Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][C:14]=1[NH:22][CH2:23][CH:24]([CH3:26])[CH3:25]>C1COCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9](=[O:11])[CH2:8][NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:14]([NH:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:15]=1)[CH3:21]
Reactant: CCOc1ccc(N)c(NCC(C)C)c1
Reactant: O=C(O)CNc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(NC(=O)CNc2ccccc2)c(NCC(C)C)c1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
A solution of N-phenylglycine (1.51 g, 0.01 mol) and N,N′-carbonyldiimidazole (1.62 g, 0.01 mol) in THF (25 mL) was heated at 50° C. for 30 min under Ar. A solution of 55 (2.08 g, 0.01 mol) in THF (50 mL) was then added over 30 min, and the resulting mixture was heated at 70° C. overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 (2×100 mL) and brine (100 mL). The organic phase was filtered through phase separation filter paper and concentrated in vacuo to give 3.0 g of a red oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:7]=[C:8]([C:22]2[N:23]=[C:24]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[C:25]3[CH2:30][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[NH:12][C:13](OC1C=CC=CC=1)=[O:14]>>[CH2:34]([O:33][C:31]([N:29]1[CH2:30][C:25]2[C:24]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])=[N:23][C:22]([C:8]3[CH:9]=[CH:10][C:11]([NH:12][C:13]([NH:1][CH2:2][CH2:3][OH:4])=[O:14])=[C:6]([F:5])[CH:7]=3)=[N:27][C:26]=2[CH2:28]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Oc4ccccc4)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Reactant: NCCO
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 36 %

Procedure:
Method as described for example 51, using 2-aminoethanol and (S)-ethyl 2-(3-fluoro-4-((phenoxycarbonyl)amino)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate as starting materials. The mixture was reduced in vacuo and purified by flash SCX2 chromatography affording the title compound (10 mg, 0.020 mmol, 36%).
Reaction SMILES: Br[CH:2]([C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]#[N:4].[NH2:11][C:12]([NH2:14])=[S:13]>>[NH2:14][C:12]1[S:13][C:2]([C:3]#[N:4])=[C:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[N:11]=1
Reactant: CC(C)(C)C(=O)C(Br)C#N
Reactant: NC(N)=S
Product: CC(C)(C)c1nc(N)sc1C#N
Yield: 66.3 %

Procedure:
Using α-bromo-pivaloylacetonitrile and thiourea as the raw materials, the same operation as the Example 181(1) gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:33](=[O:36])[CH:34]=[CH2:35])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (7.1 g, 21 mmol) was dissolved in DCM (70 ml). To this was added diisopropylethylamine (7.3 ml, 42 mmol) in one portion followed by the drop wise addition of acryloyl chloride (1.54 ml, 19 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 60% heptane, 40% ethyl acetate) to give the title compound (5.3 g, 20% yield) as a pale yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14](F)=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1.[Br:28]C1C(Cl)=NC(Cl)=NC=1>>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([Br:28])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:10]=2)[CH2:5][CH2:4]1
Reactant: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2F)CC1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2Br)CC1

Procedure:
The titled compound was synthesized analogously as compound 6-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one, by using 5-bromo-2,4-dichloropyrimidine. MS 431.4 and 433.3 (M+N, Br pattern); UV 222.3, 263.9 nm.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8])[CH3:2].[CH2:12]=O>C(O)=O>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:12][NH:8][CH2:7][CH2:6]2
Reactant: C=O
Reactant: COc1cccc(CCN)c1
Solvent: O=CO
Product: COc1ccc2c(c1)CCNC2
Reaction time: 24 h

Procedure:
To the solution of 3-methoxylphenethylamine (15.1 g, 0.1 mol) in formic acid (100 ml) at rt is added paraformaldehyde (3.0 g, 0.1 mol, 1.0 eq.). The resulting mixture is stirred at 40˜50° C. for 24 hr. After the reaction is completed, the formic acid is evaporated and the residue is diluted with water (200 ml), basified with sodium hydroxide solution (10.0N, 10.5 ml) to pH=10, and extracted with EtOAc. The combined organic layers are washed with water and brine and dried over sodium sulfate, and the solvent is removed under reduced pressure to give the title compound. MS (+VE) m/z 164.1 (M++1).
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[NH:25][OH:26].ClC(Cl)(Cl)C(O)=O>CC(C)=O>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[N:25]([OH:26])[CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=C(NO)Nc1ccccc1Br
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1Br)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 48 h

Procedure:
560 mg (2 mmol) of 4-hydroxycyclophosphamide in 10 ml of acetone were treated with 460 mg of 3-o-bromophenyl-1-hydroxyurea and a catalytic amount of trichloroacetic acid and let to stand at -25° C. After 2 days, the crystals were drawn off by suction and recrystallized from acetone.
Reaction SMILES: [Na].[CH2:2]([O:9][P:10]([O-:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].C(OP([O-])OCC1C=CC=CC=1)C1C=CC=CC=1.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CCOCC.C(O)C>[CH2:43]([O:42][C:40]([P:10](=[O:19])([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:41])[CH3:44]
Reactant: CCOC(=O)Cl
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)P(=O)(OCc1ccccc1)OCc1ccccc1

Procedure:
Ethanol (4.6 g) was added to a fine suspension of sodium metal (2.25 g) in dry ether (200 ml) under an atmosphere of nitrogen. The mixture was heated for 8 hours, after which dibenzylphosphite (25.7 g) in dry ether (50 ml) was added. After standing over-night the dibenzylphosphite sodium salt was added over a period of 2 hours to a cold solution of ethyl chloroformate (10.8 g) in ether, under an atmosphere of nitrogen. The reaction was heated at reflux for 1 hour, cooled, washed with water, a NaCl solution and dried over Na2SO4. The ether was evaporated. After evaporating and discarding components volatile at 0.01 mm and 150° C. the residue was collected (13 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][S:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:40][C:39]1[CH:43]=[CH:44][C:36]([S:35][CH3:34])=[CH:37][CH:38]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CSc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CSc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(F)c23)cc1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-(methylthio)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 451 (M+NH4) 1H-NMR (DMSO-d6) δ 2.42 (s, 3H), 3.23-3.31 (m, 1H), 3.37-3.48 (m, 3H), 3.62-3.70 (m, 2H), 4.04 (s, 2H), 4.54 (t, J=5.7 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.7 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 6.74 (dd, J=11.3, 8.0 Hz, 1H), 7.07 (td, J=8.0, 5.2 Hz, 1H), 7.15-7.22 (m, 4H), 7.24 (s, 1H), 7.36 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:32]=[C:33]([C:36]2([OH:47])[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]2)[S:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:43]([O:42][C:40]([N:38]1[CH2:37][C:36]([C:33]2[S:34][CH:35]=[C:31]([C:15]3[C:6]([O:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:25]([O:27][CH3:28])=[O:26])[C@@H:10]([CH3:29])[CH2:9][CH2:8]4)[N:32]=2)([OH:47])[CH2:39]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2nc(Br)cs2)C1
Reactant: COC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)c(OC3CCC3)c2CC[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3csc(C4(O)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Yield: 69.1 %

Procedure:
A solution of (S)-methyl 5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.400 g, 1.00 mmol), tert-butyl 3-(4-bromothiazol-2-yl)-3-hydroxyazetidine-1-carboxylate (0.367 g, 1.10 mmol), sodium carbonate (0.212 g, 2.00 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.082 g, 0.10 mmol) in 1,4-dioxane (10 mL) and water (3 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 30% ethyl acetate/petroleum ether) to afford (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.366 g, 69%) as a yellow solid. MS (ESI, pos. ion) m/z 530 [M+H]+.
Reaction SMILES: Cl[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14].OC[C@@H](C)CN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.ClC[C@H](C)CO>>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:18]2[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([CH3:11])[CH3:28])[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O[C@@H](CCl)c1ccccc1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)CO)CC2)c1
Agent: C[C@H](CO)CCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (1R)-2-chloro-1-phenylethanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 367.2 (M+H)+. N-(3-{1-[(2S)-3-HYDROXY-2-METHYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using (2R)-3-chloro-2-methyl-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 319.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOCC.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>[N+:10]([C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([CH:4]=[O:5])[C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc([N+](=O)[O-])c1-c1ccccc1
Temperature: 110 °C
Yield: 82.4 %

Procedure:
A 250-mL 3-necked round-bottom flask was placed a solution of 2-chloro-3-nitrobenzaldehyde (5.3 g, 28.57 mmol, 1.00 equiv) in toluene (50 mL), phenylboronic acid (3.83 g, 31.39 mmol, 1.10 equiv), K2CO3 (7.88 g, 57.10 mmol, 2.00 equiv) in water (30 mL) and Pd(PPh3)4 (660 mg, 0.57 mmol, 0.02 equiv). The resulting mixture was heated to 110° C. for 30 hours. Upon completion, the reaction mixture was cooled and diluted with Et2O (1000 mL). After phase separation, organic layers were dried over anhydrous magnesium sulfate, filtered off and concentrated on rotary evaporator. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:50) affording 6-nitrobiphenyl-2-carbaldehyde as yellow solid (5.35 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH:12]1([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:12]1([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:7]3[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=3[F:1])=[CH:22][CH:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3CCCCC3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99.4 %

Procedure:
Following procedure A, 3,4-difluoronitrobenzene (509 mg, 3.20 mmol, 1.00 eq) and 4-cyclohexylphenol (691 mg, 3.93 mmol, 1.23 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (664 mg, 4.81 mmol, 1.50 eq) was added and the reaction mixture was stirred at room temperature for 23 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:50) to afford the title compound as pale yellow solid (1002 mg, 3.18 mmol, 99% yield). Rf=0.51 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C18H19FNO3+ [M+H]+ 316.1343. found: 316.1348. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=10.3, 2.7 Hz, 1H, aromatic H), 7.97 (ddd, J=9.1, 2.7, 1.4 Hz, 1H, aromatic H), 7.33-7.22 (m, 2H, aromatic H), 7.08-6.99 (m, 2H, aromatic H), 6.96 (dd, J=9.1, 8.0 Hz, 1H, aromatic H), 2.58-251 (m, 1H, cyclohexyl H), 1.98-1.73 (m, 5H, cyclohexyl H), 1.52-1.20 (m, 5H, cyclohexyl H). 13C NMR (101 MHz, CDCl3) δ 153.35, 152.51, 152.01, 151.90, 150.84, 145.68, 142.39, 142.32, 128.67, 120.70, 120.66, 119.73, 117.70, 117.68, 113.30, 113.08, 44.09, 34.69, 26.97, 26.21.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>C1C=CC=CC=1>[C:1]([O:11][CH2:22][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@H](O)c1ccccc1
Yield: 9528.3 %

Procedure:
A solution of 85.1 g (559 mmol) of D-mandelic acid, 65 ml(628 mmol) of benzyl alchohol, and 1.01 g (5.35 mmol) of p-toluenesulfonic acid in 700 ml of benzene was refluxed for 6.5 hours. The mixture was washed with water and concentrated. The residue was recrystallized from ether to give 123.5 g of the aimed compound D-2 in 91% yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[OH-].[K+].ClC1C=C(Cl)C=C(F)C=1O[C:13]1[CH:18]=[C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=2[Cl:28])[CH:16]=[CH:15][C:14]=1[N+:29]([O-:31])=[O:30].CCOCC>O1CCOCC1.O>[N+:29]([C:14]1[CH:13]=[CH:18][C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=2[Cl:28])=[CH:16][C:15]=1[O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)([O-:31])=[O:30]
Reactant: OC1CCOC1
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)cc(Cl)cc2Cl)cc1Oc1c(F)cc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(Oc2c(F)cc(Cl)cc2Cl)cc1OC1CCOC1
Yield: 94.5 %

Procedure:
3.9 g (0.045 mole) of 3-hydroxytetrahydrofuran, 2.5 g (0.045 mole) of potassium hydroxide and 100 ml of dioxane were mixed with stirring. To the resulting solution was added at room temperature, a solution of 7.2 g (0.015 mole) of 2,4-bis(2,4-dichloro-6-fluorophenoxy)-nitrobenzene in 20 ml of dioxane. Then, the mixture was stirred for 2 hours while maintaining at 60° to 70° C. to perform ether exchange reaction. The reaction mixture was allowed to cool, and poured into 300 ml of cold water. It was extracted with 200 ml of benzene with shaking. The benzene layer was fully washed with water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure to afford 5.5 g (94.7%) of a pale yellow oily product. The oily product was chromatographed on a silica gel column using chloroform as an eluent to afford 4 g (68.9%) of the title compound.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.C(N(C(C)C)CC)(C)C.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(#N)C>[CH2:25]([S:27]([N:6]1[CH2:5][C:4](=[CH:3][C:1]#[N:2])[CH2:7]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCS(=O)(=O)N1CC(=CC#N)C1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 1000g, 5.2 mol) in acetonitrile (7 L) and a 3 N aqueous HCl solution (7 L) was stirred at room temperature for 18 h. When HPLC showed that all the starting material (9) was consumed, the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product (10), was then suspended in acetonitrile (12 L) and the resulting suspension was cooled to 0-5° C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equiv) was then slowly added while keeping the internal temperature below 5° C. The resulting homogeneous solution was allowed to cool down to 0° C. and ethane sulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the internal temperature below 5° C. The resulting reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for overnight. When HPLC showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The bath temperature of the rotary evaporator is set to not exceed 45° C. The concentrated residue was then diluted with dichloromethane (CH2Cl2, 10 L) and the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L). The aqueous phase was back extracted with dichloromethane (CH2Cl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure. The bath temperature of the rotary evaporator was set to not exceed 45° C. The material was then loaded onto a silica gel column (SiO2, 2.5 Kg) and eluted with 20-60 % ethyl acetate in heptane to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 882 g, 968.4 g theoretical, 91% yield) as off-white solids. For 11: 1H NMR (CDCl3, 300 MHz) δ 5.46 (m, 1H), 4.77 (m, 2H), 4.70 (m, 2H), 3.05 (q, 2H), 1.39 (t, 3H) ppm; C7H10N2O2S (MW, 186.23), LCMS (EI) m/e 187 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][OH:12]
Reactant: Oc1cccc(Br)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, 3-bromophenol 5.0 g, 2-bromoethanol 5.42 g, and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30 ml, and the mixture was stirred at 100° C. After 1 hour, the reaction mixture was cooled to room temperature and partitioned by adding water and diethyl ether. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (4.85 g, 77%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])[NH:14][C:13](=[O:22])[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]3)[CH:7]=1.[N:28]([C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=1)=[C:29]=[O:30]>C(OCC)(=O)C>[CH2:38]([O:37][C:35]([C:34]1[CH:40]=[CH:41][C:31]([NH:28][C:29]([O:1][CH2:2][C:3]2[N:4]=[CH:5][N:6]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][C:17]=3[C:18]([F:20])([F:21])[F:19])[NH:14][C:13](=[O:22])[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]4)[CH:7]=2)=[O:30])=[CH:32][CH:33]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: CCOC(=O)c1cc2cc(-n3cnc(CO)c3)c(C(F)(F)F)cc2[nH]c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)OCc2cn(-c3cc4cc(C(=O)OCC)c(=O)[nH]c4cc3C(F)(F)F)cn2)cc1
Yield: 98.2 %

Procedure:
To a suspension of the compound of Example 17 (768 mg, 2.01 mmol) in ethyl acetate (30 ml) was added ethyl 4-isocyanatobenzoate (769 mg, 4.02 mmol), and the mixture was refluxed for 48 hours. After cooling with ice, the precipitated crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure, thereby obtaining 1.13 g of title compound as colorless powder. Yield 98%.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[O:14][CH3:15].[CH3:16]O.S(=O)(=O)(O)O>C(OCC)(=O)C>[CH3:16][O:12][C:11](=[O:13])[CH2:10][C:5]1[CH:4]=[C:3]([O:14][CH3:15])[C:2]([OH:1])=[C:7]([O:8][CH3:9])[CH:6]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(OC)c(O)c(OC)c1
Yield: 75 %

Procedure:
(4-Hydroxy-3,5-dimethoxy-phenyl)-acetic acid (9.5 g, 0.042 mmol) was added to methanol (260 mL) and sulfuric acid (8 mL). After completion of addition the reaction was heated at reflux overnight. The next day, the reaction mixture was cooled down and concentrated to yield a crude oil. The oil was re-dissolved in ethyl acetate, washed with water, brine, and dried over sodium sulfate, and filtered to be concentrated again. The crude material was purified using silica gel chromatography (50%:50% ethyl acetate:pentane) to yield the desired product (1.5 g, 75% yield based on recovered starting material).