Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[CH:14][C:13]2[O:16][C:17]3[C:22]([C@@:23]4([CH2:28][CH2:27][O:26][C:25]([NH2:29])=[N:24]4)[C:12]=2[CH:11]=1)=[CH:21][C:20]([NH2:30])=[CH:19][CH:18]=3.[O:31]1[CH2:36][CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32]1>O1CCOCC1.O>[O:31]1[CH2:36][CH2:35][CH:34]=[C:33]([C:10]2[N:15]=[CH:14][C:13]3[O:16][C:17]4[C:22]([C@@:23]5([CH2:28][CH2:27][O:26][C:25]([NH2:29])=[N:24]5)[C:12]=3[CH:11]=2)=[CH:21][C:20]([NH2:30])=[CH:19][CH:18]=4)[CH2:32]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1cnc(C3=CCCOC3)cc12
Temperature: 120 °C
Yield: 74.8 %

Procedure:
A microwave reaction vessel was charged with potassium phosphate (tribasic) (0.670 g, 3.16 mmol), (S)-3-chloro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.2 g, 0.631 mmol), and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.398 g, 1.894 mmol) in dioxane (4 ml) and water (2 ml). The vessel was capped and the solution was purged with nitrogen for 10 minutes. Next, bis[di-tert-butyl(4 dimethylaminophenyl)phosphine]dichloropalladium(II) (0.022 g, 0.032 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 35 minutes. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 20:1 solution of DCM to a 2M solution of NH3 in MeOH, to provide (S)-3-(5,6-dihydro-2H-pyran-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.172 g, 0.472 mmol, 74.8% yield) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]#[N:4].Cl.[CH3:18][OH:19]>>[OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:3](=[NH:4])[O:19][CH3:18]
Reactant: N#CC(O)CCCCCCc1ccccc1
Reactant: CO
Agent: Cl
Product: COC(=N)C(O)CCCCCCc1ccccc1
Reaction time: 15 h

Procedure:
A solution of 2-hydroxy-8-phenyloctanenitrile (5 g) in methanol (50 mL) was cooled to −78° C. and a stream of HCl (g) was introduced for 4 min. The mixture was stored at −10° C. for 15 h, then concentrated to yield methyl 2-hydroxy-8-phenyloctanimidate. (MH+=286).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(N(CC)CC)C>[NH2:8][C:7]1[C:2](/[CH:13]=[CH:12]/[C:11]([O:15][CH2:16][CH3:17])=[O:14])=[N:3][CH:4]=[C:5]([O:9][CH3:10])[CH:6]=1.[CH3:10][O:9][C:5]1[CH:6]=[C:7]2[C:2]([CH:13]=[CH:12][C:11](=[O:14])[NH:8]2)=[N:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: COc1cnc(Cl)c(N)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ncc(OC)cc1N
Product: COc1cnc2ccc(=O)[nH]c2c1
Temperature: 155 °C
Reaction time: 6 h

Procedure:
To 1.0 g of 2-chloro-5-methoxypyridin-3-amine, 0.82 mL of ethyl acrylate, 4.2 mL of triethylamine, and 0.16 g of bis(tri-tert-butylphosphine)palladium(0) were added, and the mixture was stirred at an external temperature of 150 to 160° C. for 6 hours in a sealed tube. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 0.41 g of ethyl (2E)-3-(3-amino-5-methoxypyridin-2-yl)acrylate and 0.25 g of 7-methoxy-1,5-naphthyridin-2(1H)-one as light brown solids.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH:11]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][S:27]([O:16][CH:13]1[CH2:14][CH2:15][C:10]([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11][CH2:12]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cnccc1C1=CCC(O)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OC1CC=C(c2ccncc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 4-(3-nitropyridin-4-yl)cyclohex-3-enol (1.0 equiv.) and DIPEA (2.5 equiv.) in CH2Cl2 (0.15 M) was added methanesulfonyl chloride (1.8 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with sat NaCl (30 mL). The organic was dried MgSO4, filtered and concentrated to give 4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (93%). The residue was used in the next step without further purification. LC/MS (m/z): MH+=299.0, Rt=0.70
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[S:9][C:10]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Cc1nc2cccc(Cl)c2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc2nc(CBr)sc12

Procedure:
A mixture of 7-chloro-2-methyl-benzothiazole (1.00 g, 5.45 mmol), N-bromosuccinimide (1.26 g, 7.08 mmol), benzoyl peroxide (0.1 g), and CCl4 (10 mL was heated to reflux under irradiation of a UV lamp for 14 h. The reaction mixture was cooled and filtered to remove the succinimide formed in the reaction, and the filtrate was evaporated to dryness. The resulting solid was purified by flash chromatography to give the title lamp (400 mg, 1.5 mmol). 1H-NMR (CDCl3): δ 7.94 (d, 1H), 7.47 (t, 1H), 7.42 (d, 1H), 4.82 (s, 2H, CH2). HPLC Rt: 7.19 min.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]([CH3:16])[CH2:12][C:13](O)=[O:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:31][C:32]1[C:33]([NH:47][CH2:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)=[CH:34][C:35]([NH:38][C:39]2[CH:44]=[N:43][C:42]([C:45]#[N:46])=[CH:41][N:40]=2)=[N:36][CH:37]=1>CN(C=O)C>[C:45]([C:42]1[N:43]=[CH:44][C:39]([NH:38][C:35]2[N:36]=[CH:37][C:32]([NH:31][C:13](=[O:14])[CH2:12][N:11]([CH3:16])[CH3:10])=[C:33]([NH:47][CH2:48][CH:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)[CH:34]=2)=[N:40][CH:41]=1)#[N:46]
Reactant: CN(C)CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Diisopropylethylamine (16 μL, 0.092 mmol), N,N-dimethylglycine (7 mg, 0.067 mmol), HOBt (12 mg, 0.092 mmol) and EDC (17 mg, 0.092 mmol) were added to tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)-pyridin-4-ylamino)-methyl)-piperidine-1-carboxylate (26 mg, 0.061 mmol) in DMF (1.5 mL). The mixture was stirred at room temperature for 6 hours and then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried and concentrated. Preparative HPLC gave N-(6-(5-cyanopyrazin-2-ylamino)-4-(1-boc-piperidin-4-ylmethylamino)pyridin-3-yl)-2-(dimethylamino)acetamide as a white solid. The solid was dissolved in 20% trifluoroacetic acid in dichloromethane. After 20 minutes the mixture was loaded onto a MP-TsOH SPE cartridge and eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated to give N-(6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)pyridin-3-yl)-2-(dimethylamino)acetamide (7.52 mg, 30%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][O:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=O)=CC=2)[C:4]([CH3:27])=[N:3]1.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=N[C:56](OCC)=[O:57]>CCOCC>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([CH:14]=[N:15][O:16][C:17]2[CH:18]=[CH:26][C:25]([C:56]([O:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:57])=[CH:21][CH:22]=2)[C:4]([CH3:27])=[N:3]1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C(=O)O)cc1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOc1ccc(C(=O)Oc2ccccc2)cc1
Yield: 78 %

Procedure:
1.0 Gram (0.0027 mole) of 4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)methyleneaminooxymethyl]benzoic acid, 0.25 g (0.0027 mole) of phenol and 0.7 g (0.0027 mole) of triphenylphosphine were added to 50 ml of ether, and the resulting mixture was stirred. To this solution was added 0.47 g (0.0027 mole) of diethyl azodicarboxylate, and the resulting solution was heated under reflux for 3 hours. After completion of the reaction, the ether layer was filtered, and ether was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 0.9 g of the desired compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33]CC)[CH:27]=4)[CH2:23][CH2:22][C:21]([C:36]([O:38]C)=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.[O:45]1CCC[CH2:46]1>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][C:31]=4[O:45][CH3:46])[CH2:23][CH2:22][C:21]([C:36]([OH:38])=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cccc(OCCC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cc(OC)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (290 mg) in a mixture of tetrahydrofuran (21 ml) and methanol (21 ml) was added 1N sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 4 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (237 mg) as yellow crystals.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25](OCC)=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[O:8][N:7]=[C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH2:21]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(C)cc2)CC1
Reactant: ON=C1CCCCC1
Product: Cc1ccc(N2CCN(CCCc3onc4c3CCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cyclohexanone oxime and ethyl 4-(4-(4-methylphenyl)piperazin-1-yl)-n-butyrate, 3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxazole is obtained.
Reaction SMILES: [CH:1]1(Br)C[CH2:2]1.[Mg].[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13]Br)[C:8]=1[O:15][CH3:16].[CH2:17]1COCC1>>[Cl:6][C:7]1[C:12]([CH3:17])=[CH:11][N:10]=[C:9]([CH:13]2[CH2:2][CH2:1]2)[C:8]=1[O:15][CH3:16]
Reactant: C1CCOC1
Reactant: COc1c(Cl)ccnc1CBr
Reactant: BrC1CC1
Agent: [Mg]
Product: COc1c(C2CC2)ncc(C)c1Cl
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
Cyclopropyl bromide (0.5 ml) is dissolved in 5 mnl of THF and magnesium (0.15 g) is added and heat is applied to initiate the reaction. Once the reaction is completed, the solution is cooled to −45° C. and cuprous iodide (0.5 g) is added. The reaction is allowed to stir for 30 minutes and 4-Chloro-3-methoxy-2-bromomethyl-pyridine (0.154 g) is added. The reaction is stirred at −45° C. for one hour and allowed to warm at room temperature before being quenched by 5 ml of 28% ammonium hydroxide. The reaction is extracted with ether and the desired product purified by chromatography using hexane/ethyl acetate 9/1 as solvent.
Reaction SMILES: [NH2:1][C:2]12[CH2:6][C:4](C(=O)C)([CH2:5]1)[CH2:3]2.ClC1C=CC=[C:13]([C:17]([O:19]O)=[O:18])C=1>C(Cl)(Cl)Cl>[C:17]([O:19][C:4]12[CH2:3][C:2]([NH2:1])([CH2:5]1)[CH2:6]2)(=[O:18])[CH3:13]
Reactant: CC(=O)C12CC(N)(C1)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC12CC(N)(C1)C2
Reaction time: 24 h

Procedure:
A solution of 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethanone (1 mmol) in 0.5 mL of chloroform is added to a stirred mixture of m-chloroperbenzoic acid (1.5 mmol) in 2 mL of chloroform at room temperature. The solution is stirred in the dark for 24 h. The mixture is filtered, and the filtrate is washed with 10% sodium bicarbonate and then water. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified by a flash chromatography on silica gel (EtOAc/hexnaes) to give 3-aminobicyclo[1.1.1]pentan-1-yl acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].C[C:10]([CH3:13])([O-])[CH3:11].[K+].C1(C)C(S(O[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=O)=O)=CC=CC=1>>[CH2:42]([O:7][CH:4]([CH2:5][O:6][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]/[CH:31]=[CH:30]\[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:11][CH2:10][CH3:13])[CH2:3][N:2]([CH3:8])[CH3:1])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]/[CH:34]=[CH:33]\[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccccc1C
Reactant: CN(C)CC(O)CO
Agent: [K+]
Product: CCCCCCCC/C=C\CCCCCCCCOCC(CN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
In accordance with Reaction Scheme I, a mixture of 3-(dimethylamino)-1,2-propanediol (1.19 g, 10 mmol), potassium tert-butoxide (3.36 g, 30 mmol) and oleyl toluenesulfonate (12.7 g, 30 mmol) in xylenes (50 ml) was stirred at room temperature under house vacuum (approx. 30 torr) for 0.5 hour. The mixture was heated to 50° C. and stirred for an additional 0.25 hour. The vacuum was removed and the reaction vessel was filled with nitrogen gas to room pressure (approx. 1 atm.). The temperature was increased until the reaction boiled (approximately 140° C.) and the mixture was stirred at reflux for 3 hours. The mixture was diluted with hexane (100 ml) and extracted with water (2×50 ml). The organic layer was concentrated, applied to a column of silica gel (150 g) packed in hexanes in ether (1:2), then eluted with the same solvent mixture to give the title compound (4.5 g) as an oil.
Reaction SMILES: [Cl:1][C:2]([Cl:26])([Cl:25])[CH2:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](CC(O)=O)[CH:15]=1.SC1C=CC([CH2:34][C:35]([OH:37])=[O:36])=CC=1.ClC(Cl)(Cl)COC(=O)C1C=CC=CC=1CBr.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:26][C:2]([Cl:1])([Cl:25])[CH2:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:34][C:35]([OH:37])=[O:36])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Agent: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1

Procedure:
The titled compound was prepared according to the method described for 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester above from 4-mercapto-phenylacetic acid (0.73 g, 4.33 mmol), 2-bromomethyl-benzoic acid 2,2,2-trichloro-ethyl ester (1.50 g, 4.33 mmol), cesium carbonate (1.69 g, 5.20 mmol) and DMF (25 mL). The crude material (1.88 g, 100%) was used for the next step without further purification; Mass spectrum: M−H+ 432.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[CH:5]=1.C([NH2:22])=O.C[O-].[Na+]>CN(C=O)C.CO>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:22])=[O:2])[CH2:11][CH2:12]1)[CH2:17][CH3:18]
Reactant: NC=O
Reactant: CCCN1CCC(c2cccc(C(=O)OC)c2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(C(N)=O)c2)CC1

Procedure:
A solution of 3-(1-Propyl-piperidin-4-yl)-benzoic acid methyl ester (0.6 g) and formamide (320 μL) in DMF (9 ml) was heated to 100° C. under a blanket of argon. Sodium methoxide in methanol (30%, 770 μL) was added dropwise and after 1 h, GC analysis revealed the complete absence of starting material and indicated the titled compound as the sole product. After cooling, CH2Cl2 was added and the resulting solution was filtered through a pad of celite and evaporated to dryness. The residue was chromathographed on a silica column using MeOH: CH2Cl2 (1:3 (v/v)) as eluent. The fractions containing pure titled compound were collected, and the solvent was removed in vacuum, affording 400 mg of the titled compound. m.p. 182° C. (oxalate) (MS m/z (rel. intensity, 70 eV) 246 (M+, 4), 217 (bp), 131 (19), 100 (22), 70 (63).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([Cl:29])=[O:19])=[CH:21][CH:22]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Yield: 173.1 %

Procedure:
In a suspension of 1.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoic acid in 10 ml of benzene, 0.44 g of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred under reflux with heat for 2.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1.81 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoic acid chloride as pale yellow oily substance.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=[O:31]>>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])=[O:31])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: CS(C)=O
Reactant: COc1cc(OC)c(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc1OC
Product: COc1cc(OC)c(C(=O)/C(=N\C2CCCC2)n2ncc(C#N)c2N)cc1OC
Reaction time: 720 h
Yield: 10 %

Procedure:
A mixture of 3-(cyclopentylamino)-2-(2,4,5-trimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (153 mg, 0.401 mmol) and DMSO (20 mL) was heated gently to dissolve all the solids. The resulting brown solution was stored for 30 days at RT. As a result, some solids were precipitated which was collected by filtration and the filtrate was diluted with water (˜100 mL). The resulting solids were collected by filtration and washed with diethyl ether. These solids were again purified by HPLC using acetonitrile and ammonium acetate as eluent to obtain 16.5 mg (10% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(2,4,5-trimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.85 (br m, 8H), 3.65 (s, 3H), 3.67 (p, 1H), 3.79 (s, 3H), 3.91 (s, 3H), 6.72 (s, 1H), 7.35 (s, 1H), 7.63 (s, 1H), 8.06 (br s, 2H). LC/MS calcd. for C20H23N5O4 (m/e) 397.433, obsd. 398.3 (M+H, ES+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)=[N:10][N:9]=2)=[CH:4][CH:3]=1.N1CCCCC1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3=[N:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)Nc1nnc(-c2ccc(Br)cc2)s1
Solvent: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCN2N=C(c3ccc(Br)cc3)SC2=N1

Procedure:
A mixture of N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]-4-chlorobutan-amide (1.44 g, 0.004 mol) and piperidine (0.7 g, 0.8 ml, 0.008 mol) in toluene (50 ml) was heated under reflux for 3 h. The reaction mixture was cooled, poured into water and stirred. Toluene was separated dried and evaporated to give a crude product which was purified by repeated silica gel and neutral alumina column chromatography eluting with EtOAc/hexane (50:50 v/v) and CHCl3/hexane (80:20 v/v); mp 204-7° C., m/e 324, 78% (consistent with molecular formula C12H10BrN3OS, calcd. 324.20) 1H NMR CDCl3): δ 2.32-2.40 (m, 2H, —CH2), 2.76 (t, J=7.5 Hz, 2H, —CH2), 4.29 (t, J=7.5 Hz, 2H, —CH2), 7.62-7.84 (dd, J=8.5 Hz, 4H, ArH). 13C NMR: δ 18.3, 31.2, 47.9, 125.0, 128.7, 129.5, 132.3, 157.5, 162.9, 173.7.
Reaction SMILES: [CH:1]([CH:4]([C:15]#[N:16])[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2].CO[CH2:19][CH2:20][C:21]#[N:22].C[O-].[Na+].O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([C:4]([C:15]#[N:16])([CH:1]([CH3:3])[CH3:2])[CH2:19][CH2:20][C:21]#[N:22])[CH:14]=[CH:13][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Reactant: COCCC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C#N)(CCC#N)C(C)C)cc1OC
Temperature: 85 °C

Procedure:
438.4 g (2 mol) of α-isopropyl-veratryl cyanide and 204.2 g (2.4 mol) of 3-methoxypropionitrile are dissolved in 400 ml of dimethylformamide, 36 ml of a 5.5 molar solution of sodium methylate are added, and the mixture is heated to 85° C. for 1/2 hour. After cooling, water is added to the reaction mixture and the reaction product separates by crystallisation. Recrystallised from methanol/water, the product melts at 97° C.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]([CH3:27])([CH3:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH3:25])[CH:19]=1)=[O:16].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:15](=[O:16])[C:14]([CH3:26])([CH3:27])[NH:13][C:1]2=[O:12])=[CH:19][C:20]=1[CH3:25]
Reactant: Cc1cc(NC(=O)C(C)(C)N)ccc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)ccc1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 287.3 %

Procedure:
Bis(trichloromethyl) carbonate (50.6 mg, 0.171 mmol) was added to a solution of 2-amino-N-(4-bromo-3-methyl-phenyl)-2-methyl-propionamide (132 mg, 0.487 mmol) and triethylamine (0.204 ml, 1.46 mmol) in dichloromethane (5.0 ml) at 0° C., and the mixture was stirred for 21 hours while gradually warming to room temperature. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with dichloromethane. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give 3-(4-bromo-3-methyl-phenyl)-5,5-dimethyl-imidazolidine-2,4-dione (146 mg, 88%).