Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:13][C:14](=[O:27])[CH:15]([CH2:25][CH3:26])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])(C)C)=[O:19])(C)(C)C>FC(F)(F)C(O)=O>[C:18]([NH:17][CH2:16][CH:15]([CH2:25][CH3:26])[C:14]([OH:13])=[O:27])([O:20][CH2:21][CH:24]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:6]2[C:1]1=[CH:2][CH:3]=[CH:4][CH:5]=2)=[O:19]
Reactant: COc1ccccc1
Reactant: CCC(CNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
Anisole (0.5 ml) and trifluoroacetic acid (10 ml) were added to N-t-butyloxycarbonyl-α-ethyl-β-alanine-t-butyl ester (0.98 g) and the mixture was stirred at room temperature for 12 hours. After trifluoroacetic acid was distilled off, the residue was dissolved in water (5 ml) and neutralized with a 10% aqueous solution of sodium carbonate. The product was protected with Fmoc by the same procedure as in Example 2-(3). A crystal of N-Fmoc-α-ethyl-β-alanine (437 mg, 36%) was obtained upon recrystallization from hexane.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1>>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[NH2:21])=[O:9])=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc(N)c(N)c1
Product: COc1ccc(NC(=O)c2ccc(CN)cc2)c(N)c1
Yield: 35.4 %

Procedure:
The title compound (192 mg, 71% yield) was prepared as a grey solid from 4-cyano-benzoic acid (294 mg, 2 mmol) and 4-methoxy-o-phenylenediamine (331 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 272 (M+1).
Reaction SMILES: [OH:1]O.[N+:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C(O)(=O)C>[N+:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N+:15]([O-:1])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: OO
Reactant: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2cc[n+]([O-])cc2)c1
Temperature: 70 °C

Procedure:
Aqueous hydrogen peroxide (27.5 wt. %, 6.4 ml) was added to a solution of 4-(3-nitrophenyl)pyridine (5 g) in glacial acetic acid (50 ml), and the mixture was heated to approx 70° C. overnight. The mixture was then evaporated and the residue was triturated with ether. The product (6 g), still containing some acetic acid, was used without further purification. Mp 193°-196° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[O:6]>O.CO>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([C@@H:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:5]([OH:6])=[O:4])=[O:20])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1C(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A solution of NaOH (128.2 g, 3.2 mol) in 700 mL water was added to a solution of cis-2-(4-bromo-benzoyl)-cyclopentanecarboxylic acid methyl ester (166.3 g, 534.3 mmol) in MeOH (700 mL). The reaction mixture was stirred at rt overnight. NMR analysis showed that little starting material remained. After ca. 1 L solvent was removed by rotary evaporation, the mixture was diluted with 1 L water. Conc. HCl was slowly added with stirring at <15° C., to adjust the acidity to pH <6. A precipitate formed, and stirring was continued for 1 h. The solid precipitate was filtered, and rinsed with water. The dried filter cake was dissolved in 1 L EtOAc, and dried over Na2SO4. Removal of solvent and drying in vacuo afforded the desired product (131 g, 83%). 1H NMR (CDCl3) δ 7.83 (d, 2H), 7.60 (d, 2H), 4.05 (m, 1H), 3.50 (m, 1H), 2.20 (m, 2H), 2.00 (m, 1H), 1.78 (m, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.C(N(CC)CC)C.[C:30]([Cl:38])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[ClH:38].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 mg (176 μmol) of the compound from Example 35 are dissolved in 4 ml DMF, 53.5 mg (529 μmol) triethylamine and 27.3 mg (194 μmol) benzoyl chloride are added, while cooling with ice, and the mixture is stirred overnight at RT. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[OH:23][C:24]1[CH:32]=[N:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:26]([C:25]3[CH:29]=[CH:30][N:31]=[CH:32][C:24]=3[OH:23])=[O:27])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)c1ccncc1O
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3ccncc3O)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 3-hydroxyisonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.45 (m, 1H), 1.52-1.74 (m, 4H), 1.84 (m, 1H), 3.19 (m, 2H), 4.18 (dd, 1H, J=10.2, 4.0 Hz), 4.64 (t, 1H, J=10.0 Hz), 5.25 (m, 1H), 6.61 (d, 1H, J=8.2 Hz), 6.87 (d, 1H, J=8.2 Hz), 7.08 (d, 1H, J=5.5 Hz), 7.46 (t, 1H, J=8.2 Hz), 7.84 (br s, 1H), 8.07 (d, 1H, J=5.5 Hz), 8.19 (s, 1H), 8.29 (br s, 1H), 10.28 (s, 1H), 10.9 (br s, 1H). MS 432 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc2c(Cl)cccc2c1-c1ccc(OC)cc1
Yield: 9.1 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopentane (0.130 mL, 1.0 mmol) to give the title compound (0.015 g).
Reaction SMILES: [OH:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].S(OC)(O[CH3:19])(=O)=O.Cl>O>[CH3:19][O:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc(Cl)c1O
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(Cl)ccc(Cl)c1C(=O)O
Temperature: 100 °C

Procedure:
2-Hydroxy-3,6-dichlorobenzoic acid (44.4 g) is dissolved in a solution of potassium hydroxide (11.2 g, 0.2 mole) and water (100 ml). The solution is heated to reflux (about 100° C.) and stirred vigorously while dimethyl sulfate (63.1 g, 0.5 mole) is added dropwise. The reaction mixture is then treated with a solution of potassium hydroxide (14.0 g, 0.25 mole) in 25.0 ml of water and refluxed for an additional 2 hours. The reaction mixture is then cooled and acidified to Congo red with hydrochloric acid to precipitate the desired 2-methoxy-3,6-dichlorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[CH3:18][NH2:19]>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:19][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Cl
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccccc2)c1Cl
Temperature: 0 °C
Reaction time: 120 h
Yield: 70 %

Procedure:
A solution of 3.5 g of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid, ethyl ester and 20 ml of 40% aqueous methylamine in 20 ml DMF was stirred at room temperature for about 45 hours. Thin layer chromatography showed mostly starting material so an additional 10 ml of 40% aqueous methylamine was added to the reaction mixture which was stirred for an additional 5 days. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. After drying, the solid was recrystallized from toluene to afford 2.3 g of 5-chloro-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide. Yield 70%. mp=182°-183° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:20])[C:18]=1[OH:19])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:6].[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:20][C:17]1[CH:16]=[C:4]([CH:3]=[C:2]([CH3:1])[C:18]=1[O:19][CH3:21])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc(C)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C)cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1C
Yield: 94.3 %

Procedure:
A solution containing compound 1 (15.0 g, 55.4 mmol), K2CO3 (20.0 g, 0.145 mol) and CH3I (30 mL, 0.48 mol) in 250 mL acetone was refluxed for 6 hours. The solvent was evaporated and the residue partitioned between CH2Cl2 and H2O. The organic layer was dried over Na2SO4, filtered and evaporated to leave a yellow-white powder. Recrystallization from CH3OH/pet ether at -20° C. gave 14.9 g of white crystals (94%). The material was characterized by NMR, TLC, mass spectroscopy, IR and elemental analysis, m.p. 131°-132.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]([C:8]1[NH:9][CH:10]=[CH:11][N:12]=1)[CH2:6][NH2:7].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]([C:8]1[NH:9][CH:10]=[CH:11][N:12]=1)[CH2:6][NH:7][C:14](=[O:16])[CH3:15]
Reactant: COC(=O)CC(CN)c1ncc[nH]1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(CNC(C)=O)c1ncc[nH]1

Procedure:
0.01 mol of the compound obtained in stage B of Example 16 is dissolved in 50 cm3 of chloroform. 0.01 mol of acetic anhydride and 0.015 mol of sodium carbonate are added. The whole is heated under reflux for five hours while stirring. The reaction mixture is then cooled, evaporated to dryness and extracted with chloroform twice. The chloroform phases are combined and dried over calcium chloride and the solvent is evaporated in vacuo on a water bath. The residue is purified by chromatography.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[OH:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][NH2:25]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[CH2:21][CH2:20][OH:19])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: NCCN(CCO)CCO
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1NCCN(CCO)CCO
Temperature: 80 °C
Yield: 41.1 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 30 ml of N-methylpyrrolidinone, 2.29 g of N,N-bis(2-hydroxyethyl)ethylenediamine, and 1.72 g of triethylamine. The reaction medium was heated at 80° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 1.5 g of 2[[2-(4-nitro-2-methylphenylamino)ethyl]-(2-hydroxyethyl)amino]ethanol (17) were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.Cl.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:31]([NH:38][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNCc4ccccc4)cc2)CCO3)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A suspension of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1g), benzylamine hydrochloride (0.5g) and potassium carbonate (0.6g) in dimethylformamide (10ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-((benzylamino)methyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-l-benzoxepine-4-carboxamide (Compound 117) (0.08g) as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)=[N:2]1
Reactant: NCCCNc1nsc2ccccc12
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
N1-(Benzo[d]isothiazol-3-yl)propane-1,3-diamine (600 mg, 2.8 mmol) and 4′-methoxy-biphenyl-4-carboxaldehyde (614 mg, 2.8 mmol) were combined in 1,2-dichloroethane (20 mL) and treated with sodium triacetoxyborohydride (1.2 g, 5.7 mmol) and acetic acid (160 μL, 5.6 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution. The crude product was extracted with ethyl acetate (2×50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography, on silica gel, eluting with 98:2 methylene chloride: methanol to yield N1-(benzo[d]isothiazol-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (330 mg) as a light yellow foam. 1H NMR (CDCl3): 7.80 (d, 1H), 7.75 (d, 1H), 7.25-7.45 (m, 8H), 6.90 (d, 2H), 3.95 (s, 2H), 3.85 (s, 3H), 3.70 (t, 2H), 3.00 (t, 2H), 2.30-2.40 ppm (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(OCCCOc2ccccc2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCCOc2ccccc2)cc1O
Yield: 85.3 %

Procedure:
A mixture of methyl 2-hydroxy-4-(3-phenoxypropoxy)benzoate (18.55g), methanol (40ml) and 10% aqueous sodium hydroxide (100ml) was stirred at 60° until a clear solution was obtained, then cooled and acidified. The precipitated solid was collected and recrystallised from cyclohexane-ethanol to give 15.09g (85%) of acid of mp 161°. (Found; C, 66.46; H, 5.71; C16H16O5 requires; C, 66.65; H, 5.59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>CS(C)=O>[OH:15][CH2:14][CH2:13][N:12]([C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1])[CH2:16][CH2:17][OH:18]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)c(Cl)c1
Temperature: 140 °C
Yield: 63.9 %

Procedure:
Dissolved in 8 ml of DMSO were 10.0 g (57.0 mmol) of 3-chloro-4-fluronitrobenzene and 8.6 g (82 mmol) of diethanolamine. The thus-obtained mixture was stirred under heat for 2 hours at 140° C., followed by extraction with ethyl acetate. The solvent was distilled out under reduced pressure, whereby 9.5 g of the title compound were obtained as a yellow oil (yield: 64%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:13].[Na+].Cl>OO>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:12])=[O:13]
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a 500 mL round bottom flask, 6-bromo-1H-indole-2,3-dione (50 g, 0.2192 mol) and NaOH (20 g in 250 mL water) were added and cooled the reaction vessel to 0° C. To this reaction mixture 30% hydrogen peroxide (50 mL) was slowly added. The reaction mixture was stirred at 0° C. for 2 h. Subsequently, the reaction mixture was acidified with 2N HCl [pH-6] at 0° C. to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound [10 g, 21%]. 1H NMR (300 MHz, DMSO-d6): δ 7.59 (d, J=8.7 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 6.65 (dd, J′=8.7 Hz, J″=1.8 Hz, 1H) LC-MS (ESI): Calculated mass: 215.0; Observed mass: 215.9 [M+H]+ (RT: 0.83 min).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[N:24]=[C:25]([CH3:28])[S:26][CH:27]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(OCC)(=O)C>[CH:29]1([NH:34][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[N:24]=[C:25]([CH3:28])[S:26][CH:27]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[CH:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1nc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Reactant: NC1CCCC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Temperature: 80 °C
Yield: 120 %

Procedure:
To 4-[7-chloro-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyridinamine from previous reaction was added cyclopentylamine and the resulting mixture heated to 80° C. for 3 days. The resultant solution was cooled to room temperature, diluted with ethyl acetate and washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:19 methanol/dichloromethane) gave N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyridinyl]-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-7-amine (20 mg, 120% for two steps) as a brown foam. 1H NMR (CDCl3): δ 8.09 (d, 1H), 7.56 (d, 1H), 7.34 (s, 1H), 7.15 (t, 1H), 6.98 (d, 1H), 6.64 (d, 1H), 6.45 (s, 1H), 5.60 (d, 1H), 4.80 (b, 1H), 3.94 (m, 1H), 3.87 (m, 1H), 2.76 (s, 3H), 1.98–1.45 (m, 16H). MS m/z 459 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].C(O)(=O)C>C1(C)C=CC=CC=1>[O:16]=[C:15]([CH3:17])[C:14](=[CH:5][C:4]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1cc(OC)ccc1OC)C(C)=O
Yield: 76.7 %

Procedure:
A stirred solution of 25.0 grams (0.15 mole) of 2,5-dimethoxybenzaldehyde, 22.0 grams (0.17 mole) of ethyl acetoacetate, 2 mL of pipeddine, and 3 mL of glacial acetic acid in about 250 mL of toluene is placed in a reaction vessel equipped with a Dean-Stark trap, and heated at reflux for about 12 hours. After this time, the reaction mixture is cooled and washed in turn with water, a cold solution of aqueous 10% hydrochloric acid, aqueous 5% sodium bicarbonate, and aqueous 1% acetic acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. Elution is accomplished using methylene chloride The column chromatography does not provide product purification as expected. The fractions are recombined and concentrated under reduced pressure to a residual oil. The oil is distilled under vacuum, yielding 32 grams of impure ethyl 3-oxo-2-(2,5-dimethoxyphenylmethylidene)butanoate. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1

Procedure:
1.0 g (4.63 mmol) of 4-nitrobenzyl bromide (Fluka, Buchs, Switzerland), 799 mg (11.6 mmol) of 1,2,4-triazole and 0.692 mL (4.63 mmol) of 1,5-diazabicyclo[5.4.0]-5-undecene (Fluka, Buchs, Switzerland) in 10 ml of CH2Cl2 are stirred at rt for 1.5 h. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with brine, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography (CH2Cl2-MeOH 49:1 to 19:1) to provide the title compound as a pale yellow solid. ES-MS: 205 (M+H)+; analytical HPLC: tret=2.54 minutes (Grad 1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH:11]=[CH:10][CH:9]=[C:8]3[CH2:7]1)(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH:11]=[CH:10][CH:9]=[C:8]3[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1Cc2cccc3cccc1c23
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(=O)OCC1=Cc2cccc3cccc1c23
Temperature: 95 °C
Reaction time: 7 h
Yield: 121.1 %

Procedure:
The acetoxymethylacenaphthene (45 g) obtained in Step 3 was dissolved in dioxane (450 g). After the addition of dichlorodicyanobenzoquinone (60 g), the mixture was stirred for seven hours at 95° C. The reaction mixture was filtered and the solvent was evaporated from the filtrate to obtain 54 g of acetoxymethylacenaphthylene as a brown solid.