Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][C:21]1([CH2:24][O:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]5[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=5)=[CH:42][CH:41]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[C:58]([CH3:60])[N:59]=[C:33]34)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][C:21]1([CH2:24][O:25][C@H:26]2[CH2:27][CH2:28][C@H:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:41]=[CH:42][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[C:52]5[NH:3][C:4](=[O:7])[O:5][N:53]=5)=[CH:44][CH:45]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[C:58]([CH3:60])[N:59]=[C:33]34)[CH2:30][CH2:31]2)[CH2:23][CH2:22]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O[Si](C)(C)C(C)(C)C)CC3)CC2)c2nc(C)nn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O)CC3)CC2)c2nc(C)nn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.41 g), sodium hydrogen carbonate (0.66 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-[(4-{trans-4-[(1-{[tert-butyl(dimethyl)silyl]oxy}cyclopropyl)methoxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.26 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.076 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.98 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was solidified with diisopropyl ether to give the title compound as a colorless solid (0.084 g, 35%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[C:29]2[NH:28][C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](C(N)=O)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(N)=O)CC1

Procedure:
trans-4-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide (40 mg, 0.10 mmol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (33 mg, 0.12 mmol), and sodium carbonate (33 mg, 0.31 mmol) were added to DME:Water (5:1) (2 mL) and the mixture degassed with Argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.007 mmol) was then added and the reaction mixture microwaved at 110° C. for 1 h. The mixture was concentrated in vacuo, taken up in DMSO, and purified by mass-directed preparative HPLC to afford desired product. 1H NMR (d6-DMSO, 400 MHz): □ 11.50 (br s, 1H), 7.72 (m, 1H), 7.58 (m, 1H), 7.46 (dd, J=7.6, 0.4 Hz, 1H), 7.25 (br s, 1H), 7.13 (m, 1H), 7.08-7.00 (m, 2H), 6.70 (br s, 1H), 6.69 (br s, 1H), 3.16 (m, 1H), 2.20 (m, 1H), 2.10-1.80 (m, 4H) and 1.65 (m, 4H). MS (ES+): m/z 375.17 [MH+].
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].Cl.[Cl:7][C:8]1[C:9]([F:34])=[C:10]([CH:31]=[CH:32][CH:33]=1)[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:29][CH3:30])=[C:19]([O:22][C@H:23]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]3)[CH:20]=2)[N:15]=[CH:14][N:13]=1.[CH:35]([N:38]([CH:41]([CH3:43])C)CC)([CH3:37])C.N1CCCC1>C(Cl)Cl>[Cl:7][C:8]1[C:9]([F:34])=[C:10]([CH:31]=[CH:32][CH:33]=1)[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:29][CH3:30])=[C:19]([O:22][C@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:3](=[O:4])[CH2:2][N:38]4[CH2:35][CH2:37][CH2:43][CH2:41]4)[CH2:24]3)[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCNC1
Reactant: O=C(Cl)CCl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCN(C(=O)CN2CCCC2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chloroacetyl chloride (66 μl) was added to a solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazoline hydrochloride (350 mg; prepared according to Example 49) and diisopropylethylamine (522 μl) in methylene chloride (10 ml) that was cooled to 0° C. and the mixture was stirred at room temperature for 30 mins. Pyrrolidine (0.37 ml) was added, and the solution stirred for 1 hour before being purified by flash column chromatography eluting with methylene chloride/methanol (containing ammonia 7N) (97/3). The fractions containing the expected product were combined and evaporated to give a foam. This foam was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product (0.206 g); 1H NMR Spectrum: (DMSO d6, 100° C.) 1.50-1.72 (m, 5H), 1.83-1.95 (m, 2H), 2.08-2.18 (m, 1H), 2.40-2.58 (m, 4H), 3.18 (d, 1H), 3.37 (d, 1H), 3.48-3.56 (m, 1H), 3.58-3.64 (m, 1H), 3.68-3.77 (m, 1H), 3.89-3.93 (m, 1H), 3.95 (s, 3H), 4.51-4.59 (m, 1H), 7.23-7.31 (m, 2H), 7.40-7.48 (m, 1H), 7.57-7.64 (m, 1H), 7.90 (s, 1H), 8.41 (br s, 1H), 9.25 (br s, 1H); Mass Spectrum: (M+H)+ 514.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:11][O:12][CH3:13])[C:4](Br)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.S([O-])([O-])=O.[Na+].[Na+].CN(C)C=O.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]([CH2:11][O:12][CH3:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: COCn1c(Br)nc([N+](=O)[O-])c1Br
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCn1cc([N+](=O)[O-])nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Suspension of 2,5-dibromo-1-methoxymethyl-4-nitroimidazole (17.15 g), sodium sulfite (13.73 g), dimethylformamide (100 ml) and water (50 ml) was stirred at a room temperature for 8 hours. The reaction mixture was neutralized with an aqueous solution being saturated with sodium hydrogencarbonate, then ethyl acetate and water were added. The organic layer was washed with an aqueous solution being saturated with sodium chloride, and dried over anhydrous sodium sulfate, then concentrated under a reduced pressure to obtain 2-bromo-1-methoxymethyl-4-nitroimidazole (11.17 g, yield: 86.8%) of white powdery product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[F:33][C:34]([CH3:39])([CH3:38])[C@H:35]([NH2:37])[CH3:36].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[F:33][C:34]([CH3:39])([CH3:38])[C@H:35]([NH:37][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:23])[CH3:36]
Reactant: C[C@@H](N)C(C)(C)F
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.6 %

Procedure:
A 10 ml round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol) and (R)-2-fluoro-1,2-dimethyl-propylamine hydrochloride (crude from Step 3, 155 mg, 0.55 mmol). DMF (1.2 ml) was added followed by N,N-diisopropylethylamine (0.20 ml, 1.15 mmol) and HATU (114 mg, 0.30 mmol). The reaction mixture was stirred at room temperature for 5 h. Water was added and the resultant suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 95 mg (66%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)-amide as a light brown powder.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:15]=[CH:14][C:13]2[CH:9]3[CH2:10][NH:11][CH2:12][CH:8]3[CH2:7][C:6]=2[C:5]=1[O:16]C.C(Cl)Cl.B(Br)(Br)[Br:22]>CO>[BrH:22].[CH2:12]1[NH:11][CH2:10][CH:9]2[C:13]3[CH:14]=[CH:15][C:4]([OH:3])=[C:5]([OH:16])[C:6]=3[CH2:7][CH:8]12
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1OC)CC1CNCC21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Oc1ccc2c(c1O)CC1CNCC21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.00 g. of the resultant compound of Example 6 in 13 ml. CH2Cl2 under a nitrogen atmosphere at -78° C. was treated with 10 g. boron tribromide (BBr3). The mixture was stirred at 0° C. for 1 hour and then cooled to -78° C. while 50 ml. methanol was added slowly. The solution was concentrated in vacuum and the residue was crystallized from acetonitrile to get 1.97 g. product, m.p. 206°-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14]C(=O)C)[CH:5]=[CH:6][C:7]=1[C:8]([CH2:10][N+:11]([O-:13])=[O:12])=[O:9].[OH-].[Na+].C(O)(=O)C>O>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH2:10][N+:11]([O-:13])=[O:12])=[O:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(=O)Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1
Temperature: 80 °C

Procedure:
A mixture of 12.2 g (47.5 mmol) of N-[3-chloro-4-nitromethylcarbonylphenyl]acetamide prepared in Example 12, 11 g (274 mmol) of sodium hydroxide pellets and 161 ml of water is heated at 80° C. for 1 hour. After cooling, the reaction medium is diluted with 900 ml of water and acidified to pH 5 by adding acetic acid. The precipitate formed is recovered, washed with water and air-dried before being recrystallized from ethyl acetate (Yield=276).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][O:13][CH3:14])[CH:7]=[CH:6]2.CCCCCC.C([Li])CCC.[C:26](Cl)(=[O:29])[CH2:27][CH3:28].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][O:13][CH3:14])[C:7]([C:26](=[O:29])[CH2:27][CH3:28])=[CH:6]2
Reactant: COCn1ccc2cc(OC)ccc21
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc2cc(OC)ccc2n1COC
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 34.5 %

Procedure:
3.00 g of 5-methoxy-1-methoxymethylindole was dissolved in 15 ml of anhydrous tetrahydrofuran. Thereto was dropwise added 11.0 ml of 1.5 M n-butyllithium hexane solution, in 5 minutes with stirring at -30° C. The resulting mixture was stirred at 0° C. for 30 minutes. This solution was dropwise added to a solution of 1.59 g of propionyl chloride dissolved in 15 ml of anhydrous tetrahydrofuran, in 30 minutes with stirring at -60° C. The reaction mixture was stirred at room temperature for 10 minutes, and then was added to 50 ml of an aqueous saturated sodium hydrogencarbonate solution in one portion. Thereto was added 150 ml of ethyl acetate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=50/1) to obtain 1.34 g (yield: 35%) of 5-methoxy-1-methoxymethyl-2-propionylindole as a light yellow oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][O:64][C:65]([CH:67]1[CH2:71][CH2:70][CH2:69][NH:68]1)=[O:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][CH:67]1[C:65]([O:64][CH3:63])=[O:66])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-methoxycarbonyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12>CO>[O:8]1[C:7]2=[CH:2][N:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[CH2:10][CH2:9]1
Reactant: O=C(O)c1cc2ccoc2c(Cl)n1
Solvent: CO
Product: O=C(O)c1cc2c(cn1)OCC2
Reaction time: 24 h
Yield: 74 %

Procedure:
C7 (980 mg, 4.98 mmol) is dissolved in 75 mL MeOH containing 500 mg 20% palladium hydroxide on carbon in a 250 mL Parr shaker bottle. The reaction mixture is hydrogenated at 20 PSI for 24 h. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to a white solid. The solid is dissolved in MeOH and is loaded onto 20 mL Dowex 50W-X2 ion exchange resin (hydrogen form) which had been prewashed with MeOH. The column is eluted with 50 mL MeOH followed by 150 mL 5% TEA in MeOH. The fractions with the desired compound are combined and concentrated to afford 2,3-dihydrofuro[2,3-c]pyridine-5-carboxylic acid (C8) (74% yield). HRMS (FAB) calculated for C8H7NO3+H: 166.0504, found 166.0498 (M+H)+.
Reaction SMILES: [C:1]([C:4]1CNCCC=1)(=[O:3])[NH2:2].Cl[C:11]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]2[C:12]=1[N:13]([CH2:33][C:34]([NH2:36])=[O:35])[C:14](=[O:32])[N:15]2[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][C:22]=1[S:30][CH3:31].C([N:40]([CH:43]([CH3:45])C)[CH2:41][CH3:42])(C)C>C(O)C.O>[C:1]([C:4]1[CH2:45][CH2:43][N:40]([C:11]2[N:19]=[C:18]([CH3:20])[N:17]=[C:16]3[C:12]=2[N:13]([CH2:33][C:34]([NH2:36])=[O:35])[C:14](=[O:32])[N:15]3[C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][C:22]=2[S:30][CH3:31])[CH2:41][CH:42]=1)(=[O:3])[NH2:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=O)C1=CCCNC1
Reactant: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(N)=O)c2c(Cl)nc(C)nc21
Solvent: O
Solvent: CCO
Product: CSc1cc(C(C)C)ccc1-n1c(=O)n(CC(N)=O)c2c(N3CC=C(C(N)=O)CC3)nc(C)nc21
Yield: 45 %

Procedure:
In 4 ml of ethanol, 0.16 g of 5-carbamoyl-1,2,3,6-tetrahydropyridine hydrochlioride, 0.40 g of 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetamide, and 0.38 g of diisopropylethylamine were dissolved. Several drops of water were added thereto, and the reaction mixture was heated under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform—methanol=7:1), followed by crystallization from ethyl acetate to yield 0.22 g of 2-[6-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetamide.
Reaction SMILES: [S:1]([NH:11][CH:12]([C:14](Cl)=[O:15])[CH3:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:17]([NH2:19])[CH3:18]>ClCCl>[CH2:17]([NH:19][C:14](=[O:15])[CH:12]([CH3:13])[NH:11][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:18]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)NC(C)C(=O)Cl)cc1
Solvent: ClCCl
Product: CCNC(=O)C(C)NS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 125 grams of tosyl-DL-alanyl chloride (A. F. Beecham, J. Am. Chem. Soc., 79, 325-7) in 800 ml. of dichloromethane was added with stirring to 73 grams of anhydrous ethylamine and 400 ml. of dichloromethane in a reaction flask equipped with a dry ice condenser. The mixture was refluxed 4 hours after addition was completed. The reaction mixture was extracted with water then dried over magnesium sulfate. The solvent was removed in vacuo. The residue was slurried with diethyl ether and filtered to obtain tosyl-DL-alanine ethylamide, m.p. 106°-107°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To 3-(4-bromophenyl)-1H-pyrazole (2.0 g, 9.0 mmol) in DMF was added sodium hydride (0.54 g, 13 mmol) (60% in oil) and the reaction was stirred at ambient temperature for 30 minutes. (2-(Chloromethoxy)ethyl)trimethylsilane (4.5 g, 27 mmol) was added and the reaction was stirred overnight. Water was added and the aqueous phase extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated. The crude material was purified by reverse phase chromatography (SP4, 25M, water/CH3CN 60:40 to 0:100, 20 column volumes) to yield 3-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.4 g, 76% yield) as a clear oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[C:19]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN1C(=O)CCC1>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:30]2[CH2:29][CH2:28][CH:27]([NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:32][CH2:31]2)=[C:3]([N+:16]([O-:18])=[O:17])[CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])CC1
Yield: 95 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrobenzophenone (1.0 eq), 4-(N-Boc-amino) piperidine (1.1 eq), and TEA (2.0 eq) in NMP yielding tert-butyl 1-(4-benzoyl-2-nitro phenyl)piperidin-4-ylcarbamate (95%). LCMS (m/z): 426.2 (MH+); LC Rt=3.46 min.
Reaction SMILES: [C:1]([O:6][CH3:7])(=O)[C@@H:2]([CH3:4])O.[S:8](OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH2:23](S)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CC#N>[CH3:7][O:6][C:1](=[S:8])[C@H:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCS
Reactant: COC(=O)[C@@H](C)O
Solvent: CC#N
Product: CCCCCC[C@H](C)C(=S)OC
Yield: 65 %

Procedure:
(R)-Methyl lactate (0.587 g, 5.55 mmol) was treated as described in Example 5 with triflic anhydride (1.07 ml, 6.38 mmol) and TEA (0.89 ml, 6.39 mmol) in 11 ml of CH3CN. Hexanethiol (1.07 ml, 7.21 mmol) and TEA (1.01 ml, 7.21 mmol) were added and the workup described in Example 5 followed by purification by silica gel chromatography using 25 to 1 hexane to ethyl acetate as eluent gave (S)-methyl-2-hexylthiopropionate as a clear yellow oil (0.737 g, 3.61 mmol, 65%). [α]D =-128° (c=1, MeOH); 1N NMR δ3.69 (s, 3H), 3.36 (q, 1H, J=7.19 Hz), 2.54 (m, 2H), 1.60-1.17 (m, 8H), 1.39 (d, 3H, J=7.19 Hz), 0.84 (t, 3H, J=6.79 Hz); 13C NMR δ173.35, 51.85, 40.70, 31.23, 31.13, 29.11, 28.36, 22.36. 17.00, 13.81.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:14](Cl)[CH:15]=[CH2:16].[CH2:18](N(CC)CC)[CH3:19]>O>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[C:1]([C:4]1([CH2:14][CH:15]=[CH:16][CH2:18][CH3:19])[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[CH3:10][C:6]1([CH3:11])[CH2:7][CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][CH2:16][CH:15]=[CH2:14])[CH2:5]1
Reactant: CCN(CC)CC
Reactant: C=CCCl
Agent: CC(=O)C1CCCC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCCC(=O)C1CCCC(C)(C)C1
Product: CCC=CCC1(C(C)=O)CCCC(C)(C)C1
Temperature: 25 °C

Procedure:
A mixture of 1-acetyl-3,3-dimethylcyclohexane (156 grams, 1 mole), sodium hydroxide (60 grams, 1.5 moles), allyl chloride (114 grams, 1.5 moles) and triethylamine (10 grams) is stirred and heated at 80°-84° C. for 12 hours. The reaction mass is cooled to room temperature. Water is added with stirring, and the aqueous layer is discarded. The organic layer is distilled to afford 119 grams of 1-acetyl-3,3-dimethylcyclohexane, 31 grams of 1-acetyl-3,3-dimethyl-1-(2-pentenyl) cyclohexane, and 5 grams of 3,3-dimethyl-1-(4-pentenoyl) cyclohexane.