Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)N(c1ccc([N+](=O)[O-])cc1)c1cncnc1

Procedure:
Starting compounds: 5-[N-(4-nitrophenyl)amino]pyrimidine and phenylacetyl chloride
Reaction SMILES: [I-].[N+:2]([C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[CH3:15])([O-])=O>[Pt]=O.C(O)C>[NH2:2][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH3:15]
Reactant: C[n+]1ccccc1C=Cc1ccccc1[N+](=O)[O-]
Agent: O=[Pt]
Agent: [I-]
Solvent: CCO
Product: CN1CCCCC1CCc1ccccc1N
Yield: 87 %

Procedure:
A suspension of 2-(o-nitrostyryl)-1-methylpyridinium iodide (40.5 mg., 0.11 mole) prepared according to the method of L. Horwitz, J. Org. Chem., 21, 1039 (1956) in 200 ml. of ethanol is hydrogenated in a Parr hydrogenation apparatus employing 0.3 g. of platinum oxide catalyst while maintaining a reaction temperature of from about 50° to 75°C. When the hydrogen uptake ceases (about 3 hours), the reduction mixture is filtered, the filtrate evaporated and the resulting residue taken up in 500 ml. of water. The aqueous solution is basified with 40% sodium hydroxide and extracted with several 200 ml. portions of ether. Ethereal extracts are combined, washed with water, dried over magnesium sulfate, and the ether evaporated. Distillation of the residue thus obtained provides 20.8 g. (87% yield) of 2-(o-aminophenethyl)-1-methylpiperidine base having a boiling point of 121°-125°C. at 0.04 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[C:17](Cl)(=O)[C:18](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:17][CH2:18][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (3-bromophenyl)acetic acid (˜10 g, 50 mmol) in 200 mL of DCM was added DMF (183 mg, 2.5 mmol) and then oxalyl dichloride (6.3 g, 50 mmol) was added dropwise over 30 min. The resulting mixture was stirred at room temperature for 6 hr and then concentrated under reduced pressure. A mixture of prepared acid chloride in 200 mL of DCM was added AlCl3 (13.2 g, 100 mmol) portion-wise at 0° C. After the mixture was stirred at 0° C. for 30 min, the solution was bubbled with ethene gas for 2 h and the resulting mixture was warmed to room temperature and stirred overnight. Then 300 mL of water was added dropwise over 30 min with stirring. Then separated the organic layer and extracted the aqueous layer with 200 mL of DCM. The combined organic layers were washed with 1N HCl (200 mL), saturated NaHCO3 (200 mL) and brine (200 mL) and then dried over Na2SO4. Then the organic layer was concentrated under reduced pressure to remove the solvent. The crude product was purified via chromatography (EtOAc/petrol ether 1:20 to 1:5) to give the desired 7-bromo-3,4-dihydronaphthalen-2(1H)-one along with the isomeric side product 5-bromo-3,4-dihydronaphthalen-2(1/1)-one. 1H-NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 3.01 (t, J=6.8 Hz, 2H), 2.54 (t, J=6.8 Hz, 2H); MS m/e 225 (M+1)+.
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:11]([C:9]1[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])#[CH:12]
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Temperature: 0 °C

Procedure:
A solution of (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (806 mg, 2.3 mmol) in 70 mL THF/methanol (1:1 ratio) at room temperature was degassed with argon. The solution was cooled to 0° C. and K2CO3 (937 mg, 6.8 mmol) added. After 5 minutes the solution was decanted from the solids and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and concentrated. The brown oil was purified by chromatography (silica gel, CHCl3/EtOAc) to the title compound as a thick pale orange oil (630 mg, 98%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:2].Br[CH2:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=1)[C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:30][C:31]2[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOCCCN(Cc1ccc(C(C)C)cc1)C(=O)CCc1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCCN(Cc1ccc(C(C)C)cc1)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
N-(3-ethoxypropyl)-3-(4-hydroxyphenyl)-N-(4-isopropylbenzyl)propanamide (0.18 g, 0.47 mmol) and methyl 2-(bromomethyl)benzoate (0.12 g, 0.52 mmol) was dissolved in acetonitrile (10 ml) and potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was stirred at 60° C. for three hours. Polymer-supported trisamine (0.3 eqv) was added and stirred overnight. The polymer was filtered off, solvent was removed by evaporation, addition of EtOAc (10 ml) and the organic phase was washed with three portions of water. After drying the crude (MgSO4) and the solvent had been removed by evaporation, the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two potions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.16 gram of methyl 2-[(4-{3-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (yield 63.5%).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17]O.[OH-].[K+]>>[CH3:17][C:16]1([CH3:20])[CH2:19][O:14][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15]1
Reactant: CC(C)(N)CO
Reactant: CCCCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCC1=NC(C)(C)CO1
Reaction time: 4 h
Yield: 86.9 %

Procedure:
64 g (320 mmoles) of dodecanoic acid and 61.1 ml (640 mmoles) of 2-amino-2-methylpropanol was placed in a two neck flask equipped with a vigreux column, distillation condenser and a thermometer. The temperature of the reaction mixture was slowly brought to 180° C. and maintained there for 9 hours. After cooling, a 10% alcoholic KOH solution (2 g, 3.6 mmoles) was added and the reflux was continued at 180° C. for 4 hours. The excess 2-amino-2-methylpropanol was distilled at aspirator pressure (86° C./18 mm). When the vapor temperature reached 103° C., the distillation was discontinued and the residue was taken in petroleum ether and filtered. The filtrate was washed with dilute KOH, water, dried and concentrated. The oil was distilled at 120° C./1.2 mm Hg to give 70.5 g (87%) of product.
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=1[NH2:23].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>O1CCCC1.O>[C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:27][C:21]=2[CH3:20])=[O:14])[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(-c2c(Cl)cccc2C(=O)O)co1
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(OC(F)(F)F)ccc1NC(=O)c1cccc(Cl)c1-c1coc(C(C)(C)C)n1
Yield: 28 %

Procedure:
0.4 Gram of 2-(2-t-butyloxazol-4-yl)-3-chlorobenzoic acid was dissolved in 30 ml of tetrahydrofuran, then 0.3 g of 2-methyl-4-trifluoromethoxyaniline, 0.4 g of DEPC and 0.3 g of triethylamine were added thereto, the resulting mixture was heated under reflux for 3 hours with stirring. After completion of the reaction, the reaction mixture was poured into water, and the objective product was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the residue obtained by removal of the solvent by distillation under reduced pressure was purified by the silica gel column chromatography to obtain 0.18 g (yield: 28%) of the objective product.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH3:19])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9]1)(=O)=O.Cl.[C:21]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.[I-].[K+]>O.CN(C=O)C>[C:21]([N:25]1[CH2:30][CH2:29][N:28]([CH2:6][CH2:7][C:8]2([CH3:19])[O:12][C:11]3=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]3[CH2:9]2)[CH2:27][C:26]1=[O:31])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)N1CCNCC1=O
Reactant: CC1(CCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CCN2CCN(C(C)(C)C)C(=O)C2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 70 °C
Reaction time: 4 h
Yield: 7.7 %

Procedure:
A mixture of 2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl methanesulfonate prepared in Example 42 (290 mg, 1 mmol), 1-tert-butylpiperazin-2-one hydrochloride (200 mg, 1.28 mmol), triethylamine (242 mg, 2.39 mmol), potassium iodide (250 mg, 1.5 mmol) and DMF (3 ml) was stirred at 70° C. for 4 hours. The reaction mixture was allowed to return to room temperature. To the solution, water was added, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water twice and a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford 1-tert-butyl-4-[2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)ethyl]piperazin-2-one (27 mg, yield 8%) as a white powder.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:19]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:22][N:21]4[CH2:30][CH2:31][CH2:32][C:20]=34)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1.C1CC=CCC=1.CO>[Pd].C(O)C>[CH3:34][O:33][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:22][N:21]2[CH2:30][CH2:31][CH2:32][C:20]=12
Reactant: COc1cc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Solvent: CCO
Product: COc1cc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 7-benzyloxy-6-methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (17 mg, 0.04 mmol) and 10% palladium on activated carbon (3 mg) in absolute ethanol (2 mL) is added 1,4-cyclohexadiene (100 mg, 1.2 mmol). The mixture is stirred at room temperature for 3 h, treated with methanol (500 μL), and heated at 60° C. for 3 h. The mixture is cooled, filtered, and loaded onto an SCX column. The column is washed with water, methanol, and 7 N ammonia in methanol. The appropriate fraction is concentrated in vacuo to yield the title compound, 10 mg (77%), as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[F:35][C:36]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:37]=1[NH2:38].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:35][C:36]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:37]=1[NH:38][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Nc1cc(F)c(F)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(F)c(F)cc4F)cc3)c2cc1OC
Yield: 73.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,4,5-Trifluoroaniline (75 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 58 mg of the title compound (yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31]C)=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 429, step C) in water/methanol (1:1) was treated with lithium hydroxide (1N, 5 eq) at room temperature for 15 h. The mixture was concentrated and purified by reversed phase HPLC (Sunfire™ Prep C18 OBD 10 um column; Waters, Milford, Mass.; 40-90% water/acetonitrile gradient with 0.1% TFA). Desired fractions were then pooled and concentrated to give the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH3:14])[CH:16]=2)[NH:20][C:19]1=[O:24]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: Cc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 42.2 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 74 mg 5-methyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 65 mg (42%) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][C:18](Br)=[CH:19][N:20]=2)=[O:14])=[C:8]([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:7]=1)[CH3:2].[SH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][C:18]([S:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:19][N:20]=2)=[O:14])=[C:8]([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ccccn1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ncc(Sc3ccccn3)s2)c(C(=O)C2CCCC2)c1
Yield: 30 %

Procedure:
(3-Cyclopentanecarbonyl-4-{3-[5-(pyridin-2-ylsulfanyl)-thiazol-2-yl]-ureido}-phenyl)-acetic acid ethyl ester (153 mg, 30%) was prepared from {4-[3-(5-bromo-thiazol-2-yl)-ureido]-3-cyclopentanecarbonyl-phenyl}-acetic acid ethyl ester (480 mg, 1 mmol) and 2-mercaptopyridine (222 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(N)(=[S:11])C>Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[S:11])[NH2:2]
Reactant: CC(N)=S
Reactant: N#Cc1ccccn1
Agent: Cl
Product: NC(=S)c1ccccn1
Reaction time: 1.33 h

Procedure:
Adapting the general method of Taylor, a mixture of 2-cyanopyridine (7.28 g, 7.0 mmol) and thioacetamide (10.52 g, 14.0 mmol) was treated with 60 ml of HCl-saturated DMF, and the solution was stirred vigorously in an open flask on an oil bath set initially at 80° C. (the temperature gradually rising to 95° C. over the coarse of the reaction). Taylor, E. C. et al., J. Am. Chem. Soc. 1960, 82, 2656-2657. After 80 minutes (TLC monitoring), the resulting orange suspension was cooled, neutralized with con. NaOH/ice, and extracted with EtOAc. The extract was washed with water (3×) and then concentrated to a light brown solid which was triturated with warm water and collected. The dried product was passed over a silica gel column eluting with EtOAc:hexanes (2:1) to give, after removal of most of the solvent and dilution with hexanes, a yellow crystalline solid (6.36 g, 66%), mp 136-137° C.; lit mp 137° C.
Reaction SMILES: C(N1C2C=CC(N[N:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])=CC=2C2C1=CC=CC=2)C.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([CH2:37][CH3:38])[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3.C(#N)CC#N.O.[NH2:45][NH2:46]>>[CH2:37]([N:28]1[C:27]2[CH:26]=[CH:25][C:24]([NH:23][N:17]=[C:18]3[C:19]([NH2:20])=[N:46][N:45]=[C:21]3[NH2:22])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:38]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCn1c2ccccc2c2cc(NN=C(C#N)C#N)ccc21
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Product: CCn1c2ccccc2c2cc(NN=C3C(N)=NN=C3N)ccc21
Temperature: 25 °C

Procedure:
4-[(9-ethyl-9H-carbazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 143 mg (0.5 mmol) of 2-[(9-ethyl-9H-carbazol-3-yl)hydrazono]malononitrile, which was derived from 3-amino-9-ethylcarbazole (210 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Solids had not formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 46 mg (29%) of the compound as a black solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[CH:5]2.[OH-].[K+].Cl.[CH:16]([N:19]([CH:23]([CH3:25])[CH3:24])[CH2:20][CH2:21]Cl)([CH3:18])[CH3:17].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:21][CH2:20][N:19]([CH:23]([CH3:25])[CH3:24])[CH:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=c1[nH]ncc2cc(Br)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N(CCn1ncc2cc(Br)ccc2c1=O)C(C)C
Reaction time: 18 h

Procedure:
6-Bromophthalazinone (11.2 gm, 0.05 mole) was slurried in 80 ml dimethylsulfoxide. To this was added 22 ml 45% KOH (0.25 mole). After stirring 10 minutes 16 gm 2-(diisopropylamino)ethyl chloride hydrochloride was added and the mixture stirred for 18 hours. A water bath was used to moderate the slightly exothermic reaction (temperature <=25°). Water (100 ml) was added to the reaction mixture, which was then stirred another hour.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16]N1C(=O)CCC1=O.C(O)(=O)C>O>[Cl:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nccc(O)c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2ncc(Cl)c(O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A mixture of methyl 4-hydroxyquinoline-6-carboxylate (2.07 g), N-chlorosuccinimide (1.36 g), and acetic acid (56 mL) was stirred at room temperature for one day. The reaction mixture was diluted with water, and then, the precipitate was collected by filtration to obtain methyl 3-chloro-4-hydroxyquinoline-6-carboxylate (2.13 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9]>CCCCCC>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[Cl:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][CH:12]=1)[C:8]([O-:10])=[O:9]
Reactant: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Reactant: CCNCC
Solvent: CCCCCC
Product: CC[NH2+]CC
Product: O=C([O-])C(Cl)c1ccc(-c2ccccc2Cl)cc1

Procedure:
Anhydrous diethylamine (0.11 moles) is added dropwise to a stirred solution of α, 2'-dichloro-4-biphenylylacetic acid (0.10 moles) in 100 ml. of n-hexane at 0°C. The precipitate is collected on a filter, washed with n-hexane, and dried in a vacuum desiccator to obtain α, 2'-dichloro-4-biphenylylacetic acid, diethylammonium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a stirring suspension of 4-chloro-2-nitrobenzoic acid (20 g, 99 mmol) in dichloromethane (500 mL) was added a few drops of DMF, followed by oxalyl chloride (15.1 g, 119 mmol). After 1 h, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (500 mL); To this stirring solution was added pyridine (24 mL, 297 mmol) followed by 2-amino-5-chloropyridine (12.7 g, 99 mmol). After stirring overnight, the solvents were removed in vacuo and the residue was stirred vigorously with ethyl acetate and water for several hours. The mixture was filtered to give a white solid, which was washed with ethyl acetate and dried in vacuo to give 23 g (74%) of the title compound. The combined ethyl acetate washings and extract were then washed twice with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate, and again with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The solid was then suspended in diethyl ether, sonicated and filtered to give a second crop of the title compound as a white solid (5.79 g, 19%).