Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C=O)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[NH:18][CH:17]=C2.[OH-].[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[NH:18][CH:17]=[C:2]2[CH:1]=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc2[nH]ccc2cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc2[nH]cc(C=O)c2cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (0.68 mL) in DCM (10 mL) at 0° C. was dropwise added a solution of DMF (0.60 mL) in DCM (2 mL). The mixture was stirred for 0.5 h at 0° C. and then 5-fluoro-1H-indole-6-carbonitrile (D151) (250 mg) in DCM (3 mL) was added in one portion. The reaction mixture was allowed to warm to rt and stirred overnight. Afterwards, the reaction mixture was added with 2 M aqueous NaOH (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and then concentrated under vacuo to give the designed product 5-fluoro-3-formyl-1H-indole-6-carbonitrile (D152) (280 mg), which was used without purification. MS (ES): C10H5FN2O requires 188.0; found 189.1 (M+H+).
Reaction SMILES: [CH3:1][C:2](=O)[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][CH2:18][CH2:19][CH2:20][CH3:21].O.NN.[OH-].[K+]>C(O)CO>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCCC(C)=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCCCCCCCCCCCCCCCCCCC

Procedure:
reacting 2,4-alkaneanedione with 1-bromooctadecane in absolute ethanol in the presence of 18-crown-6 as catalyst to produce 2-heneicosanone; and (b) reducing said 2-heneicosanone using hydrazine hydrate and potassium hydroxide in ethylene glycol to obtain n-heneicosane.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].FC1C=CC(C[N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=CC=1.C(O)(=O)C>CO>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:1][CH2:2][N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:18]2[NH:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)[CH2:32][CH2:31]1
Reactant: C=Cc1cnccn1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2[nH]c(NC3CCN(CCc4cnccn4)CC3)nc2c1

Procedure:
A mixture of 1.27 parts of 2ethenylpyrazine, 6.48 parts of 1-[(4 fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 0.3 parts of acetic acid and 40 parts of methanol was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (88:12 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was washed with 2,2'-oxybispropane and crystallized from 27 parts of methylbenzene, yielding 2.4 parts of 1-)4-fluorophenylmethyl)-N-[1-[2-(2-pyrazinyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 165.3° C. (compound 101).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:23](OCC)=[O:24].O.[NH2:29][NH2:30]>C(O)C>[Cl:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:21])[C:14]=1[C:13]([NH:12][C:7]1[C:6]2[N:5]=[CH:4][C:3]3[C:23](=[O:24])[NH:29][NH:30][C:2]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:22]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C(Nc1cccc2c1ncc1c(=O)[nH][nH]c12)c1c(Cl)cccc1Cl
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (297 mg) and hydrazine monohydrate (175 mg) in ethanol (3 ml) was refluxed for 1 hour. To the mixture was added ice-water, and the resulting precipitate was collected by filtration and washed with water to give 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1H-pyrazolo[4,3-c]-quinolin-3-one (250 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N:34]2[CH2:39][CH2:38][N:37](CCC3C=C(C=CC=3)N)[CH2:36][CH2:35]2)[N:25]=1.[N:49]1([C:54]2[CH:55]=[C:56]([CH2:60][C:61]([OH:63])=O)[CH:57]=[CH:58][CH:59]=2)[CH:53]=[CH:52][CH:51]=[N:50]1>CN(C)C=O>[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N:34]2[CH2:39][CH2:38][N:37]([C:61](=[O:63])[CH2:60][C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([N:49]4[CH:53]=[CH:52][CH:51]=[N:50]4)[CH:55]=3)[CH2:36][CH2:35]2)[N:25]=1
Reactant: O=C(O)Cc1cccc(-n2cccn2)c1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)Cc4cccc(-n5cccn5)c4)CC3)cccc2n1

Procedure:
EDC.HCl (1.5 eq), HOBt (2 eq) and 2-methyl-5-(1-piperazinyl)quinoline (D3) (1 eq) were added sequentially to a stirred solution of [3-(1H-pyrazol-1-yl)phenyl]acetic acid (D19) (1.1 eq) in dimethylformamide at room temperature under an inert atmosphere.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]([CH2:17]Br)=[CH2:16]>>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:17][C:15]([Br:14])=[CH2:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Product: C=C(Br)CC(C(=O)OCC)C(=O)OCC
Temperature: -22.5 °C
Yield: 137.9 %

Procedure:
The oil was removed from 21.70 g (0.542 mol) of 60% sodium hydride in oil by washing with hexanes. To the residue suspended in 200 ml tetrahydrofuran, 84.38 ml (0.556 mol) diethyl malonate was added slowly via addition funnel. While the reaction was cooled to −35 to −10° C., 100 g (0.400 mol) of 2,3-dibromopropene was added slowly via addition funnel. After heating to reflux for 1 hour, the reaction was cooled to room temperature and concentrated ill vacuo. Hexanes and water were added to the residue and the resulting mixture was transferred to a separatory funnel where the-phases were separated. The isolated organic layer was washed with IN hydrochloric acid then dried over magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo to yield 154 g of 2-(2-bromo-allyl)-malonic acid diethyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27](=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:35])[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]([CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[C:27](=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])[O:10][C:9]1([CH3:35])[CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)NC(=O)C1CC=CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)C1CCCCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Yield: 99.6 %

Procedure:
A solution of 4-benzyl-5-(6-tert-butylcarbamoyl-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg) in ethanol (20 ml) was hydrogenated over 10% palladium on carbon for 3 hours at atmospheric pressure and ambient temperature. The catalyst was removed by filtration and the filtrate evaporated to give 4-benzyl-5-(2-tert-butylcarbamoyl-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg, 100%) Mass spectrum 487 [M+H]+.
Reaction SMILES: [Br:1]Br.[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[O:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=1)=[O:8])(=[O:5])[CH3:4]>ClCCl>[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[O:12][C:13]([C:16](=[O:18])[CH2:17][Br:1])=[CH:14][CH:15]=1)=[O:8])(=[O:5])[CH3:4]
Reactant: CC(=O)NC(=O)NCc1ccc(C(C)=O)o1
Reactant: BrBr
Solvent: ClCCl
Product: CC(=O)NC(=O)NCc1ccc(C(=O)CBr)o1
Reaction time: 1.5 h

Procedure:
A solution of bromine (0.23 ml) in dichloromethane (5 ml) was dropwise added to a mixture of 1-acetyl-3-(5-acetylfuran-2-ylmethyl)urea (1.0 g) in dichloromethane (20 ml) at ambient temperature for 20 minutes and the mixture was stirred at the same temperature for 1.5 hours. The solvent was removed by concentration and residue was triturated with isopropyl ether to give 1-acetyl-3-[5-(bromoacetyl)furan-2-ylmethyl]urea (1.27 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[C:19](=[O:20])[O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH:19]([OH:20])[O:18][C@H:17]3[C:21]4[C@@:26]([CH3:29])([CH2:27][CH2:28][C:16]23[OH:31])[CH2:25][CH2:24][CH2:23][C:22]=4[CH3:30])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C2[C@@H]3OC(=O)C(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1=C2[C@@H]3OC(O)C(CN4CCN(Cc5ccccc5)CC4)C3(O)CC[C@@]2(C)CCC1
Reaction time: 3 h

Procedure:
Compound of example 27 (200 mg, 0.47 mmol) was dissolved in anhydrous DCM and toluene (1:1) (2 mL) and solution was cooled to −78° C. DIBAL in toluene (1.0 M, 1.4 mL, 1.2 equivalents) was added dropwise at −78° C. and mixture was stirred for 3 hours. Saturated sodium sulphate solution was added and reaction mixture was extracted by DCM (3×50 mL), dried over sodium sulphate and was concentrated to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15]([OH:17])=O)[C:8]2=[O:21])=[CH:4][CH:3]=1.[CH3:24][N:25]1CCOCC1.ClC(OCC(C)C)=O.Cl.CN>O1CCCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15]([NH:25][CH3:24])=[O:17])[C:8]2=[O:21])=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid (0.18 g, 0.56 mmol) and 4-methylmorpholine (0.12 g, 1.18 mmol) in anhydrous tetrahydrofuran (15 mL) was added isobutyl chloroformate (0.10 g, 0.69 mmol) at 0° C. The resulting solution was stirred at ambient temperature for 3 hours, followed by the addition of methylamine hydrochloride (0.08 g, 1.12 mmol) and 4-methylmorpholine (0.06 g, 0.56 mmol) at 0° C. The reaction mixture was stirred for 17 hours and concentrated in vacuo. The residue was purified by column chromatography to give 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-methylisonicotinamide as a colorless solid (0.08 g, 43%): mp 118-120° C.; 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.36-8.34 (m, 1H), 7.40-7.37 (m, 1H), 7.29-7.24 (m, 2H), 7.06-6.99 (m, 2H), 6.47 (br s, 1H), 4.44 (s, 2H), 4.07-4.01 (m, 2H), 3.40-3.35 (m, 2H), 2.98 (d, J=4.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.5, 153.0, 148.4, 143.1, 132.1, 129.9, 129.8, 116.1, 115.9, 115.6, 108.8, 47.3, 41.3, 41.0, 26.8; MS (ES+) m/z 329.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:12]([O-])=O.[Na+]>Cl.O>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([C:4]([NH2:12])=[N:5][NH:1]2)=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(C#N)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(N)n[nH]c2c1
Temperature: 0 °C
Yield: 91.9 %

Procedure:
To an ice-cooled suspension of 66.35 g (0.448 mol) of 2-amino-4-methoxybenzonitrile in 530 ml of concentrated HCl, a solution of 37.07 g (0.537 mol) of sodium nitrite in 55 ml of water was added dropwise. After 1.5 hours the cold suspension was added dropwise to a preformed solution of 679.25 g (3.58 mol) of stannous chloride in 530 ml of concentrated hydrochloric acid (HCl), at SOC. After 3 hours the cold suspension was filtered and the moist solid was treated with 1.7 l of boiling water for 30 min. The hot cloudy solution was clarified by filtration through a cloth filter. The liquors were ice-cooled and treated dropwise with 0.8 l of 17% NaOH. The solid was filtered off and dried under vacuum at 50° C.: 67.2 g of product were obtained as light brown solid. Yield=91.9%. mp=195-197° C. dec. HPLC r.t. 1.9 [M+H]+=164
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: c1ccc2c(c1)CCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(CCCBr)N1CCCc2ccccc21
Reaction time: 3 h

Procedure:
A solution of 4-bromobutyryl chloride (3.4 g) in ether (25 ml) was added to a mixture of 1,2,3,4-tetrahydroquinoline (6.8 g), ether (20 ml) and 10% aqueous sodium hydroxide (34 ml). The mixture was refluxed with stirring for 3 hours then the ethereal solution was washed with dilute hydrochloric acid, dried and evaporated to yield the title compound as an oil.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-:5])=O.[O-]CC.[Mg+2].[O-]CC.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>CO.O1CCCC1>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])=[O:5]
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccco1
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
In 100 mL of methanol, was dissolved 5.90 g (50.0 mmol) of monomethyl malonate, and the resulting solution was mixed with 2.86 g (25 mmol) of magnesium ethoxide followed by stirring at room temperature for 4 hours. The reaction solution was concentrated and the residue was dried under reduced pressure. In 100 mL of tetrahydrofuran, was dissolved 2.80 g (25 mmol) of 2-furancarboxylic acid and the resulting solution was mixed with 4.45 g (27.4 mmol) of carbonyldiimidazole, followed by stirring for 1 hour. The reaction solution was added to a dry magnesium salt and stirred at room temperature for 19 hours. The reaction solution was concentrated; the residue was mixed with 100 mL of 1.5 N hydrochloric acid, extracted with ethyl acetate, and washed with an aqueous sodium hydrogencarbonate solution and saturated sodium chloride water. The resultant was dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled (0.06 mmHg, 69 to 75) to give 2.93 g (17.4 mmol, 69.6%) of methyl 2-furancarbonylacetate as an anhydrous liquid. Similarly to Example 133, 65 mg (1.34 mmol, 58.1%) of dark yellow crystals were obtained from 2.93 g (17.4 mmol) of methyl 2-furancarbonylacetate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: C1CCNCC1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCN4CCCCC4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[7-(3-Bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (70 mg), potassium carbonate (54 mg), and piperidine (39 μl) were dissolved in N,N-dimethylformamide (2 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol (20/1) to give 35 mg (yield 50%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:30]I>CN(C=O)C>[C:1]([N:4]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:7][CH:6]=1)[CH3:30])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Br)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Br)cc3)CC2)cc1

Procedure:
In a manner analogous to that described in Example 5, 1.6 g of 1-(4-acetylaminobenzoyl)-4-[2-(4-bromophenyl)ethyl]-piperazine, dissolved in 15 ml DMF, are treated first with 0.2 g NaH in 10 ml DMF and then with 0.6 g methyl iodide in 5 ml DMF. The crude product is crystallised from ether. Thus 1-[4-(N-acetyl-N-methylamino)benzoyl]-4-[2-(4-bromophenyl)ethyl]-piperazine is obtained, m.p. 161°-162°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]1[O:19][C@H:18]1[CH2:20]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:20][C@H:18]1[CH2:17][O:19]1
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(Br)cc(OC[C@H]2CO2)c1F
Temperature: 25 °C
Yield: 97 %

Procedure:
To an acetone solution (0.1 M, 240 mL) of commercially available 5-bromo-2,3-difluorophenol (5.0 g, 23.93 mmol) was added K2CO3 (9.92 g, 71.77 mmol), and the mixture was heated to reflux for 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (6.20 g, 23.93 mmol) was added, and the resulting mixture was heated to reflux overnight. After cooling to RT, the solids were removed by filtration and washed well with ethyl acetate. The filtrate was concentrated and partitioned between ethyl acetate and 1N HCl. The organic portion was washed successively with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by FCC (15% ethyl acetate/hexanes) gave the product as a white solid in 97% yield (6.19 g).
Reaction SMILES: [CH:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([C:11]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]([C:23](=O)[C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH2:32][CH3:33])[CH3:31])=[CH:26][CH:25]=3)=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=O)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:17]2[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([CH2:9][C:8]3[CH:35]=[CH:36][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:6][CH:7]=3)=[CH:19][C:18]=2[C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1)([CH2:32][CH3:33])[CH3:31]
Reactant: CCC(C)c1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(C(C)CC)cc3)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(C)c1ccc(Cc2cc(C(=O)O)c(Cc3ccc(C(C)CC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture of 120 grams of 2,5-bis(4-sec-butylbenzoyl)terephthalic acid, 1.5 L of tetrahydrofuran, and 9.65 grams of 10% palladium on carbon (as a catalyst) was heated at 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The reaction mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give a solid. The solid was triturated with 10% ethyl acetate in heptane, collected and dried to give 2,5-bis(4-sec-butylbenzyl)terephthalic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CNCc1ccccc1

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.263 g, 1.0 mmol) and benzylamine (0.11 mL, 1.0 mmol) gives the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:12][C:4]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1c(C)nc2ncccc2c1Cl
Product: CCOC(=O)c1c(C)nc2ncccc2c1N1CCCCC1
Temperature: 80 °C
Yield: 63.3 %

Procedure:
In a screw cap pressure tube ethyl 4-chloro-2-methyl-1,8-naphthyridine-3-carboxylate (250 mg, 1.0 mmol) was suspended in piperidine (2.0 ml, 20 mmol). The tube was sealed and the mixture heated to 80° C. for 1.0 h. The mixture was then adsorbed on silica and chromatographed (CH2Cl2/MeOH 98:2→97:3) giving 189.4 mg (63%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][CH2:26][C:25]3[CH:24]=[C:23]([CH:30]=[CH:29][CH:28]=3)[C:21]#[N:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: N#Cc1cccc(CBr)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(CCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloroquinaldine (17.7 g) in THF (80 mL) at -78° was added a solution of 100 mL lithium diisopropyl amide (LDA) (1M) dropwise. After addition the solution was warmed to -20° and added dropwise to 3-cyanobenzyl bromide (20 g) in THF (80 mL) at 0°. The reaction mixture was stirred 1 hr at 0° and warmed to room temperature (30 min). The mixture was partitioned between pH 7 buffer (25% NH4OAc) and ethyl acetate. The organic layer was dried and evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.