Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH3:36])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:32]([CH3:35])[CH2:33][CH3:34])[C@H:25]([O:30][CH3:31])[CH2:26][C:27]([OH:29])=O)[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:44][C@@H:45]([CH2:54][C:55]1[CH:60]=[CH:59]C(O)=C[CH:56]=1)[C:46]([N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1)=[O:47].C(OC(N(C)[C@H](C(N[C@H](C(N([C@@H]([C@@H](C)CC)[C@H](OC)CC([N:90]1[CH2:94][CH2:93][CH2:92][C@H:91]1[C@H:95]([O:101][CH3:102])[C@H:96]([C:98](O)=[O:99])[CH3:97])=O)C)=O)C(C)C)=O)C(C)C)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.FC(F)(F)C(O)=O>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH3:36][NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:32]([CH3:35])[CH2:33][CH3:34])[C@H:25]([O:30][CH3:31])[CH2:26][C:27]([N:90]1[CH2:94][CH2:93][CH2:92][C@H:91]1[C@H:95]([O:101][CH3:102])[C@@H:96]([CH3:97])[C:98]([NH:44][C@@H:45]([CH2:54][C:55]1[CH:56]=[CH:38][C:39]([OH:41])=[CH:59][CH:60]=1)[C:46]([N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1)=[O:47])=[O:99])=[O:29])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCCCO1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C

Procedure:
First, in analogy to Intermediate 5, trifluoroacetic acid-(2S)-2-amino-3-(4-hydroxyphenyl)-1-(1,2-oxazinan-2-yl)propan-1-one (1:1) was prepared. This reagent was then used, in analogy to the synthesis described in Intermediate 75, by coupling with N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 26) in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and subsequent detachment of the Boc protecting group by means of trifluoroacetic acid, to prepare the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[CH:35]([NH:37][NH2:38])=[O:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:38][NH:37][CH:35]=[O:36])=[O:26])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: NNC=O
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NNC=O)ccn34)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylic acid (26 mg, 0.057 mmol; prepared as in Example 28, Step A) in DMF was added formohydrazide (6.9 mg, 0.11 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.11 mmol), 1H-benzo[c/][1,2,3]triazol-1-ol hydrate (15 mg, 0.11 mmol) and triethylamine (17 mg, 0.17 mmol). The reaction mixture was stirred for 16 hours at ambient temperature, diluted with DCM (30 mL), washed with H2O, dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated with Et2O (30 mL) to give the product (20 mg).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][CH2:6][C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N+:16]([CH:19]=[C:20](SC)[S:21]([CH3:23])=O)([O-:18])=[O:17]>CO>[CH3:23][S:21][C:20]1[NH:5][CH:6]=[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: NCC(=O)Cc1ccccc1
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSc1[nH]cc(Cc2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.42 h
Yield: 28.3 %

Procedure:
A solution of sodium methoxide (sodium (1.9 g, 0.084 mol) dissolved in methanol (100 ml)) and a solution of 1-amino-3-phenylpropan-2-one hydrochloride (7.9 g, 0.042 mol) in methanol (100 ml) were simultaneously added dropwise, to a stirred solution of 1-nitro-2-methylthio-2-methylsulphinylethylene (7.7 g, 0.042 mol) in methanol. The temperature was maintained at about 60° during the addition, which took 25 minutes. The solvent was then removed in vacuo, and the residual dark red oil was chromatographed on a silica gel column. Elution and recrystallisation with petroleum ether/ethyl acetate (7:3) gave 2-methylthio-3-nitro-4-benzylpyrrole (2.95 g, 28.5%) m.p. 190°-192.5°.
Reaction SMILES: COCCCN=C=O.[CH2:9]([C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20](=[O:31])[N:19]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[CH:36][CH:35]=3)[C:18]=2[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.NN.[H][H]>[Pd]>[NH2:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][CH2:32][N:19]2[C:18]3[N:17]=[C:16]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:24][C:23]=3[C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20]2=[O:31])=[CH:39][CH:38]=1
Reactant: COCCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: COCCCN=C=O
Agent: NN
Solvent: O
Product: COCCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By methods well known in the art 3-methoxypropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-methoxypropyl)xanthine, which in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-methoxypropyl)xanthine.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=O)N)[CH3:9])(C)(C)C.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:26][C:27]1[C:28]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:29]([CH2:34][C:35]#[N:36])[C:30]([F:33])=[CH:31][CH:32]=1.C(Cl)[Cl:45]>>[ClH:45].[ClH:45].[NH2:7][C@H:8]([C:10]1[N:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:28]2[C:29]([CH2:34][C:35]#[N:36])=[C:30]([F:33])[CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:9]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: N#CCc1c(F)ccc(N)c1Nc1ccccc1
Reactant: ClCCl
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: C[C@H](N)c1nc2ccc(F)c(CC#N)c2n1-c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (435 mg, 2.31 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (369 mg, 1.94 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (5 mL). (3-Amino-6-fluoro-2-phenylaminophenyl)acetonitrile (223 mg, 0.92 mmol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) LCMS (Method C): RT=3.36 min, [M+H]+=395. The product was dissolved in HCl in dioxane (4N, 10 mL) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title product as an off white solid (227 mg, 67%). LCMS (Method C): RT=1.88 min, [M+H]+=295.
Reaction SMILES: F[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].[NH2:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][N:31]=[CH:32]2)=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>CC(O)(C)C>[CH:32]1[C:33]2[C:28](=[CH:27][CH:26]=[C:25]([NH:24][C:2]3[N:23]=[CH:22][CH:21]=[CH:20][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)=[O:5])[CH:34]=2)[CH:29]=[CH:30][N:31]=1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1F
Reactant: Nc1ccc2ccncc2c1
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1Nc1ccc2ccncc2c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-fluoro-N-(4-pentafluoroethyl-phenyl)-nicotinamide (112 mg) and 7-aminoisoquinoline (40 mg) in t-BuOH (0.5 mL) was added TFA (94 μL). The resulting mixture was stirred for 24 h at 90° C., cooled to RT and purified by flash chromatography (4:1:0.1; MeOH/CH2Cl2/MeOH) to give the title compound as a yellow solid. MS (ES+): 459 (M+H)+. Calc'd for C23H15F5N4O— 458.12.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CO)=CC=CC=1.C(O)C.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1ccn2ccnc2c1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2ccn3ccnc3c2)cc1
Temperature: 80 °C
Yield: 82.7 %

Procedure:
A mixture of 7-chloro-imidazo[1,2-a]pyridine (15.0 g, 98.6 mmol), 4-fluorophenylboronic acid (16.55 g, 118.3 mmol), potassium carbonate (81.5 g, 590 mmol) in toluene-methanol-ethanol-water (1:1:1:1, 800 mL) was degassed with N2 and then bis(tri-tert-butylphosphine)palladium(0) (400 mg) added. The mixture was degassed and then heated to 80° C. for 18 h. The mixture was cooled to ambient, transferred to a separating funnel and the layers separated. The organic portion was reduced under reduced pressure and the residue extracted with dichloromethane. The dichloromethane extracts were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to afford 17.3 g (83%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.22 (1H, d), 7.87 (1H, s), 7.71 (1H, s), 7.69-7.58 (3H, m), 7.20 (2H, t), 7.11 (1H, d).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCc1cccc(C(=O)OC)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Triethylamine (1.57 g, 18.5 mmol) was added to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The mixture was cooled in an ice bath to 4° C. Ethyl chloroformate (1.0 g, 9 mmol) was added slowly keeping the mixture at 4-6° C. After addition was complete, the mixture was stirred in an ice bath for 30 minutes and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the residue was purified by flash chromatography (dichloromethane/ethyl acetate 95 to 5) to give 1.59 g (70%) of the product as an oil: 1H NMR (CDCl3) δ 7.87 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 5.30 (b, 1H), 4.32 (d, J=6.3 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Cl:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[ClH:23].[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:2]([CH2:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=2)[CH3:1])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CNCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc2ccccc12
Product: Cl
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 3.43 g of N-methyl-naphthylmethylamine, 3.65 g of 4-tert-butylbenzyl chloride, 2.33 g of anhydrous sodium carbonate and 20 ml of dimethyl formamide was stirred at 50° C. for 16 hours. The reaction mixture was poured into water and extracted with benzene, and the benzene solution was washed with water. After distilling away benzene, 3 ml of concentrated hydrochloric acid was added at cooling. An excess of hydrochloric acid was removed under reduced pressure and a suitable amount of acetone was added. White crystal (5.9 g) was precipitated and was filtered. N-(4-tertbutylbenzyl)-N-methyl-lnaphthylmethylamine hydrochloride of white plate crystal (Compound of Example 1) was obtained by recrystallization from acetone/ethanol. Melting point: 210° to 212° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3cccs3)cc2)CC1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared starting from 1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)-piperidine-4-carboxylic acid ethyl ester (3 g, 6.05 mmol) and 2-(tributylstannyl)-thiophene (6.8 g, 18.14 mmol) in the presence of tetrakis palladium (0) in boiling tolune. Yield 1.58 g (52%); brown solid; mp 130° C.; MS: 500 (M+H)+
Reaction SMILES: [CH2:1]=O.[CH:3](=[O:7])[CH:4]([CH3:6])[CH3:5].[CH2:8]([CH2:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:5][C:4]([CH3:1])([CH2:6][NH:16][CH2:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]=[O:7]
Reactant: C=O
Reactant: CC(C)C=O
Reactant: NCCc1ccccc1
Product: CC(C)(C=O)CNCCc1ccccc1

Procedure:
Under the same conditions as for the preparation of 2,2-dimethyl-3-(N-morpholino)propanal, 39.2 g (0.47 mol) of 36% aqueous formaldehyde were reacted with 35.6 g (0.49 mol) of isobutyraldehyde and 57.0 g (0.47 mol) of N-benzylmethylamine, and worked up. The product distilled at a top temperature of 74° C. and a pressure of 4·10−2 mbar. Yield: 80.6 g (83% of theory) as a colorless, clear and almost odorless liquid which had an amine content of 4.83 mmol N/g.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=C=O.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>>[OH:32][CH:30]1[CH2:31][N:28]([C:10]([C@@H:9]2[CH2:13][C:14](=[O:16])[CH2:15][N:8]2[C:6]([NH:17][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[O:7])=[O:12])[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: COc1cccc(N=C=O)c1
Reactant: OC1CNC1
Product: COc1cccc(NC(=O)N2CC(=O)C[C@H]2C(=O)N2CC(O)C2)c1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-oxoproline, 1-isocyanato-3-methoxybenzene, and 3-azetidinol the title compound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=334.2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.I[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(I)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: Cc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)O4)CC2)cc1
Yield: 32.9 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (700 mg, 2.69 mmol) synthesized in Reference example 56 and 4-iodotoluene (1.76 g, 8.08 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 310 mg (yield 33%). Melting point was 150 to 151° C. (ethanol).
Reaction SMILES: [H-].[Na+].CCCCCC.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>C(OCC)(=O)C.O>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:18][C:15]1[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COCCOCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COCCOCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
To 200 mg (0.5 mmol) of sodium hydride (60% dispersion in oil) was added 10 mL of hexane. After settling, the hexane was decanted. To the residue was added 10 mL of freshly distilled tetrahydrofuran and the slurry mixture was cooled at 0° C. To this was added slowly 200 mg (1.43 mmole) of 4-nitrophenol (20) as a solid portionwise. The reaction mixture was stirred at 0° C. for 5 minutes and 197 μL (1.71 mmol) of 2-methoxyethoxy methyl chloride was added. The mixture was stirred at room temperature for 18 hours. To the reaction mixture 25 mL of water was slowly added and the reaction mixture was diluted with 50 mL of ethyl acetate. The organic part was separated and the aqueous layer was extracted with 2×50 mL of ethyl acetate. The organic layers were combined and washed with 7×100 mL of saturated sodium carbonate solution, followed by 100 mL of water. The ethyl acetate layer was dried over MgSO4 and concentrated to yield 225 mg (0.99 mmol, 69%) of 1-[(2-methoxyethoxy)methoxy]-4-nitrobenzene (21) as a pale yellow oil. NMR, IR and MS data confirmed compound identity.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][CH2:6][O:7][C:8]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])=[O:9]>O.C(O)(=O)C>[CH2:6]([O:7][C:8](=[O:9])[C:10](=[N:1][OH:3])[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of sodium nitrite (56.5 g, 0.815 mol) in water (400 mL) was added to a solution of ethyl benzoyl acetate (120 g, 0.625 mol) in glacial acetic acid (300 mL) at 0-10° C. over a period of 2 h. The product started precipitating during the course of addition and the reaction mixture was warmed to room temperature and stirred for 30 min. Water (2.5 L) was added and the mixture was stirred for a further 30 min and then filtered under suction. The solid was washed with water (20 mL), petroleum ether (200 mL) and then dissolved in chloroform (700 mL). The filtrate was extracted with chloroform (2×100 mL) and the combined organic phase was washed with water (2×200 mL), brine solution (2×250 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (122.5 g, 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:12][CH:11]=2)[CH:3]=1.[CH2:24]([Li])CCC.C[Si](C)(C)[O:31][C@@H:32]1[C@@H:37]([O:38][Si](C)(C)C)[C@H:36]([O:43][Si](C)(C)C)[C@@H:35]([CH2:48][O:49][Si](C)(C)C)[O:34][C:33]1=[O:54]>C1COCC1.C1(C)C=CC=CC=1.CCCCCC.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:33]2([O:54][CH3:24])[C@H:32]([OH:31])[C@@H:37]([OH:38])[C@H:36]([OH:43])[C@@H:35]([CH2:48][OH:49])[O:34]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: FC(F)COCCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC1(c2ccc(Cl)c(Cc3ccc(OCCOCC(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a cold (−60° C.) solution of 4-bromo-1-chloro-2-(4-(2-(2,2-difluoroethoxy)ethoxy)benzyl)benzene (4 g, 9.9 mmol) in dry THF/toluene (2:1, 18 mL) was slowly added dropwise a solution of n-butyllithium in hexane (2.5 M, 4.7 mL), and the pale yellow solution was stirred for 30 minutes at −60° C. A solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (6 g, 12.8 mmol) in toluene (15 mL) was added dropwise at a rate that maintained the temperature below −55° C., and the mixture was stirred for 2 hr at −60° C. The reaction mixture was quenched by addition of MeOH (24 mL) containing methanesulfonic acid (2 mL). The reaction was stirred overnight at RT, and then aqueous sodium hydrogen carbonate solution (30 mL) was added. The organic layer was separated, the aqueous phase was extracted with ethyl acetate (30 mL) and the combined organic extracts were dried over sodium sulfate. The product was concentrated to give a residue (5.4 g), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([CH2:24][OH:25])[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:33](Cl)([CH3:36])(=[O:35])=[O:34]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([CH2:24][O:25][S:33]([CH3:36])(=[O:35])=[O:34])[O:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CO)COCCCCCCCCCCCCC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a mixture of 1.70 g (4.78 millimole) of 1-O-(12-cyclohexyl)dodecyl-2-O-methylglycerol, 580 mg (5.74 millimole) of triethylamine and 10 ml of dichloromethane, 657 mg (5.74 millimole) of mesyl chloride was added dropwise under ice cooling. After stirring for 1 hour under ice cooling, the reaction mixture was washed with water, saturated solution of sodium hydrogencarbonate, and water, successively, and dried (MgSO4), followed by evaporation of the solvent. The residue was subjected to silica gel (60 g) column chromatography, and eluted with hexane-ethyl acetate (5:1), to give the above-captioned compound as colorless solid. Yield: 1.93 g (97%).