Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:4].[O:16]1C2C=CC=CC=2[O:18][BH:17]1>>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][CH:7]=1)([CH3:1])/[CH:3]=[CH:4]/[B:17]([OH:18])[OH:16]
Reactant: B1Oc2ccccc2O1
Reactant: C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Product: CC(C)(/C=C/B(O)O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 25.2 grams (0.12 mole) of 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne and 12.7 mL (0.12 mole) of 1,3,2-benzodioxaborole was warmed to 70° C. where it stirred for six hours. The reaction mixture was then cooled and poured slowly into 500 mL of ice-water while flushing with nitrogen. The mixture was then allowed to warm to ambient temperature where it stirred for about 18 hours. The mixture was cooled in an ice-bath, and the resultant solid was collected by filtration. The solid was washed with water and then dissolved in diethyl ether. The solution was washed with 100 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a residual solid. The solid was dried under vacuum without heat, yielding 27.6 grams of trans-3-methyl-3-(4-trifluoromethylphenyl)-1-butenylboronic acid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][NH:7][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: CN(CCc1ccccc1OCCCO)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCc1ccccc1OCCCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
{2-[2-(3-Hydroxypropoxy)phenyl]ethyl}-N-methylcarbamic acid tert-butyl ester (0.587 g, 1.90 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. Trifluoroacetic acid (5 ml) was added. The reaction mixture was stirred for 30 min at 0° C. Dichloromethane (50 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (50 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous solution was extracted with dichloromethane (3×70 ml). The aqueous phase was made basic to pH 14 with a 20% aqueous sodium hydroxide solution. It was extracted with tert-butyl methyl ether (3×100 ml). The tert-butyl methyl ether extracts were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 227 mg of crude 3-[2-(2-methylaminoethyl)phenoxy]propan-1-ol. The crude product was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](O)=[N:8][CH:9]=1)([O-:3])=[O:2].O=S(Cl)[Cl:17].CN(C=O)C>>[Cl:17][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
To a mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2 g, 9.61 mmol) and SOCl2 (21.04 mL, 288 mmol) was added DMF (0.074 mL, 0.961 mmol). Then the mixture was stirred at 80° C. for 16 h. The mixture was concentrated and extracted with EA (2×100 mL) and washed with H2O (100 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4 and concentrated to yield a brown solid of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 5.30 mmol, 55.1% yield): 1H NMR (400 MHz, CD3OD) δ 8.91 (d, J=2.43 Hz, 1H), 9.42 (d, J=2.43 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[C:27]=2[F:36])[CH2:22][CH2:21]1>CN(C=O)C>[F:36][C:27]1[C:28]([F:35])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=[CH:31][C:26]=1[C@H:23]1[CH2:24][CH2:25][C@H:20]([CH2:19][O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:21][CH2:22]1
Reactant: CCOc1ccc(C2CCC(CCl)CC2)c(F)c1F
Reactant: Oc1cccc(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([C@H]2CC[C@H](COc3cccc(F)c3F)CC2)c(F)c1F
Temperature: 70 °C
Reaction time: 7 h

Procedure:
2,3-Difluorophenol (46) (13.8 g) and tripotassium phosphate (K3PO4; 73.4 g) were added to DMF (200 ml) under a nitrogen atmosphere, and the mixture was stirred at 70° C. The compound (15) (20.0 g) was added thereto and the stirring was continued at 70° C. for 7 hours. After the reaction mixture obtained had been cooled to 30° C., solids were separated by filtration, and then toluene (100 ml) and water (100 ml) were added to and mixed with the filtrate. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed with brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by means of recrystallization from a mixed solvent of Solmix A-11 and ethyl acetate (Solmix A-11:ethyl acetate=2:1 by volume) and dried, giving 19.8 g of 2,3-difluoro-4-ethoxy-[trans-4-(2,3-difluorophenoxymethyl)cyclohexyl]benzene (47). The yield based on the compound (15) was 74.8%.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=[O:2].[CH2:26]1COCC1.C[Mg]Br.[NH4+].[Cl-]>CCOCC>[OH:2][CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:15]=[CH:16][CH:17]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)[CH3:26]
Reactant: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CSc1ncc(C(C)O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Temperature: 0.5 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A 3-necked 2 L RBF equipped with an addition funnel, temperature probe and nitrogen inlet was charged with tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50) (25.0 g, 69.4 mmol) and THF (400 mL). The mixture was cooled to 0.5° C. using an ice water bath. Methylmagnesium bromide (3.0 M in Et2O, 74.0 mL, 222 mmol) was added dropwise via an addition funnel over 35 min. The temperature was kept below 8° C. during the addition. The reaction mixture was stirred for 90 min at 0.5° C. and then saturated NH4Cl (aq.) was added slowly via an addition funnel while cooling in ice. The mixture was stirred for 1 h then extracted with EtOAc (2×300 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated furnishing a yellow solid. The yellow solid was suspended in Et2O (ca. 200 mL), filtered, washed with additional Et2O (2×50 mL), and dried under vacuum overnight affording tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (23.17 g, 61.5 mmol, 89% yield) as a light yellow solid. m/z (ESI, +ve ion) 377.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (1H, s), 8.86 (1H, s), 8.07 (1H, s), 7.80 (1H, s), 7.32 (1H, dd, J=8.1, 1.1 Hz), 7.19 (1H, t, J=8.1 Hz), 6.95-7.07 (1H, m), 5.87 (1H, d, J=4.1 Hz), 4.93 (1H, dd, J=6.5, 4.3 Hz), 2.43 (3H, s), 1.47 (9H, s), 1.40 (3H, d, J=6.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][O:11][CH3:12])[N:5]=[CH:6][C:7]=1Cl.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][O:11][CH3:12])[N:5]=[CH:6][C:7]=1[O:15][CH3:14]
Reactant: COCCn1ncc(Cl)c(Cl)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCn1ncc(OC)c(Cl)c1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=219.1, 221.1 (M+H+), was prepared in accordance with the general method of example 23e by treatment of 4,5-dichloro-2-(2-methoxy-ethyl)-2H-pyridazin-3-one with sodium methoxide in methanol.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].ClCCl>C(#N)C>[F:15][C:16]1[CH:23]=[C:22]([O:24][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Yield: 84.3 %

Procedure:
15.2 ml (0.127 mol) of benzyl bromide and 29.3 g (0.212 mol) of potassium carbonate are added to a solution of 13.3 g (0.106 mol) of 2-fluoro-4-hydroxybenzonitrile in 150 ml of acetonitrile. The mixture is stirred at reflux for 1 hour 30 minutes and then filtered, the filtrate is concentrated under reduced pressure, and the oil obtained is diluted in the minimum amount of dichloromethane. After crystallization by addition of diisopropyl ether, filtration and drying, 20.3 g of product are obtained. Melting point : 87° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO[C:23](OC)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1(C)C=CC=CC=1>[CH3:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:8][O:9][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:1][CH2:2]1
Reactant: CC(CO)(CO)C(=O)O
Reactant: COC(OC)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C(=O)O)COC(c2ccccc2)(c2ccccc2)OC1
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
In a round bottom flask, (12 g) 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid and 35 ml toluene was taken. (99.4 mg) p-toluene sulfonic acid was added into the reaction mixture at 25-30° C. temperature. The reaction mixture was heated at reflux temperature, and 20.5 g (1 equiv.) dimethoxy diphenylmethane [IIa3] in 35 ml toluene was added and it was further refluxed under dean stark. Continuous removal and addition of toluene done upto 3 hrs. Then reaction mixture was cooled at 25-30° C. and dumped into water. The reaction mixture was stirred at 20-30° C. and filter it and wash the solid mass with water to obtain white solid product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:15][C:16]([C:17]([NH:19][C@@H:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O/[N:56]=[C:57](\[NH2:59])/[CH3:58]>CN(C=O)C.O>[NH2:59]/[C:57](=[N:56]\[O:22][C:21](=[O:23])[C@@H:20]([NH:19][C:17]([C:16]1[N:15]=[C:14]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=12)=[O:18])[C:24]([CH3:26])([CH3:27])[CH3:25])/[CH3:58]
Reactant: C/C(N)=N/O
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Reaction time: 0.5 h

Procedure:
Intermediate 22B (0.25 g, 0.55 mmol) was dissolved in DMF and EDCI (0.17 g, 0.87 mmol) was added, followed by HOBt (0.12 g, 0.87 mmol). The resulting mixture was stirred for 30 min and (Z)-N′-hydroxy-acetimidamide (0.06 g, 0.82 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water, 2N Na2CO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was used in the next step without purification. LCMS (+ESI) m/z 1025.2 [2M+H]+.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[CH:9][N:8]=1.[Sn:15](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:14][S:13][C:11]1[CH:12]=[C:7]([Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19])[N:8]=[CH:9][N:10]=1
Reactant: CSc1cc(I)ncn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(SC)ncn1
Reaction time: 0.17 h

Procedure:
A solution of iPrMgCl (2M in THF solution, 5 mL, 10 mmol) is added slowly to a solution of 4-iodo-6-methylsulfanyl-pyrimidine 35 (2.53 g, 10 mol) in THF (50 mL) at −78° C. After 10 minutes, Bu3SnCl (2.75 mL, 10 mmol) is added. After reaction overnight, the reaction mixture is concentrated. The crude product is purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 0% to 10% to afford 4-methylsulfanyl-6-tributylstannanyl-pyrimidine (36).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC2CCc3[nH]c(C(=O)O)cc32)cc1OC

Procedure:
The title compound was synthesized from methyl 4-(3,4-dimethoxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.050 g, 0.16 mmol) and lithium hydroxide (0.067 g, 1.6 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane) to afford the title compound: 11 mg, 23% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.06-2.18 (m, 1H), 2.50-2.68 (m, 3H), 2.68-2.81 (m, 2H), 3.20-3.35 (m, 1H), 3.77 (s, 3H), 3.81 (s, 3H), 6.35 (s, 1H), 6.72 (m, 2H), 6.86 (d, J=8.0 Hz, 1H); LCMS-MS (ESI−) 300.0 (M−H); HPLC (UV=96%), (ELSD=100%).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl.C(OCC)(=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Reactant: CC(C)(C)OC(=O)COc1cccc(N)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=N)N)sc1C(=O)Nc1cccc(OCC(=O)OC(C)(C)C)c1

Procedure:
2-Guanidino-4-methyl-thiazole-5-carboxylic acid is reacted with tert-butyl (3-amino-phenoxy)-acetate in the same manner as in Example 3. Chromatography on silica gel with methylene chloride-ethyl acetate and methylene chloride-alcohol gives 176 mg of tert-butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate, m.p. 204° C., MS: 406 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: BrBr
Reactant: O=C(O)c1ccc2ccccc2c1O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Br)c2ccccc2c1O

Procedure:
To a solution of 2.50 g 1-hydroxy-2-naphthoic acid in 50 ml chloroform a solution of 0.68 ml bromine in 5 ml chloroform was added dropwise. After 16 h the reaction was concentrated to yield 3.40 g 4-bromo-1-hydroxy-naphthalene-2-carboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5]C)=[O:4].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:2][C:3]([OH:5])=[O:4])[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: COC(=O)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CCN(CC(=O)O)CC1
Temperature: 70 °C
Yield: 70 %

Procedure:
165 g of methyl 2-chloroacetate are dropped into a solution of 152 g of N-methylpiperazine and 212 ml of triethylamine in 1.5 l of toluene, with stirring and under inert gas atmosphere; then the reaction mixture is heated to 70° C. for 4 hours. After that, the reaction mixture is cooled to room temperature, the resulting precipitate is filtered and washed on the filter with 100 ml of toluene. The resulting organic solution is extracted with water (5×200 ml) and the combined organic extracts are refluxed for about 20 hours, then water is distilled off under reduced pressure. The residue is crystallized from isopropanol, to obtain 168 g of 2-(N-methylpiperazino) acetic acid, m.p. 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]#[N:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:20][C:21]([CH2:23]Cl)=[CH2:22].[NH4+]=[S:26]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:23][C:21]([Cl:20])=[CH2:22])[C:10]([NH2:11])=[S:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Cl)CCl
Reactant: N#CNc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)CN(C(N)=S)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Yield: 90 %

Procedure:
N-(3,5-dichlorophenyl)cyanamide (2.81 g) was dissolved in DMF (14.03 g), to which powdered potassium carbonate (3.11 g) and potassium iodide (0.26 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (2.00 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 2.5 hours. After cooling to room temperature, DMF (9.00 g) and ammonium sulfide solution, yellow (8.00 g) having an S content of 6% were added dropwise to the reaction mixture at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 4 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 4.00 g of N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)thiourea as a dark red solid (90% yield in appearance). The percentage area of liquid chromatography was 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1>[Pd].C(O)C>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:20])[NH:10][C:4]2[C:5]([CH:6]=1)=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:16])[CH3:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2ccc(Cl)cc2[nH]c1=O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 4-chloro-2-nitrobenzaldehyde (9-1, 495 mg, 2.64 mmol, 1 equiv) and 10% palladium on carbon (0.280 g, 0.264 mmol, 0.100 equiv) in ethanol (20 mL) was stirred under a hydrogen balloon for 1 h at 23° C. The catalyst was filtered onto a pad of celite and washed with ethanol (20 mL). The combined filtrate was concentrated to 20 mL, then diethyl malonate (0.801 mL, 5.28 mmol, 2.00 equiv) and piperidine (0.130 mL, 1.32 mmol, 0.500 equiv) were added. The resulting mixture was heated at reflux for 5 h. The mixture was allowed to cool to 23° C., and the precipitate was filtered and washed with cold ethanol (10 mL) to give 7-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (9-2) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(OC(Cl)=O)C.[NH2:20][CH:21]1[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:20][CH:21]2[CH2:25][N:24]([CH3:26])[N:23]([CH3:27])[CH2:22]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CC(N)CN1C
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CN(C)N(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of equal molar amounts of 4-amino-5-chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0°-5° C.) was treated dropwise with a slight excess of ethylchlorocarbonate. After 1.0 hour a solution of 4-amino-1,2-dimethylpyrazolidine in methylene chloride was added and the mixture stirred for about two hours at room temperature. An aqueous solution of sodium bicarbonate was added to the reaction mixture, the organic phase separated and concentrated to give the product which melted at 169°-171° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: O=CO
Reactant: CNc1cc(C)ccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1ccc(C)cc1N(C)C=O
Reaction time: 1.5 h

Procedure:
A mixture of acetic anhydride (23.3 ml) and formic acid (15.9 ml) was stirred at 50 to 60° for 90 minutes and then cooled to 0 to 5° in an ice/salt bath. 4'-Methyl-2'-(methylamino)acetophenone (17.25 g) was added and the solution stirred at 20° for 3 hours. The reaction mixture was cooled to 0° and water (80 ml) added dropwise whilst maintaining the temperature below 8°. Aqueous sodium hydroxide (specific gravity 1.5, 60 ml) was added dropwise whilst maintaining the temperature below 10°. The mixture was extracted with dichloromethane (3×30 ml). The combined extracts were washed with aqueous sodium chloride (6M, 100 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (100:1) to give the novel compound 2'-acetyl-5'-methyl-N-methylformanilide, m.p. 58°-60°.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=3)[CH3:2].[CH:21]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CS(C)=O>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:28][CH2:27][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3cc(NC(C)=O)ccc3nc21
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(NC(C)=O)ccc3nc21
Temperature: 110 °C
Yield: 78.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-acetamido-1H-pyrazolo[3,4-b]quinoline (0.2 g, 0.7 mmol), cyclohexanemethylamine (0.5 ml, 3.5 mmol) and DMSO (3 ml) was heated at 110° C. for 6 hours. The reaction mixture was poured into water (50 ml), extracted with CH2Cl2 (4×25 ml) and the organic layers were combined and evaporated. The residue was slurried in ether and a yellow solid was collected by filtration and recrystallized from ethanol/ethyl acetate to afford 200 mg of 1-ethyl-6-acetamido-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 277°-278° C.