Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH2:72])=[N:68]2)[CH2:63][O:62]1>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH:72][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:68]2)[CH2:63][O:62]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cc(F)ccc2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cc(F)ccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A solution of (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.36 g, 1.10 mmol) in N,N-dimethylformamide (4.25 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.54 mL, 3.31 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.73 g, 1.65 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.22 g, 1.16 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-70% ethyl acetate/hexanes) afforded (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.36 g, 64%) as a red/orange foam: HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]− 505.2257, observed 505.2254; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.64 (m, 2H), 1.68-1.85 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.95-4.14 (m, 3H), 4.22 (d, J=18.6 Hz, 1H), 4.29-4.42 (m, 1H), 4.60 (d, J=18.6 Hz, 1H), 4.89 (dd, J=10.6, 4.5 Hz, 1H), 5.03 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.12-7.32 (m, 1H), 7.43-7.59 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[C:10]([C:13]34[CH2:20][CH:19]5[CH2:21][CH:15]([CH2:16][CH:17]3[CH2:18]5)[CH2:14]4)[NH:9][C:8]=2[C:7](=[O:22])[NH:6][C:5]1=[O:23])[CH:2]=[CH2:3].[H-].[Na+].I[CH2:27][CH2:28][CH3:29].O>CN(C)C=O>[CH2:1]([N:4]1[C:12]2[N:11]=[C:10]([C:13]34[CH2:14][CH:15]5[CH2:21][CH:19]([CH2:18][CH:17]3[CH2:16]5)[CH2:20]4)[NH:9][C:8]=2[C:7](=[O:22])[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: CCCI
Reactant: C=CCn1c(=O)[nH]c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)n(CCC)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
1.00 g (3.21 mmol) of Compound G was dissolved in 30 ml of dimethylformamide, and 256 mg of sodium hydride (60%, 6.41 mmol) was added slowly to the solution at 0° C. After 30 minutes, 0.33 ml (3.4 mmol) of 1-iodopropane was added dropwise slowly at the same temperature and stirred at room temperature overnight. The resulting reaction mixture was poured into 300 ml of water, neutralized and extracted three times with 100 ml of chloroform. The organic layer was washed with a saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: 30% ethyl acetate/hexane) to give 225 mg (yield 20%) of Compound H as a colorless needle crystal.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:11])[CH3:8]>O.CO>[CH2:7]([O:9][C:10]([NH:12][CH2:13][CH2:14][S:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:2])=[O:11])[CH3:8]
Reactant: CCOC(=O)CSCCNC(=O)OCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CS(=O)CCNC(=O)OCC
Reaction time: 7 h
Yield: 78.8 %

Procedure:
There was dissolved 149.7 g (0.7 mol) of sodium metaperiodate in 1400 ml of water, and thereto was added dropwise a solution of 164.5 g (0.7 mol) of ethyl 2-[2-(ethoxycarbonylamino)ethylthio]acetate in 125 ml of methanol under cooling with ice. After dropping the mixture was stirred for 7 hours under cooling with ice. The precipitate was removed by filtration and washed with water and with chloroform, successively. The filtrate was extracted with chloroform and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure to give 138.6 g of white solid. The solid was recrystallized from ethanol-n-hexane (1:4) to give 113.5 g of the titled compound.
Reaction SMILES: [OH:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][O:4][CH2:5][O:6][CH3:7].[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].C1CCN2C(=NCCC2)CC1>C1COCC1.O>[O:1]([CH:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][O:4][CH2:5][O:6][CH3:7])[Si:17]([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCOCC(O)c1nccs1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: COCOCC(O[Si](C)(C)C(C)(C)C)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A mixture of 2-(1-hydroxy-2-(methoxymethoxy)ethyl)thiazole (0.93 mmol, 0.18 g), TBSCl (1.1 mmol, 0.17 g) and DBU (1.1 mmol, 0.16 mL) in THF (1 mL) was stirred at rt overnight. The reaction was diluted with water and extracted with ethyl ether, dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (10% ethyl acetate/hexane) to afford 0.20 g (70%) of 2-(1-(t-butyldimethylsiloxy)-2-(methoxymethoxy)ethyl)thiazole.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].N(OC(C)(C)C)=O.N[C:15]1[C:16]([Cl:32])=[CH:17][C:18]([Cl:31])=[C:19]([N:21]2[C:25](=[O:26])[N:24]([CH:27]([F:29])[F:28])[C:23]([CH3:30])=[N:22]2)[CH:20]=1.[ClH:33]>C(#N)C.[Cu](Cl)Cl>[Cl:33][CH:2]([CH2:3][C:15]1[CH:20]=[C:19]([N:21]2[C:25](=[O:26])[N:24]([CH:27]([F:29])[F:28])[C:23]([CH3:30])=[N:22]2)[C:18]([Cl:31])=[CH:17][C:16]=1[Cl:32])[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: Cl
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Temperature: 0 °C

Procedure:
To a cold (0° C.), stirred mixture of 28.7 g (0.333 mole) of methyl acrylate, 2.51 g (0.0244 mole) of tert-butyl nitrite, and 2.6 g (0.019 mole) of copper (II) chloride in 50 mL of acetonitrile was added dropwise a solution of 5.0 g (0.016 mole) of 1-(5-amino-2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 15 mL of acetonitrile. After complete addition the reaction mixture was allowed to war to room temperature and was stirred for approximately 18 hours. The reaction mixture was diluted with 15 mL of 2N hydrochloric acid solution. The mixture was extracted with four portions of diethyl ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give an oil. The oil was purified by column chromatography on silica gel, eluting with n-heptane:ethyl acetate (4:1) to give 5.0 g of methyl 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionate as an oil, Compound A3 of Table 1A.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24]>>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:19])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1

Procedure:
condensing the N-benzyloxycarbonyl-L-aspartic acid with the L-phenylalanine methyl ester through the action of the papain at a temperature of between 25° C. and 49° C to yield N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester; and
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1>ClCCl>[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH:43][C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH2:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]2=[O:13])=[CH:38][CH:37]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.050 g, 0.169 mmol) and (4-fluorophenyl)methanamine (0.023 g, 0.186 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.20-7.30 (m, 9H), 7.06-7.12 (m, 2H), 6.93-6.99 (m, 2H), 6.24-6.27 (m, 1H), 4.26 (d, J=5.9 Hz, 2H), 4.04 (s, 3H), 3.49 (t, J=6.5 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H); MS (ESI−) m/z 401 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
4-Hydroxybenzaldehyde of the formula (7) (100 g), potassium carbonate (226 g) and acetone (500 ml) were taken in a reaction flask and stirred for 15 minutes. Benzylbromide (154 g) was then added at room temperature and the reaction mass was stirred at the same temperature for a period of 8–10 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with 10% aq. sodium hydroxide solution followed by water. The solvent was removed under reduced pressure and the resulting residue was triturated with pet. ether to afford 4-benzyloxybenzaldehyde of the formula (8) (160–165 g, 93–95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:14]([OH:15])[C:13]2[CH:16]=[CH:17][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(Oc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of 4-fluorophenol (41.3 g, 0.37 M), 4-fluorobenzaldehyde (45.7 g, 0.37 M) and K2CO3 (55 g) in 450 mL DMF was refluxed for 4 h, cooled, poured into ice water (1.5 L) to give a suspension. The mixture was filtered, washed with water, dried at 50° C. under vacuum to generate 78.3 g of the aldehyde 20 as a brownish solid. This compound was slurried in 2-propanol (1 L), then NaBH4 (14 g, 0.378 M) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h, then concentrated. The residue was poured into water (1.5 L) to give a suspension. After filtration, the resulting solid, washed with water, dried at 50° C. under vacuum to give 76 g of 4-fluorophenoxybenzyl alcohol 26 as a yellowish crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4cnc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.49) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.186 g, 78%). MS (ISP) 476.1 [(M+H)+]; mp 244° C.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].O>C1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH:1]1[CH:6]2[C:7]3[C:12]([C:13](=[O:14])[N:5]2[CH2:4][CH2:3][NH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:23]
Reactant: O=C1c2ccccc2C2CNCCN12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1NCCN2C(=O)c3ccccc3C12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A solution of 1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindol-6-one (described in Example 8, 7.5 g, 0.04 mol) in 150 ml of benzene is added to sodium hydride (1.7 g of a 50% dispersion in mineral oil, 0.036 mol) in 200 ml of benzene and stirred at room temperature for 30 min. A solution of ethyl bromoacetate (8.8 g, 0.044 mol) in 150 ml of benzene is added and the reaction is refluxed with stirring for 3 hr and cooled. Water is cautiously added and the benzene layer is separated, washed with water, dried, and evaporated. The residue is chromatographed on silica gel using 50% acetone in benzene and the eluates are evaporated to give 6-oxo-1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-1-acetic acid ethyl ester (5.5 g), nmr (CDCl3) δ1.3(t), 2.4-2.6(m), 2.8-3.5(m), 4.2(q), 4.6(m) and 7.3-7.7(m).
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][C:6](=[O:21])[N:7]([CH2:9][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=[O:12])[CH3:8].[CH:24]1([Mg]Cl)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[C:17]([O:16][C:14]([NH:13][C@H:10]([CH2:9][N:7]([CH3:8])[C:6]([O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:22])[CH3:23])=[O:21])[C@@H:11]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[OH:12])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CN(C[C@H](C=O)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CN(C[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1CCCCC1)C(=O)OCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of above crude (2-(trimethylsilyl)ethyl)(R)-2-(t-butoxycarbonylamino)-2-formylethylmethylcarbamate (0.71 g, 2.05 mmol) in toluene (6 mL) at −78° C. was added cyclohexylmagnesium chloride (2 M in ether, 5.13 mL) dropwise. The resulting solution was stirred at −78° C. for 1 h, allowed to warm slowly to rt, and quenched with sat'd aq NH4Cl (5 mL). The organic layer was separated, and aqueous layer was extracted with ether (2×5 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by flash column chromatography to give (1R,2R)-2-(t-butoxycarbonylamino)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol (209.7 mg, 24%). 1H NMR (400 MHz, CDCl3): 4.94 (d, 1H), 4.16 (m, 2H), 3.80 (m, 1H), 3.78 (m, 1H), 3.04 (m, 1H), 2.88 (m, 1H), 2.86 (s, 3H), 2.10 (m, 1H), 1.64 (m, 4H), 1.42 (m, 1H), 1.40 (s, 9H), 1.28-1.02 (m, 4H), 0.98 (m, 2H), 0.82 (m, 4H), 0.02 (s, 9H); MS m/z 431 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][S:6](=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:17].[Na+].Cl.CCOC(C)=O>C(#N)C.O>[CH3:1][C@H:2]1[O:7][S:6](=[O:17])(=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reaction time: 0.08 h
Yield: 46.8 %

Procedure:
To a solution of tert-butyl (6R)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (2.3 g, 9.6 mmol) in acetonitrile (25 mL) and water (15 mL) cooled to 0° C. is added sodium periodate (3.1 g, 14.3 mmol) in one portion. After 5 min, the pH of the mixture is adjusted to 7-8 by addition of saturated Na2HPO4 solution. A solution of RuCl3 (9.9 mg, 0.05 mmol) in water (0.5 mL) is added and the reaction mixture is stirred for 2 h, keeping the pH between 6 and 9 by addition of Na2HPO4 solution. Water (100 mL) is added and the pH is adjusted to 6 by addition of 2M HCl solution. EtOAc is added and the organic layer is separated, washed with NaHCO3 and brine. The combined aqueous layers are back extracted once with EtOAc. The combined organic phases are dried (MgSO4) and concentrated to afford the crude compound which is purified by flash column chromatography using EtOAc in hexanes affords the title compound (1.13 g, 47%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12](O)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:46][N:47]([CH2:54][C@H:55]1[CH2:60][CH2:59][C@H:58]([NH2:61])[CH2:57][CH2:56]1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[C:11]([C:12]([NH:61][C@H:58]2[CH2:57][CH2:56][C@H:55]([CH2:54][N:47]([CH3:46])[CH:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[CH2:60][CH2:59]2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[CH:8]=2)[N:3]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3nc(C)c(C(=O)O)cc3c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2ccc3nc(C)c(C(=O)N[C@H]4CC[C@H](CN(C)C5CCOCC5)CC4)cc3c2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 2-methyl-6-(4-methylphenyl)-quinoline-3-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (109 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (156 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (242 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (246 mg) and triethylamine (0.15 ml) in acetonitrile (15 ml), and the resulting mixture was stirred for 4 days. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:2→1:1) and to recrystallization (ethyl acetate/hexane) to obtain trans-2-methyl-6-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]quinoline-3-carboxamide (compound 70) (142 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:14].[CH3:15][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:4][C:3]=1[Br:14]
Reactant: Nc1c(Br)cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 4-amino-3-bromo-5-nitrobenzoic acid (3.65 g, 14.0 mmol) in dichloromethane (35 mL) and methanol (35 mL) at 0° C. was slowly added trimethylsilyl-diazomethane (8.74 mL, 17.5 mmol). The mixture was allowed to warm to ambient temperature and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (1.54 g). LC-MS [M]=275.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([N:21]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.N1C=CC=CC=1.N1(C2C=CN=CC=2)CCCC1.[C:44](Cl)(=[O:47])[O:45][CH3:46]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([C:15]2[C:16]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][C:44](=[O:47])[O:45][CH3:46])[CH2:22]3)=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:14]1
Reactant: COC(=O)Cl
Reactant: NC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine (0.0974 g, 0.281 mmol), pyridine (commercially available through Aldrich, 0.045 ml, 0.562 mmol), and 4-(pyrrolidin-1-yl)pyridine (PPY) (commercially available through Alfa Aesar, 0.042 g, 0.281 mmol) to stir at RT in DCM (0.937 ml). Methyl carbonochloridate (commercially available through Aldrich, 0.027 ml, 0.422 mmol) was added and allowed to stir overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage 50 g SNAP HP-silica column, eluting with a gradient of 1% to 6% MeOH in CH2Cl2, to provide methyl (1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:12])[CH3:11])(C)C.[C:13]1([CH:20]=CC=C(O)[CH:15]=1)O.[O-]O>>[CH:10]([C:5]1[CH:4]=[CH:9][CH:8]=[C:7]([CH:13]([CH3:20])[CH3:15])[CH:6]=1)([CH3:11])[CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)c1ccccc1C(C)C
Agent: [O-]O
Product: CC(C)c1cccc(C(C)C)c1

Procedure:
By well-known processes, diisopropylbenzene (DIPB) is oxidized to produce, among other products, the dihydroperoxides (DHP) and hydroxyhydroperoxides (HHP) of diisopropylbenzene, for the preparation of resorcinol. Almost all acid-catalyzed decompositions of m-DHP to resorcinol require the use of pure m-DHP. For example, U.S. Pat. No. 3,928,469 disclosed that a crude hydroperoxide mixture which is obtained from the oxidation product of m-diisopropylbenzene, and which has a composition consisting of 72% m-DHP, 20% m-HHP, and 8% others, is cleaved in a usual manner, using a mineral acid catalyst, to give only a low cleavage yield of about 70 to 73% resorcinol based on moles m-DHP used. Yet, there is no practical way to make pure DHP by the hydroperoxidation of m-DIPB and there is no economical way to separate HHP and other products from the hydroperoxidation product to obtain pure DHP.