Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[C:10]([Br:25])=[C:9]1[C:26]1[C:27]2[S:40][CH:39]=[CH:38][C:28]=2[N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([Br:25])=[C:9]1[C:26]1[C:27]2[S:40][CH:39]=[CH:38][C:28]=2[N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2c(Br)c3ccc(O[Si](C)(C)C(C)(C)C)cc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2c(Br)c3ccc(O)cc3n2C(=O)OC(C)(C)C)c2sccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0.8 %

Procedure:
To a solution of 3-bromo-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester [0.32 g, 49 mmol, Intermediate (64)] in tetrahydrofuran at 0° C. was added a 1.0 M TBAF solution in tetrahydrofuran (0.51 mL, 0.51 mmol). The resulting solution was stirred at 0° C. for 30 minutes. The solvent was removed. The residue was chromatographed through silica gel (dichloromethane/ethyl acetate, 95/05 as eluant) to produce 3-bromo-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [0.22 g, 83%, Intermediate (65)] as an orange foam.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)O1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].O.[OH-].[Na+].Cl>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:41]=[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])=[CH:13][CH:14]=2)=[CH:30][CH:31]=1)[CH2:36][CH2:37][C:38]([OH:40])=[O:39]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Reaction time: 24 h

Procedure:
Heat in a sealed tube with stirring propane-2-sulfonic acid{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (0.5 mmol), 4-(4-Bromo-phenyl)-4-oxo-butyric acid (0.75 mmol), 2M Na2CO3 water solution (0.2 mL) and Pd(PPh3)4 (0.05 mmol) in 4.0 ml of an anhydrous DME to 100° C. for 24 h. Evaporate and purify the filtrate by flash chromotography (Silica gel-hexane/EtOAc). Add NaOH 2M (1 ml) to a suspension of the resultant ester (0.128 mmol) in ethanol (1 ml) and stir 24 h. Add 6N HCl until pH is approximately 1 and a white solid precipitates. Filter the solid to provide the title compound. MS (ES−): 456 (M−1).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[C:8]3[N:13]([C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.C1C(=O)N([Br:21])C(=O)C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:21][C:7]1[C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12]2
Reactant: c1cnc2cc3n(c2c1)CCCC3
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1c2n(c3cccnc13)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a solution of 6,7,8,9-tetrahydropyrido[2,3-b]indolizine (170 mg) in DMF (3 mL) was added NBS (193 mg) at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was added saturated NaHCO3 aqueous solution at 0° C. and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (217 mg).
Reaction SMILES: C(O[N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[CH:29]([CH2:38][C:39]([O:41]C)=[O:40])[CH2:28]2)=[CH:22][CH:21]=1)[C:7]([CH:9]=[N:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:8])(C)(C)C.[OH-].[Na+].Cl>CO>[C:15]([O:14][C:12]([NH:11][N:10]=[CH:9][C:7]([NH:6][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[CH:29]([CH2:38][C:39]([OH:41])=[O:40])[CH2:28]2)=[CH:22][CH:21]=1)=[O:8])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)CC1CN(Cc2ccc(CN(OC(C)(C)C)C(=O)C=NNC(=O)OC(C)(C)C)cc2)CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NN=CC(=O)NCc1ccc(CN2CCc3ccccc3C(CC(=O)O)C2)cc1
Reaction time: 18 h

Procedure:
To a stirring solution Methyl 2-[3-({4-[((tert-butoxy)-N-{[(tert-butoxy)carbonylamino]iminomethyl}carbonylamino)methyl]phenyl}methyl)-1H,2H,4H,5H-benzo[d]azepinyl]acetate in methanol (0.1 M) was added 1N NaOH (3 eq). After 18 hrs, the reaction was neutralized with 10% HCl, concentrated by rotary evaporation and purified by recrystalization from 2% MeOH/CH2Cl2. EI-MS m/z 466.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cccc(N)c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(N)c2)c1
Reaction time: 24 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl {3-[(3-aminophenyl)ethynyl]phenyl}carbamate (0.5 g, 2.0 mmol) in methanol (10 mL) was added 10% palladium on carbon (0.50 g, 0.43 mmol) and the mixture was stirred under an atmosphere of hydrogen for 24 h. The reaction mixture was filtered through a pad of celite, rinsed with methanol and dichloromethane. The solvents were evaporated to give a crude oil. This material was purified by flash column chromatography to yield the desired product (430 mg, 85%). LCMS for C19H25N2O2(M+H)+: m/z=313.2.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:48]=[CH:47][C:25]([O:26][C:27]([CH3:46])([CH3:45])[CH:28]([OH:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]([CH3:46])([CH3:45])[C:28](=[O:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:47][CH:48]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(OCC(O)C(C)(C)Oc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(OCC(=O)C(C)(C)Oc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
A solution of (2R and 2S)-3-[4-[3-(tert-butyldiphenysilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanol (0.60 g, 0.89 mmol) in dry dichloromethane (30 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (1.50 g, 3.57 mmol) and the resulting mixture was stirred at 22° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% sodium thiosulfate, saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the organic phase was concentrated and chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (98:2) gave 0.587 g (98%) of the title material as a clear oil.
Reaction SMILES: Br[C:2]1[N:3]2[C:8]3[N:9]4[CH2:37][CH2:36][C:12]([CH3:38])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:35])[O:19][C:20]5[CH:21]=[CH:22][C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[C:5]([Cl:50])=[C:6]([CH3:49])[C:7]=3[C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[CH:29]=[CH:28][CH:27]=5)[CH2:11][CH2:10]4.C(O)CCC.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:45]([O:44][C@@H:39]([C:7]1[C:6]([CH3:49])=[C:5]([Cl:50])[C:4]2=[N:32][C:31]3=[CH:2][N:3]2[C:8]=1[N:9]1[CH2:10][CH2:11][C:12]([CH3:38])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:35])[O:19][C:20]2[CH:21]=[CH:22][C:23]([F:34])=[CH:24][C:25]=2[C:26]2[CH:33]=[C:30]3[CH:29]=[CH:28][CH:27]=2)[CH2:36][CH2:37]1)[C:40]([O:42][CH3:43])=[O:41])([CH3:48])([CH3:46])[CH3:47]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Cl)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Cl)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Methyl(2S)-2-[(22S)-8-bromo-5-chloro-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate (45 mg, 0.058 mmol, 1 equiv), 1-butanol (17.30 mg, 0.233 mmol, 4 equiv) were mixed in DMF (1.1 mL) and water (0.11 mL). To this solution was added Pd(OAc)2 (13.10 mg, 0.058 mmol, 1.0 equiv), Sphos (48 mg, 0.12 mmol, 2 equiv) and cesium carbonate (28.5 mg, 0.088 mmol, 1.5 equiv). The solution was degassed by N2 for five minutes. Then it was stirred at 80° C. for 2 hours. The mixture was loaded onto 12 g ISCO column and purified by 0-100% Ethyl Acetate[2% TEA]/Hexane to provide the product (25 mg, 61.9%) as a brown oil. LCMS (ESI, M+1): 692.3
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[C:6]([NH:30][C:31](=[O:33])[CH3:32])([CH2:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:29])[C:7](OC)=[O:8]>C1COCC1>[OH:4][CH2:5][C:6]([NH:30][C:31](=[O:33])[CH3:32])([CH2:7][OH:8])[CH2:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:19]=2)[CH2:14][CH:13]1[OH:29]
Reactant: CCCCCCCCc1ccc2c(c1)CC(=O)C2CC(NC(C)=O)(C(=O)OC)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)CC(O)C2CC(CO)(CO)NC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of LiBH4 (450 mg, 20.4 mmol) in THF (20 mL) at 0° C. is added 17 (1.35 g, ˜3.1 mol). The reaction mixture is warmed to room temperature and stirred under inert atmosphere for 2 days. The reaction is quenched with water and extracted with EtOAc. The product is then purified over silica gel eluting with 8% methanol/92% methylene chloride to yield 18 (FIG. 7).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:19])[CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([OH:17])=O)=[C:7]1[CH3:18])[CH3:5].Cl.[NH2:21][CH2:22][C:23]1[C:24](=[O:32])[NH:25][C:26]([CH3:31])=[CH:27][C:28]=1[O:29][CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Cl-].[Na+].O>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([CH3:31])[NH:25][C:24](=[O:32])[C:23]=1[CH2:22][NH:21][C:15]([C:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:6]([CH:4]([CH:3]([O:2][CH3:1])[CH3:19])[CH3:5])[C:7]=1[CH3:18])=[O:17]
Reactant: COC(C)C(C)n1c(C)c(C(=O)O)c2cccnc21
Reactant: COc1cc(C)[nH]c(=O)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C(C)OC)c2ncccc12
Temperature: 27 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of 1-(3-methoxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (2.4 g, 9.15 mmol) in DMF (30 mL) was added TEA (4.2 g, 41.50 mmol), 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(1H)-one hydrochloride (2.1 g, 12.81 mmol) After stirred for 10 minutes at 27° C., the mixture was cooled and added HATU (5.56 g, 14.64 mmol). The mixture was stirred at 27° C. for 72 hours and 30% of S.M. remained. Then the mixture was heated at 80° C. for 5 hours. The solution was diluted with brine (100 mL) and extracted with CH2Cl2 (100 mL*3). The extractions were combined and dried over Na2SO4. The solvent was evaporated under vacuum and the residue was purified by flash column (Eluent: dichloromethane:methanol=95:5) to give N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(3-methoxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide. (3.6 g, yield 95%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].S(=O)(O)[O-].[Na+].[Cl:19][C:20]1[CH:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=1[Cl:28]>C(O)C>[Cl:19][C:20]1[C:21]([Cl:28])=[CH:22][C:23]2[NH:27][C:7]([C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=3)=[N:26][C:24]=2[CH:25]=1
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1[N+](=O)[O-]

Procedure:
4-Methoxy-3-nitrobenzaldehyde (4.65 g, 27.6 mmol) and sodium bisulfite (5.79 g, 55.2 mmol) were added to ethanol (200 mL) and refluxed for 4 hours at which time 1,2-dichloro-4,5-phenylenediamine (4.56 g, 27.6 mmol) was added and the mixture was refluxed overnight. The reaction mixture was filtered while hot, and the pea-green solid washed with ethanol.(3.09 g) mp 250° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14]CC2C=CC=C(C#N)C=2)[C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)(C)(C)C.[BH4-].[Na+].[CH3:32]O>>[OH:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][C:9]1([CH3:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OCc2cccc(C#N)c2)[C@H]1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(c2ccccc2)NCCCC1O
Reaction time: 0.5 h

Procedure:
The ketone of (a) above (3.2 g) was suspended in methanol under nitrogen and the temperature brought to -40° C. Sodium borohydride (0.3 g) was added portionwise. The mixture was stirred for 30 min and then concentrated in vacuo, azeotroping with tetrahydrofuran. Borane tetrahydrofuran complex (64 ml, 1.0M in tetrahydrofuran) was added and the mixture was heated at reflux overnight. The mixture was cooled and quenched carefully with methanol, and the mixture was then concentrated in vacuo. The resulting residue was dissolved in ethanol (100 ml) and potassium carbonate (4.2 g) was added. The mixture was heated at reflux for 12 h. The mixture was cooled and evaporated and the residue was extracted with ethyl acetate and water. The organic extract was washed with brine, dried (MgSO4) and evaporated to afford 3-hydroxy-2-methyl-2-phenylpiperidine as a white solid. 1H NMR (360 MHz, CDCl3) δ7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (1H, m, ArH), 3.89 (1H, mc), 2.89-3.01 (2H, m), 1.67-1.91 (4H, m), 1.39 (3H, s, CH3).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[O:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:20]1[C:24]2([CH2:29][CH2:28][N:27]([S:16]([C:14]3[S:15][C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])=[CH:12][CH:13]=3)(=[O:18])=[O:17])[CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCC4(CC3)OCCO4)s2)s1
Reaction time: 1 h
Yield: 37 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of example 9 (200 mg; 0.59 mmol; 1 eq.), is dissolved in DCM (10 ml). 1,4-Dioxa-8-azaspiro[4.5]decane (170.0 mg; 1.19 mmol; 2 eq.) and DIEA (460.4 mg; 3.56 mmol; 6 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (18) as yellow solid (96 mg; 37%). 1H NMR (DMSO-d6) δ 1.66-1.78 (m, 4H), 2.15 (s, 3H), 2.45 (s, 3H), 3-3.15 (m, 4H), 3.83 (s, 4H), 7.31 (d, J=3.8 Hz, 1H), 7.61 (d, J=3.8 Hz, 1H), 12.15 (br s, 1H). M−(ESI): 444.25; M+(ESI): 442.23. HPLC, Rt: 3.39 min (purity: 99.6%).
Reaction SMILES: C1(N2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([B:22]3[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]3)=[CH:18][CH:17]=2)C=CC=CC=1.C([O-])(=[O:33])C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:25]1([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23][B:22]([C:19]2[CH:20]=[CH:21][C:16]([C:8]3[O:33][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:17][CH:18]=2)[O:26]1
Reactant: CC(=O)[O-]
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(-c3nc4ccccc4o3)cc2)OC1(C)C
Temperature: 85 °C
Yield: 81 %

Procedure:
A mixture of 10 (4.45 g, 16 mmol), bis(pinacolate)diborane (4.09 g, 16.1 mmol), anhydrous potassium acetate (3.14 g, 32 mmol) and Pd(dppf)Cl2 (0.48 g, 0.66 mmol) in anhydrous 1,4-dioxane (80 mL) was degassed and the resulting mixture was heated at about 85° C. for about 48 hours under argon. After cooling to room temperature, the mixture was poured into ethyl acetate (˜200 mL) and filtered. The filtrate was absorbed on silica gel and purified by column chromatography (hexanes/ethyl acetate, 4:1) to give a white solid (Compound 28) (4.15 g, in 81% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:79])([CH3:78])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[C:12]([CH2:28][NH:29][C:30](=[O:75])[C@H:31]([CH3:74])[NH:32][C:33](=[O:73])[C@H:34]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[CH:64][CH:63]=1)[NH:35][C:36](=[O:60])[C@H:37]([C@H:56]([CH2:58][CH3:59])[CH3:57])[NH:38]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:11]([O:76][CH3:77])=[CH:10][CH:9]=3.C(NCC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:79])([CH3:78])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[C:12]([CH2:28][NH:29][C:30](=[O:75])[C@H:31]([CH3:74])[NH:32][C:33](=[O:73])[C@H:34]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][C:69]([CH3:70])([CH3:71])[CH3:72])=[CH:64][CH:63]=1)[NH:35][C:36](=[O:60])[C@H:37]([C@H:56]([CH2:58][CH3:59])[CH3:57])[NH2:38])[C:11]([O:76][CH3:77])=[CH:10][CH:9]=3
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Yield: 85.3 %

Procedure:
A solution of 0.74 g (0.73 mmol) of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(N-(9H-fluoren-9-ylmethoxycarbonyl)-L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate in 7 ml of dimethylformamide was stirred at 0° for 1 hour in the presence of 0.7 ml of diethylamine. The reaction mixture was brought to dryness. The residue obtained was chromatographed over silica gel in chloroform/methanol, whereby 0.53 g of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate was obtained; IR 3292, 2970, 1742, 1672, 1655, 1627, 1605, 1536, 1502, 1499 cm-1.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH3:24][NH:25][C@@H:26]1[C@@H:31]([OH:32])[C@H:30]([O:33][C@@H:34]2[O:39][C@H:38]([CH2:40][OH:41])[C@H:37]([OH:42])[C@@H:36]3[O:43][C:44]4([O:50][C@H:49]([C@@H:51]([NH2:54])[CH2:52][OH:53])[C@H:48]([OH:55])[C@@H:47]([OH:56])[C@H:46]4[OH:57])[O:45][C@H:35]23)[C@@H:29]([OH:58])[C@H:28]([NH2:59])[CH2:27]1>>[CH3:24][NH:25][C@H:26]1[C@H:31]([OH:32])[C@@H:30]([O:33][C@H:34]2[O:39][C@H:38]([CH2:40][OH:41])[C@H:37]([OH:42])[C@@H:36]3[O:43][C@:44]4([O:50][C@H:49]([C@H:51]([NH2:54])[CH2:52][OH:53])[C@H:48]([OH:55])[C@H:47]([OH:56])[C@H:46]4[OH:57])[O:45][C@@H:35]23)[C@H:29]([OH:58])[C@@H:28]([NH2:59])[CH2:27]1
Reactant: CN[C@H]1C[C@@H](N)[C@H](O)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@@H]3OC4(O[C@H]23)O[C@H]([C@@H](N)CO)[C@H](O)[C@@H](O)[C@H]4O)[C@@H]1O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: CN[C@@H]1C[C@H](N)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@H](O)[C@@H]3O[C@@]4(O[C@@H]23)O[C@H]([C@H](N)CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]1O
Reaction time: 2 h

Procedure:
After completion of the electroshock, 1 ml of Vogel's minimal medium that contained 1.2% sucrose was added to the resultant, and the obtained mixture was then incubated at 30° C. for 2 hours. 200 μl of the obtained solution was applied to and expanded on an agar medium that contained hygromycin B (500 μg/ml). A hygromycin-resistance colony was isolated, and it was then confirmed by PCR whether or not substitution took place in the target locus. In addition, it was also confirmed by the Southern blot method whether or not it contained redundant Hygr gene copies.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.C1(C)C=CC(S(O[CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)(=O)=O)=CC=1>CN(C)C=O>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH2:26][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:10][CH:11]=1
Reactant: Oc1ccc(Cn2cccn2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OCCOc2ccc(Cn3cccn3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 72 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous N,N-dimethyl-formamide (5 ml) solution of 300 mg of 4-(1-pyrazolyl)methylphenol under stirring over 10 minutes. After stirring at room temperature for 1 hour, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 505 mg of 2-(2-pyridyloxy)ethyl p-toluenesulfonate was added dropwise over 30 minutes. The mixture was stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. The reaction mixture was poured into 50 ml of ice water, which was extracted twice with 30 ml of ethyl acetate. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 208 mg of 4-(1-pyrazolyl)methylphenyl 2-(2-pyridyloxy)ethyl ether (compound 1). Yield, 41%.