Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].Cl>CO.[Pd]>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC=C(c2cccc(S(C)(=O)=O)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
4-(3-Methanesulfonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester (2.0 g) was dissolved in methanol (40 ml). Concentrated hydrochloric acid (2 ml) and Pd/C (500 mg) were added. The resulting mixture was hydrogenated under a hydrogen gas pressure (50 psi) for 8 h and then filtered through a pad of celite. The solvent was evaporated in vacuum and the residue was purified by flash chromatography (CH2Cl2: MeOH, 3:1 (v/v)). Yield 0.92 g MS m/z (relative intensity, 70 eV) 297 (M+, 54), 282 (62), 238 (bp), 115 (92), 56 (93).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:9]#[N:10]>O.Cl>[OH:2][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:9]#[N:10]
Reactant: O=N[O-]
Reactant: Cc1ccc(C#N)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C#N)cc1O
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of 49.2 g (0.72 mol) of NaNO2 in 217 ml of water was added dropwise over the course of 30 min to 85 g (0.72 mol) of 3-amino-4-methylbenzonitrile in 1.8 l of 6N HCl at 0-5° C. The mixture was then stirred at 0-5° C. for a further 30 min and then at the boiling point for 1 h. After the solution had cooled it was possible to extract the product with ethyl acetate and, from this, the phenolate with ice-cold 5N NaOH. The aqueous phase was then acidified to pH 3 with 6N HCl and the product was extracted with ethyl acetate. 41 g (43%) of the phenol were obtained. 1H-NMR (DMSO-d6; δ in ppm): 10.3 (s, OH); 7.25 (dd, 1H); 7.15 (d, 1H); 7.1 (dd, 1H); 2.20 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.O>O1CCCC1>[NH2:1][C:2]1[C:7]([NH:18][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1
Reactant: NC1CCCC1
Reactant: N#Cc1nc(N)c(Cl)nc1C#N
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc(N)c(NC2CCCC2)nc1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
4.2 g (0.023 mol) of 2-amino-3-chloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 4.0 g (0.047 mol) of cyclopentylamine was dropwise added thereto at room temperature. After completion of the dropwise addition, the mixture was stirred at 40° C. for 1 hour, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from isobutyl alcohol to obtain 4.9 g of slightly yellow crystals (yield: 93.4%, decomposition point: 222° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:6]=1>CO>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Solvent: CO
Product: Cc1nc(-c2ccc(N)cc2)c[nH]1

Procedure:
Prepared by hydrogenation of 2-methyl-4-(4-nitro-phenyl)-imidazole in MeOH on palladium/charcoal (10%) at 20° C. and 3.5 bar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:27]1[CH2:32][CH2:31][CH:30]([CH:33]([OH:35])[CH3:34])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:27]4[CH2:32][CH2:31][CH:30]([CH:33]([OH:35])[CH3:34])[CH2:29][CH2:28]4)=[O:26])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Reactant: CC(O)C1CCNCC1
Product: CC(O)C1CCN(C(=O)c2cc(C(=O)NCCc3ccc(-c4ccc(Cl)c(Cl)c4)o3)[nH]n2)CC1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 1-(piperidin-4-yl)ethanol. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-90:10). 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30-1.41 (3H, m), 1.62 (1H, m), 1.77 (1H, m), 2.00 (1H, m), about 2.78 (1H, m), 3.01 (2H, t), about 3.18 (1H, m), about 3.64 (1H, m), 3.77 (2H, q), about 4.48 (1H, m), about 4.75 (1H, m), 6.20 (1H, d), 6.58 (1H, d), 7.02 (1H, s), about 7.28 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.75 (1H, d), 11.44 (1H, broad s).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(#N)C.[N-:11]=[N+:12]=[N-:13].[Na+]>O>[N:11]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:12]=[N-:13]
Reactant: CCOC(=O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN=[N+]=[N-]
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 490 g. (4 moles) of ethyl chloroacetate in 1500 ml. of acetonitrile were added 260 g. (4 moles) of sodium azide, and the mixture was heated at the reflux temperature for 20 hours. After heating, the reaction mixture was poured into 1 liter of water with stirring for 1/2 hour. The organic phase was separated from the aqueous phase and evaporated in vacuo to dryness. The yellow residual oil was dissolved in 1200 ml. of diethyl ether and the solution was dried over magnesium sulfate. Evaporation of the diethyl ether in vacuo gave 391 g. (76% yield) of ethyl azidoacetate.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.[C:12]([O-:15])([O-])=[O:13].[Na+].[Na+]>C1COCC1.O>[O:11]=[C:8]1[CH2:9][CH2:10][C:5]2([CH2:1][N:2]([C:12]([O:15][C:5]([CH3:6])([CH3:1])[CH3:4])=[O:13])[CH2:3][CH2:4]2)[CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC2(CCNC2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.9 %

Procedure:
To a solution of 2-azaspiro[4.5]decan-8-one (10 g, 65.26 mmol) in a mixture of THF and H2O (3/1 (v/v), 200 mL) were added (Boc)20 (28.48 g, 130.53 mmol) and Na2CO3 (13.83 g, 130.53 mmol). The reaction mixture was stirred at rt for 2 h, then quenched with H2O (200 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (500 mL), dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the product as colorless oil (9 g, 54.5%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[C:26]([O:35][C:36]2[CH:37]=[C:38]([CH:41]=[C:42]([O:44][CH3:45])[CH:43]=2)[C:39]#[N:40])=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:40]=[C:39]([C:38]2[CH:41]=[C:42]([O:44][CH3:45])[CH:43]=[C:36]([O:35][C:26]3[C:25]([Cl:24])=[CH:30][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:28][N:27]=3)[CH:37]=2)[N:2]([CH3:1])[N:3]=1
Reactant: COc1cc(C#N)cc(Oc2ncc(C(F)(F)F)cc2Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: COc1cc(Oc2ncc(C(F)(F)F)cc2Cl)cc(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (0.90 g), 3-(3-chloro-5-trifluoromethylpyridine-2-yloxy)-5-methoxybenzonitrile (0.80 g), anhydrous iron (III) chloride (0.80 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][C:22]3([CH3:26])[CH2:24][CH2:25][CH:19]2[C:20](=[O:27])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[NH2:32][OH:33]>NO.CO.Cl>[OH:33][NH:32][C:20]([CH:19]1[CH2:25][CH2:24][C:22]([OH:21])([CH3:26])[CH2:23][N:18]1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16])=[O:27]
Reactant: NO
Reactant: CC12CCC(C(=O)O1)N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(O)CCC(C(=O)NO)N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
5-(4-Benzyloxy-benzenesulfonyl)-1-methyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (0.035 g, 0.09 mmol) was dissolved in 0.80 mL of a 0.81 M solution of hydroxylamine in methanol (prepared by treating 7.25 mL of a 0.81 M solution of sodium methoxide in methanol with 0.52 g of hydroxylamine hydrochloride). The resulting mixture was shaken at 60° C. for 10 minutes. After cooling to room temperature, the mixture was diluted with 1M HCl, extracted twice with ethyl acetate, and the combined organic layers were washed twice with 50% saturated aqueous NaHCO3, once with 1M pH 7.0 phosphate buffer, dried over Na2SO4, filtered and concentrated in vacuo. Trituration of the residue with CH2Cl2-hexane afforded 0.027 g of 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-5-methyl-piperidine-2-carboxylic acid hydroxyamide as a colorless solid:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][N:4]([CH2:3][CH2:2][O:1][C:27]1[CH:28]=[CH:29][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: N#Cc1ccc(N(CCOc2ccc(C(F)(F)F)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-(trifluoromethyl)phenol: MS (El) m/z 456 (M+, 4%), 295 ([M-C7H4F3O]+, 9%), 281 (100%).
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[Cl:32][C:33]1[N:38]=[C:37](B(O)O)[CH:36]=[CH:35][CH:34]=1>>[Cl:32][C:33]1[N:38]=[C:37]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])[CH:36]=[CH:35][CH:34]=1
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OB(O)c1cccc(Cl)n1
Product: CNc1cnccc1-c1cccc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 68, intermediate, from (4-bromo-pyridin-3-yl)-methyl-amine (example 25, intermediate b) and 6-chloropyridine-2-boronic acid (CAS RN 652148-90-8). Brown sticky solid (90%). MS (ESI): m/z=220.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[NH:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C:26](=[O:31])[CH:25]([CH3:24])[NH:29][C:28]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: CC1NC(=O)NC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(C)C4=O)cc3)CC2)c(C)c1
Yield: 20.2 %

Procedure:
Using (4-bromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 5-methylimidazolidine-2,4-dione (55 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (33 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]=[CH:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([OH:3])=[O:2]
Reactant: COC(=O)c1nccc2c1[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nccc2c1[nH]c1ccccc12
Yield: 74.6 %

Procedure:
In 30 ml of methanol was dissolved 0.5 g of 1-carbomethoxy-9H-pyrido[3,4-b]indole and to this solution was added 2 ml of 10% aqueous sodium hydroxide. The mixture was refluxed at water bath temperature for 6 hours, the methanol removed by distillation, the residue neutralized with 10% hydrochloric acid and the resultant crystals recovered by filtration. Recrystallization from methanol yields 350 mg of 1-carboxy-9H-pyrido[3,4-b]indole as colorless needles, m.p. 239°-240° C. (decomp.). Mol. wt. (based on mass spectrum) 212. The IR absorption spectrum shows absorption at 1680 cm-1 in the starting compound has disappeared and, instead, an absorption of the carboxyl group is observed at 1580-1600 cm-1.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[O-]CC.[Na+].[CH2:9]([C:11]1[NH:15][N:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=1)[CH3:10]>C(O)C>[CH2:2]([C:1]1[N:15]([CH2:11][CH2:9][CH3:10])[N:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=1)[CH3:3]
Reactant: CCOC(=O)c1cc(CC)[nH]n1
Reactant: CCCI
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCn1nc(C(=O)OCC)cc1CC
Reaction time: 8 h

Procedure:
Propyl iodide (0.43 mL, 4.46 mmol) and a solution of sodium ethoxide in ethanol (21%, 0.95 g, 3.27 mmol) were added to a solution of ethyl 5-ethyl-1H-pyrazole-3-carboxylate (0.5 g, 2.97 mmol) in ethanol (5 mL) at ambient temperature. The reaction was stirred overnight, and additional propyl iodide (0.05 mL) and sodium ethoxide in ethanol (21%, 0.1 g) were added. After 3 hours, the solvent was removed under reduced pressure and the residue was partitioned between an aqueous sodium chloride solution and methyl tert-butyl ether. The aqueous phase was extracted with methyl tert-butyl ether twice. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield impure ethyl 5-ethyl-1-propyl-1H-pyrazole-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10](=O)[NH:11][N:12]=[C:13]([CH3:22])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:22])=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cccc2Cl)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2c(F)cccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2.16 g of 4-(2-chloro-6-fluorophenyl)-5-(4-chlorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.21 g of 3-chloro-4-(2-chloro-6-fluorophenyl)-5-(4-chlorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xvi) of the present invention).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[C:4]([N:22]2[CH2:23][CH2:24][CH:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([F:11])([F:25])[F:26])[CH2:20][CH2:21]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc(Cl)cc(N2CCC(c3ccccc3C(F)(F)F)CC2)n1
Temperature: 210 °C
Reaction time: 0.33 h
Yield: 117.7 %

Procedure:
2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step.
Reaction SMILES: CS(O)(=O)=[O:3].N(=[CH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])O>>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:3])[C:9]1=[O:10]
Reactant: O=C(C=NO)Nc1ccccc1
Reactant: CS(=O)(=O)O
Product: O=C1Nc2ccccc2C1=O
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
5 mL methanesulfonic acid was heated to 50° C. and slowly added to oximino acetanilide in batches, with the temperature being maintained at 60-70° C. After feeding, the temperature was raised to 70-80° C., and the reaction was carried out for 15 min. The reaction was finished by TLC detection. The reaction solution was poured into a crushed ice, and a red solid was precipitated. After placing at low temperature (0° C.) for 10 min, the red solid was filtered and dried to give crude isatin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2([CH3:28])[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:17]2)[CH2:11][CH2:10]1.[CH2:29](Br)[CH:30]=[CH2:31].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH2:31]([N:19]1[C:20](=[O:21])[C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)([CH3:28])[N:17]=[C:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:30]=[CH2:29]
Reactant: COc1ccccc1N1CCN(CC2(C)N=C(c3cccnc3)NC2=O)CC1
Reactant: C=CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCN1C(=O)C(C)(CN2CCN(c3ccccc3OC)CC2)N=C1c1cccnc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one (3.7 g; prepared in a similar manner to that described in Example 36), allyl bromide (1.05 ml), finely-powdered potassium hydroxide (0.79 g), 18-Crown-6 (0.26 g) and tetrahydrofuran (50 ml) was stirred at ambient temperature under nitrogen for 120 hours, then poured onto ice-water (30 ml). The product was extracted into ethyl acetate, the extracts were dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 9:1 mixture of ethyl acetate and ethanol as eluant. Appropriate fractions were combined, and the solvents removed in vacuo to leave 1-allyl-4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one as an off-white solid (0.25 g), m.p. 66-69° C.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1.S(=O)(=O)(O)[OH:14].[OH-].[Na+]>>[CH:2]([C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1)=[O:14]
Reactant: O=S(=O)(O)O
Reactant: Cn1c([N+](=O)[O-])cnc1C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c([N+](=O)[O-])cnc1C=O

Procedure:
210 parts of 2-dichloromethyl-1-methyl-5-nitroimidazole are stirred in 800 parts by volume of 10 percent strength by weight sulfuric acid for 2 hours at 100° C. The mixture is then neutralized with 550 parts of 6 N sodium hydroxide solution, with intense cooling, and the resulting solution is extracted with 4 times 500 parts by volume of methylene chloride. The combined extracts are dried. 126 parts (82% of theory) of 2-formyl-1-methyl-5-nitroimidazole of melting point 93° C. (after recrystallization from toluene) are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:19](I)([CH2:21][CH3:22])[CH3:20]>C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH:19]([CH2:21][CH3:22])[CH3:20])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CCC(C)I
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C)Sc1cc(C(=O)O)cc(N)c1Oc1ccccc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (2.6 g), sodium hydrogen carbonate (2 g), saturated sodium hydrogen carbonate (100 ml), and sec.-butyl iodide (2.2 g) is stirred for 6 hours at 55° C. After cooling, 5-amino-3-sec.-butylthio-4-phenoxybenzoic acid is precipitated by addition of hydrochloric acid until pH 2.5. After collection, recrystallization from aqueous ethanol, and drying in vacuo at 80° C, the compound is obtained with a melting point of 157°-159° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:31]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:38][CH2:37][CH2:36][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: NCCN1CCCC1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCN4CCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 2 mL of dioxane and 32.3 mg of 2-pyrrolidin-1-ylethanamine. After chromatography on a column of silica, eluting with a mixture of dichloromethane/methanol/28% aqueous ammonia (95/4/1 by volume), 42.4 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]-methyl}pyridin-2-yl)-3-(2-pyrrolidin-1-ylethyl)urea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:21][CH2:20][C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([NH:46][C:22]([C:10]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[CH2:20][CH2:21][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=2)[CH:9]=1)=[O:24])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a suspension of 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylic acid (176 mg, 0.5 mmol) in DCM (3 mL) was added carbonyldiimidazole (97 mg, 0.6 mol) and the mixture was stirred for 1 hour at 20° C. Benzylamine (109 μL, 1 mmol) was added and the mixture was stirred overnight. Solid was collected by filtration and washed by DCM and dried under high vacuum to give the title compound (90 mg); 93% MS (ES): 442 (MH+).