Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[NH:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:23]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:14]([CH3:23])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)n[nH]1
Reactant: CI
Product: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)nn1C

Procedure:
Using methyl 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate and iodomethane, and in the same manner as in Example 8, step B, the title compound was obtained.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:18]=1.O>O1CCCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:31]=[CH:30][C:27](/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][CH:25]=2)[CH:18]=1
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
In 6 ml of anhydrous tetrahydrofuran was suspended 700 mg of sodium hydride (purity: 50%), and into the suspension was dropped a mixture of 3.65 g of ethyl diethylphosphonoacetate and 3 ml of anhydrous tetrahydrofuran at a temperature of 30° to 35° C., after which the resulting mixture was subjected to reaction at room temperature for one hour. To the reaction mixture was added dropwise a mixture of 3.0 g of 4-(pyridin-3-yloxy)benzaldehyde and 3 ml of anhydrous tetrahydrofuran at room temperature, and the temperature thereof was gradually elevated. The mixture was subjected to reaction at 60° C. for 15 minutes. Subsequently, the reaction mixture was cooled to room temperature, and 20 ml of water was added to the mixture, after which the resulting mixture was subjected to extraction with 20 ml of ethyl acetate. The extract was washed with 10 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform], to obtain 3.64 g (yield 89.8%) of colorless, oily ethyl (E)-3-[4-(pyridin-3-yloxy)phenyl]acrylate.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:11][CH:10]=1.[C:36]([O:39][CH2:40][CH2:41]Br)(=[O:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:31][CH2:32][N:33]([CH2:41][CH2:40][O:39][C:36](=[O:38])[CH3:37])[CH2:34][CH2:35]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:11][CH:10]=1
Reactant: CC(=O)OCCBr
Reactant: O=C(NN1CCNCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OCCN1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
5-(4-Chloro-phenyl)-N-piperazin-1-yl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxamide trifluoroacetate (1:1) (200 mg, 378 μmol, example 13b) was combined with acetonitrile (10 mL) to give a yellow solution. To this solution 2-bromoethyl acetate (760 mg, 500 μl, 4.55 mmol) and K2CO3 (157 mg, 1.13 mmol) were added successively. The reaction mixture was heated to 60° C., stirred for 20 h, filtered through a Celite® pad after cooling to ambient temperature and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20 g, 0% to 50% methanol in ethyl acetate) to give the title compound (107 mg, 57%) as white solid; LC-MS (UV peak area/ESI) 97.8%, 501.1510 (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][NH2:14])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)[CH3:11]
Reactant: CCCCC(CC)CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCC(CC)CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of cyanuric chloride (0.2 mol, 36.8 g) in acetone (300 ml) is introduced dropwise into crushed ice (100 g) in a round-bottom flask, with vigorous stirring, followed by a solution of 2-ethylhexylamine in acetone (100 ml), while maintaining the temperature between 0° and 5° C., and finally a solution of sodium carbonate (11.2 g, 0.1 mol) in 300 ml of water. The mixture is left stirring for one hour at 0°-5° C. The oil is extracted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate. After evaporation of the solvent, 2-(2-ethylhexylamino)-4,6-dichloro-s-triazine (52 g, yield=95%) having the following characteristics, is obtained:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23].Br.Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[N:21]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[N:20]=[N:19][N:18]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23]
Reactant: BrCCCCc1cccnc1
Reactant: CCCc1c(OCCCCCc2nnn[nH]2)ccc(C(C)=O)c1O
Agent: Br
Product: CCCc1c(OCCCCCc2nnnn2CCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
1-[2-Hydroxy-3-propyl-4-[5-(1H-tetrazol-5-yl)pentyloxy]phenyl]ethanone was allowed to react with 3-(4-bromobutyl)pyridine hydrobromide according to procedure B and the product was purified by high pressure liquid chromatography to give 1-[2-hydroxy-3-propyl-4-[5-[1-[4-(3-pyridinyl)butyl]-1H-tetrazol-5-yl]pentyloxy]phenyl]ethanone, which is the N-1 isomer, and 1-[2-hydroxy-3-propyl-4-[5-[2-[4-(3-pyridinyl)butyl]-2H-tetrazol-5-yl]pentyloxy]phenyl]ethanone, which is the N-2 isomer.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]Cl)#[N:8]>ClC1C=CC=CC=1>[N:1]1([C:7]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1SCl
Reactant: C1CNCCN1
Solvent: Clc1ccccc1
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
86.2 g (1.00 mol) of piperazine and 7.5 g of chlorobenzene were placed in a 500 ml four-neck flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser and 42.4 g (0.25 mol) of molten 2-cyanobenzenesulfenyl chloride was added dropwise thereto at about 130° C. over one hour while stirring, followed by stirring for four hours to complete the reaction. The excess piperazine was removed with water, followed by acidification with hydrochloric acid and extraction into the aqueous layer. The aqueous layer was basified with an aqueous sodium hydroxide solution to obtain 40.9 g (m.p.: 89°-90° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. The yield starting from 2-cyanobenzenesulfenyl chloride was 74.7%.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>>[CH2:5]([O:4][CH2:3][CH2:2][N:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[C:21]([CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)=[O:22])[CH:6]=[CH2:7]
Reactant: C=CCOCCO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Product: C=CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21

Procedure:
Prepare by the method of Preparation 4 using allyl hydroxyethyl ether and 1-(t-butoxycarbonyl)-4-(1 H-benzoimidazole-2-carbonyl)-piperidine to give the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[CH:7]([C:13]([O:15]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:14])[CH:6]1[CH3:29])(=[O:3])[CH3:2].C(Cl)(Cl)Cl>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[CH:7]([C:13]([OH:15])=[O:14])[CH:6]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1C(C)C(C(=O)O)N2C(=O)C[C@@H]12
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Benzhydryl 1-acetoxy-2-methylcarbapenam-3-carboxylate (26 mg.) was dissolved in 3 ml. of ethyl acetate. Hydrogenation catalyst (10% palladium on carbon, 26 mg.) was added and the reaction mixture hydrogenated at room temperature and atmospheric pressure for 1 hour, at which time tlc (4:1 chloroform:ethyl acetate) indicated no starting material remained. The catalyst was recovered by filtration and the filtrate evaporated in vacuo to yield 1-acetoxy-2-methylcarbapenam-3-carboxylic acid [15 mg.; Rf 0.0 (4:1 chloroform:ethyl acetate); ir (CH2Cl2) 1770, 1730 cm-1 ].
Reaction SMILES: [OH:1][CH:2]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]2[C:11]3[CH:10]=[C:9]([CH3:17])[CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[OH:1][CH:2]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]2[C:11]3[CH:10]=[C:9]([CH3:17])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(=O)N(C)C(O)C3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC(O)N(C)C1=O

Procedure:
The title compound is prepared from a mixture of 3,4-dihydro-3-hydroxy-2,8-dimethyl-2H-pyrido[4,3-b]indol-1(5H)-one, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:3]=1.[Li]C(C)(C)C.[F:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=[O:48]>C1COCC1.CCCCC>[F:43][C:44]1[CH:45]=[C:46]([CH:47]([OH:48])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=5)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:3]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(C(O)c3cccc(F)c3)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 52.5 %

Procedure:
To a solution of toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol, prepared as exemplified in method 6) in THF (2 mL) at −90° C. under nitrogen atmosphere was added a solution of tBuLi in pentane (1.7 M, 90 uL) dropwise. After stirring for 5 min, 3-fluoro-benzaldehyde (40 uL, 0.38 mmol) was added and the reaction mixture was slowly warmed up to 10° C. over 2 h, then quenched with a saturated solution of ammonium chloride and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 26 mg of toluene-4-sulfonic acid 3-[3-[(3-fluoro-phenyl)-hydroxy-methyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo [2,3-b]pyridine-5-yl]-phenyl ester. The material was dissolved in dichloromethane (0.3 mL) under nitrogen atmosphere. Triethylsilane (24 uL, 0.149 mmol) was added, followed by boron trifluoride etherate (7 μL, 0.149 mmol) dropwise. After stirring for 15 h, the reaction was quenched with a saturated solution of sodium bicarbonate and extracted with dichloromethane three times. The extracts were combined and concentrated under vacuum. The crude was treated with 2 mL of EtOH and 2 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 70° C. for 1 h. The mixture was acidified to pH 4 with 1 N aqueous HCl, and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(3-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a beige solid (8 mg, 66% yield). 1H NMR (500 MHz, DMSO-d6) δ 4.11 (s, 3H), 6.74 (dd, J=2.5, 8.5 Hz, 1H), 6.97 (dt, J=2.0, 8.5 Hz, 1H), 7.00 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.13 (d, J=10.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.30 (q, J=8.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 9.56 (broads, 1H), 11.6 (s, 1H). MS: m/z 319 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][O:26][C:16]1[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[CH3:25]
Reactant: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The product from step 1 was dissolved in MeOH (18.8 mL) and HCl was added (4M in dioxane, 18.8 mL, 75.2 mmol). The reaction was stirred at room temperature for 2 h, then concentrated. CH2Cl2 was added and this solution was washed with sat. aq. NaHCO3, then brine. The organic was dried over MgSO4, filtered, and concentrated to give the product (1.30 g, 96% yield) as an oil.
Reaction SMILES: [Na].[OH:2][CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH3:16][C:17]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)[O:19][N:18]=1>C1C=CC=CC=1>[CH:14]1[C:15]2[CH:3]([O:2][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:20]3[O:19][N:18]=[C:17]([CH3:16])[CH:21]=3)[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cc(CCCCCCCBr)on1
Reactant: OC1c2ccccc2-c2ccccc21
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cc(CCCCCCCOC2c3ccccc3-c3ccccc32)on1

Procedure:
The sodium salt of 9-hydroxyfluorene was made by reacting sodium metal in anhydrous benzene before the etherization with 7-(3-methylisoxazol-5-yl)-heptyl bromide in the same solvent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(F)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred solution of methyl 5-chloro-2-fluoro-4-methylbenzoate (Preparation 20, 340 mg, 1.68 mmol) in 12 mL of dioxane/water (5:1) was added aqueous sodium hydroxide (5 M, 1.63 mL, 8.39 mmol). The reaction mixture was stirred at room temperature for 18 hours and then evaporated in vacuo. The resulting residue was suspended in water and extracted with diethyl ether (3×20 mL). The aqueous layer was cooled in an ice bath, acidified with aqueous hydrochloric acid (6 M) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (2×20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to yield the title compound as a white solid (266 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1ccc(F)cc1[N+](=O)[O-]
Yield: 89.9 %

Procedure:
Dimethyl 4-fluoro-2-nitrophenylmalonate (5.0 g) was heated to reflux in 20 mL of 6 N hydrochloric acid for 24 hours. The reaction was cooled and the white solid collected by vacuum filtration, washed with water and dried to give 3.3 g (87% yield) of 4-fluoro-2-nitrophenylacetic acid. Thin layer chromatography (ethyl acetate:hexane 1:2, silica gel) Rf 0.6.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[CH:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.[C:33]([O:37][C:38]([N:40]([CH3:49])[C@H:41]([C:46](O)=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([NH:27][C:46](=[O:47])[C@@H:41]([N:40]([CH3:49])[C:38](=[O:39])[O:37][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:42][CH2:43][S:44][CH3:45])[CH2:25][CH2:26]3)[CH:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: CSCC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](C(=O)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexanamine (700 mg) and N,N-dimethylformamide (7.0 mL) were added N-(tert-butoxycarbonyl)-N-methyl-L-methionine (622 mg), 1H-benzotriazol-1-ol (319 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (452 mg), followed by stirring at room temperature overnight. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=90:10-40:60) to obtain tert-butyl [(2S)-1-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-(methylsulfanyl)-1-oxobutan-2-yl]methylcarbamate (859 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([OH:12])[C:5]=1[CH3:13].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5]([CH3:13])=[C:6]([OH:12])[CH:7]=[C:8]([O:10][CH3:11])[C:9]=1[Br:15]
Reactant: COC(=O)c1cc(OC)cc(O)c1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C)c(O)cc(OC)c1Br
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 23.5 g of 3-hydroxy-5-methoxy-2-methylbenzoic acid methyl ester in 1.3 1 of chloroform was added over 1 h at -50° to -60° C. a solution of 19.2 g of bromine in 0.2 l of chloroform. Stirring was continued for 2.5 h at -40° C. and for 2 h at 0° C. The reaction mixture was evaporated in vacuo at 0° C.; the residue was dissolved in a mixture of toluene/ethanol (1:1, v/v) and the solvent was again evaporated in vacuo. This procedure was repeated twice With toluene/ethanol (1:1, v/v), and finally once with toluene. The residue was chromatographed on silica gel using ethyl acetate as eluent and the pure product was crystallized from ethyl acetate to yield 28 g of 2-bromo-3-methoxy-5-hydroxy-6-methylbenzoic acid methyl ester as white crystals, m.p. 105°-110° C.
Reaction SMILES: [Br:1][C:2]([C@H:5]1[C@H:9]([OH:10])[O:8][C:7](=[O:11])[CH2:6]1)([CH3:4])[CH3:3].[CH:12](O)([CH3:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]([C@H:5]1[C@H:9]([O:10][CH:12]([CH3:14])[CH3:13])[O:8][C:7](=[O:11])[CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)(Br)[C@@H]1CC(=O)O[C@H]1O
Reactant: CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)O[C@@H]1OC(=O)C[C@H]1C(C)(C)Br
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 1.95 g of dl trans 4-(2-bromo-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one, 2 ml of isopropanol, 100 mg of p-toluene sulfonic acid and 30 ml of benzene was stirred at room temperature for 60 hours and was then washed with aqueous sodium bicarbonate solution. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure to obtain 2 g of dl trans 4-(2-bromo-prop-2-yl)-5-isopropyloxy-tetrahyrofuran-2-one as an oily product which was used as is for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[CH:5]=1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH2:10][O:11][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[CH:5]=1
Reactant: COC(=O)c1cc(CO)cc(-c2cccc(C#N)c2)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccccc2)cc(-c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
30 mg of the 3-(3-cyanophenyl)-5-(hydroxymethyl)benzoic acid methyl ester produced in the production example 4 was dissolved in dry THF in the atmosphere of nitrogen, mixed with 10.5 mg of phenol, 35.4 mg of triphenylphosphine and 21 μl of azodicarboxylic acid diethyl ester at room temperature, and then stirred at room temperature overnight. The solvent was distilled away, and the residue was purified by silica gel chromatography to obtain 31 mg (77%) of the title compound (colorless, crystal).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([O:15][CH2:16][CH:17](O)[CH2:18][O:19][CH2:20][CH3:21])[CH3:14]>>[C:1]([O:12][CH:17]([CH2:18][O:19][CH2:20][CH3:21])[CH2:16][O:15][CH2:13][CH3:14])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOCC(O)COCC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OC(COCC)COCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1,3-diethoxy-2-propanol as starting materials to give the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[Cl:16]N1C(C)(C)C(=O)N(Cl)C1=O.O>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:16]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Solvent: CC#N
Solvent: O
Product: CC(C)OC(=O)c1nc(Cl)c(F)c(N)c1Cl
Yield: 163.1 %

Procedure:
Propan-2-yl 4-amino-6-chloro-5-fluoropicolinate (634 milligrams (mg), 2.73 mmol) was slurried in acetonitrile (11 mL). 1,3-Dichloro-5,5-dimethyl-hydantoin (303 mg, 1.54 mmol) was added as a solid, and the reaction mixture was stirred at reflux for 2.5 h. Additional 1,3-dichloro-5,5-dimethylhydantoin (50 mg, 0.25 mmol) was added, and the reaction mixture was stirred at reflux for an additional hour. Water (20 mL) was added. Acetonitrile was then removed by rotary evaporation to give an oily, yellow solid which was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with 10% sodium bisulfite (NaHSO3) solution, satd aq NaHCO3 solution and brine, dried (MgSO4) and concentrated under reduced pressure to provide a pale orange solid (671 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 5.29 (septet, J=6.3 Hz, 1H, CHMe2), 5.19 (br s, 2H, NH2), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 19F NMR (376 MHz, CDCl3) δ −136.5.