Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:42]([CH3:43])=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:54][NH2:55]>C(O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:35]([CH3:44])=[CH:36][C:37]([C:38]([NH:54][NH2:55])=[O:40])=[CH:41][C:42]=5[CH3:43])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: NN
Reactant: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CCO
Product: COc1ncc(-c2c(C)cc(C(=O)NN)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (EXAMPLE 34 Step A, 0.051 g, 0.067 mmol) was dissolved in ethanol (0.45 mL). Added hydrazine (0.063 mL, 2.014 mmol) and stirred at 85° C. in a screw cap vial (pressure relief type) under a nitrogen blanket. Once complete, the solvent was removed by rotary evaporation and the crude isolate was partitioned between ethyl acetate and water. Washed the organic twice more with water, then once with brine, dried over sodium sulfate, filtered and evaporated to give an off-white foam as the product. The compound was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.16 (s, 1H), 8.00 (d, 1H), 7.88 (s, 1H), 7.73 (s, 2H), 7.49 (s, 2H), 7.35 (s, 1H), 7.26 (d+s, 1H+CHCl3), 5.66 (d, 1H), 4.71 (d, 1H), 4.33 (m, 1H), 4.10 (m, 1H), 4.00 (s, 3H), 3.85 (m, 4H), 3.80 (m, 4H), 2.15 (s, 3H), 2.13 (s, 3H), 1.60 (br, 2H), 0.72 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)=[O:18].[CH3:25][C:26](C)=[O:27]>>[C:26]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)=[O:18])(=[O:27])[CH3:25]
Reactant: CCOC(=O)n1c(C(=O)c2cnccn2)c(N)c2ccc(Cl)cc21
Reactant: CC(C)=O
Product: CCOC(=O)n1c(C(=O)c2cnccn2)c(NC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-1-(ethoxycarbonyl)-2-(pyrazine-2-carbonyl)indole (step 1). tlc: Rf=0.4 (50% acetone in hexanes)
Reaction SMILES: [Mg].II.F[C:5]1C=C(Br)C=CC=1OC(F)(F)F.[CH3:17][O:18][C:19](=[O:27])[CH:20]([N:22]1[N:26]=[N:25][CH:24]=[N:23]1)[CH3:21].Cl>O1CCCC1.O>[CH2:17]([O:18][C:19](=[O:27])[CH:20]([N:22]1[N:26]=[N:25][CH:24]=[N:23]1)[CH3:21])[CH3:5]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: COC(=O)C(C)n1ncnn1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)n1ncnn1
Yield: 43.5 %

Procedure:
Magnesium turnings (1.22 g) and iodine (1 crystal) were added to dry tetrahydrofuran (10 ml) under a nitrogen atmosphere. A solution of 3-fluoro-4-trifluoromethoxybromobenzene (12.95 g) in dry tetrahydrofuran (30 ml) was placed in a dropping funnel. About 10% of this was added to the mixture, and the Grignard reaction began immediately. The rest of the mixture was added dropwise with stirring, and the temperature rose until the solvent was at reflux. After the addition was complete the mixture was allowed to cool, then a solution of methyl-2-(2H-tetrazol-2-yl)propionate (3.9 g) in dry tetrahydrofuran (10 ml) was added with stirring. An exotherm was noted, and the reaction was allowed to stir at room temperature for 30 minutes. The mixture was then poured into water (100 ml). The mixture was acidified by adding 3M hydrochloric acid (100 ml) and then extracted with diethyl ether (3×100 ml). The combined ethereal extracts were dried over anhydrous sodium sulphate and evaporated to a brown oil (10 g). This was chromatographed on silica gel eluting with 4:1 hexane/ethylacetate to give an oil (1.85 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CC(=O)C(C)(C)CSc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
97 g (0.4 mol) of 1-(4-chlorophenylmercapto)-2,2-dimethyl-butan-3-one were dissolved in 400 ml of carbon tetrachloride, and 64 g (0.4 mol) of bromine were added dropwise in the course of 30 minutes. The mixture was subsequently stirred at room temperature for 1 hour and was then concentrated by distilling off the solvent. 127 g (99% of theory) of crude 1-bromo-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one were obtained as a yellowish oil, which was further reacted directly.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([Br:12])[C:3]=1O.CCN(CC)CC.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Na+].[I-:37]>C(Cl)Cl.CN(C=O)C.CCOCC>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([Br:12])[C:3]=1[I:37]
Reactant: [I-]
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(O)c1Br
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c([N+](=O)[O-])cc(Br)c(I)c1Br
Temperature: 20 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a stirred solution of 2,6-dibromo-3-methyl-4-nitrophenol (2 g, 6.43 mmol) in CH2Cl2 (20 mL) at 0° C. was added Et3N (1.34 mL, 9.5 mmol) followed by dropwise addition of Tf2O (1.2 mL, 7 mmol). After warming to 20° C. and stirring 2 hr, the reaction was quenched with H2O . The organic layer was washed 1× with H2O and brine before drying over MgSO4. Without further purification, the resulting black oil, obtained after removal of the volatiles under vacuum, along with NaI (2 g, 13 mmol) was heated at 100° C. in DMF (15 mL) for 16 hr. Upon cooling, the reaction was diluted with Et2O, washed 2× with H2O and once with brine. After drying over MgSO4, the residue, obtained after removal of the volatiles under vacuum, was chromatographed on silica gel using 2-5% EtOAc/hexane as an eluent to yield 1.38 g of 3,5-dibromo-4-iodo-2-methylnitrobenzene (50%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:15]1COCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C@@H:5]1[CH2:15][C@H:6]1[C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
To a solution of E-3-(4-bromo-phenyl)-acrylic acid ethyl ester and Pd(OAc)2 (0.05 eq.) in THF (0.2M) was added portionwise CH2N2 until the reaction was completed. NMR of aliquots monitored the reaction. The resulting mixture was concentrated and filtered on celite to afford the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][CH3:34])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.Cl.C([O:39][C:40]1[C:45]([O:46]C(=O)C)=[CH:44][N:43]=[C:42]([C:50](Cl)=[O:51])[CH:41]=1)(=O)C.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][CH3:34])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][N:22]([C:50]([C:42]5[CH:41]=[C:40]([OH:39])[C:45]([OH:46])=[CH:44][N:43]=5)=[O:51])[CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(=O)Oc1cnc(C(=O)Cl)cc1OC(C)=O
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (255 mg) in a mixture of water (5 ml) and acetone (5 ml) was added 4,5-diacetoxy-2-pyridinecarbonyl chloride hydrochloride (309 mg), with maintaining the pH of the solution to 8.0-8.5 by addition of saturated aqueous sodium bicarbonate. After stirring for 30 minutes, acetone was removed by evaporation in vacuo and the residue was adjusted to pH 8 and stirred for 2 hours. The mixture was adjusted to pH 3.0 with 1N hydrochloric acid and chromatographed on Diaion HP-20 (50 ml), and the elution was carried out with 10% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (155 mg).
Reaction SMILES: [NH:1]([C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C@H:2]([C:28]([N:30]([CH3:60])[C@H:31]([C:47]([NH:49][CH2:50][CH2:51]OCC1C=CC=CC=1)=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)=[O:29])[CH2:3][C:4]1[N:8]=[CH:7][N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=1.C(O)(C(F)(F)F)=O.C(OCC)C.[CH3:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88]>C(Cl)Cl>[CH2:64]([O:63][C:61](=[O:62])[NH:1][CH:2]([C:28](=[O:29])[N:30]([CH:31]([C:47](=[O:48])[NH:49][CH2:50][CH2:51][C:85]1[CH:84]=[CH:83][CH:88]=[CH:87][CH:86]=1)[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[CH3:60])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: CN(C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCOCc1ccccc1
Reactant: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)C(Cc1c[nH]cn1)NC(=O)OCc1ccccc1)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cbz-His(Trt)-NMe-Tyr(OBn)-NH—CH2—CH2-OBn (from Step 3, 0.5 g, 0.55 mmol) was treated with 50 mL of 50% TFA in methylene chloride. The solution was stirred at room temperature for 2 hours. The solvent was reduced in volume and diethyl ether/hexane (200 mL) was added to the residue. The solution was cooled to −40° C. overnight. The ether/hexane was decanted and the residue dried in vacuo. Purification was carried out by reverse-phase preparative HPLC (C-18) reverse-phase column, 20% to 60% of 0.1% TFA in acetonitrile against 0.1% TFA in water, 100 minutes, 13 mL/min) to give 37.5 mg of a white foam; MS-ES 661 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[C:11]1([Si:17]2(CCCCC)[CH2:22][CH2:21][CH:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)C=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:11]([Si@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)=[O:28])=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: Oc1cc(F)c(F)c(F)c1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3cc(F)c(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4,5-trifluorophenol and 4-(4-phenyl-4-n-pentyl-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].C(=O)(O)[O-].[Na+]>ClCCl>[Br:41][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)COc1ccc(CCO)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(CCBr)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)-2-(trifluoromethyl)phenoxy]acetate (224 mg) in dichloromethane (2 ml) were added triphenylphosphine (260 mg) and carbon tetrabromide (396 mg), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent:dichloro-methane/hexane=1/1) gave ethyl 2-[4-(2-bromoethyl)-2-(trifluoromethyl)phenoxy]acetate (178 mg).
Reaction SMILES: C(O[C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])=O)(C)(C)C.CCO.[CH3:22][O:23][C:24](=[O:33])/[C:25](=C\N(C)C)/[C:26](=O)[CH3:27]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:22][O:23][C:24]([C:25]1[CH:6]=[N:8][N:9]([CH2:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[OH:18])[C:26]=1[CH3:27])=[O:33]
Reactant: COC(=O)/C(=C\N(C)C)C(C)=O
Reactant: CC(C)(C)OC(=O)NNCc1cc(Br)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1cnn(Cc2cc(Br)ccc2O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
A suspension of N′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acid tert-butyl ester 1 2 g (6.3 mmol) in a mixture of CH2Cl2 (8 mL) and TFA (8 mL) was stirred at RT for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in abs. EtOH (7 mL) and added to 2-[1-Dimethylamino-meth-(Z)-ylidene]-3-oxo-butyric acid methyl ester (12 mmol) at RT. The resulting mixture was stirred at RT for 1 hour, refluxed for 2 h, let cool down and stirred at RT for 16 h. The oily residue obtained after removing the volatiles in vacuo was purified by MPLC (10 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) to give 0.38 g of 1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester, 5 and 1-(5-Bromo-2-hydroxy-benzyl)-3-methyl-1H-pyrazole-4-carboxylic acid methyl ester 6 as a mixture.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:18][CH:19]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(=O)cc(C)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccccc3C#N)cc2)cc(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
369 mg of 2,6-dimethyl-4(1H)-pyridone was dissolved in 5 ml of N,N-dimethylformamide. To this solution was added 144 mg of 60% sodium hydride, followed by stirring at room temperature for 15 minutes. Subsequently, 900 mg of 4-bromomethyl-2'-cyanobiphenyl was added to the mixture, and the mixture was stirred at room temperature for two hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, to which was added ethyl acetate. The precipitated crystals were collected by filtration and then dried, and, on the other hand, the filtrate was purified by a silica gel column chromatography (80 g, chloroform:ethyl acetate=3:1 to 2:3), whereby 296 mg and 329 mg of 2,6-dimethyl-4-(2'-cyanobiphenyl-4-yl)methoxypyridine were obtained, respectively (total amount: 625 mg, yield: 66%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:56])=[N:14][C:15]2[N:16]([N:50]=[C:51]([C:53](O)=[O:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OC(C)C)=O.C1(C)C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:56])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH2:53][OH:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CO)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a stirred solution of 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (900 mg, 1.143 mmol) and Et3N (0.207 mL, 1.487 mmol) in THF (20 mL) was added 1M isopropyl chloroformate/toluene (1.487 mL, 1.487 mmol) at 0° C. After 1 h, a solution of NaBH4 (216 mg, 5.72 mmol) in cold water (20 mL) was added at once and stirred for additional 1 h at 0° C. Then the reaction was quenched with MeOH (1 mL), diluted with Et2O (100 mL), washed with water (2×50 mL) and brine (25 mL). The organic layer dried (Na2SO4), filtered and concentrate. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (580 mg, 0.750 mmol, 65.6% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.74-7.70 (m, 4H), 7.46-7.35 (m, 6H), 6.48 (s, 1H), 5.90 (br. s., 1H), 4.91-4.83 (m, 2H), 4.29-4.11 (m, 2H), 3.94-3.84 (m, 1H), 3.41-3.29 (m, 3H), 2.61 (s, 3H), 2.17 (q, J=5.8 Hz, 1H), 1.94-1.87 (m, 2H), 1.87 (br. s., 1H), 1.66 (br. s., 1H), 1.59 (s, 3H), 1.58-1.40 (m, 5H), 1.33-1.26 (m, 3H), 1.26-1.21 (m, 12H), 1.09 (d, J=6.1 Hz, 3H), 1.07 (s, 9H). LCMS (M+H)=773.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[CH2:16][CH2:17][S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:31]O>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][C:6]2[CH2:7][C:8](=[O:26])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:25])[CH2:16][CH2:17][S:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: OO
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCSc1ccccc1)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCS(=O)c1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-(2-phenylthioethyl)-methylamine and hydrogen peroxide analogously to Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:15])=[C:10]([C:12]([OH:14])=O)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:27][O:28][C:29](=[O:51])[C@@H:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH:31]([CH3:33])[CH3:32]>N1C=CC=CC=1>[CH3:27][O:28][C:29](=[O:51])[C@@H:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[C:9]=3[CH3:15])=[O:14])=[CH:48][CH:49]=2)=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: COc1cccc2oc(C(=O)O)c(C)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To 110 mg (0.53 mmol) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 2 mL of oxalyl chloride and the resulting mixture was refluxed for 4 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 232 mg (0.64 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 95 mg (33% yield) of (S)-2-{4′-[(4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as off white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:26][CH2:25][CH2:24][N:23]([C:27](OC(C)(C)C)=O)[CH2:22]5)=[N:17]4)[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:36]=1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:36]=1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:18]2[CH:19]=[CH:20][N:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[NH:9][N:8]=[C:7]4[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:17]=2)[CH2:22]1
Reactant: COc1cccc(F)c1C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccn(-c3ccc4[nH]nc(-c5ccncc5)c4c3)n2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(F)c1CN1CCCC(c2ccn(-c3ccc4[nH]nc(-c5ccncc5)c4c3)n2)C1
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To tert-butyl 3-(1-(3-(pyridin-4-yl)-1H-indazol-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (30 mg, 0.09 mmol) in THF (2 mL) were added 2-fluoro-6-methoxybenzaldehyde (20 mg, 0.13 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol). After 3 h, the reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc. After concentration, crude mixture was column purified with mixture of methanol, dichloromethane and ammonia to give 5-(3-(1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl)-1H-pyrazol-1-yl)-3-(pyridin-4-yl)-1H-indazole (37 mg).
Reaction SMILES: [CH3:1][C:2](C)=O.[F:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:17])[C:14]=2[F:16])[CH:9]=[CH:8][C:7]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].C(I)C>C1(C)C=CC=CC=1>[CH2:1]([O:18][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[C:14]([F:16])[C:13]([F:17])=[CH:12][CH:11]=2)[C:6]=1[F:5])[CH3:2]
Reactant: CC(C)=O
Reactant: Oc1ccc2ccc(F)c(F)c2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: Cc1ccccc1
Product: CCOc1ccc2ccc(F)c(F)c2c1F

Procedure:
An acetone (80 ml) solution of 1,7,8-trifluoro-2-naphthol (15 g), potassium carbonate (16 g), and ethyl iodide (26 g) was stirred for 10 hours at room temperature. Toluene (200 ml) was added in this reaction solution. The organic layer was removed, and the aqueous layer was extracted with toluene. The organic layers were combined, washed with brine, and concentrated. The residue was evaporated under reduced pressure, and 2-ethoxy-1,7,8-trifluoronaphthalene was obtained.