Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[N:11]([CH2:24][CH2:25][CH3:26])[N:12]=[C:13]2[C:22]=1[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]=[C:14]2[NH2:23].C(N(CC)CC)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[NH2:23][C:14]1[C:13]2=[N:12][N:11]([CH2:24][CH2:25][CH3:26])[C:10]([CH2:9][C:8]([NH:7][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])([CH3:28])[CH3:27])=[C:22]2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
2-Methylpropanoyl chloride (786 μL, 7.50 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 892 mg, 3.00 mmol) and triethylamine (1.32 mL, 9.5 mmol) in dichloromethane (26.7 mL). After 10 minutes at 0° C., the solution was stirred for 2 hours at ambient temperature. The solution was concentrated to afford a white solid that was dissolved in methanol (20 mL) and concentrated hydrochloric acid (4 mL). The solution was heated at reflux for 3.5 hours, then was left to stand at ambient temperature overnight. To the solution was added 2 M aqueous sodium carbonate until the pH was basic. The mixture was concentrated under reduced pressure to remove the methanol. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to yield an off-white solid that was purified by IFC (silica gel, eluted with CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure to yield a white foam that was crystallized from 50% ethyl acetate in hexanes. The solid was isolated by filtration, washed with 50% ethyl acetate in hexanes, and dried to yield 815 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-2-methylpropanamide as a white solid, mp 177-178.5° C.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].C(O)(=O)C.[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>C(C(C)=O)C>[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@H]1CC(=O)OC1=O
Solvent: CCC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
14.3 g of N-formyl-L-aspartic anhydride (0.1 mole) was added to a mixture of 100 ml of methyl ethyl ketone and 24.0 g of acetic acid (0.4 mole). The solution was stirred at room temperature for 15 minutes. A solution of 17.9 g of L-phenylalanine methyl ester (0.1 mole) dissolved in 200 ml of methyl ethyl ketone was added to the above solution and stirred at room temperature for 6 hours to produce N-formyl-α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [CH:1]1(S)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OO)(=O)C.[S:12](=[O:15])([OH:14])[O-:13].[Na+].Cl>O.C(Cl)Cl>[CH:1]1([S:12]([OH:14])(=[O:13])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S([O-])O
Reactant: SC1CCCC1
Agent: CC(=O)OO
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(O)C1CCCC1
Temperature: 15 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A one liter three-neck flask was charged with 300 mL of methylene chloride and 25 grams (245 mmole) of cyclopentyl mercaptan to produce a reaction solution. The reaction solution was chilled to 15° C. in an ice-water bath and followed by the addition of 190 mL of 35% peroxy acetic acid. Said peroxy acetic acid was added over a period of about 3 hours and the reaction solution was maintained at a temperature of about 18°-26° C. After the reaction solution was stirred overnight at room temperature, 100 mL of water and 25 grams of sodium bisulfite were added followed by 2 additional hours of stirring. The reaction solution was then reduced on a rotovap and the pH was adjusted with dilute hydrochloric acid until a white solid precipitate formed. Said precipitate was isolated via filtration and dried in vacuo (50% yield of cyclopentane sulfonic acid).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][C@@H:14]2[O:19][C:18]3[C:20]([OH:25])=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH:14]2[CH2:15][O:16][C:17]3[CH:23]=[CH:22][C:21]4[N:24]=[CH:26][O:25][C:20]=4[C:18]=3[O:19]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(O)c3O2)cc1
Agent: Cl
Solvent: COC(OC)OC
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4ncoc4c3O2)cc1

Procedure:
[(2R)-7-Amino-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methyl-benzenesulfonate hydrochloride (1.05 g, 2.99 mmole) in trimethyl orthoformate (7 mL) was heated to reflux in the presence of 0.20 g of p-toluenesulfonic acid for 3 hours. The solvent was removed under high vacuum to yield a beige solid. The crude product was recrystallized from ethanol to give 0.81 g (75%) of the (R)-enantiomer of the title compound, MS (ESI) m/z 361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C1(C)C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([F:19])[CH:13]=1)[O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[CH3:10]
Reactant: Cc1cc(N)cc(C)c1O
Reactant: Fc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N)cc(C)c1Oc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
A mixture of 4-amino-2,6-dimethylphenol (6.92 g), 1,3,5-trifluorobenzene (10.00 g), anhydrous potassium carbonate (13.93 g) and anhydrous cuprous chloride (0.50 g) in dry dimethylsulfoxide (100 ml) was heated under reflux for 4 hours, whereby the inner temperature raised from 120° C. to 150° C. After completion of the reaction, the reaction mixture was cooled to room temperature, and cold water (200 ml) and toluene (100 ml) were added thereto. After continuation of stirring for 30 minutes, the resultant mixture was filtered on celite to remove insoluble materials. The toluene layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of methylene chloride and n-hexane (1:1) as an eluting solvent to give 9.50 g of 4-(3,5-difluorophenoxy)3,5-dimethylaniline as yellowish white crystals. M.P., 67.6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH:9][C:10](=[O:23])[C:11]2[C:12](=[CH:16][C:17]([C:20](=O)[NH2:21])=[CH:18][CH:19]=2)[C:13](N)=[O:14])[CH:3]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=[C:11]3[C:10]2=[O:23])[CH:3]=1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc(C(N)=O)cc1C(N)=O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(C#N)cc2C1=O

Procedure:
The mixture of 0.3 g of N-(4-amino-o-tolyl)-4-carbamoylphthalamide, 2 ml of dioxane and 5 ml of phosphorus oxychloride is refluxed for 1 hour and evaporated. The residue is taken up in methylene chloride, the solution washed with cold aqueous sodium carbonate, dryed and evaporated, to yield the N-(4-amino-o-tolyl)-4-cyanophthalimide, which is identical with that obtained according to Example 20.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1)#[CH:14].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[F:23][C:17]1[CH:16]=[C:15]([C:13]#[C:14][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc(OC)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#Cc1ccc(OC)c(F)c1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To the mixture of diisopropylamine (0.262 mL, 1.87 mmol) in tetrahydrofuran (5 mL) at −78° C. under nitrogen was added slowly the solution of n-butyllithium (1.17 mL, 1.87 mmol, 1.6M in hexanes). After stirring for 30 minutes, the solution of 4-ethynyl-2-fluoro-1-methoxybenzene (622) (0.180 g, 0.94 mmol) in tetrahydrofuran (1 mL) was added slowly into the reaction mixture. The mixture was allowed to reach 0° C. over 1 hour and ethyl chloroformate (0.134 mL, 1.4 mmol) was added. The resulting mixture was stirred to room temperature for 12 hours, quenched with saturated ammonium chloride and extracted with ethyl ether. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide ethyl 3-(3-fluoro-4-methoxyphenyl)propiolate (623) (0.070 g, 6.3%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7](Cl)[N:6]=[C:5]([Cl:10])[N:4]=1.[F-:11].[K+]>S1(CCCC1)(=O)=O>[Cl:10][C:5]1[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=[C:7]([F:11])[N:6]=1
Reactant: [F-]
Reactant: ClCc1cc(Cl)nc(Cl)n1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(CCl)nc(Cl)n1
Temperature: 0 °C

Procedure:
5 g (0.027 mol) of 4-chloromethyl-2,6-dichloro-pyrimidine (see Examples 73 and 92) and 3.3 g (0.056 mol) of anhydrous potassium fluoride in 8 ml of sulpholane are heated at 140° C. for 24 hours. The mixture is then cooled to 0° C. and filtered over silica gel using diethyl ether/n-hexane (1:4). After removing the solvent by evaporation there is obtained 2-chloro-4-chloromethyl-6-fluoro-pyrimidine in the form of a yellow oil, 1H-NMR (CDCl3): 4.70 (s, CH2Cl), 7.30 (d, JFH =2 Hz, H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[C:20]([OH:25])[CH:19]=1>>[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[C:20]([O:25][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=2[Cl:13])[CH:19]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(CC(=O)OC)c2)c(Cl)c1

Procedure:
The subtitle compound was prepared as described in example 2 step (iii) but instead using the product from example 3 step (i) and methyl(3,5-dihydroxyphenyl)acetate.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.[CH3:37][NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][N:40]=1>>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([N:38]([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][N:40]=2)[CH3:37])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1
Reactant: CNc1ccc(C(=O)OC)cn1
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cn2)C1
Yield: 60 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 6-methylaminonicotinate in 60% yield according to a procedure similar to that described in Example 29 (i).
Reaction SMILES: FC(F)(F)C(O)=O.O=C1C2C(=CC=CC=2)C(=O)[N:10]1[CH2:19][C:20]1[S:24][C:23]([NH:25][C:26]2[CH:27]=[C:28]([CH:44]=[CH:45][CH:46]=2)[CH2:29][NH:30][C:31]2[C:40]3[C:35](=[C:36]([C:41]([NH2:43])=[O:42])[CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][N:32]=2)=[N:22][CH:21]=1.O.NN>C(O)C>[NH2:10][CH2:19][C:20]1[S:24][C:23]([NH:25][C:26]2[CH:27]=[C:28]([CH:44]=[CH:45][CH:46]=2)[CH2:29][NH:30][C:31]2[C:40]3[C:35](=[C:36]([C:41]([NH2:43])=[O:42])[CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][N:32]=2)=[N:22][CH:21]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(Nc4ncc(CN5C(=O)c6ccccc6C5=O)s4)c3)ncnc12
Agent: NN
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: NCc1cnc(Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
24 mg (0.04 mmol) 4-{3-[5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-thiazol-2-ylamino]-benzylamino}-quinazoline-8-carboxylic acid amide trifluoroacetic acid salt were dissolved in 1 ml ethanol and treated with 10 μl (0.21 mmol) hydrazine hydrate. The mixture was stirred overnight at 50° C. in a closed vessel. Additional 40 μl hydrazine hydrate were added and the mixture was stirred at 60° C. for 24 h. The reaction mixture was evaporated and the crude product was purified using preparative HPLC. The product was treated with HCl in methanol and concentrated in the SpeedVac.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].O[N:28]1[C:33](=[O:34])[CH2:32][CH2:31][C:29]1=[O:30].C1CCC(N=C=NC2CCCCC2)CC1.C1CCC(NC2CCCCC2)CC1>C1COCC1.C(OCC)(=O)C>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11])[C@H:2]([C:7]([O:9][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][C:29]1=[O:30])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Fmoc-Met-OSu was prepared in situ by the reaction of Fmoc-Met-OH (14.87 g), HOSu (5.52 g) and DCC (8.26 g) in THF (tetrahydrofuran, 200 ml) at 0° C. for 3.5 hours. Precipitated dicyclohexylurea (DCU) was removed by filtration and the THF filtrate was added to a cold solution of H-Asp(OtBu)-OH in 220 ml of 10:1 water/THF to which had been added 40 ml of 1N sodium hydroxide. After stirring the reaction mixture at room temperature overnight, solid citric acid (20 g) was added along with ethyl acetate (600 ml). The ethyl acetate layer was separated, washed with 10% citric acid and brine, then dried (MgSO4). Evaporation of the ethyl acetate solution gave a residue which was dissolved in ethyl acetate (200 ml) and treated with DCHA (7.84 ml) to precipitate 17.93 g of the DCHA salt of the title compound, mp 159°-162° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[N:12][C:11]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:10]1=2)[CH:6]=O.[NH2:22][CH2:23][C@@H:24]1[CH2:28][N:27]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[C:26](=[O:40])[CH2:25]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][CH:5]([CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[N:12][C:11]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:10]1=2)[CH2:6][NH:22][CH2:23][C@@H:24]1[CH2:28][N:27]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[C:26](=[O:40])[CH2:25]1
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COCOC(C=O)Cn1c(=O)cnc2ccc(OC)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COCOC(CNC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1)Cn1c(=O)cnc2ccc(OC)nc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 35 %

Procedure:
In a mixed solvent (6 ml) of dichloromethane/N,N dimethylformamide (5:1) were dissolved 2-(methoxymethoxy)-3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (as 0.217 mmol) and 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 54; 57 mg, 0.217 mmol). Acetic acid (0.025 ml, 0.434 mmol) and anhydrous sodium sulfate (100 mg) were added to the solution and the mixture was stirred at room temperature for 14 hours. Sodium triacetoxyborohydride (92 mg, 0.434 mmol) was added to the reaction solution, the mixture was stirred for 8 hours and then the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue, the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice and extracted with a lower layer solvent of chloroform/methanol/water (7:3:1). After drying the extract with anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 41 mg (35%) of the title compound in the form of an orange oily product.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C=O)C.CCOC(C)=O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: COC(=O)CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (1 g, 5.37 mmol) in DMF (20 mL) was added Cs2CO3 (589 mg, 1.81 mmol) and methyl 3-bromopropanoate (744 mg, 4.46 mmol). The resulting mixture was stirred at room temperature overnight. Water (50 m) and EtOAc (50 mL) was added. Phases were separated. The aqueous phase was extracted with EtOAc (50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 3.5% MeOH in DCM. Collection of appropriate fractions and evaporation of solvent afforded tert-butyl 4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (895 mg, 74%) as yellow oil. TLC: Rf=0.3; ethyl acetate/petroleum ether=1/2.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22]1([CH:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:33]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:2]3([CH3:1])[CH2:6][C:5]4[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=4[O:3]3)[CH2:17][CH2:18]2)=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 72 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 3,3-diphenylpropionic acid, the procedure of Example 10 was otherwise repeated to provide the title compound. Yield 72%.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[Br:13][C:14]1C=C(C#N)[CH:17]=[CH:16][C:15]=1C.CC(C[AlH]CC(C)C)C.Cl>CCOC(C)=O.CCCCCC.C1COCC1>[Br:13][CH2:14][C:15]1[CH:3]=[CH:2][C:1]([CH:5]=[O:4])=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(C#N)cc1Br
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=Cc1ccc(CBr)cc1
Reaction time: 1.5 h

Procedure:
To a THF-toluene (2.4 L -0.24 L) solution of α bromo p tolunitrile (266.4 g, 1.36 mol) maintained at an internal temperature below 0° C. was added DIBAL-H in hexane (1.0 M) (1.49 L, 1.49 mol) over a period of 2 h. After a period of 1.5 h, the reaction mixture was transferred via canula to a 3N HCl solution (8 L) at 0° C. To the resulting suspension EtOAc (4 L) and THF (0.8 L) were added. After stirring, the organic phase was separated and evaporated to give a yellow solid. The solid was stirred, in 20% EtOAc in hexane (1.3 L) for 3 hours. After filtration and drying, the title compound was obtained (210 g).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>[Cu](F)F.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccccc1
Reactant: CCO
Agent: F[Cu]F
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), copper fluoride (0.5 mg, 1 mol %), and Xantphos (2.9 mg) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 12 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 15%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 9 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 91%.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1>O1CCCC1.C(OCC)C.[Cl-].[NH4+]>[CH2:3]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)[CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCc1ccc(F)cc1
Reaction time: 16 h

Procedure:
Allyl bromide (4.33 mL, 50 mmol) was added dropwise to a solution of 4-fluorophenyl magnesium bromide (50 mmol) in tetrahydrofuran (25 mL) and diethyl ether (25 mL). After 16 hours, the reaction suspension was diluted with diethyl ether (100 mL) and saturated aqueous ammonium chloride (50 mL). The layers were separated, and the organic layer was washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated to afford 1-allyl-4-fluorobenzene.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].[CH2:34]([OH:36])[CH3:35]>>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:28](=[O:32])[C:29]([O:36][CH2:34][CH3:35])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Reactant: FC(F)(F)Oc1ccc(-c2cccc3c2ccn3Cc2ccccc2)cc1
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(OC(F)(F)F)cc3)c12
Yield: 55 %

Procedure:
Ethyl {1-benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate was prepared from 1-benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indole (0.243 g, 0.661 mmol), oxalyl chloride (1.03 mL, 13.0 mmol), and ethanol (5 mL) according to the procedure described in Step 3 of Example 1. Purification was carried out by reverse phase HPLC using 22% water in acetonitrile as the mobile phase. Extraction with ethyl acetate, washing with brine, and evaporation to dryness afforded the title compound as a yellow gum (0.169 g, 55%). 1HNMR (300 MHz, DMSO-d6): δ 8.65 (s, 1H), 7.65 (d, 1H, J=7.5 Hz), 7.3-7.45 (m, 10H), 7.2 (d, 1H, J=7.5 Hz), 5.65 (s, 2H), 4.25 (q, 2H, J=7.3 Hz), and 1.35 ppm (t, 3H, J=7.5 Hz).