Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.[Cl-].[NH4+:14]>>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([NH2:14])=[O:12])=[N:3]1
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: [NH4+]
Agent: [Cl-]
Product: Cn1cc([N+](=O)[O-])c(C(N)=O)n1

Procedure:
The product was obtained according to the method described in example 1, step 1 starting from 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid and two equivalents of ammonium chloride as amine source as light yellow solid (110 mg, 37%).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][O:13][C:14]1[C:19]2[CH:20]=[CH:21][S:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>O1CCCC1>[CH3:12][O:13][C:14]1[C:19]2[CH:20]=[C:21]([B:27]([OH:28])[OH:26])[S:22][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cccc2sccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc2sc(B(O)O)cc12
Reaction time: 0.5 h
Yield: 62 %

Procedure:
2.5 M Hexane solution of normal butyl lithium (1.07 mL, 2.67 mmol) was slowly added under nitrogen to the 4-methoxybenzothiophene (92a, 368 mg, 2.24 mmol) obtained in Preparation Example 1 dissolved in an anhydrous tetrahydrofuran solution at −78° C., and the reaction mixture was stirred for 30 minutes. To the reaction mixture was slowly added a triisopropylborate solution (i-PrO)3B) (0.55 mL, 2.69 mmol) at room temperature, stirred for one hour, and the reaction was terminated by adding a solution of 2N hydrochloride. The resulting product was extracted with ethyl acetate, evaporated after a treatment with sodium sulfate, and concentrated under reduced pressure, recrystallized and filtered using hexane and ethyl acetate to give the target product 4-methoxybenzothiophene-2-boronic acid (95a, 289 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[O-:27][C:28]#[N:29].[K+]>O>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:28]([NH2:29])=[O:27])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#C[O-]
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: [K+]
Solvent: O
Product: COc1cc(NC(N)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a 2 ml water/4 ml acetic acid solution of 200 mg (0.567 mmol) of the compound obtained in Example 44, 377 mg (4.65 mmol) of potassium cyanate was added, and the mixture was stirred at room temperature for 3 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain 126 mg (56%) of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[C:21]([CH3:33])[CH:20]=3)[C:9]=2[CH3:34])=[CH:4][CH:3]=1.[CH2:35]1COC[CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:35][CH3:36])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:31])=[O:32])=[C:21]([CH3:33])[CH:20]=3)[C:9]=2[CH3:34])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)c(C)c1
Reactant: C1CCOC1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)c(C)c1
Temperature: 0 °C
Yield: 18.1 %

Procedure:
Grignard reagent (Ethyl magnesium bromide, 0.42 g, 3.17 ml 1M solution in THF, 3.17 mmol) was added drop wise to a stirred solution of (5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)-3-methylphenyl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide (41e, 0.33 g, 0.63 mmol) in anhydrous THF (20 ml) at 25° C. The reaction mixture was then heated to about 70° C. to 75° C. for 1 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 0° C. The cooled reaction mixture was quenched by adding saturated solution of ammonium chloride (10 ml) and the mixture was then extracted with ethyl acetate (2×30 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by preparative HPLC to obtain the title compound (0.05 g, 18.1%)
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Na].[CH2:8]([OH:11])[CH2:9][CH3:10]>>[CH2:8]([O:11][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][CH3:10]
Reactant: Ic1cccs1
Reactant: CCCO
Agent: [Na]
Product: CCCOc1cccs1
Yield: 13.5 %

Procedure:
Iodothiophene (59 g, 281 mmole) and cupric oxide (11.2 g, 141 mmole) were placed in propanol (420 g) containing sodium (19.7 g, 857 mmole). The mixture was stirred at reflux for 48 hours and then filtered. The filtrate was added to cold water and the water extracted with ethyl ether. The ether layers were combined, dried over magnesium sulfate, filtered, concentrated, and then vacuum distilled from over sodium at 50° C. and 10 torr to provide 5.4 g of product.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=1)[CH3:2].O.[NH2:26][NH2:27]>Cl.CC(O)C>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:11][CH:12]=3)[C:7](=[N:26][NH2:27])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc2c(c1)C(=O)c1cc(N(CC)CC)ccc1-2
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCN(CC)c1ccc2c(c1)C(=NN)c1cc(N(CC)CC)ccc1-2
Temperature: 25 °C
Yield: 79.2 %

Procedure:
2,7-Bis(diethylamino)-9-fluorenone (11.5 g, 35.66 mmol), 50 ml of 2-propanol, 98% hydrazine monohydrate (5.2 ml, 0.11 mol, from Aldrich), and 8 drops of concentrated hydrochloric acid (obtained from Aldrich) were added to a 100 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The mixture was refluxed with an intensive stirring until 2,7-bis(diethylamino)-9-fluorenone disappeared (1.5 hours). The reaction mixture was cooled to room temperature to form crystals. The crystals were filtered off, washed first with water, and then with a mixture of 2-propanol and n-hexane to yield 9.5 g (79%) of the hydrazone. The melting point was found to be 150–151° C. (recrystallized from 2-propanol). The 1H NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 7.50–7.20 (m, 4H, Ar); 6.82–6.50 (m, 2H, Ar); 7.10 (s, br, 2H, NH2); 7.00 (q, 8H, N(CH2CH3)2); and 3.75 (t, J=7.1 Hz, 12H, N(CH2CH3)2). An elemental analysis yielded the following results in weight percent: C, 74.69; H, 8.28; N, 16.52, which compared with the following calculated values for C21H28N4 in weight percent: C, 74.96; H, 8.39; N, 16.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2([CH3:13])[CH3:12].[BH4-].[Na+].II.[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2ccc(Cl)cc21
Agent: II
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)CNc2ccc(Cl)cc21
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
To a solution of 630 mg of 5-chloro-3,3-dimethyl-1,3-dihydro-2H-indole-2-one in 6.30 mL of tetrahydrofuran was added 609 mg of sodium borohydride, followed by stirring for 10 minutes. Then, a solution of 1.63 g of iodine in 3.78 mL of tetrahydrofuran was added dropwise thereto at −10° C. or lower under cooling in an ice-acetone bath, followed by stirring at the same temperature for 30 minutes, then warming to room temperature, and stirring overnight. After diluting with chloroform, a saturated aqueous ammonium chloride solution was added dropwise thereto. The aqueous layer was separated and then the organic layer was washed with a saturated aqueous sodium sulfite solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 480 mg of 5-chloro-3,3-dimethylindoline as a colorless oily substance.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>C(#N)C>[CH2:34]([NH:36][C:37]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:16]=1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.1 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.45 g, 1.1 mmol), potassium carbonate (0.47 g, 3.4 mmol) and acetonitrile (26 ml) was stirred at room temperature for 20 minutes. Successively ethyl isocyanate (0.36 g, 5.1 mmol) was added to the mixture, and the mixture was refluxed for 3 hrs. After cooling, the precipitates were collected by filtration, dissolved in chloroform and subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (15:1, v/v) were collected, concentrated and recrystallized from chloroform-hexane to give the titled compound (0.25 g, 63%) as white crystals.
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[C:11](=[CH:14]N(C)C)[CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].Cl.[CH3:20][N:21]([CH3:25])[C:22]([NH2:24])=[NH:23]>C(O)C>[CH3:20][N:21]([CH3:25])[C:22]1[N:24]=[CH:14][C:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][CH2:2][CH3:3])[CH2:9][C:10]=2[N:23]=1
Reactant: CCCN1CCC[C@@H]2CC(=O)C(=CN(C)C)C[C@H]21
Reactant: CN(C)C(=N)N
Agent: Cl
Solvent: CCO
Product: CCCN1CCC[C@H]2Cc3nc(N(C)C)ncc3C[C@@H]21

Procedure:
A reaction mixture was prepared from 4.7 g. of trans-(±)-1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline and 2.5 g. of 1,1-dimethylguanidinehydrochloride in 50 ml. of anhydrous ethanol. The reaction mixture was heated overnight under a nitrogen atmosphere, and was then cooled and the volatile constituents removed in vacuo. The resulting residue was dissolved in ethyl acetate and the ethyl acetate solution contacted with an excess of 10% aqueous sodium hydroxide. Trans-(±)-2-dimethylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline formed in the above reaction, being insoluble in the basic layer, remained in the ethyl acetate layer. The aqueous layer was separated and the ethyl acetate layer extracted once with water and once with saturated aqueous sodium chloride. The ethyl acetate layer was dried and the ethyl acetate removed in vacuo to leave 0.75 g. of an orange oil. The oily residue was chromatographed over florisil using hexane containing increasing amounts (1-50%) of ethyl acetate as the eluant. Fractions shown by TLC to contain the desired trans-(±)-2-dimethylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline were combined and the solvent removed from the combined fractions in vacuo. The resulting residue was dissolved in ethanol and gaseous hydrogen chloride passed into the solution thus forming the corresponding dihydrochloride salt. The ethanol was removed therefrom in vacuo and the dihydrochloride salt crystallized from a methanol ethyl acetate solvent mixture to yield 0.170 g. of a white solid having a molecular ion at 274.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.O.C([O-])=[O:19].[K+]>ClCCl>[CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH2:12][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[O-]
Reactant: CC(=O)CC(=O)NCc1ccccc1
Agent: BrBr
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CO)CC(=O)NCc1ccccc1
Temperature: 7.5 °C
Reaction time: 1.5 h
Yield: 38.7 %

Procedure:
To a solution of N-benzyl-3-oxobutanamide (compound A 50 g, 261 mmol) in dichloromethane (350 ml) was added bromine (14.82 ml, 288 mmol) at 0-5° C., then stirred at 20-25° C. for 3 hours (bromine colour disappeared). Water (300 ml) was added to the mixture with stirring, stirred for 10 min. Organic phase was separated, washed with sodium bicarbonate solution, dried, evaporated to dryness (compound B). The solid residue (compound B) dissolved in methanol (900 ml), added potassium formate (44.0 g, 523 mmol) and the mixture was heated under reflux for 2 hours. Methanol was removed on a rotavap, the residue was taken up into ethyl acetate (EA) (500 ml) under reflux, filtered hot, the filter cake washed with warm EA (100 ml). The combined filtrate was cooled to 5-10° C., aged for 1.5 hours. The precipitate was collected, washed with cold EA (50 ml), dried to give 25 g (46.1%) of crude product, light beige. Re-crystallised from water (300 ml), with active carbon (1 g). Filtered hot on celite, cooled in ice, aged for 1 hour, crystals collected, washed with cold water (20 ml), dried on air overnight to give N-benzyl-4-hydroxy-3-oxobutanamide (21 g, 101 mmol, 38.8% yield).
Reaction SMILES: N.C([N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([N:26]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[N:27]1)=[N:13][C:14]=2[NH:18][C:19]1[CH:24]=[CH:23][C:22](Cl)=[CH:21][CH:20]=1)C1C=CC=CC=1.C(N1C2C(=NC(N3C(C)=CC(C)=N3)=NC=2NC2C=CC(Cl)=CC=2)N=C1)C1C=CC=CC=1.[Na].[Cl-].[NH4+].Cl>O>[CH3:32][C:28]1[CH:29]=[C:30]([CH3:31])[N:26]([C:12]2[N:11]=[C:10]3[C:15]([N:16]=[CH:17][NH:9]3)=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=2)[N:27]=1
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(Cc4ccccc4)c3n2)n1
Agent: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3c(ncn3Cc3ccccc3)n2)n1
Agent: Cl
Agent: N
Solvent: O
Product: Cc1cc(C)n(-c2nc(Nc3ccccc3)c3nc[nH]c3n2)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 50 %

Procedure:
Ammonia (75 mL) was condensed in a reaction flask equipped with a mechanical stirrer and cooled on an acetone dry-ice bath. A mixture of [9-benzyl-2-(3,5-dimethyl-pyrazol-1-yl)-9H-purin-6-yl]-(4-chloro-phenyl)-amine and [7-benzyl-2-(3,5-dimethyl-pyrazol-1-yl)-7H-purin-6-yl]-(4-chloro-phenyl)-amine (1.5 g, 3.49 mmol) was added. Under vigorous stirring small pieces of sodium (2 equiv) were added. When the addition was completed the reaction mixture turned dark blue. The mixture was stirred for 2 minutes followed by careful addition of ammonium chloride. The reaction mixture was allowed to warm to room temperature. Water and a small amount of concentrated hydrochloric acid were added. The resulting solid was collected by filtration, washed with water and ether and dried to give [2-(3,5-dimethyl-pyrazol-1-yl)-9H-purin-6-yl]-phenyl-amine (590 mg, 50%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CSC.B>C1COCC1>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:9][OH:10])[CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of the crude acid 139 (6.14 mmol) in 30 mL THF at 0° C. was added borane-dimethyl sulfide complex (2.0 M soln in THF, 4.6 mL, 9.2 mmol), and the mixture was allowed to warm slowly to ambient temperature overnight. Additional BH3-DMS was added until the acid was completely consumed (ca. 5 mL). The reaction was quenched by addition of MeOH, then partitioned between Et2O and sat. NaHCO3 (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide alcohol 140. LRMS: m/z 226.1; 1H NMR (CDCl3): δ 3.63 (dd, J=11.0, 4.2 Hz, 1H), 3.42 (dd, J=11.0, 6.8 Hz, 1H), 2.30 (dd, J=14.9, 7.6 Hz, 1H), 2.20 (dd, J=14.9, 5.6 Hz, 1H), 2.03 (m, 2H), 1.42 (s, 9H), 1.24 (m, 6H), 1.02 (m, 2H), 0.85 (m, 6H). The crude product was used without purification.
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[O:4][CH:5]([CH:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][CH:12]=2)[CH3:10])[C:6](=[O:8])[N:7]=1.CN>>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:11]([CH:9]([CH:5]1[O:4][C:3]([NH:2][CH3:1])=[N:7][C:6]1=[O:8])[CH3:10])=[CH:12][NH:13]2
Reactant: COc1cccc2[nH]cc(C(C)C3OC(N(C)C)=NC3=O)c12
Agent: CN
Product: CNC1=NC(=O)C(C(C)c2c[nH]c3cccc(OC)c23)O1
Yield: 67.1 %

Procedure:
2-dimethylamino-5-[1-(4-methoxyindol-3-yl)ethyl]-2-oxazolin-4-one (50 mg) was added to methylamine (5 ml). The mixture was refluxed for 5 hours and additional methylamine (5 ml) was added. The whole was further refluxed for 2.5 hours. The-methylamine was distilled off to give a residue, which was subjected to silica gel chromatography. Elution with hexane-acetone (1:1) provided the titled compound (32 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1([CH2:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+]>CCOCC.O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:18][CH2:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C

Procedure:
p-Toluenesulphonyl chloride (2.12 g, 11.1 mmol) was added to a solution of cyclopentanemethanol (1 ml, 9.25 mmol) in ether (25 ml), and the solution cooled in an ice/salt bath. Freshly powdered potassium hydroxide (4.7 g, 83.3 mmol) was added and the reaction mixture allowed to warm to room temperature, over 2 hours. The reaction was diluted with water, the phases separated, and the aqueous layer extracted with ether. The combined organic solutions were dried (MgSO4), and evaporated under reduced pressure, to give the title compound as a clear oil, 2.18 g.
Reaction SMILES: [CH:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)([CH3:3])[CH3:2].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CC(C)Sc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SC(C)C)n1

Procedure:
A mixture of 5.75 g. 3-isopropylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 2.5 hours. The reaction mixture was worked up as described in Example 1 to produce an oily residue which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-isopropylthio-1,2,4-triazole, b.p. 133°C./0.4 mm. - 144°C./0.9 mm. (97.2% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][C:2]([C:14]1[N:18]([CH3:19])[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[N:16][N:15]=1)([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH3:3].S(=O)(=O)(O)O.[CH3:35]O>C(OCC)(=O)C>[CH3:3][C:2]([C:14]1[N:18]([CH3:19])[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:28])([F:29])[F:27])=[N:16][N:15]=1)([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:35])=[O:10])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CO
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)(C)c2nnc(-c3ccccc3C(F)(F)F)n2C)cc1
Temperature: 25 °C

Procedure:
4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (400 mg) was dissolved in methanol (12 ml), concentrated sulfuric acid (0.160 ml) was added thereto, followed by heating to reflux for 2 days. The reaction solution was cooled to room temperature, diluted with ethyl acetate and was washed with a 1M aqueous sodium hydroxide solution, water and saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The resulting solid was washed with diisopropylether to obtain methyl 4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoate (249 mg), as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1>>[CH3:20][NH:19][C:17]([C:13]1[CH:12]=[C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[Cl:9])[CH:16]=[CH:15][N:14]=1)=[O:18]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CNC(=O)c1cc(Cl)ccn1
Product: CNC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1

Procedure:
Entry 87: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]1([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[CH:31]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(CCN(C)C)C.CN([CH:50]=[O:51])C>O1CCCC1>[C:21]1([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[C:31]2[CH:50]=[O:51])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of diisopropylamine (4.13 mL, 0.029 mol) in anhydrous tetrahydrofuran (THF) (50 mL) stirred under nitrogen at −78° C. was added nBuLi (10.42 mL, 0.026 mol) over 15 min. The reaction mixture was stirred at −78° C. for 30 min. then warmed to r.t. and stirred for 1 h. To this solution of LDA in anhydrous tetrahydrofuran (THF) (250 mL) stirred under nitrogen at −30° C. was added a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5 g, 19.36 mmol) and TMEDA (4.38 mL, 29.0 mmol) in tetrahydrofuran (THF) (150 mL) dropwise over 15 min. The reaction mixture was stirred at −30° C. for 2.5 h, then DMF (3 mL, 38.7 mmol) was added dropwise over 1 min. The reaction mixture was stirred at −30° C. for another 2 h, TLC and LC-MS showed complete conversion. The reaction mixture was quenched with water and partitioned between dichloromethane (700 mL) and water (100 mL). The organic phase was washed with water (3×100 mL), dried over sodium sulfate and evaporated in vacuo to give the crude product as a yellow solid. This was purified by recrystallization (EtOAc and PE) to give the desired product—1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (4.8 g, 78%) as a yellow solid.