Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:19]=1)(C)(C)C.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:27]([S:24]([C:20]1[CH:19]=[C:18]([C:17]#[C:16][C:10]2[CH:11]=[C:12]([C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:5])=[O:30])[CH:23]=[CH:22][CH:21]=1)(=[O:25])=[O:26])[CH2:28][CH3:29]
Reactant: OB(O)c1ccsc1
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(-c3ccsc3)ccc2OCC(=O)O)c1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of tert-butyl (4-bromo-2-{[3-(propylsulfonyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 191, 200 mg; 0.41 mmol), 3-thienylboronic acid (78 mg; 0.61 mmol), caesium fluoride (185 mg; 1.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (28 mg; 0.04 mmol) was placed in a microwave tube. The tube was sealed and degased with nitrogen before adding dioxane (4 ml) and water (2 ml). The reaction mixture was heated at 150° C. for 15 minutes in a microwave reaction system. The reaction mixture was taken up in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM (1.00 ml), treated with a 4 N solution of HCl in dioxane (2.0 ml) and stirred for 1 day. The solvents were removed under reduced pressure and the residue purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12]CC)=[O:11])=[N:8][CH:9]=1)[CH3:2].O.O.[OH-].[Li+].C([O-])(O)=O.[Na+]>O1CCOCC1.CCOCC>[CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(OCC)cn1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CCOc1cnc(C(=O)O)cn1
Reaction time: 0.17 h

Procedure:
Ethyl 5-ethoxypyrazine-2-carboxylate (0.65 g, approx. purity 85%) was dissolved in dioxan (3 mL) and water (3 mL) was added, followed by lithium hydroxide monohydrate (255 mg, portionwise over 10 mins). After stirring at RT for 24h, Et2O (25 mL) and NaHCO3 (sat., aq., 25 mL) were added. The layers were separated and the organic layer was extracted with NaOH (1 N, aq., 25 mL). The combined aqueous portions were acidified with 6N HCl to pH 2, and the mixture extracted with EtOAc (3×40 mL). The combined EtOAc extracts were dried over MgSO4 and evaporated to afford the title compound as an off-white powder. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (t, J=7.1 Hz, 3 H), 4.53 (q, J=7.1 Hz, 2 H), 8.16 (d, J=1.2 Hz, 1 H), 8.98 (d, J=1.2 Hz, 1 H)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C(O[CH:9]([O:16][CH2:17][CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])C.[C:19](=O)([O-])[O-:20].[K+].[K+].O>CN(C)C=O.ClCCl>[CH2:17]([O:16][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[CH:19]=[O:20])[CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCC(OCC)OCC
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C#CCCCCC(C=O)OCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
In 18.74 kg of dimethyl formamide (DMF) was added 11.48 kg of phosphorus oxychloride at 10° C., and stirred at the same temperature for 1 hour. To the sticky solution thus obtained was added 25 l of a solution of 6.0 kg (31.9 mol) of 1,1-diethoxyheptane in dichloromethane at 10° C., stirred at the same temperature for 2 hours, and then heated up to 70° C. in 30 min. The reaction solution was cooled down, gradually added to an aqueous solution of 33.2 kg of potassium carbonate and 100 l of water so that the temperature did not exceed 30° C., and then stirred at room temperature for 5 hours. The product was extracted with chloroform. The extract was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was purified by distillation to obtain 2.6 kg (15.3mol) of 2-ethoxymethylidenylheptanal. Yield of this product was 48%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16]C(=O)C)[C:13]2[C:8](=[CH:9][C:10]([CH3:20])=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[OH:16][C:14]1[C:13]2[C:8](=[CH:9][C:10]([CH3:20])=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2ccc(C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(O)cc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 860 mg of 4-Acetoxy-7-methyl-naphthalene-2-carboxylic acid ethyl ester in 3 ml ethanol/water (9:1), 12.6 ml of a 1M NaOH was added and stirred for 5 h at RT. Then, the reaction mixture was acidified to pH 2 with diluted hydrochloric acid to precipitate the product. The product was then collected by filtration and dried under reduced pressure. Yield: 550 mg.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=[O:5].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C)C=O.[Cl-].[Na+].C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:9][C:8](=[O:10])[CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[CH:18][CH:17]=1
Reactant: CC(C)(CC(=O)O)CC(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)CC(C)(C)CC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 3,3-dimethylglutaric acid (6.4 g) in dry dimethylformamide (100 ml) was added in four portions sodium hydride (50%) (1.92 g) at 30° to 40° C. under nitrogen atmosphere. The resulting mixture was stirred for 30 minutes, and p-methoxybenzyl chloride (6.28 g) in dry dimethylformamide (20 ml) was added to the mixture. The reaction mixture was stirred at 60° to 70° l C. for 10 hours, diluted with saturated aqueous sodium chloride and ethyl acetate. The ethyl acetate layer was extracted with aqueous potassium carbonate. The aqueous layer was acidified on ice-bath with concentrated hydrochloric acid and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 3,3-dimethylglutaric acid mono-p-methoxybenzyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=O)[CH2:10][CH2:11][Cl:12].P(Cl)(Cl)(Cl)=O>ClCCl>[Cl:12][CH2:11][CH2:10][C:9]1[N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[CH:7][N:8]=1
Reactant: O=C(CCCl)NCc1cnccn1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: ClCCc1ncc2cnccn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
To a solution of N-(2-pyrazinylmethyl)-3-chloropropionamide (4.52 g) in dichloromethane (30 ml) was added phosphorus oxychloride (1.29 g) under ice cooling. The mixture was stirred for 3 days at room temperature. The mixture was concentrated, and the residue was poured into ice water (400 ml), followed by neutralization with sodium carbonate. The reaction mixture was subjected to salting out with sodium chloride, and extracted with ethyl acetate-THF (1:1, 150 ml×3). The organic layers were combined and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography [carrier: silica gel, 100 g, developing solvent: ethyl acetate→ethyl acetate-ethanol (9:1)]. The eluate was concentrated and residual solid was washed with diethylether to give the title compound (3.07 g) as colorless solid product.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]([O:16][C:17]1[C:21](OCC)=[N:20][S:19](=[O:26])(=[O:25])[N:18]=1)[CH3:15]>C(O)C>[CH2:8]([N:7]([C:21]1[C:17]([O:16][CH2:14][CH3:15])=[N:18][S:19](=[O:26])(=[O:25])[N:20]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC1=NS(=O)(=O)N=C1OCC
Reactant: CCCCCCNCCCCCC
Solvent: CCO
Product: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
Dihexylamine (90 mg, 0.48 mmol) was added to a solution of 3,4-diethyloxy-1,1-dioxo-1,2,5-thiadiazole (100 mg, 0.48 mmol) in ethanol (5 mL) and the reaction stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue absorbed onto silica gel, and purified by flash column chromatography (silica, hexane:EtOAc 3:1) to yield the title intermediate (120 mg, 72%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2onc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(-c2onc3ccccc23)cc1
Yield: 87.2 %

Procedure:
A solution of 24.5 g (0.11 mole) of 3-(4-ethylphenyl)-2,1-benzisoxazole in 330 ml of carbon tetrachloride was heated to reflux and treated with 19.6 g (0.11 mole) of N-bromosuccinimide and 10 mg of benzoyl peroxide. The mixture was maintained at reflux by illumination with a floodlamp for 20 min, at which time all insoluble material was floating. The mixture was cooled and filtered. The filtrate was washed with dilute sodium bicarbonate solution and the organic fraction was concentrated to a yellow solid. The solid was recrystallized from 200 ml of isopropanol to give 29.0 g (87%) of yellow crystals, m.p. 105.5°-8.0° C.
Reaction SMILES: [CH2:1]([Si:19](Cl)(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33]>CCCCCCC>[CH2:1]([Si:19]([O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])([O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])[O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC[Si](Cl)(Cl)Cl
Reactant: COCCOCCOCCO
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCCC[Si](OCCOCCOCCOC)(OCCOCCOCCOC)OCCOCCOCCOC

Procedure:
The procedure of Example 1 was repeated with 387.5 g (1.0 mole) of octadecyltrichlorosilane and 800 mL of heptane. Under nitrogen 508.4 g (3.10 mole) of 2-(2-(2-methoxyethoxy)ethoxy)ethanol was added at 80° C. over 4 hours. After heating the reaction for an additional 48 hours and removal of all volatile components under vacuum, 780 g of the pale yellow liquid product were obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]3[C:18]4[NH:17][C:16](=[O:19])[NH:15][C:14]=4[CH:13]=[C:12]([C:20]4[C:21]([CH3:26])=[N:22][O:23][C:24]=4[CH3:25])[CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>CO.C(Cl)Cl>[CH:1]1([C:4]2[C:9]([C:10]3[C:18]4[NH:17][C:16](=[O:19])[NH:15][C:14]=4[CH:13]=[C:12]([C:20]4[C:21]([CH3:26])=[N:22][O:23][C:24]=4[CH3:25])[CH:11]=3)=[CH:8][CH:7]=[CH:6][N+:5]=2[O-:32])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1noc(C)c1-c1cc(-c2cccnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Solvent: ClCCl
Solvent: CO
Product: Cc1noc(C)c1-c1cc(-c2ccc[n+]([O-])c2C2CC2)c2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (35 mg, 0.1 mmol) was dissolved in MeOH/DCM (1/1 mL). To the solution was added 3-Chloroperoxybenzoic acid (69.75 mg, 0.4 mol) and the mixture stirred at RT overnight. The organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 2-cyclopropyl-3-(6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pyridine 1-oxide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[N:30]1([CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NCCCCN1CCCCC1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCCCCN1CCCCC1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (0.745 g, 4.6 mmol) in 20 mL dimethylformamide, was added 1,1'-carbonyldiimidazole (0.745 g, 4.6 mmol). This mixture was stirred at room temperature for 4 h, and to it was added dropwise a solution of 1-(4-aminobutyl)piperidine (0.718 g, 4.6 mmol) dissolved in 3 mL dimethylformamide. This solution was then stirred at room temperature for 18 h, the volatiles were evaporated and the residue was diluted with water. Extraction with ethyl acetate followed by water and brine washes gave 1.40 g of an oil which was sufficiently pure for use in the next reaction. Mass spectrum, m+ =301.
Reaction SMILES: C(OC([NH:8][O:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[C:23]3[C:24]([Cl:32])=[CH:25][N:26]=[CH:27][C:28]=3[CH:29]=[CH:30][CH:31]=2)(=[O:21])=[O:20])[CH2:15]1)=[O:12])=O)(C)(C)C.Cl.C(OC(NOCC(O)=O)=O)(C)(C)C.COCC(O)=O>>[NH2:8][O:9][CH2:10][C:11]([NH:13][C@@H:14]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[C:23]3[C:24]([Cl:32])=[CH:25][N:26]=[CH:27][C:28]=3[CH:29]=[CH:30][CH:31]=2)(=[O:21])=[O:20])[CH2:15]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NOCC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Agent: CC(C)(C)OC(=O)NOCC(=O)O
Agent: COCC(=O)O
Agent: Cl
Product: NOCC(=O)N[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1

Procedure:
(S)-3-[2-(tert-Butoxycarbonylaminooxy)acetyl]amino-1-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine can be prepared from hydrochloride of the compound prepared in Example 19-2 by using 2-(tert-butoxycarbonylaminooxy)acetic acid in the method of Example 56-1 instead of 2-methoxyacetic acid, and the protective group of the obtained compound can be removed according to the method described in Example 1-1, Step B to obtain the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][N:11]=[C:10]([CH2:13][CH2:14][C:15](OC)=[O:16])[CH:9]=1.O>O1CCCC1>[CH3:7][C:8]1[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=1
Reactant: COC(=O)CCc1cc(C)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCCO)no1
Yield: 81.4 %

Procedure:
To a suspension of 7.6 g of lithium aluminum hydride in 250 ml of tetrahydrofuran was added a solution of 64.9 g of methyl 5-methyl-3-isoxazolepropanoate in 100 ml of tetrahydrofuran. The reaction mixture was stirred at reflux for three hours, then cooled and 15.2 ml of water in 30 ml of tetrahydrofuran added. The mixture was filtered and the filtrate concentrated in vacuo. The residue was distilled to give 44.1 g of 5-methyl-3-(3-hydroxypropyl)isoxazole, b.p. 84°-85° C.(0.1 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[CH:29](=O)[CH2:30][CH2:31][CH3:32]>>[CH2:29]([N:26]([CH2:4][CH2:3][CH2:12][CH3:11])[CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC=O
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Product: CCCCN(CCCC)CC(C)(C)c1nc(-c2ccc3cc(OC)ccc3c2)c(-c2ccncc2)[nH]1
Yield: 47 %

Procedure:
The title compound (12 mg, 47%) was prepared starting from the product of Example 2 and butyraldehyde using the method described in Example 25; MS(ES) m/e 485 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:22]=[CH:21][C:10]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)=[N:12][S:13][C:9]=3[CH:8]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: Clc1ccc(-c2nsc3cc(OCCCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and Azetidine were converted to yield 6-(4-Azetidin-1-yl-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole, MS: 373 (MH+, 1Cl).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[CH2:9]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:11][CH2:12][NH2:13]>CN(C)C=O>[C:5]([CH2:4][O:3][CH2:2][C:1]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:14][CH2:15][NH:16][C:5]([CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[O:8])([OH:7])=[O:6]
Reactant: O=C1COCC(=O)O1
Reactant: NCCCCCCN
Solvent: CN(C)C=O
Product: O=C(O)COCC(=O)NCCCCCCNC(=O)COCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a solution of Diglycolic anhydride (30 g) in Dimethylformamide (85 ml) at 60° C. was added dropwise a solution of 1,6-Hexamethylene diamine (11.6 g) in Dimethylformamide (50 ml). The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was cooled to 0° C. and maintained for 3 hours. The solid was filtered and washed with chloroform and dried to get pure {[6-(2-Carboxy methoxy-acetylamino) -hexylcarbamoyl]-methoxy}-acetic acid (9 g) as white powder with a melting point of 178-180° C. The compound was characterized by IH NMR (DMSO-d6) δ1.25 (m, 2H, CH2), 1.55 (m, 2H, CH2), 2.80 (m, 2H, CH2), 3.90 (s, 4H, 2X CH2), 7.90 (bs, 1H, NH).
Reaction SMILES: Cl[C:2](=[O:25])[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.N1C=CC=CC=1>O1CCOCC1>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:2](=[O:25])[CH2:3][CH2:4][C:5]2[CH:14]=[CH:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][CH:9]=[N:10]3)[CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc(-c2ccc(CCC(=O)Cl)c3cccnc23)cc1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(CCC(=O)N3CCN(C)CC3)c3cccnc23)cc1

Procedure:
A mixture of Example 201I (300 mg, 0.85 mmol), 1-methylpiperazine (111 mg, 1.11 mmol), and pyridine (74 mg, 0.94 mmol) in dioxane (4 mL) at room temperature was stirred for 75 minutes and purified by flash column chromatography on silica gel with 90:10:0.5 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:12][CH:13]3[O:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:12][CH:13]3[O:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1oc2ccc(OCC3CN(C)CCO3)cc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)oc2ccc(OCC3CN(C)CCO3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 3-methyl-5-(4-methyl-morpholin-2-ylmethoxy)-benzofuran-2-carboxylate (0.12 mmol) was dissolved in 300 μl of tetrahydrofuran. Then 300 μl of a 1.0 M solution of lithium hydroxide were added and the mixture stirred at room temperature for 3 hours. The tetrahydrofuran was removed under vacuo and the water eliminated by lyophilisation to yield the tilted compound as a white solid: m/z=304 in MS ES−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:11]([CH3:17])[NH:12]2)[CH3:6])[CH3:2].[CH2:26](Br)[CH2:27][CH3:28]>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:11]([CH3:17])[N:12]2[CH2:26][CH2:27][CH3:28])[CH3:6])[CH3:2]
Reactant: CCCBr
Reactant: CCOC(=O)C(C)(C)Oc1cccc2[nH]c(C)c(-c3ccccc3)c12
Product: CCCn1c(C)c(-c2ccccc2)c2c(OC(C)(C)C(=O)OCC)cccc21

Procedure:
The above compound was prepared from 2-methyl-2-[2-methyl-3-phenyl-1H-indole-4-yloxy]-propanoic acid ethylester and propylbromide using a procedure analogous to that of Example 63.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21]([C:23]5([NH:31]C(=O)OC(C)(C)C)[CH2:28][O:27]C(C)(C)[O:25][CH2:24]5)=[CH:20][C:19]=4[CH:39]=3)[N:11]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:31][C:23]([C:21]1[O:22][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:11]=[C:10]([C:8]4[CH:7]=[N:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:9]=4)[O:14][N:13]=3)=[CH:39][C:19]=2[CH:20]=1)([CH2:24][OH:25])[CH2:28][OH:27]
Reactant: CCCCn1cc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cn1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCCn1cc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cn1
Yield: 46 %

Procedure:
When the product of Step D was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 46% yield, as light creamy solid. 1H NMR (CD3OD) 8.46 (broad s, 1H); 8.32 (broad s, 1H); 8.13 (broad s, 1H); 8.02 (d, 1H, J=7.98 Hz); 7.62 (d, 1H, J=8.31 Hz); 6.97 (s, 1H); 4.25 (t, 2H, J=6.21 Hz); 3.93 (b, 4H); 1.91-1.86 (m, 2H); 1.36-1.31 (m, 2H); 0.95 (t, 3H, J=7.02 Hz).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.[Cl:18][C:19]1[C:24]([S:25](Cl)(=[O:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[C:24]([S:25]([N:3]([CH3:2])[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:12]=2[NH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:9]3)(=[O:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine monohydrochloride (132 mg) in pyridine (3 mL) was added 2-chloropyridine-3-sulfonyl chloride (120 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (126 mg, yield 62%) as pale-yellow crystals. melting point 203° C.