Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])C.O1CCCC1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[NH2:1][C:2]1[NH:3][C:4]([C:14]#[C:13][CH:11]([OH:15])[CH3:10])([CH3:9])[CH:5]=[CH:6][N:7]=1
Reactant: C#CC(C)(C)O
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)C#CC1(C)C=CN=C(N)N1

Procedure:
A mixture of 10.0 g of 2-amino-4-chloro-6-methylpyrimidine, 8.8 ml of 2-methyl-3-butyn-2-ol, 400 ml of tetrahydrofuran (THF), 0.06 g of copper (I) iodide, 0.5 g of bis(triphenylphosphine)palladium (II) chloride and 20.4 ml of triethylamine was heated overnight at reflux under a nitrogen atmosphere. The reaction mixture was allowed to cool. It was then partitioned between 200 ml of ethyl acetate and 100 ml of sodium bicarbonate. The organic layer was washed successively with 100 ml of water and 100 ml of brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was placed on a silica gel dry column and eluted with dichloromethane/ethyl acetate/THF (10:90:0.1). The product band was extracted with THF. The organic extract was concentrated. Trituration of the residue (butyl chloride) gave 4.44 g of the title compound as a solid, m.p. 155°; PMR (90 MHz, CDCl3) δ1.65(s, 6H, CH3), 2.3(s, CH3, 3H), 2.8(s, OH, 1H), 5.2(bs, 2H, NH2), 6.6(s, Het-H, 1H); IR(nujol) 2221(w, C≡C) cm-1.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12]([OH:14])=O)[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>C(Cl)Cl>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:14])[NH:32][C:31]1[CH:33]=[CH:34][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)OC(=O)C(C(=O)O)=C1SCS1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)C(C(=O)Nc1ccc(Cl)cc1)=C1SCS1
Reaction time: 1 h

Procedure:
A solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-carboxyacetate (10 g) in methylene chloride (100 ml) was cooled to -10° C. and thereto phosphorous pentachloride (8.9 g) was added portionwise and then stirred for 1 hr. To the reaction mixture pyridine (13.8 ml) and 4-chloroaniline (5.45 g) were added and stirred for 2 hrs. The mixture was washed with dil-HCl, 10% aqueous sodium hydroxide solution and water and then evaporated. The residue was purified with ethyl acetate to afford the titled compound as a white solid. (8.9 g, 61%).
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:32]2[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:38]([C:35]1[CH:36]=[N:37][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:40])=[O:5])[S:12][CH:13]=2)=[N:33][CH:34]=1)[CH3:39]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(N3CCOCC3)cc2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(N3CCOCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.4 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)(4-morpholin-4-ylbenzyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (200 mg) synthesized in Example 408-1 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=20:1) to give the title compound (111 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([O:21]C)=[O:20]>Cl>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1ccccc1OCCCN1CCC[C@H]1CO
Agent: Cl
Product: O=C(O)Cc1ccccc1OCCCN1CCC[C@H]1CO
Yield: 92.1 %

Procedure:
A suspension of 1.65 g of methyl 2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]phenylacetate in 20 cm3 of 6N hydrochloric acid is refluxed for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is triturated in ether. 1.45 g of 2-[3-(2-hydroxymethyl-(S)-1-pyrrolidinyl)propoxy]phenylacetic acid are obtained in the form of a brown oil.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1)[C:16]#[CH:15]
Reactant: Nc1nc2ccccc2c2[nH]cnc12
Reactant: C#CCBr
Product: C#CCn1cnc2c(N)nc3ccccc3c21
Yield: 15.8 %

Procedure:
Using the general method of Example 1, 2.1 g of 1H-imidazo[4,5-c]quinolin-4-amine was reacted with 1.7 g of propargyl bromide to provide 0.4 g of 1-(2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 220°-222° C. The structure was confirmed by nuclear magnetic resonance spectroscopy. Analysis: Calculated for C13H10N4 : % C, 70.3; % H, 4.5; % N, 25.2; Found: % C, 70.5; % H, 4.6; % N, 25.4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:38]=[CH:37][CH:36]=[CH:35][C:23]=1[CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][C:26]1=[O:34]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:31]([C:28]3[CH:29]=[CH:30][N:25]([CH2:24][C:23]4[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=4[Cl:21])[C:26](=[O:34])[CH:27]=3)=[O:32])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccn(Cc2ccccc2Cl)c(=O)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2ccccc2Cl)c(=O)c1

Procedure:
1-(2-Chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(2-chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C29H22Cl2N3O3 [(M+H)+] 530.1, obsd. 530.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cnn2c(-c3ccc(Cl)cc3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnn2c1NCC=C2c1ccc(Cl)cc1
Yield: 61.7 %

Procedure:
To a stirred mixture of 46.8 g of 7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 1.2 liters of glacial acetic acid under nitrogen and heated on a steam bath was added portionwise 30.0 g of sodium cyanoborohydride, heating and stirring was continued until all the solid was dissolved. The heat was removed and stirring was continued. A solid mass formed and was collected by filtration. The solid was washed with water, then with aqueous ammonia, followed by water again. The solid was dried in vacuo to give 29.1 g of the product of the example as a white solid, mp 208°-209° C.
Reaction SMILES: O[C:2]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][CH2:15]2)([CH:4]1[O:9][CH2:8][CH2:7][NH:6][CH2:5]1)C.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:21][C:15]1[C:16]2[C:12](=[C:11]([O:10][CH2:2][CH:4]3[O:9][CH2:8][CH2:7][NH:6][CH2:5]3)[CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(O)(Oc1cccc2c1CCC2)C1CNCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=CCc2c(OCC3CNCCO3)cccc21
Yield: 74.5 %

Procedure:
In 20 ml. of anhydrous toluene was dissolved 100 mg. of 2-(1-hydroxy-1-methyl-4-indanyloxymethyl)morpholine and after adding thereto 10 mg. of p-toluenesulfonic acid monohydrate, the mixture was refluxed for 4 hours. After cooling, the reaction mixture was washed successively with aqueous 3% sodium hydrogencarbonate solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue formed was subjected to a silica gel column chromatography (diameter 1.5 cm., height 7 cm.) and from the fraction recovered therefrom using a 98 : 2 mixture of chloroform and methanol as an eluting solution, 69 mg. (yield 74.5%) of sticky 2-(3-methyl-7-indenyloxymethyl)morpholine was obtained. The oxalate of the product had a melting point of 151°-152° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[CH2:25]([CH2:27][NH2:28])[OH:26]>C(O)(C)C>[CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([NH:28][CH2:27][CH2:25][OH:26])=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:6]=1[OH:24])([CH3:3])[CH3:4]
Reactant: NCCO
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Solvent: CC(C)O
Product: CC(C)(C)c1cc(-c2nnc(NCCO)s2)cc(C(C)(C)C)c1O
Yield: 84 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]phenol (4.0 g, 0.0109 mole) in isopropyl alcohol (15 ml) is added ethanolamine (1.9 g, 0.0326 mole). The resulting mixture is heated to reflux for 18 hours. The reaction is cooled and concentrated in vacuo. The resulting solid is recrystallized from methanol/water to give 3.2 g (3.8 g theor., 83%) of 2,6-bis(1,1-dimethylethyl)-4-[5-[(2-hydroxyethyl)amino]-1,3,4-thiadiazol-2-yl]phenol after drying in vacuo at 65° C., mp 212°-213.5° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1
Reactant: Oc1ccncc1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(CCOC2CCCCO2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Sodium hydride (1.27 g of a 50% suspension in mineral oil, 26.4mmol) was added to a solution of 4-hydroxypyridine (2.5 g, 26 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (5.0 g, 23.9 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), in DMF (5 ml) was added and the mixture heated at 80° C. for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (1.5 g, 28%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CSc1ccc(O)cc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(OC(C)=O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
3-Methyl-4-methylsulfanylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (724 mg) and acetyl chloride (615 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform to give 3-methyl-4-methylsulfanyl-phenyl acetate (1.00 g, yield 80%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[CH:3]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(NCCc3ccc(S(N)(=O)=O)cc3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture can be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)=[O:11].CS(O[CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:44][O:43][CH2:42][CH2:41][CH2:40][CH2:39][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)=[O:11]
Reactant: COCCCCOS(C)(=O)=O
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 70 °C
Reaction time: 12 h
Yield: 80.5 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (30 g) and 4-methoxybutyl methanesulfonate (12.5 g) were dissolved in DMA (600 ml), cesium carbonate (32 g) was added, and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was poured into ice water (1000 ml), and the mixture was extracted twice with ethyl acetate (1000 ml). The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give the object product (28.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][CH2:28][CH2:29][N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN(CCN)S(C)(=O)=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: CN(CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O)S(C)(=O)=O
Yield: 92.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.056 mmol) described in example 92 and N-(2-aminoethyl)-N-methylmethanesulfonamide (55 mg, 0.364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-{2[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (24 mg, 96% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.39 (br s, 1 H), 8.55 (s, 1 H), 7.38 (s, 1 H), 7.16-7.12 (m, 2 H), 7.03-6.99 (m, 2 H), 4.12 (s, 2 H), 3.68-3.63 (m, 2 H), 3.56 (s, 3 H), 3.42-3.38 (m, 2 H), 2.94 (s, 3 H), 2.82 (s, 3 H). HRMS m/z calcd for C21H24N4O5FS: 463.1451; Found: 463.1443.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with Bromomethyl-benzene using the conditions described in Example 237C to provide 4-benzyloxy-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide 4-(2-amino-4-benzyloxy-phenylsulfanyl)-phenol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1)[CH3:20]
Reactant: CCOc1ccccc1B(O)O
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: CCOc1ccccc1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-ethoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 350.0 (M+H)+, retention time 1.40 minutes.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[C:1]([NH:9][C:10]([NH:20][CH:12]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCCCC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NC1CCCCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl isothiocyanate (7.40 mL, 54.0 mmol) was added to a solution of cyclooctanamine (6.25 g, 49.1 mmol) in 200 mL of chloroform. The mixture was stirred at ambient temperature overnight. The solvents were removed in vacuo to give the title compound as a viscous light yellowish oil. MS m/z: 291.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)[CH2:12][CH2:13]OS(CC1C=CC(C)=CC=1)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:33].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[N:11]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)[CH2:12][CH2:13][F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CS(=O)(=O)OCCN(C(=O)OCc2ccccc2)c2ccc(Br)cc2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N(CCF)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.9 g (6 mmol) toluene-4-methanesulfonic acid 2-[benzyloxycarbonyl-(4-bromo-phenyl)-amino]-ethyl ester are dissolved in 100 mL THF and stirred for 18 hours at room temperature after addition of a 1 M solution of tetrabutyl-ammonium fluoride in THF. The reaction mixture is poured onto ice and extracted with tertbutyl-methyl ether and a saturated aqueous solution of sodium bicarbonate. The combined organic phases are washed with brine, dried with sodium sulfate and evaporated to dryness. The crude product is column chromatographed (petroleum ether/ethyl acetate 4:1) to yield 920 mg desired product as a yellow resin. MS(ES+): 352 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[Cl:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:16]2[C:17]([Cl:18])=[C:13]([CH3:12])[N:14]=[CH:15]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nc[nH]c1Cl
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ncn(C(=O)Nc2cc(Cl)cc(Cl)c2)c1Cl
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Using a procedure similar to that described in Example 1, a solution of 47 g of 3,5-dichlorophenyl isocyanate in 100 ml of chloroform was added dropwise to 29 g of 4-methyl-5-chloroimidazole, likewise dissolved in 100 ml of chloroform. Refluxing was carried out for 2 hours, after which the solution was cooled and the residue was filtered off under suction, washed with chloroform and dried to give 60 g (78.8%) of 1-N-(3,5-dichlorophenylcarbamyl)-4-methyl-5-chloroimidazole of melting point 136.9°-138.6° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13]C)[CH:4]=1)=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:13])[CH:4]=1)=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C=O)cc1O
Yield: 91.1 %

Procedure:
A mixture of product from Step 2 (2.6 g, 13.4 mmol) and AlCl3 (3.6 g, 26.8 mmol) in anhydrous DCM (50 mL) was refluxed for 3 minutes. The resulting mixture was cooled and poured into water (100 mL), followed by a standard aqueous/DCM workup to give Intermediate 5 (2.2 g, yield 92%).
Reaction SMILES: [Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9]C)=[O:8])[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Cl)c1

Procedure:
Methyl 5-chloropyrrole-3-carboxylate (900 g.) was refluxed for 9 hours with 20 ml. of methanol and 10 ml. of 1N sodium hydroxide. Methanol was removed by evaporation, the aqueous residue was diluted with approximately 10 ml. of water and extracted twice with ether. The aqueous phase was acidified with conc. hydrochloric acid and product extracted into ethyl acetate. The three ethyl acetate extracts were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to product (715 mg., m.p. 175°-178° C.). Recrystallization from methylene chloride/hexane afforded purified 5-chloropyrrole-3-carboxylic acid (300 mg., m.p. 178°-180° C.).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[O:18][CH:19]=2)=[O:14])=[C:8]([Cl:24])[CH:7]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[O:18]1[CH:19]=[C:15]([C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:25])=[O:3])=[CH:7][C:8]=2[Cl:24])=[O:14])[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]1=2
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2coc3ccccc23)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)c2coc3ccccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
[4-[(Benzo[b]furan-3-ylcarbonyl)amino]-3-chlorophenyl]acetic acid ethyl ester (2.08 g, 5.81 mmol) was dissolved in tetrahydrofuran (15 mL) and methanol (5 mL), and a 1N-aqueous solution of sodium hydroxide (11.60 mL, 11.60 mmol) was added thereto. The mixture was stirred for three hours at room temperature. The reaction liquor was poured onto ice-1N-hydrochloric acid, and precipitated solids were collected by filtration, and dried under reduced pressure, to obtain the title compound (1.70 g, 89%) as a solid.