Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:2]([CH3:3])[CH3:41])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCC(C)C)c4)cc23)CC1
Yield: 22.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (21 mg, 0.42 mmol) for methanamine to afford 10 mg of the title compound (22.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:34][CH2:33][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NCC1CCNCC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCC1CCNCC1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to piperidin-4-ylmethanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(piperidin-4-ylmethyl)terephthalamide. MS (Q1) 483 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[Cl:15][C:16]1[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][N:18]=3)[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Clc1cnc(N2CCNCC2)c(Cl)c1
Product: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Yield: 101.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methanesulfonylbenzoic acid (279 mg) and 1-(3,5-dichloropyridin-2-yl)piperazine (232 mg), the title compound (0.5 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH3:20][N:21]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([OH:37])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[N:22]1.O.[Cl-].[Na+]>C(Cl)(Cl)Cl.CN(C)C(=O)C>[Cl:8][C:7]1[C:2]([O:37][C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][N:28]=[C:27]3[NH:26][C:23]2[CH:24]=[CH:25][N:21]([CH3:20])[N:22]=2)=[N:3][CH:4]=[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=1
Reactant: COCCOc1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: COCCOc1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 180 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
2,3-Dichloro-5-(2-methoxyethoxy)pyridine (127 mg, 0.57 mmol) and potassium tert-butoxide (70 mg, 0.62 mmol) were added to an N,N-dimethylacetamide solution (2 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (60 mg, 0.25 mmol), and stirred overnight at 180° C. under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, then sodium chloride water and chloroform were added, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by reversed-phase liquid chromatography (YMC CombiPrep Pro C18 AS-360-CC) to obtain the entitled compound (30 mg, yield: 28%) as a pale orange amorphous solid.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[CH:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([CH2:32][N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1)#[N:2].OO.C(=O)([O-])[O-:43].[K+].[K+]>CS(C)=O>[CH3:39][N:36]1[CH2:35][CH2:34][N:33]([CH2:32][C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]3[CH:16]=[CH:17][C:12]([N:11]4[C:7]5[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:43])[C:8]=5[N:9]=[CH:10]4)=[CH:13][CH:14]=3)[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=2)[CH2:38][CH2:37]1
Reactant: CN1CCN(Cc2cc(NC(=O)Nc3ccc(-n4cnc5c(C#N)nccc54)cc3)cc(C(F)(F)F)c2)CC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(Cc2cc(NC(=O)Nc3ccc(-n4cnc5c(C(N)=O)nccc54)cc3)cc(C(F)(F)F)c2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
In 1 mL of dimethyl sulfoxide, 40 mg (0.07 mmol) of 1-[4-(4-cyano-imidazo[4,5-c]pyridin-1-yl)phenyl]-3-[3-(4-methylpiperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl]urea was dissolved, and 40 μL (0.35 mmol) of a 30% hydrogen peroxide aqueous solution and 21 mg (0.15 mmol) of potassium carbonate were added thereto and the mixture solution was stirred at 50° C. for one hour. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and a saturated sodium chloride solution in the order named and concentrated under reduced pressure. The crude product was purified by a silica gel column (dichloromethane:methanol=10:1) to obtain 19 mg (45%) of a target product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(F)cc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 32.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0290 g, 0.0628 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2-chloro-4-fluorobenzenesulfonyl chloride (0.0447 g, 0.195 mmol) to obtain 4-(2-chloro-4-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0133 g, yield 34%).
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)Cl.[S:7]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8]1>O>[Br:1][C:8]1[S:7][C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[O:21])[C:10]=2[CH:9]=1
Reactant: BrBr
Reactant: O=C1c2ccccc2CCc2sccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1c2ccccc2CCc2sc(Br)cc21
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Bromine (8.5 mL, 165 mmol) was added dropwise to a chloroform (300 mL) solution of 9,10-dihydro-1-thiabenzo[f]azulen-4-one (23.2 g, 108 mmol), and the mixture was stirred for 4 hours. Water was added to the reaction mixture, the product was extracted with ethyl acetate, the organic layer was then washed with a saturated aqueous sodium bicarbonate solution and with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate), to give 22.0 g (69%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[Cl:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][C:13]([Cl:12])([F:22])[F:23])=[CH:16][CH:17]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 6-chloro-5-iodonicotinic acid and 4-(chlorodifluoromethoxy)aniline to afford an off-white powder. HPLC (Condition 4) tR=6.47 min, UPLC-MS (Condition 3) tR=1.26 min, m/z=456.8 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([N:24]=[C:25]=[S:26])=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C.O.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:25]2[S:26][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Reactant: S=C=Nc1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnc(Nc2nc3cccnc3s2)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-(Benzyloxy)-5-bromopyridin-2-amine (10.0 g, 35.83 mmol) was added to a mixture of 2-chloro-3-isothiocyanatopyridine (6.112 g, 35.83 mmol) in DMF. The reaction was stirred at 80° C. for an hour, then at 110° C. for two hours. The reaction was cooled, diluted in water (200 mL) and 2N NaOH (35 mL), stirred for 30 minutes, and then filtered. The wet solids were washed with water, then dissolved in dichloromethane (300 mL) dried over MgSO4, and filtered. Hexane (300 mL) was added to the combined filtrates, the mixture was concentrated to 500 mL, and then mixture stirred for 30 minutes. The mixture was filtered to afford the first crop of the title compound. The mother liquor was concentrated to 500 mL (until most of the dichloromethane was removed), filtered, washed with hexanes to afford a second crop of the title compound. The two crops combined afforded the title compound (10.2 g, 68.7%) as light yellow crystals: 1H NMR (CDCl3) δ 5.14 (s, 2H), 7.30-7.33 (m, 2H), 7.42-7.48 (m, 5H), 7.87 (d, 1H), 8.10 (s, 1H), 8.40 (d, 1H), 8.67 (bs, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][CH3:25])=[C:17]([O:26][CH3:27])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[CH3:22][O:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([O:26][CH3:27])[C:18]=1[O:23][CH2:24][CH3:25])[CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOc1c(OC)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: Cl
Solvent: CCO
Product: CCOc1c(OC)cc(CN2CCNCC2)cc1OC
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To 4.1 g of N-(tert-butyloxycarbonyl)-N′-(3,5-dimethoxy-4-ethoxy-benzyl)piperazine 40 ml of 10% HCl and 10 ml of ethanol are added, the mixture is stirred for 5 h at 20° C., and evaporated to dryness in vacuum at 50÷80° C. Then 30 ml of dry acetone is added to the residue, the mixture is boiled with stifling for 20 min, cooled down to 10° C. White precipitate is filtered off in an hour, washed with 10 ml of acetone and dried at the air. The product (2 g) is used on the next step without further purification.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@:17]2([CH2:23][O:24][P:25](=[O:36])([O:31]C(C)(C)C)[O:26]C(C)(C)C)[CH2:21][O:20]C(C)=[N:18]2)=[CH:11][CH:10]=1.Cl>C(O)C>[NH2:18][C@:17]([CH2:21][OH:20])([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][F:1])=[CH:10][CH:11]=1)[CH2:23][O:24][P:25](=[O:26])([OH:31])[OH:36]
Reactant: CC1=N[C@](CCc2ccc(OCCCCCCF)cc2)(COP(=O)(OC(C)(C)C)OC(C)(C)C)CO1
Agent: Cl
Solvent: CCO
Product: N[C@](CO)(CCc1ccc(OCCCCCCF)cc1)COP(=O)(O)O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of phosphoric acid di-tertbutyl ester (S)-4-{2-[4-(6-fluoro-hexyloxy)-phenyl]-ethyl}-2-methyl-4,5-dihydro-oxazol-4-ylmethyl ester (33 mg, 0.050 mmol) in ethanol (2 ml) is added conc. HCl (2 ml). The reaction mixture is stirred at 85° C. for 2 hours, then concentrated to dryness. The residue is re-dissolved in ethyl acetate and precipitated with hexanes. The solid is filtered off, washed with dry ether and dried under vacuum to afford phosphoric acid mono-{(S)-2-amino-4-[4-(6-fluoro-hexyloxy)-phenyl]-2-hydroxymethyl-butyl}ester as a colorless powder.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[N:9]1(C(OC(C)(C)C)=O)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O>[N:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(Br)s1
Solvent: O
Product: O=Cc1ccc(N2CCNCC2)s1
Yield: 71.5 %

Procedure:
A suspension of 1.09 g (5.7 mmol) of 5-bromothiophene-2-carboxaldehyde and 3.19 g (17.1 mmol) of tert-butyl piperazine-1-carboxylate in 30 ml of water is heated under reflux for 48 h. The aqueous phase is extracted three times with methylene chloride. The organic phases are combined, dried over sodium sulfate, filtered, and evaporated. The residue is purified by chromatography on silica (MeOH gradient in dichloromethane: 5 to 10%) to yield 0.80 g (70%) of 5-(piperazin-1-yl)thiophene-2-carboxaldehyde in the form of a blue-grey solid.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH2:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(OCC)=O>O.C(#N)C>[C:31]1(=[O:40])[N:17]([CH:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][C:6]([O:5][CH2:2][CH2:3][CH3:4])=[O:18])[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]12
Reactant: CCCOC(=O)CC(N)c1ccc(OC)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCOC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid propyl ester hydrochloride (1.50 g, 5.52 mmol) and sodium carbonate (0.59 g, 5.52 mmol) in 50 mL of water was added N-carboethoxy-phthalimide (1.21 g, 5.52 mmol) in 12 mL of acetonitrile. The reaction was complete in one hour. The acetonitrile was removed in vacuo and 5 mL of ether was added to the mixture, which was stirred overnight at room temperature. The resulting slurry was filtered and the solid was washed with 60 mL of water. The solid was dried in vacuo (24° C., <1 mm) to afford 1.69 g (83.2%) of propyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white powder: mp 51.2-52.8° C.; 1H NMR (DMSO-d6 250 MHz) δ7.86 (m, 4H), 6.92-7.33 (m, 4H), 5.66 (dd, 1H, J1=7.5, 2.5 Hz), 3.90 (t, 2H, J=5 Hz), 3.72 (S, 3H), 3.3-3.63 (m, 2H), 1.42 (hex, 2H, J=7.5 Hz), 0.75 (t, 3H, J=7.5 Hz); 13C (DMSO-d6) δ170.2, 167.5, 158.7, 134.7, 131.0, 130.5, 128.3, 123.2, 113.9, 65.6; 55.0, 49.5, 21.3, 9.98. Anal. Calcd for C19H17NO5: =C, 68.65; H, 5.76; N, 3.81; Found=C, 68.42; H, 5.49; N, 3.76.
Reaction SMILES: NN.[Cl:3][C:4]1[S:8][C:7]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[O:10])=[CH:6][C:5]=1[C:33]1[N:37]([CH2:38][CH3:39])[N:36]=[CH:35][C:34]=1[CH3:40]>CO>[NH2:14][CH2:13][C@@H:12]([NH:11][C:9]([C:7]1[S:8][C:4]([Cl:3])=[C:5]([C:33]2[N:37]([CH2:38][CH3:39])[N:36]=[CH:35][C:34]=2[CH3:40])[CH:6]=1)=[O:10])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: CCn1ncc(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Product: CCn1ncc(C)c1-c1cc(C(=O)N[C@H](CN)Cc2cccc(F)c2)sc1Cl
Reaction time: 10 h
Yield: 66.7 %

Procedure:
At RT, NH2NH2 (0.1 mL, 3.19 mmol) was added to 5-chloro-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (201 mg, 0.36 mmol) in MeOH (3 mL). After 10 h, the solvent was removed under vacuum. The resulting residue was taken into DCM (10 mL) and washed with H2O (10 mL×3). To the DCM solution was added HCl (36%, 2 mL). After 1 h, the aqueous phase was separated and washed with DCM (10 ml×3). Water was removed under high vacuum to give the title compound (101 mg, 53%) as an off-white solid: LC-MS (ES) m/z 421 (M+H)+, 1H NMR (d6-DMSO, 400 MHz) δ ppm 9.02 (d, J=8.3 Hz, 1H), 8.08 (s, 2H), 7.97 (s, 1H), 7.42 (s, 1H), 7.32 (m, 1H), 7.15-7.09 (m, 1H), 7.06-7.01 (m, 1H), 4.35 (m, 1H), 3.95 (m, 2H), 3.05-2.98 (m, 2H), 2.96-2.88 (m, 2H), and 1.92 (s, 3H), and 1.24 (t, J=6.6 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=[O:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.OS([O-])=O.[Na+]>ClCCl.CCOCC>[CH3:12]/[C:7](/[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:1])=[CH:8]/[C:9]([OH:11])=[O:10]
Reactant: C/C(=C/C(=O)O)CCCCC(O)c1ccc2ccccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(=C/C(=O)O)CCCCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of 192 (98 mg, 0.33 mmol) in dry dichloromethane (6 mL) was added a solution of Dess-Martin reagent (162 mg, 0.38 mmol) in dry dichloromethane (1 mL) via cannula. The mixture was stirred at room temperature for 24 hours. The mixture was diluted with ether and NaHSO3 (221 mg) in aqueous solution was added with stirring until the phases are homogeneous. The product was extracted, washed with 5% KHSO4, brine, dried over Na2SO4, and finally isolated by chromatography over silica gel (hexanes:Et2O: 4:1 to 1:1) to give 193 in 94% yield. 13CNMR: (75 MHz, CD3OD) δ: 25.2, 25.3, 28.7, 33.7, 39.1, 117.4, 124.7, 127.8, 128.7, 129.0, 129.5, 130.6, 131.0, 137.8, 161.9, 170.1. MS (ESI)=297 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1[CH:16]=O.Cl.O>CO>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1[CH:16]=[C:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=2[O:8]1
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1ccc(OC)c(C=O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(OC)c(C=C2Oc3cc(O)ccc3C2=O)c1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 2,5-dimethoxybenzaldehyde 1.23 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, water 400 ml was added and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.21 g.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C@@H:7]2[C@@H:14]3[C@@H:10]([O:11][C:12]([CH3:16])([CH3:15])[O:13]3)[CH2:9][S:8]2)[CH2:4][O:3]1>CC(O)=O>[CH3:15][C:12]1([CH3:16])[O:11][C@H:10]2[CH2:9][S:8][C@H:7]([C@H:5]([OH:6])[CH2:4][OH:3])[C@H:14]2[O:13]1
Reactant: CC1(C)O[C@@H]2[C@@H]([C@H]3COC(C)(C)O3)SC[C@@H]2O1
Solvent: CC(=O)O
Product: CC1(C)O[C@@H]2[C@@H]([C@H](O)CO)SC[C@@H]2O1
Yield: 76.8 %

Procedure:
A solution of 109 (5.4 g, 20.1 mmol) in 30% aqueous AcOH (150 mL) was stirred at room temperature for 50 h. The reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1) to give the diol 110 (3.4 g, 75%) as a syrup: 1H NMR (CDCl3) δ 1.34 (s, 3H, CH3), 1.53 (s, 3H, CH3), 2.90 (dd, 1H, J=12.9, 2.2 Hz, 6′-CHH), 3.09 (dd, 1H, J=12.9, 4.8 Hz, 6′-CHH), 3.27 (dd, 1H, J=7.8, 1.9 Hz, 4′-H), 3.49 (br s, 2H, 2×OH), 3.58–3.72 (m, 2H, HOCHHCH(OH)), 3.79 (dd, 1H, J=11.0, 2.9 Hz, HOCHH), 4.93 (m, 2H, 3a-H, 6a-H); Anal. Calcd for C19H16O4S: C, 49.07; H, 7.32; S, 14.56 . Found: C, 49.24; H, 7.72; S, 14.23.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N+:3]=1[O-].[C:14](OC(C(F)(F)F)=O)(C(F)(F)F)=[O:15].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][C:2]1([CH2:14][OH:15])[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][NH:3]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C(F)(F)F)c[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC1=CC(C(F)(F)F)=CNC1(C)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a solution of 2,3-dimethyl-5-trifluoromethyl-pyridine 1-oxide (0.620 g, 3.24 mmol) in CH2Cl2 (20 mL) was added TFAA (1.36 g, 6.48 mmol) at room temperature. After the mixture was stirred at room temperature for 3 h, brine (5 mL) and K2CO3 (20 mL) were added. The mixture was stirred at room temperature for 1 h and then extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed, and the residue was purified on silica gel column (4:1, CH2Cl2/Et2O), affording (2,3-dimethyl-5-trifluoromethyl-pyridin-2-yl)-methanol as a pale yellow oil (0.300 g, 48%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH2:37][O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH2:37][O:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(OCCOc1ccccc1)c2CN1CCNCC1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0380 g, 0.0637 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, and added with water (4 mL) and saturated aqueous sodium hydrogencarbonate (4 mL), and the mixture was stirred for 1 hour. The reaction mixture was filtered, and then the resulting solid was washed with water to obtain the objective (Z)-2-((1H-indazol-3-yl)methylene)-6-(2-phenoxyethoxy)-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0280 g, 88%).