Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([C:23]2[CH:24]=[N:25][C:26](F)=[CH:27][CH:28]=2)[C:5]([O:21][CH3:22])=[C:6]([CH:8]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[C:12]([CH3:20])=[N:11]2)[CH3:9])[CH:7]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C(O)CCC>[NH2:19][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:10]([CH:8]([C:6]3[C:5]([O:21][CH3:22])=[C:4]([C:23]4[CH:28]=[CH:27][C:26]([NH:34][CH2:33][CH2:31][OH:32])=[N:25][CH:24]=4)[C:3]([CH3:30])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:11]=[C:12]([CH3:20])[C:13]=12
Reactant: NCCO
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(F)nc1
Solvent: CCCCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(NCCO)nc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 15 %

Procedure:
A mixture of 1-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 mg, 0.023 mmol) and ethanolamine (0.10 mL) in 1-butanol (1 mL) was stirred at 130° C. for 5 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.6 mg, 15%). The product was isolated as a single enantiomer. LCMS calculated for C23H27ClN7O2 (M+H)+: m/z=468.2; Found: 468.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([N:28]2[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]2)=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[Li+].[OH-].O.Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([C:26]([N:28]2[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]2)=[O:27])=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Temperature: 45 °C

Procedure:
Phenylmethyl 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 64; 444 mg, 0.92 mmol) was dissolved in tetrahydrofuran (4 ml) and LiOH (66.6 mg, 2.78 mmol) and water (1 ml) were added. The solution was heated at 45° C. for 90 minutes. 2M Hydrochloric acid (1.39 ml, 2.78 mmol) was added and the solvent was removed in vacuo. The solid was partitioned between 2M HCl (5 ml) and ethyl acetate (40 ml), and the organic layer separated, dried (MgSO4) and the solvent removed in vacuo to give the title compound as a brown solid. 374 mg.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[O:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1.[NH2:23][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C(OCC)C>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[NH:23][C:9]1[O:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Reactant: Nc1ncccn1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1oc(Nc2ncccn2)nc1C(F)(F)F
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A reaction vessel was charged with 50 ml toluene, 4 g (16.4 mmol) ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate and 3.12 g (32.8 mmol) 2-aminopyrimidine. The reaction mixture was heated at a temperature of 100°-110° C. for 16 hours. The mixture was cooled to room temperature, diluted with ethyl ether, washed with 5% hydrochloric acid, and then washed with large amounts of water. The ether portion was dried over magnesium sulfate and then concentrated under reduced pressure to yield 3.14 g of a yellow oily-solid material. This material was recrystallized from an ethanol-water solution to provide a yellow solid material which was air dried at room temperature, then triturated in warm hexane, and finally recrystallized from ethanol-water solution to yield 2.06 g of a yellow solid material (m.p. 199°-205° C.) identified in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[N:23][C:22]([NH:25][NH:26]C(=O)CC2CCOCC2)=[CH:21][C:20]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:26][NH:25][C:22]2[N:23]=[N:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[CH:21]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CC1CCOCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Yield: 62 %

Procedure:
The title compound (90 mg, 62%) as a white solid was prepared from 2-(4-chlorophenyl)acetic acid (62 mg, 0.36 mmol) and 1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (99 mg, 0.3 mmol) according to the procedures described for N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetohydrazide (Example 9A). HPLC/MS (method A): retention time=3.57 min, (M+H)+=483.2.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:7][C:6]=1C)[CH3:3].N1CC(OC2C=CC(CN(C)C)=C(C)C=2)[CH2:25]1.N1CCC1.OC1C=CC(C=O)=CC=1>>[NH:12]1[CH2:13][CH:10]([O:9][C:8]2[CH:21]=[CH:22][C:5]([CH2:4][N:2]3[CH2:3][CH2:25][CH2:1]3)=[CH:6][CH:7]=2)[CH2:11]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN(C)C
Reactant: Cc1cc(OC2CNC2)ccc1CN(C)C
Agent: C1CNC1
Agent: O=Cc1ccc(O)cc1
Product: c1cc(OC2CNC2)ccc1CN1CCC1
Yield: 39 %

Procedure:
Using similar protocols as described in Examples 20A, 20B and 20C employing azetidine and 4-hydroxybenzaldehyde as starting material afforded 0.44 g (39%) of 41A as an oil. 1H NMR (500 MHz, CDCl3): δ 2.06 (m, 2H), 3.18 (m, 4H), 3.35 (t, 1H), 3.48 (s, 2H), 3.66 (t, 1H), 3.8-5.0 (m, 3H), 6.71 (m, 2H), 7.16 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].Cl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>COCCO.CO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: COCCO
Solvent: CO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)cc2CC1
Temperature: 120 °C

Procedure:
31 g) 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (650 mg/2.2 mmol), 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (500 mg/2.6 mmol) and 4 N HCl in dioxane (650 μL/2.6 mmol) were suspended in 2-methoxyethanol (5 mL) and heated to 120° C. until judged complete by HPLC. The resulting tan solution was cooled to room temperature, diluted with methanol (2 mL) and treated with solid potassium carbonate (carbon dioxide evolves). The mixture was filtered and the filtrate concentrated onto silica gel and purified by column chromatography to afford 2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamideas a tan solid (200 mg/20%). 1H NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 8.68 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 7.52-7.40 (m, 2H), 7.33 (s, 1H), 7.23 (s, 1H), 7.09-6.98 (m, 2H), 6.87 (s, 1H), 6.20 (s, 1H), 3.05 (d, J=3.8 Hz, 3H), 2.91 (m, 4H), 2.60 (m, 6H), 1.11 (t, J=6.9 Hz, 3H). LC/MS found 451 (M+H). mp 201° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[C@H:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:9](=[O:22])[N:8]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=O)=O.[CH2:34]([CH2:36][NH2:37])[OH:35].CCN(C(C)C)C(C)C>C(#N)C.CCOC(C)=O>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][N:8]1[C:9](=[O:22])[C@@H:10]([NH:11][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:7]1[CH2:6][NH:37][CH2:36][CH2:34][OH:35]
Reactant: NCCO
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2COS(C)(=O)=O)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CNCCO)c(OC)c1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a solution of ((2S,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl methanesulfonate (6.43 g, 13.4 mmol) in Acetonitrile (44.8 ml) was added ethanolamine (8.13 ml, 134 mmol) followed by DIPEA (7.0 ml, 40 mmol). The solution was heated to 80° C. for 20 h, whereupon it was cooled to rt, diluted with EtOAc, washed with water, dried over Na2SO4 and concentrated in vacuo, afford the title compound (4.47 g, 75%) as a white solid. LCMS: Rf=0.60 min, m/z=444.2 (M+1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[C:12]2[N:13]=[C:14](Cl)[CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O-:20].[Na+]>CO.O>[CH2:1]([S:8][C:9]1[N:18]=[C:12]2[N:13]=[C:14]([O:20][CH3:19])[CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccn2nc(SCc3ccccc3)nc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccn2nc(SCc3ccccc3)nc2n1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A mixture of 6.0 g (22 mmol) of 2-benzylthio-5-chloro-1,2,4-triazolo[1,5-a]pyrimidine in 25 ml of methanol was treated with 5.0 g (23.8 mmol) of a 25% solution of sodium methoxide in methanol. After stirring for 1.5 hours the reaction mixture was diluted with 100 ml of water and neutralized with 3N HCL (aq). The solid which separated was collected by filtration, washed with water and dried to afford 5.0 g (84%) of the desired product as a white solid, m.p. 126°-128° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Sc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: The solution of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 50 ml of water containing 0.4 g of sodium hydroxide is adjusted to pH = 7.4 by the addition of 4N aqueous sodium hydroxide whereupon 1.3 g of benzylchloride are added while stirring under nitrogen. As soon as the pH remains constant the mixture is filtered and the filtrate acidified with glacial acetic acid to a pH of 4-5. The precipitate formed is recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-benzylamino-5-sulfamoylbenzoic acid melting at 255°-258°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH:5]=[N:6][OH:7].ClN1C(=O)CCC1=O.[OH:20][CH2:21][C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:28][C:22]([CH2:21][OH:20])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:7][N:6]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: ON=Cc1cc(Cl)cc(Cl)c1
Reactant: C=C(CO)C(=O)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CO)CC(c2cc(Cl)cc(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.00 g (15.8 mmol) of 3,5-dichlorobenzaldehyde oxime were stirred in 100 ml of DMF together with 2.21 g (16.6 mmol) of N-chlorosuccinimide at RT for 4 h. 3.08 g (23.7 mmol) of ethyl 2-(hydroxymethyl)acrylate and 2.40 g (23.7 mmol) of triethylamine were then added, and the mixture was stirred at RT for 18 h. The reaction solution was concentrated under reduced pressure, and CH2Cl2 and water were then added. The aqueous phase was re-extracted once with CH2Cl2, and the combined organic phases were washed twice with water, dried over Na2SO4, filtered and concentrated. After chromatography on silica gel using n-heptane:ethyl acetate (3:1), the product was obtained. Yield: 3.10 g (62%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=O)=[CH:4][C:3]=1[S:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16].C(OC(=O)C)(=[O:25])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11](=[O:25])[CH:14]=2)=[CH:4][C:3]=1[S:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(S(=O)(=O)N2CCCC2)c1
Product: O=C1C=C(c2ccc(Cl)c(S(=O)(=O)N3CCCC3)c2)OC1

Procedure:
3.9 g of 4-[4-chloro-3-(1-pyrrolidinylsulfonyl)-phenyl]-4-oxobutanoic acid are boiled under a reflux condenser in 50 ml of acetic anhydride for 1 hour, the solvent is driven off under reduced pressure and the residue is caused to crystallize under diisopropyl ether. 5-[4-Chloro-3-(1-pyrrolidinylsulfonyl)-phenyl]-2,3-dihydro-3-oxofuran is obtained in the form of light red-colored crystals of melting point 108°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[N:16]=1.[C:17]([O:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:27]3[CH2:26][CH2:25][CH:24]([NH:23][C:22](=[O:30])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:29][CH2:28]3)[C:7]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a solution of 0.18 g of (6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde in 4 mL of dichloromethane, 0.16 g of tert-butyl(piperidin-4-yl)carbamate and 47 μL of acetic acid and 0.26 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 3 hours. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, diethyl ether, methanol and hexane were added, and the solid was filtered off to obtain 0.23 g of tert-butyl (1-(2-(6-methoxy-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O.[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[C:20]=1[CH3:21].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:22]2[CH:23]=[C:24]([NH:25][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)[CH:26]=[CH:27][CH:28]=2)[C:20]=1[CH3:21]
Reactant: Cc1ncn(-c2cccc(N)c2)c1C
Reactant: O=C(O)c1cccc(-c2cccs2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncn(-c2cccc(NC(=O)c3cccc(-c4cccs4)c3)c2)c1C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a suspension of 3-(2-thienyl)benzoic acid (103 mg) and 3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-3-(2-thienyl)benzamide (117 mg, 62.6%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.CN1CCOCC1.[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>C(Cl)Cl>[CH3:37][C:27]1[CH:28]=[C:29]([S:33]([NH:1][C:2]2[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:5]([CH:8]([CH3:9])[CH3:10])=[CH:6][CH:7]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)c1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
3-Amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (assumed to be 3.37 mmol), as prepared in the preceding step, and N-methylmorpholine (1.0 mL, 9.1 mmol) were dissolved in methylene chloride (20 mL) and cooled to 0° C. A solution of m-toluenesulfonyl chloride (0.67 g, 3.5 mmol) in methylene chloride (5 mL) was added and the reaction stirred at ambient temperature for 16 hours. After evaporation in vacuo, the crude product was dissolved in methylene chloride, washed with 10% aqueous citric acid, saturated NaHCO3, and brine, dried over MgSO4, and filtered. The evaporated filtrate gave the title compound (1.24 g, 88%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.65 (m, 2H), 7.58 (br s, 1H), 7.46 (d, 1H, J=7.8 Hz), 7.33 (m, 2H), 6.08 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 2.67 (m, 1H), 2.38 (s, 3H), 1.41 (s, 9H), 1.22 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [O-2:1].[O-2].[O-2].[U+6:4].[N+:5]([O-])([O-])=[O:6].[NH4+:9]>>[NH4+:5].[NH4+:9].[O-2:6].[O-2:1].[O-2:6].[O-2:6].[O-2:6].[O-2:6].[O-2:6].[U:4].[U:4]
Reactant: O=[N+]([O-])[O-]
Reactant: [U+6]
Agent: [NH4+]
Agent: [O-2]
Product: [U]

Procedure:
reacting solid uranium trioxide with aqueous ammonium nitrate to form an insoluble ammonium uranate;
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13][N:14]=[C:15]=[O:16].N12CCN(CC1)CC2.C1C=CC=CC=1>O>[CH3:13][NH:14][C:15]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:16]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: CN=C=O
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Solvent: O
Product: CNC(=O)OC1CC(C)(C)N(C)C(C)(C)C1
Reaction time: 24 h

Procedure:
A mixture of 16.4 parts of 1,2,2,6,6-pentamethyl-piperidin-4-ol, 6.27 parts of methyl isocyanate and 0.5 parts of 1,4-diazabicyclo[2,2,2]octane was refluxed in 150 parts of dry benzene for 24 hours. Removal of the benzene solvent by distillation under reduced pressure yielded an oily solid which was poured on to 200 parts of water and allowed to stand for 24 hours. The solid formed was collected by filtration, dried and crystallised from n-hexane to give 14.2 parts of 4-methylcarbamoyloxy-1,2,2,6,6-pentamethylpiperidine having a melting point of 96°-7° C. and the following elemental analysis by weight:
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[C:4](=O)[C@@H:5](Cl)[CH3:6])[CH3:2].[K].[S:12]1C=CC=C1CC(O)=O.[CH2:21]([OH:23])[CH3:22]>ClCCl>[CH2:1]([N:3]([CH2:9][CH3:10])[C:4](=[S:12])[C@@H:5]([C:21](=[O:23])[CH3:22])[CH3:6])[CH3:2]
Reactant: CCO
Reactant: O=C(O)Cc1cccs1
Reactant: CCN(CC)C(=O)[C@H](C)Cl
Agent: [K]
Solvent: ClCCl
Product: CCN(CC)C(=S)[C@H](C)C(C)=O
Temperature: 60 °C

Procedure:
(S)-N,N-Diethyl-2-chloropropionamide (88.3 g) dissolved in ethanol (150 cc) is added to a suspension of the potassium salt of thiolacetic acid (72.6 g) in ethanol (300cc). The reaction mixture is then heated for 2 hours at a temperature in the vicinity of 60° C. and then filtered and concentrated to dryness under reduced pressure (130 Pa) at a temperature in the vicinity of 50° C. The residue obtained is taken up and stirred in dichloromethane (500 cc) and then washed with distilled water (300 cc), with a 10% aqueous potassium bicarbonate solution (300 cc) and then with distilled water (300 cc). The organic phase is decanted, dried over sodium sulphate and charcoal 3S (1 g) filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30° C. The residue obtained is distilled under reduced pressure (17 Pa). (R)-N,N-Diethyl-2-acetylthiopropionamide (105.5 g) in the form of a slightly yellow oil [b.p.17Pa =105°-107° C.; [α]D20 =+156° (c=18.1 ; CHCl3)] is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9].[CH2:19](OC(OCC)OCC)C>C(O)C>[CH2:8]([O:10][C:11](=[O:18])[C:12](=[CH:19][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ccccn1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccccn1)C(=O)OCC
Temperature: 130 °C

Procedure:
The reaction vessel was charged with 564 parts of 2-aminopyridine, 1,008 parts malonic acid diethyl ester and 3,110 parts orthoformic acid triethyl ester and heated with stirring at about 130° C. In the course of the reaction the ethanol that formed was distilled out of the reaction mixture through a short column within 4 to 5 hours. Then most of the unreacted orthoformic acid triethyl ester was evaporated from the solution, first at atmospheric pressure and then at 40 mm Hg. After the mixture was cooled, the crystallized pyridylaminomethylenemalonic acid diethyl ester was filtered out and repeatedly washed with alcohol. The filtrate and the washing liquids were combined and, after the distillation process described in Example 1, they were recycled with the next batch. The yield of the above-named product amounted to 96% of the theory with reference to amino-pyridine.