Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[O:18])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH3:19]N(C=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=3)[N:8]2[CH3:19])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A flask is charged with 5-(6-chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde (Example 104, 7.8 g, 28.9 mmol), Mel (5.33 g, 37.5 mmol) and DMF (300 mL), and 60% NaH in mineral oil (1.386 g, 34.6 mmol) is added at 0° C. The mixture is stirred for 2 h. Water (100 mL) is added. The mixture is extracted with EtOAc twice and the combined organic phase is washed with water (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography with a 0 to 2% methanol-DCM gradient to give 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole. MS (ESI) m/z 271.0, 272.9 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH2:20]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH:21]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:20]2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCc2cccc(OCc3ccccc3)c2)C1
Agent: [Pd]
Solvent: CO
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCCCc2cccc(O)c2)C1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
(RS)-4-{1-[4-(3-Benzyloxy-phenyl)-butyl]-pyrrolidine-3-sulfonyl}-phenol (88.4 mg, 0.2 mmol) and Pd/C (40 mg, 10% Pd on charcoal) in MeOH (5 ml) were refluxed for 2 hours under an atmospheric pressure of hydrogen. The reaction mixture was then cooled to room temperature, the catalyst was filtered and the filtrate was concentrated. The residue was chromatographed over silica gel (CH2Cl2—MeOH, 19:1) to provide (RS)-4-{1-[4-(3-hydroxy-phenyl)-butyl]-pyrrolidine-3-sulfonyl}-phenol (53 mg, 69%) as a light beige solid, MS: m/e=376.3 (M+H+).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11]1O[CH:12]1[CH3:13].S(=O)(=O)(O)O>>[CH2:1]([O:8][CH2:13][C:12]1[CH:11]=[CH:4][CH:3]=[CH:2][CH:1]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CO1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2297.75 g (21.24 moles) of benzyl alcohol was placed in a dry, stirred pressure vessel fitted with a nitrogen inlet. A catalytic amount (6 g) of KOH was added as a 40% aqueous solution. The vessel was purged with nitrogen and heated to 110° C. Vacuum was applied for 1 hour to remove the water vapors from the headspace of the vessel, and the mixture was further heated to 130° C. After 3702.25 g (63.74 moles) of propylene oxide were added, the reaction mixture was stirred for additional 3 hours to complete the reaction. The progress of the reaction was monitored by the uptake of the reagent and the measurement of the pressure in the vessel. The reaction mixture was cooled to 110° C., and a vacuum was applied for approximately 1 hour. To neutralize KOH in the reaction mixture, 29 g of 25% sulfuric acid was added. The mixture was stirred for 10 minutes, and the pH was adjusted to 5.7. Upon cooling, PPG-3 Benzyl Ether, a thin light yellow liquid, was isolated as the major product.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].Cl.[CH3:16][C@@H:17]([NH2:22])[C:18]([F:21])([F:20])[F:19].C(O)(=O)C>CO>[CH3:16][C@@H:17]([NH:22][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C[C@@H](N)C(F)(F)F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NCc1ccc(C#N)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
Add sodium cyanoborohydride (3.36 g, 53.5 mmol) to a solution of 4-cyanobenzaldehyde (1.75 g, 13.35 mmol) and (R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (2 g, 13.37 mmol) in methanol (17 mL) containing acetic acid (1.53 mL, 26.75 mmol). Stir the mixture at room temperature overnight. Partition the mixture between 1N aqueous NaOH/DCM (1:1, 500 mL) and extract the aqueous layer twice with DCM. Dry the combined organic extracts over MgSO4, concentrate in vacuo and purify by chromatography on silica gel (120 g) eluting with hexane/EtOAc (19:1, 9:1, 85:15 and 4:1) to obtain the desired intermediate (0.83 g, 27%). MS (ES+) m/z: 229 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]5[CH2:29][O:28]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]([OH:28])[CH2:29][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCC4CO4)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CC(O)COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Yield: 56.9 %

Procedure:
A mixture of 0.021 g (0.05 mmole) of 4-(3-chloro-phenyl)-2-(6-oxiranylmethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.39a), 0.5 mL of dimethylformamide, 0.035 g (0.25 mmole) of potassium carbonate and 0.017 mL (0.15 mmole) of 1-methyl-piperazine was heated at 100 degrees for 5 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 20:80-100:0) to give 0.015 g of 4-(3-chloro-phenyl)-2-{6-[2-hydroxy-3-(4-methyl-piperazin-1-yl)-propoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.39) as a white powder. MH+/Z=527
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[CH:9][CH:8]=2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[C:32]([CH2:38][CH2:39][CH3:40])=[N:31][C:30]([OH:41])=[CH:29]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:15]([O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[C:4]([CH2:3][C:29]1[C:28]3[C:33](=[CH:34][C:35]([O:36][CH3:37])=[C:26]([O:25][CH3:24])[CH:27]=3)[C:32]([CH2:38][CH2:39][CH3:40])=[N:31][C:30]=1[OH:41])=[CH:13]2)[CH3:16]
Reactant: CCOc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OCC)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-(3-(chloromethyl)-6-ethoxyquinolin-2-ylamino)ethyl)acetamide hydrochloride SMA 44092 (231 mg, 0.65 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (159 mg, 0.65 mmol) followed by a 2 N aq. LiOH solution (0.65 mL, 1.29 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) provided N-(2-(6-ethoxy-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of 0.49 M HCl in MeOH (2 mL) and the solution was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford N-(2-(6-ethoxy-3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide dihydrochloride 88 as a yellow solid (25 mg, 6% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3ccccc3n2)CC1

Procedure:
A mixture of 9.1 mmol 2-chloroquinoxaline, 10.0 mmol piperazine-1-carboxylic acid tert-butyl ester, 22.8 mmol potassium carbonate and 2.1 mmol potassium iodide in 20 ml of toluene was refluxed overnight. The reaction mixture was cooled, poured into water and extracted 3 times with ethyl acetate. The organic phase was dried, evaporated and the title compound was crystallised from methanol. Yellowish solid.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([C:18]([NH2:20])=O)[N:3]=1.P(Cl)(Cl)([Cl:23])=O>C(OCC)(=O)C>[Cl:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([C:18]#[N:20])[N:3]=1
Reactant: NC(=O)c1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
4-Hydroxy-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carboxylic acid amide (340 mg) was heated to reflux in ethyl acetate (2 ml) and phosphorous oxychloride (8 ml) for four hours. Solvent was evaporated under reduced pressure and the remaining residue dissolved in ethyl acetate (30 ml) and washed with saturated sodium chloride (20 ml). Organics were separated, dried over sodium sulphate and solvent was removed to yield product 4-chloro-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (362 mg) as a brown solid. This product was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)nc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(1-propylimidazol-2-yl)methyl]sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.66 g) was dissolved in methylene chloride (20 ml), and a solution of m-chloroperbenzoic acid (0.26 g) in methylene chloride (13 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(1-propylimidazol-2-yl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 293) (0.39 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH3:23][N:24]([CH3:28])[C:25]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)[CH2:11][CH2:12]1)=[O:26]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Yield: 94.7 %

Procedure:
A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.30 g, 1.0 mmol), dimethylcarbamic chloride (0.09 ml, 1.0 mmol) and triethylamine (0.16 ml, 2.0 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. 5-(4-dimethylcarbamylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (0.35 g, 95%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.88 (s, 6H), 3.31 (dd, J=1.5, 6.4 Hz, 4H), 3.42 (dd, J=1.5, 6.4 Hz, 4H), 6.34 (dd, J=2.6, 9.6 Hz, 1H), 6.41 (d, J=2.6 Hz, 1H), 7.26-7.47 (m, 5H), 8.17 (d, J=9.6 Hz, 1H), 9.88 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 38.9, 46.6, 47.0, 60.9, 96.5, 106.2, 125.0, 126.0, 129.4, 130.2, 139.4, 145.9, 156.0, 164.8.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:30][N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37](Cl)=[O:38])=[N:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:30][N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37]([NH:23][C:14]2[CH:15]=[C:16]([Sn:19]([CH3:20])([CH3:22])[CH3:21])[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:38])=[N:32]1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: Cc1cn(C)nc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(Phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (250 mg) was dissolved in DCM (10 ml) and pyridine (0.051 ml) was added. 1,4-Dimethyl-1H-pyrazole-3-carbonyl chloride (100 mg) in DCM (5 ml) was added dropwise. The reaction was stirred at RT for 2 h. After this time saturated sodium bicarbonate aq (25 ml) was added and the reaction was stirred vigorously for 5 min before the DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DCM, and then applied to the top of a 20 g silica cartridge preconditioned with cyclohexane. The column was washed with 50% cyclohexane:ether (100 ml), before the compound was eluted with ether, then 5% methanol in ether. The product containing fractions were evaporated to dryness to afford the title compound, 310 mg.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[C:3]=1[Cl:13].C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C>O1CCCC1>[Cl:13][C:3]1[C:4]2[O:8][C:7]([F:10])([F:9])[O:6][C:5]=2[CH:11]=[CH:12][C:2]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: FC1(F)Oc2ccc(Br)c(Cl)c2O1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3c(c2Cl)OC(F)(F)O3)OC1(C)C
Temperature: -25 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
5-Bromo-4-chloro-2,2-difluorobenzo[d][1,3]dioxole (1.0 g, 3.7 mmol) was dissolved in dry tetrahydrofuran (12 mL), cooled to −20 to −30° C. and treated in portions with isopropylmagnesium chloride-lithium chloride complex solution (1.3 M; 3.1 mL, 4.1 mmol). After 90 min at −20 to 0° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (830 μL, 750 mg, 4.1 mmol) was added, and stirring was continued at 0-20° C. for 90 min. The reaction was quenched by addition of saturated NH4Cl (10 mL), and the mixture was extracted with ethyl acetate (30 mL). The aqueous phase was extracted again with ethyl acetate (15 mL), and the combined organic phases were washed with saturated NaCl (15 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (1.2 g, ca. 100%): 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.1 Hz, 1H), 6.99-6.94 (m, 1H), 1.36 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.62 (s); EIMS m/z 318.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:8][C:7]=1[N+:26]([O-:28])=[O:27].O.[OH-].[Li+]>O1CCCC1.O>[CH2:30]([O:29][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:8][C:7]=1[N+:26]([O-:28])=[O:27])[C:3]([OH:32])=[O:2])[CH3:31]
Reactant: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1[N+](=O)[O-])C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1[N+](=O)[O-])C(=O)O
Yield: 92.9 %

Procedure:
2-Ethoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)-2-nitrophenyl]propanoic acid methyl ester (described in Example 35) (0.8 g; 1.71 mmole) was dissolved in tetrahydrofuran (8 ml). A solution of lithium hydroxide monohydrate (0.086 g; 2.05 mmole) in water (8 ml) was added under stirring. The reaction mixture was stirred at room temperature for 5 hours and then evaporated to remove tetrahydrofuran. The residue was extracted with diethyl ether, acidified to pH˜3 with hydrochloric acid (10%) and extracted with ethyl acetate. The organic phase was washed with water and brine, dried with magnesium sulfate. The solvent was removed and 0.72 g (93% yield) of 2-ethoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)-2-nitropheny]propanoic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36](OS(C(F)(F)F)(=O)=O)=[CH:35][CH:34]=1.[C:47]([C:49]1[CH:53]=[CH:52][S:51][CH:50]=1)#[CH:48]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:48]#[C:47][C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)=[CH:35][CH:34]=1
Reactant: C#Cc1ccsc1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccsc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The compound was obtained starting from 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzene and 3-ethynyl-thiophene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][C@H:9]1[CH:15]=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of Compound 2b (1.33 g; 5.61 mmol) in CH2Cl2 (20 mL) was added 3,3,3-triacetoxy-3-iodophthalide (3.56 g; 8.39 mmol) at ambient temperature. The reaction mixture was stirred at room temperature for 2 h. The resultant mixture was diluted with EtOAc, and washed sequentially with saturated NaHCO3(aq) and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2c (0.58 g; 44% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 9.59 (d, 1H), 4.28-4.45 (m, 1H), 3.77-3.89 (m, 2H), 2.43-2.63 (m, 2H), 1.46-1.51 (m, 9H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:32]([O:34][CH:35]([O:42][CH2:43][CH3:44])[C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH3:33]>C1COCC1.O>[CH2:43]([O:42][CH:35]([O:34][CH2:32][CH3:33])/[C:36](/[O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)=[CH:37]/[C:38]([O:40][CH3:41])=[O:39])[CH3:44]
Reactant: CCOC(C#CC(=O)OC)OCC
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)/C(=C/C(=O)OC)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 2.43 g (15 mmol) of 4-trifluoromethylphenol in 40 mL of THF was added 1.12 g (20 mmol) of powdered KOH and 5.28 g (20 mmol) of 18-crown-6. The solution was heated to 50° C. for 15 minutes, whereupon 3.73 g (20 mmol) of methyl 4,4-diethoxy-2-butynoate was added. The mixture was stirred for 30 minutes, then allowed to cool to room temperature. The solution was then poured into water, and extracted 3 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude oil was subjected to column chromatography on SiO2. Elution with 20% ethyl acetatehexane yielded 2.31 g (65%) of an oil, used in the next step without further purification.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10]OCC1C=CC=CC=1)=O)(C)(C)C.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[CH2:10][C@@H:9]([NH:8][CH3:6])[CH2:19][OH:21]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: CN[C@@H](CO)CN(C)C

Procedure:
By using N-(t-butoxycarbonyl)-O-benzyl-(L)-serine (2.50 g) and 50% aqueous dimethylamine (3 ml) as starting materials, the title compound (0.58 g) was obtained in the same manners as those of Reference Example 34, (1), Reference Example 107, (2) and Reference Example 7, (2).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19][CH2:20][CH2:21][C:22]#[N:23]>>[C:22]([CH2:21][CH2:20][O:19][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:23]
Reactant: N#CCCO
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: N#CCCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 113° C. and MS:.m/e=308.3 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and 3-hydroxy-propionitrile.