Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:15][C:16]([C:25]([F:28])([F:27])[F:26])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>CC#N>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:15][C:16]([C:25]([F:27])([F:26])[F:28])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: OCc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A mixture of 310 mg (0.77 mmol) of 3-[4-(hydroxymethyl)phenyl]-5-(4-phenyl-5-trifluoromethyl-2-thienyl)-1,2,4-oxadiazole (from Step E), 527 mg (1.5 mmol) of 4-methylmorpholine N-oxide and 500 mg of 4 A molecular sieves in 15 mL of CH3CN was treated with 12 mg (0.034 mmol) of tetrapropylammonium perruthnate and the resulting mixture was stirred ar rt for 2 h. The solids were filtered and the filtrated was concentrated. Chromatography on a Biotage 40 S cartridge using 9:1 v/v hexanes/EtOAc (1L) as the eluant afforded 205 mg (66%) of the title compound: 1H NMR (500 Mhz) δ 7.48 (app s, 5H), 7.93 (app s, 1H), 8.03 (d, J=8.5, 2H), 8.33 (d, J=8.5, 2H), 10.1 (s, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[CH3:12][C:13]1S[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][C:14]=1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.[S:30]([O-:33])(O)=[O:31].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:12][C:13]1[S:30](=[O:33])(=[O:31])[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][C:14]=1[C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1
Reactant: CC1=C(c2ccc(O)cc2)Oc2ccccc2S1
Reactant: O=S([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1=C(c2ccc(O)cc2)Oc2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
M-chloroperbenzoic acid (content, 65% or more, 200 mg) was added to a chloroform (2 mL) solution of 4-(3-methyl-1,4-benzoxathiin-2-yl)phenol (100 mg, 0.39 mmol) synthesized in Reference Example 1-2, and stirred at room temperature for 90 minutes. Aqueous saturated sodium hydrogensulfite solution and aqueous saturated sodium hydrogencarbonate solution were added to the reaction solution, and stirred. The organic layer was collected, dried with magnesium sulfate, and concentrated under reduced pressure to obtain the entitled compound (106 mg, 94%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[NH:40]1[CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:1][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[C@@H:21]3[CH2:30][CH2:29][C:28]4[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=4[CH2:22]3)=[CH:38][CH:39]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: C1CNC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN3CCC3)cc2)c1
Yield: 20.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and azetidine (10 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.4 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[NH:11][N:12]=2)=[C:4]([F:14])[CH:3]=1.[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:10](=[O:13])[N:11]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[N:12]=2)=[C:4]([F:14])[CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Br)cc2F)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2F)n(COCC[Si](C)(C)C)c1=O

Procedure:
Compound 59b (0.26 g, 1.0 mmol) was treated with SEMCl using the procedure described in Example 51, Step C to obtain compound 59c as a yellow oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H33BrFN3O3Si2: 518.1 (M+H). Found: 518.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[N:19]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[N:23][C:18]2=[N:17][CH:16]=1)CCC>>[CH3:9][O:8][C:4]1[N:3]=[C:2]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[N:23][C:18]3=[N:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: COc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 10.4 %

Procedure:
2-Chloro-6-methoxypyridine (305 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-(6-methoxypyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (43 mg) as a white solid: δH (400 MHz, DMSO) 4.04 (3H, s), 6.84 (1H, d, J 8.2), 7.73 (2H, t, J 6.7), 7.88 (1H, t, J 7.8), 8.81 (1H, s), 10.37 (1H, d, J 7.0); m/z (ES+) 295 (M++H).
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:37](O)=[O:38])[CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[C:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:37][OH:38])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
157 mg (1.56 mmol) of 4-methylmorpholine and 169 mg (1.56 mmol) of ethyl chloroformate are added to a solution of 570 mg (1.56 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine in 10 ml of tetrahydrofuran at −10° C., and the mixture is stirred for 30 min. At this temperature, 3.11 ml (3.11 mmol) of a 1M solution of lithium aluminium hydride in tetrahydrofuran are slowly added dropwise. The mixture is slowly warmed to RT and stirred at RT for 12 h. While cooling in ice, 0.2 ml of water and 0.3 ml of a 4.5% sodium hydroxide solution are cautiously added, and stirring is continued at RT for 3 h. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and again evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[NH2:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][N:46]3[C:49]([C:52](OCC)=[O:53])=[CH:50][N:51]=[C:45]3[CH:44]=2)[CH2:36][CH2:35]1>C1COCC1>[Cl:1][C:2]1[C:3]([NH:22][C:52]([C:49]2[N:46]3[CH:47]=[CH:48][C:43]([O:42][CH2:41][CH2:40][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[CH:44][C:45]3=[N:51][CH:50]=2)=[O:53])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=1)[N:6]=[CH:5]2
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Reactant: Nc1c(Cl)ccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4c(Cl)ccc5c4cnn5Cc4cccc(C(F)(F)F)c4)cnc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4 %

Procedure:
A solution of 5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine (0.024 g, 0.074 mmol) in THF (0.750 mL) was cooled to −10° C. and LHMDS (0.096 mL, 0.096 mmol) was added. The mixture was stirred for 15 minutes, and ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.049 g, 0.15 mmol) was added as a THF solution (0.750 mL). The mixture was slowly warmed to 0° C. where it stirred for 3 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (1 mm, 10% MeOH/CH2Cl2 with 1% NH3 (7N MeOH)). The resulting solid was slurried in Et2O and filtered and the solid washed with Et2O and then finally with hexanes to provide the title compound (0.002 g, 4%) as a tan powder. MS (ES+APCI) m/z=612 (M).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH3:21])[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[Cl:11])[CH:7]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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>[Cl:11][C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:47]3[CH:46]=[CH:45][C:44]([N:41]4[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:43][CH2:42]4)=[CH:49][CH:48]=3)[CH:3]=[C:4]([O:12][C@@H:13]([C@@H:15]3[CH2:16][C:17](=[O:30])[N:18]([C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH3:21])[CH2:19]3)[CH3:14])[C:5]=12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(Cl)c34)CC2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(Cl)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To an appropriate sized microwave vial, (R)-4-((R)-1-((6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.36 (118 mg, 0.239 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (73.3 mg, 0.239 mmol), cesium carbonate (234 mg, 0.718 mmol), dioxane (2.0 mL) and water (0.5 mL) were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) catalyst (27.7 mg, 0.0239 mmol) was added and the solution was heated at 100° C. for 18 h. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 4-(4-(3-chloro-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate 6.38.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([CH:14]2[N:27]([CH3:28])[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[N:24]=4)[N:19]=[CH:18][C:17]=3[O:16][CH2:15]2)=[CH:12][CH:13]=1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40]([C:43]([OH:45])=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[CH3:30][O:29][C:23]1[N:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C:11]3[N:10]=[CH:9][C:8]([NH:7][C:43]([C:40]4[CH:41]=[CH:42][C:36]5[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)=[O:45])=[CH:13][CH:12]=3)[N:27]([CH3:28])[C:26]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2n1)N(C)C(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Product: COc1ccc2ncc3c(c2n1)N(C)C(c1ccc(NC(=O)c2ccc4c(c2)NC(=O)CS4)cn1)CO3

Procedure:
The titled compound is prepared as a light yellow lyophilizated powder following Scheme 5 and in analogy to Example 1 using [6-(6-methoxy-4-methyl-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid acid as starting materials.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:17][C:18]1[O:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:19]=1.C(O)(=O)C>CN(C)C=O.C(OCC)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:11](=[O:13])[CH3:12])[CH2:17][C:18]2[O:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:19]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(CC(C(C)=O)c2ccc([N+](=O)[O-])cc2)o1
Yield: 105.3 %

Procedure:
3.00 g of 4-nitrophenylacetone in 50 ml of dimethylformamide was mixed with 0.70 g of 60% oily sodium hydride under cooling with ice under stirring and stirred at the same temperature for 10 minutes. After addition of 3.40 g of ethyl 5-(chloromethyl)-2-furancarboxylate in 5 ml of dimethylformamide, the reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was acidified with acetic acid, and water and ethyl ether were added for extraction. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1→2/1] to give 5.84 g of the title compound as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:38]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]([CH3:28])[CH:30]=3)=[O:39])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNC(=O)c2cn(C)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.9 %

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.00 g) was dissolved in dimethylformamide (30 ml). 1-Methylindole-3-carboxylic acid (0.48 g) and 1-hydroxybenzotriazole (0.37 g) were added and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.53 g) was added, and the mixture was stirred at room temperature for 19 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.25 g of N-(6-(4-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)-piperidin-1-yl)hexyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C@H:10]1[C:15]([O:16]C)=N[C@H](C(C)C)C(OC)=[N:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.C1C[O:37][CH2:36]C1>CC#N>[NH2:11][C@@H:10]([C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=1)[C:15]([O:37][CH3:36])=[O:16]
Reactant: C1CCOC1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](N)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Yield: 84 %

Procedure:
To a solution of (2S,5R)-2-((S)-(tert-butyldimethylsilyloxy)(4-(trifluoromethyl)phenyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.1 g, 6.6 mmol) in THF (15 mL) and CH3CN (30 mL) was added 0.25 N hydrochloric acid (53 mL, 13 mmol) at room temperature. The mixture was stirred over the weekend and then concentrated in vacuo. The residue was neutralized with saturated NaHCO3 and extracted with EtOAc three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-25%-50% EtOAc-hexane) to provide the product as colorless oil (2.1 g, 84%). LCMS (API-ES) m/z: 378 (M+H+).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[N:9][C:8]=1[C:19](=[O:21])[NH2:20].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([NH:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[N:9][C:8]=1[C:19](=[O:21])[NH:20][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1nnn(Cc2ccccc2)c1N
Agent: O=S(=O)(O)O
Product: O=C(NC(=O)c1nnn(Cc2ccccc2)c1NC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Concentrated sulphuric acid (1.5 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-1benzyl-4-carbamoyl-1,2,3-triazole (2.17 g.; prepared as described by J. R. E. Hoover and A. R. Day, J.Amer.Chem.Soc., 1956, 78, 5832) in benzoyl chloride (24 ml.). Stirring was continued at room temperature overnight. The clear solution which formed was then poured into ice-water, the precipitated solid was filtered off, washed well with water and diethyl ether to give 5-benzamido-4-benzoylcarbamoyl-1-benzyl-1,2,3-triazole (1.8 g.), m.p. 171°-173° C., suitable for use in the next stage of the preparation. An aliquot was recrystallised from ethanol to give pure 5-benzamido-4-benzoylcarbamoyl-1-benzyl-1,2,3-triazole, m.p. 182°-186° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1([CH3:19])[CH2:13][C:12](=O)[C:11]2[C:6](=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([OH:16])[C:10]=2[CH3:15])[O:5]1.[BH4-].[Na+].[OH-].[Na+].Cl>CO>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1([CH3:19])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([OH:16])[C:10]=2[CH3:15])[O:5]1
Reactant: COC(OC)C1(C)CC(=O)c2c(C)c(O)c(C)c(C)c2O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
9.4 g (32 mmoles) of the product from Example 2 were reacted with 2.43 g (64 mmoles) of NaBH4 in 100 ml of methanol at 20°-60° C. After 6 hours, a further 2.43 g of NaBH4 were added, after which the reaction mixture was stirred at room temperature for 16 hours. 100 ml of 3N NaOH were then added, and the mixture was neutralized with dilute hydrochloric acid and then extracted with ether, a brown oil being obtained as the crude product in 95% yield. IR: 3,600 (broad) cm-1.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]#[C:4][CH2:5][C:6]1([CH2:9]OS(C)(=O)=O)[CH2:8][CH2:7]1.[Na+].[I-:18]>>[I:18][CH2:9][C:6]1([CH2:5][C:4]#[C:3][Si:2]([CH3:16])([CH3:15])[CH3:1])[CH2:8][CH2:7]1
Reactant: C[Si](C)(C)C#CCC1(COS(C)(=O)=O)CC1
Reactant: [I-]
Agent: [Na+]
Product: C[Si](C)(C)C#CCC1(CI)CC1

Procedure:
In analogy to the procedure described in example 34G], methanesulfonic acid 1-(3-trimethylsilanyl-prop-2-ynyl)-cyclopropylmethyl ester and NaI gave after 30 min at reflux temperature the title compound as orange oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:9][N:10]([CH:12]=O)[CH3:11]>>[CH3:9][N:10]([CH3:12])[CH:11]=[C:2]([CH2:3][CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCC(=O)OCC
Reactant: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)CC

Procedure:
In a distillation apparatus, 86 g of t-butylaminal ester and 87 g of ethyl butyrate in 100 ml of DMF were heated so that the alcohol distilled off slowly. Distillation of the product gave 73.8 g of ethyl β-dimethylamino-2ethylacrylate, corresponding to 87.3% of the theoretical yield.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:14]2)=[O:12])=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:27]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]2)=[O:12])=[O:8])=[CH:25][CH:26]=1)(=[S:27])[NH2:2]
Reactant: S
Reactant: COC(=O)COC1CCN(C(=O)CNC(=O)c2ccc(C#N)cc2)CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)COC1CCN(C(=O)CNC(=O)c2ccc(C(N)=S)cc2)CC1
Reaction time: 24 h

Procedure:
A solution of 1.5 g of methyl [[1-[N-(p-cyanbenzoyl)glycyl]-4-piperidinyl]oxy]acetate in 215 ml of pyridine/triethylamine 40:3 is saturated with hydrogen sulphide and left at room temperature for 24 hours. After removing the solvent, the residue is taken up in ethyl acetate and washed with saturated sodium chloride solution. The organic extracts are dried and concentrated. After chromatography of the residue on silica gel with ethyl acetate followed by ethyl acetate/methanol, there are isolated 1.34 g of methyl [[1-[N-[p-(thiocarbamoyl)benzoyl]-glycyl]-4-piperidinyl]oxy]acetate, MS (FAB): 394 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:32](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[Si:32]([O:23][CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][CH2:10][C:11]1=[O:26])[CH2:24][CH3:25])([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 2.03 g (5.2 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 121, Step H) and 877 mg (12.9 mmol) of imidazole in DMF (32 mL) was added 1.9 mL (7.3 mmol) of tert-butyldiphenylsilyl chloride. The resulting light yellow solution was stirred at room temperature for 4.5 h. The reaction was partitioned between water and EtOAc (2×), and then the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0 to 4% MeOH/DCM, gradient elution) provided the title compound as a white solid.