Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@H:4]([NH:24]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])[N:10]=[CH:9]2.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:35])[C@H:4]([NH2:24])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])(=[O:16])=[O:17])[N:10]=[CH:9]2
Reactant: [H][H]
Reactant: COC(=O)[C@@H](Cc1ccc2c(cnn2S(=O)(=O)CC[Si](C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](N)Cc1ccc2c(cnn2S(=O)(=O)CC[Si](C)(C)C)c1
Yield: 95.5 %

Procedure:
A mixture of (R)-2-Benzyloxycarbonylamino-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid methyl ester (1.24 g, 2.40 mmol) and 10% palladium on carbon (124 mg) in methanol (50 mL) was agitated for 2 h under 50 psi hydrogen using a Parr hydrogenator. The reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give 879 mg (96%) of the title compound as a sticky gum. 1H-NMR (CDCl3, 300 MHz) δ 8.21 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.59 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 3.72 (s, 3H), 3.38-3.32 (m, 2H), 3.21 (dd, J=13.9, 5.1 Hz, 1H), 2.98 (dd, J=13.9, 7.9 Hz, 1H), 0.91-0.85 (m, 2H), −0.02 (s, 9H). Mass spec.: 384 (MH)+
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][C:17](=[O:21])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].FC(F)(F)C1C=CC(C2C3CCCC=3C=NC=2)=CC=1>>[F:11][C:8]([F:9])([F:10])[C:7]1[CH:2]=[CH:3][C:4]([C:12]2[C:20]3[CH2:19][CH2:18][C:17](=[O:21])[C:16]=3[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCc2c1cncc2-c1ccc(C(F)(F)F)c(F)c1
Agent: FC(F)(F)c1ccc(-c2cncc3c2CCC3)cc1
Product: O=C1CCc2c1cncc2-c1ccc(C(F)(F)F)cc1
Yield: 24 %

Procedure:
In analogy to the procedure described for the preparation of 4-(3-fluoro-4-trifluoromethyl-phenyl)-5,6-dihydro-[2]pyrindin-7-one (intermediate A-14 [C1]), replacing 4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindine with 4-(4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindine. The title compound was obtained as a light brown oil in 24% yield. MS: 278.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1.[OH-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>CN(C)C=O>[CH2:31]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)n(C)c(=O)c1C(=O)C=Cc1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.71 g of 4-hydroxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 5 ml of dimethylformamide was added 0.09 g of sodium hydroxide (60% oily), and this was stirred at room temperature for 1 hour. 0.26 ml of allyl bromide was added, and this was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, 5 ml of tetrahydrofuran was added, insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.30 g of 4-allyloxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (1b)] as a pale yellow crystal.
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C@@H:16]([O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:18]([O:17][C@@H:16]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)=[CH:12][CH2:13][NH:14][CH2:15]1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@@H](OC(=O)C(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@H]1CNCC=C1c1ccc(F)cc1

Procedure:
To a dichloromethane solution (3.0 mL) of tert-butyl (R)-4-(4-fluorophenyl)-5-(pivaloyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (1.69 g, 4.48 mmol) synthesized in Reference Synthesis Example 131, trifluoroacetic acid (1.4 mL) was added and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, saturated sodium bicarbonate aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([S:15][C:9]1[N:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[C:12](=[O:13])[CH2:11][N:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(Cl)cc1NC(=S)NCC(N)=O
Reactant: ClCc1ccccc1
Solvent: CCO
Product: Cc1ccc(Cl)cc1N1C(=O)CN=C1SCc1ccccc1
Yield: 53.7 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (20.6 g), benzyl chloride (25.0 g), and ethanol (350 mL) was heated at reflux for 2.5 hours. The insolubles were removed by filtration and discarded. The filtrate was concentrated to one-half volume. Diethyl ether (300 mL) was added. The precipitated solid was separated by filtration and discarded. The filtrate was evaporated to dryness. The residue was dissolved in chloroform (300 mL) and washed with water. The organic phase was dried over anhydrous MgSO4, decolorized on carbon then evaporated to dryness. The residue was triturated with diethyl ether to give the title compound (14.2 g) as an off-white solid, m.p. 140°-142° C. Anal. Calcd. for. C17H15Cl N2O S: C, 61.72; H, 4.57; N, 8.47. Found: C, 61.62; H, 4.39; N, 8.37. Mass spectrum (EI, M.+) m/z 330/332. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.46 (m, 1H), 7.42 (m, 2H), 7.38 (d, 2H), 7.22-7.32 (m, 3H), 4.31-4.48 (m, 4H), and 2.06 ppm (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(OCCCBr)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a mixture of 20.4 g of 1,3-dibromopropane, 7.1 g of potassium carbonate and 100 ml of N,N-dimethylformamide was added dropwise a solution of 9 g of 4-trifluoromethoxyphenol dissolved in 30 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 9.1 g of 1-(3-bromopropyloxy)4-trifluoromethoxybenzene (60% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CBr
Reactant: OCc1cccc(Br)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Part A: 3-Bromobenzyl alcohol (2.0 g) was dissolved in dimethyl formamide (50 ml) in a dry 100 ml flask under nitrogen. Sodium hydride (0.5 g of a 60% suspension in mineral oil, washed with hexane, 11.8 mmol) was added in portions and the mixture was stirred for one hour at room temperature. Ethyl bromoacetate (1.2 ml, 11.8 mmol) was added drop-wise and the reaction was stirred overnight at room temperature then mixed with water (150 ml) and extracted with methylene chloride (3×20 ml). The extracts were combined, washed with water (50 ml), saturated sodium chloride solution (50 ml) and then dried (MgSO4). The solution was filtered and concentrated and the residue was purified by flash chromatography (SiO2, gradient hexane to ethyl acetate) which gave 2.35 g (80%) of ethyl 3-bromobenzyloxyacetate as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([Cl:29])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1.Cl>[ClH:29].[ClH:29].[Cl:29][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=1
Reactant: COc1cc2nc(Cl)nc(NC3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2nc(Cl)nc(NC3CCNCC3)c2cc1OC

Procedure:
A solution of 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.65 g, 8.6 mmol) in dioxane (35 mL) and conc. HCl (5 mL) was stirred at rt for 18 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ESP): 323.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:21][CH2:22][CH3:23])[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[N:3]=1
Reactant: CCCBr
Reactant: COC(=O)c1cccc2[nH]c(C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(C)nc2c(C(=O)OC)cccc21
Reaction time: 48 h

Procedure:
To a solution of methyl 2-methyl-1H-benzimidazole-4-carboxylate (250 mg) in N,N-dimethylformamide (4 ml) were added potassium carbonate (363 mg) and n-propyl bromide at ambient temperature and the mixture was stirred at the same temperature for 2 days. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water and brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (1:1˜1:2˜1:3˜ethyl acetate only) to give methyl 2-methyl-1-propyl-1H-benzimidazole-4-carboxylate (173 mg) as an oil.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])=[CH:27][CH:28]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2[N+](=O)[O-])cc1
Yield: 81 %

Procedure:
1-Nitronaphthalen-2-yl triflate (2.50 g, 7.78 mmol) and tert-butyl 4-aminophenylcarbamate (1.62 g, 7.78 mmol) were used in a process similar to Example 1(1) to give the titled compound (2.39 g, yield 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+].[NH2:20][C:21]1([C:30]#[N:31])[CH2:26][CH2:25][N:24]([O:27][CH2:28][CH3:29])[CH2:23][CH2:22]1>C(#N)C>[C:30]([C:21]1([NH:20][C:11](=[O:12])[CH2:10][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])[CH2:26][CH2:25][N:24]([O:27][CH2:28][CH3:29])[CH2:23][CH2:22]1)#[N:31]
Reactant: CCON1CCC(N)(C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCON1CCC(C#N)(NC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
3.0 g of (2,4,6-trimethyl-phenyl)-acetyl chloride and 10 g of potassium carbonate in 90 ml of acetonitrile are treated at 0° C. with a solution of 3.6 g of 4-amino-1-ethoxy-piperidine-4-carbonitrile in 30 ml of acetonitrile. After stirring for 18 hours at room temperature the reaction mixture is poured into 100 ml of ice water and extracted with ethyl acetate. The organic phase is washed with brine and concentrated. Chromatography (heptane/ethyl acetate 5:1) yielded 4.5 g of N-(4-cyano-1-ethoxy-piperidin-4-yl)-2-(2,4,6-trimethyl-phenyl)-acetamide as a solid, mp: 194-195° C. LC-MS (EI, ES+): 330 (M+H)+
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:10][C:11]1[C:12]([Cl:21])=[CH:13][C:14]([F:20])=C([CH:19]=1)C(O)=O)[CH:8]=[CH2:9]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:7]([O:10][C:11]1[C:12]([Cl:21])=[CH:13][C:14]([F:20])=[C:1]([CH:19]=1)[C:2]([Cl:4])=[O:3])[CH:8]=[CH2:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOc1cc(C(=O)O)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)Cl)c(F)cc1Cl

Procedure:
With ice-cooling, 1 drop of dimethylformamide and 49.2 g (0.38 mol) of oxalyl chloride were added in succession to a solution of 59.7 g (0.26 mol) of 5-allyloxy-4-chloro-2-fluorobenzoic acid in 0.5 1 of toluene. After the evolution of gas had ceased, the mixture was concentrated to about half its volume. In this form, the product solution was used for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:14][N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]2[O:9][C:8]([N:18]3[CH2:19][CH2:20][CH2:21][N:15]([CH3:14])[CH2:16][CH2:17]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CCc1cc(Cl)cc2nc(S)oc12
Reactant: CN1CCCNCC1
Solvent: Cc1ccccc1
Product: CCc1cc(Cl)cc2nc(N3CCCN(C)CC3)oc12

Procedure:
5-Chloro-7-ethyl-2-mercaptobenzoxazole (200 mg) was dissolved in toluene (10 ml), N-methylhomopiperazine (1.17 ml) was added dropwise to the solution and then the mixture was stirred with heating for 5 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 5-chloro-7-ethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (211 mg).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].O.Br[C:9]1[C:10]([NH2:17])=[N:11][C:12]([CH3:16])=[C:13]([Br:15])[N:14]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I>[Br:15][C:13]1[N:14]=[C:9]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:10]([NH2:17])=[N:11][C:12]=1[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(N)c(Br)nc1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N)c(C#C[Si](C)(C)C)nc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A solution of trimethylsilylacetylene (1.03 g, 29.4 mmol) in tetrahydrofuran (2 mL) was added dropwise to a cooled (water bath at ca. 15° C.) mixture of 3,5-dibromo-6-methyl-pyrazin-2-ylamine (7.48 g, 28 mmol), copper (I) iodide (1.07 g, 5.6 mmol), bis-triphenylphosphine palladium dichloride (1.97 g, 2.3 mmol), triethylamine (3.542 g, 35 mmol) and tetrahydrofuran (75 mL). The mixture was stirred under an atmosphere of argon, for 16 hours, during which time the reaction was allowed to warm to ambient temperature. The reaction mixture was poured onto water and extracted with hexanes-ethyl acetate (2:1). The organic layer was washed successively with saturated ammonium chloride solution, water, and then again with saturated ammonium chloride solution, water, then dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered through celite and concentrated under reduced pressure. Purification by chromatography (silica, 20% ethyl acetate in hexanes) gave (6.19 g, 77%) of 5-bromo-6-methyl-3-trimethylsilanylethynyl-pyrazin-2-ylamine as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.26 (s, 9H), 2.39 (s, 3H), 6.71 (br s, 2H, —NH2).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Si:13]([O:30][CH2:31][C@@H:32]([N:36]1[C@H:41]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@@H:40]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=2)[CH2:39][C@@:38]([CH2:57][C:58]([O:60][CH3:61])=[O:59])([CH3:56])[C:37]1=[O:62])[CH:33]1[CH2:35][CH2:34]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.[CH2:71]=[O:72]>C1COCC1.N#N>[Si:13]([O:30][CH2:31][C@@H:32]([N:36]1[C@H:41]([C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[C@@H:40]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=2)[CH2:39][C@@:38]([C@@H:57]([CH2:71][OH:72])[C:58]([O:60][CH3:61])=[O:59])([CH3:56])[C:37]1=[O:62])[CH:33]1[CH2:34][CH2:35]1)([C:26]([CH3:27])([CH3:29])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)[C@H](CO)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (249 μL, 1.75 mmol) in THF (1.2 mL) was added 1.6 M n-BuLi in hexanes (984 μL, 1.57 mmol) slowly at −15° C. After 30 minutes, a solution of methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (255 mg, 0.35 mmol; Example 263, Step B) in THF (1.2 mL) was added dropwise to the LDA solution and the resulting solution was stirred at −15° C. for 30 min (the solution turned bright yellow). Then, formaldehyde in N2 stream was carried over the reaction surface for 5 min (formaldehyde was generated by cracking para-formaldehyde (105 mg, 3.50 mmol) with heat gun) at −15° C. After being stirred at −15° C. for 30 min, the reaction was allowed to warm to rt and stirred for 4 h. The reaction was quenched (ice cold sat. NH4Cl), extracted (2×EtOAc) and washed (brine×3). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, 20% and 50% EtOAc/Hex) provided the title compound as a colorless film.
Reaction SMILES: [CH2:1]([C:8]([NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C:8]([NH:10][C@@H:11]([CH3:14])[CH:12]=[O:13])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)NC(=O)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@@H](C=O)NC(=O)Cc1ccccc1
Reaction time: 2 h

Procedure:
(S)-2-(benzylcarbonylamino)-propanol (5 g, 23.9 mmol) was dissolved in CH2Cl2 (200 mL) and treated with Dess-Martin periodinane (12.26 g, 1.1 eq). The mixture was stirred for 2 hours, then quenched with sodium thiosulphate, and the solvent removed in vacuo. The residue was then separated between sodium hydroxide (1M, 500 mL) and ethyl acetate (500 mL). The organics were washed with brine, dried (MgSO4) and evaporated in vacuo to yield a clear oil which was used immediately in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:35])=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:11]1[C:12]([CH:14]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=2)(=[O:25])=[O:24])[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=1
Reactant: COc1cc(S(=O)(=O)C(c2cc(F)ccc2F)c2cc(NC(=O)OC(C)(C)C)ncc2Cl)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)C(c2cc(F)ccc2F)c2cc(N)ncc2Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a dichloromethane (5 ml) solution of t-butyl[5-chloro-4-[(4-chloro-3-methoxyphenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate (300 mg, 0.54 mmol) was added trifluoroacetic acid (5 ml) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane. The resulting solution was washed with a 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with diethyl ether and then collected by filtration to give the title compound (208 mg, 0.45 mmol, 84%) as a white solid.
Reaction SMILES: COC1N=C(C[S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])C([N+]([O-])=O)=CC=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH3:29]
Reactant: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccc(C)cc2)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CS(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C

Procedure:
A mixture of 5.0 g (15.5 mmol) of 6-methoxy-3-nitro-2-(toluene-4-sulfonyl methyl)-pyridine and 1.8 mL (16 mmol) of ethyl bromoacetate is dissolved in 20 mL of DMF. To this solution is added 4.4 g (32 mmol) of K2CO3 and the reaction mixture is heated to 50° C. for 18 hours. The reaction mixture is cooled to room temperature and diluted with 300 mL of water. The mixture is extracted with ethyl acetate. The ethyl acetate extracts are dried (Na2SO4) and evaporated to yield 7.2 grams of 6-methoxy-3-nitro-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethyl ester. 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.60 (d, 2H), 7.30 (d, 2H), 6.80 (d, 1H), 6.30 (m, 1H), 4.0 (q, 2H), 3.80 (s, 3H), 3.60 (m, 1H), 3.10 (m, 1H), 2.40 (s, 3H), 1.10 (t, 3H). Mass spectrum: m/e=409.0 (p+1). TLC (7/3: hexanes/ethyl acetate) Rf=0.5. Step 3: