1[CH3:30])[CH:16]=[CH2:17]
Reactant: C=CCOc1c(C)cnc2c1CCCC2Br
Reactant: NC(N)=S
Reactant: Clc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1c(C)cnc2c1CCCC2Sc1nc2ccccc2[nH]1

Procedure:
0.46 Gram of 2-chlorobenzimidazole, 0.2 g of thiourea and 10 ml of ethanol were mixed together and the mixture was refluxed for 2 hours. To this reaction mixture was added 0.62 g of 4-allyloxy-8-bromo-3-methyl-5,6,7,8-tetrahydroquinoline and 0.3 g of sodium hydroxide, then the whole reaction mixture was refluxed for 5 hours. After the reaction was completed, ethanol was removed by evaporation, and to the residue thus obtained was added water and then extracted with chloroform, and the chloroform extract was dried with anhydrous magnesium sulfate, and the chloroform was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: methylene chloride/methanol=100/1) to obtain 0.5 g of 4-allyloxy-8-(2-benzimidazolyl)thio-3-methyl-5,6,7,8-tetrahydroquinoline in the form of light brown oily substance.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].O>O1CCCC1.O.CO>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:3]([OH:19])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cccc(C(CC2CCCC2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
A solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid methyl ester (1.39 g, 5.29 mmol) in tetrahydrofuran/water/methanol (13.2 mL, 3:1:1) at 25° C. was treated with a 2N aqueous sodium hydroxide solution (3.97 mL, 7.94 mmol). The reaction was stirred at 25° C. for 48 h. At this time, the reaction mixture was poured into water (50 mL) and extracted with chloroform (3×25 mL). The aqueous layer was acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The aqueous layer was extracted with a solution of chloroform/methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate with glacial acetic acid) afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid (1.05 g, 79.8%) as a clear wax: EI-HRMS m/e calcd for C15H20O3 (M+) 248.1412, found 248.1409.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][C@@H:12]([CH:14]([CH2:16][CH3:17])[CH3:15])[CH2:11][S:10]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:12]([CH:14]([CH2:16][CH3:17])[CH3:15])[CH2:11][S:10]2)=[CH:4][C:3]=1[C:18]([F:19])([F:21])[F:20]
Reactant: CC(C)CBr
Reactant: CCC(C)[C@H]1CSC(=Nc2ccc(Cl)c(C(F)(F)F)c2)N1
Product: CCC(C)[C@H]1CSC(=Nc2ccc(Cl)c(C(F)(F)F)c2)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Chloro-3-(trifluoromethyl)aniline was converted to 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate according to Method A2a, Step 3 4-Chloro-3-(trifluoromethyl)phenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-chloro-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(4-chloro-3-(trifluoromethyl)phenylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1C=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][N:33]=1.BrC1[N:48](C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:35]4[C:36]([O:38][CH3:39])=[N:48][C:32]([O:31][CH3:30])=[N:33][CH:34]=4)=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[N:16]([CH3:22])[CH:15]=2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Reactant: Cc1cc(=O)n(C)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Reactant: COc1cc(OC)c(B(O)O)cn1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cn(C)c(=O)cc2C)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-6-(4-chloro-phenyl)-5-(1,4-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AC) and 2,4-dimethoxypyridine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white solid. tR=2.94 min (HPLC 5); ESI-MS: tR=0.98 min, [M+H]+ 534/536 (LC-MS 1)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]([CH3:32])[CH2:27][CH2:28][CH2:29][NH:30][CH3:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]([CH2:29][CH2:28][CH2:27][N:26]([CH3:32])[CH3:25])[CH3:31])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CNCCCN(C)C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CCCN(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N1,N1,N3-trimethylpropane-1,3-diamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (br. s., 2 H) 2.43 (s, 3 H) 2.68-2.95 (m, 7 H) 3.00 (s, 3 H) 3.13 (br. s., 1 H) 3.23-3.61 (m, 2 H) 7.60-7.89 (m, 3 H) 7.99-8.82 (m, 4 H) 9.53 (br. s., 1 H) 12.69-13.62 (m, 1 H). ESI-MS m/z [M+H]+ 419.3.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]3[C:11](=[CH:12][N:13]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:14]=3)[CH:10]=2)[NH:5][CH:6]=1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[C:4]1[CH:7]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:8][C:9]1[CH:17]=[C:16]([CH3:18])[C:15]2[C:11](=[CH:12][N:13]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[N:14]=2)[CH:10]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1c[nH]c(C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(Cc2cccc(F)c2)c(C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 1-(4-methyl-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (38.4 mg, 0.079 mmol), 3-fluoro benzylbromide (10.8 μL, 0.083 mmol, 1.05 equiv), and potassium carbonate (22.0 mg, 0.16 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 31.0 mg (64%). 1H-NMR (CD3OD, 300 MHz) δ −0.02 (s, 9H), 0.87-0.98 (m, 2H), 1.31 (s, 9H), 2.23 (s, 3H), 2.47 (s, 3H), 3.08-3.18 (m, 2H), 3.56-3.71 (m, 2H), 4.89-5.13 (m, 3H), 5.72 (s, 1H), 6.83-7.14 (m, 2H), 7.21 (s, 1H), 8.20 (s, 1H). Mass spec.: 594.47 (MH)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([C:24](=[O:45])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:26]=1OC1CCCC1)[C:19]([O:21]CC)=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][CH2:16][CH2:17][C:18]1[C:19](=[O:20])[O:21][C:26]2[C:25]([C:24]=1[OH:45])=[CH:30][CH:29]=[C:28]([O:31][CH3:32])[C:27]=2[O:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)c1ccc(OC)c(OC2CCCC2)c1OC1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(O)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1

Procedure:
Trifluoroacetic acid (35 mL) was added dropwise to a solution of ethyl 4-(benzyloxy)-2-(2,3-bis(cyclopentyloxy)-4-methoxybenzoyl)butanoate (14 g, 25 mmol) and dichloromethane (280 mL) at rt. The reaction was maintained overnight, diluted with dichloromethane (200 mL), and washed with sat'd NaHCO3 (200 mL×2) and then brine (200 mL). The organic layer was dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate:petroleum ether) to give 3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one: MS (ESI): 411.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@H:14]1[C@@H:17]([NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16](=[O:29])[NH:15]1.C(O)(=O)C(C)O.CCCCCC>N1C=CC=CC=1.C(OCC)(=O)C>[O:29]=[C:16]1[NH:15][C@@H:14]([CH2:13][O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C@H:17]1[NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CO
Agent: CC(O)C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)COc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4.30 g (0.022 mole) of 98% p-toluenesulfonyl chloride in 24 ml of anhydrous pyridine at 0° (ice bath) was added 2.64 g (0.011 mole) of cis-2-hydroxymethyl-4-oxo-3-phenoxyacetylaminoazetidine in one portion. The solution was stirred at 0° for 3 hours then was stored at -25° overnight. After warming to 0°, 1.0 ml of 85% lactic acid was added and stirring was continued for 1 hour. The reaction mixture was poured into ethyl acetate and extracted successively with water, dilute aqueous hydrochloric acid, aqueous sodium bicarbonate and brine and was dried (MgSO4). Filtration followed by removal of the solvent in vacuo resulted in a yellow solid. Clarification of a hot solution of this material in ethyl acetate (375 ml), followed by the addition of hexane (200 ml) and recrystallization afforded cis-4-oxo-3-phenoxyacetylamino-2-p-toluenesulfonyloxymethyl-azetidine; tlc: ethyl acetate, silica gel GF, Rf = 0.47; mp 136°(dec.).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2)([CH3:3])[CH3:2].[CH:15]1[C:20]([NH:21][NH2:22])=[CH:19][CH:18]=[C:17]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:16]=1.Cl>>[CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:22][NH:21][C:20]1[CH:19]=[CH:18][C:17]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:16][CH:15]=1)[C:7](=[O:13])[NH:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc2c1C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CC(C)c1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 73 %

Procedure:
The title compound was prepared from 4-isopropyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 73% yield: 1H NMR (DMSO-d6): δ 1.30 (d, J=6.7 Hz, 6H), 3.82 (septet, J=6.7 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.24 (s, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H). 11.10 (s, 1H), 13.05 (s, 1H); APCI−MS m/z 357 (M−1)−. Anal. Calcd for C17H18N4O3S: C, 56.97, H, 5.06; N, 15.63; S. 8.95. Found C, 56.88, H, 5.12; N, 15.73; S, 8.91.
Reaction SMILES: C[O-].[Na+].Cl[CH2:5][C:6]1([CH2:9][Cl:10])[CH2:8][O:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>C(#N)C>[Cl:10][CH2:9][C:6]1([CH2:5][S:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH2:8][O:7]1
Reactant: Sc1ccc(Cl)cc1
Reactant: ClCC1(CCl)CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: ClCC1(CSc2ccc(Cl)cc2)CO1
Reaction time: 4 h
Yield: 73 %

Procedure:
5.4 g (0.1 mole) of sodium methylate are introduced in portions into a mixture of 16.9 g (0.12 mole) of 2,2-di(chloromethyl)-oxirane and 14.5 g (0.1 mole) of 4-chlorothiophenol in 200 ml of acetonitrile. The reaction mixture is subsequently stirred for 4 hours and filtered and the filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride and the solution is washed with water, dried over sodium sulphate and concentrated. The oil which remains is distilled. 18.2 g (73% of theory) of 2-chloromethyl-2-(4-chlorophenylthiomethyl)-oxirane of refractive index nD20 1.5895 are obtained.
Reaction SMILES: [Na].[CH:2]([OH:5])([CH3:4])[CH3:3].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:5][CH:2]([CH3:4])[CH3:3]
Reactant: BrCCCCCCBr
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)OCCCCCCBr
Reaction time: 16 h

Procedure:
1.15 g (0.05 mol) of finely cut sodium are added to 30 g (0.5 mol) of absolute isopropanol in an atmosphere of nitrogen; the mixture is stirred at 60° for 16 hours in order to dissolve the sodium completely. After cooling to 20°, 12.2 g (0.05 mol) of 1,6-dibromohexane are added and the mixture is stirred at reflux temperature for 18 hours. The precipitated sodium bromide is filtered off, the excess isopropanol is removed and the filtrate is distilled under vacuum. The main fraction (6.0 g), having a B.P. of 96°-98°/15 mm, is chromatographed on 300 g of silica gel with hexane/ethyl acetate (99:1), whereby 1-bromo-6-isopropoxy-hexane is obtained as a colourless oil.