Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[S:8]([OH:11])(=[O:10])=[O:9]
Reactant: Cn1cncc1Cl
Reactant: O=S(=O)(O)O
Product: Cn1cnc(S(=O)(=O)O)c1Cl

Procedure:
33 g (0.28 mol) of 5-chloro-1-methylimidazole in 200 ml of fuming sulfuric acid are heated at 160°-180° C. for 4 hours. After cooling, the reaction mixture is cautiously added to ice. The product crystallizes out from the cold aqueous solution (about 1.5 l). After recrystallizing twice from water, the title compound is obtained in the form of coarse yellowish crystals of melting point 309°-310° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:18]([CH:19]=1)=[N:17][C:16]1[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22]Cl)[CH:15]=1)[CH:10]=2.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:18]([CH:19]=2)=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:20][CH2:21][CH2:22][N:17]4[CH2:18][CH2:9][CH2:10][CH2:11][CH2:16]4)[CH:15]=2)[CH:10]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: ClCCOc1ccc2cc3ccc(OCCCl)cc3nc2c1
Agent: Cl
Product: c1cc2cc3ccc(OCCN4CCCCC4)cc3nc2cc1OCCN1CCCCC1

Procedure:
A suspension of 3,6-bis(2-chloroethoxy)acridine hydrochloride in piperidine was heated in a steel bomb at 80° C. for 24 hours. The excess piperidine was removed in vacuo and the residual solution was washed twice with 30 ml portions of saturated aqueous sodium bicarbonate, then dried and filtered. The filtrate was evaporated to a residue, giving 3,6-bis(2-piperidinoethoxy)acridine as yellow crystals, mp 129°-130° C.
Reaction SMILES: [F:1][C:2]([F:17])([CH:8]([O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[CH2:9][CH3:10])[C:3]([O:5][CH2:6]C)=[O:4]>CO>[F:1][C:2]([F:17])([CH:8]([O:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])[CH2:9][CH3:10])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCC
Solvent: CO
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OC
Yield: 95 %

Procedure:
100 g of ethyl 2,2-difluoro-3-(methacryloyloxy)pentanoate was dissolved in 1000 g of dehydrated methanol in a nitrogen atmosphere. After the addition of 0.1 g of N,N-dimethylaminopyridine (DMAP), the mixture was heated and refluxed for 5 hours. After evaporating the solvent, the residue was dissolved in 1000 g of dehydrated methanol, and the mixture was heated and refluxed for 5 hours. After evaporating the solvent, the residue was dissolved in 300 g of n-hexane. The solution was filtered through 50 g of silica gel to remove DMAP. 89.7 g of methyl 2,2-difluoro-3-(methacryloyloxy)pentanoate (M-29) was thus obtained (yield: 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:16][CH:15]=[N:14][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:27]Br>CN(C=O)C>[Br:27][C:11]1[O:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:18]=2[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2occ(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: BrBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncnc2oc(Br)c(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 0° C. solution of Example 27A (350 mg, 0.98 mmol) in DMF (10 mL) was treated with Br2 (0.102 mL, 1.98 mmol), warmed to room temperature, and stirred for 1 hour. The reaction was cooled to 0° C., quenched with 1:1 10% NaHSO3/saturated NaHCO3, and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide 400 mg (93%) of the desired product. MS (ESI(−)) m/e 433, 435 (M−H)−.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:6][CH3:7])=[O:5].[N+:8]([C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH3:21])=O)[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].CI>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH3:21][O:20][CH:18]=[C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: COC=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Combine freshly prepared sodium methoxide (9.3 g, 172 mmol) and tetrahydrofuran (125 mL). Cool to 0° C. Add methyl formate (10.6 mL, 172 mmol). Add dropwise a solution of methyl (3-nitrophenyl)acetate (15.3 g, 78.3 mmol) in tetrahydrofuran (125 mL). After the addition is complete, warm the reaction mixture to ambient temperature. After 16 hours, evaporate in vacuo to give a residue. Dissolve the residue in dimethylformamide (125 mL). Add dropwise, methyl iodide (19.5 mL, 313 mmol). After 4 hours, dilute the reaction mixture with ethyl acetate and extract with water, saturated aqueous solution of sodium thiosulfate, and brine. Dry over MgSO4, filter through a plug of silica gel eluting with dichloromethane to give the title compound: mp; 101-103° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[S:7][CH:6]=[C:5]([CH2:8][OH:9])[CH:4]=1.CC(C)([O-])C.[K+].Cl[C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:33]=[CH:32][C:31]3[C:27](=[C:28]([CH3:37])[N:29]([CH:34]4[CH2:36][CH2:35]4)[N:30]=3)[CH:26]=2)[C:21](=[O:38])[CH:20]=1.O>CC(N(C)C)=O>[CH:34]1([N:29]2[C:28]([CH3:37])=[C:27]3[C:31]([CH:32]=[CH:33][C:25]([N:22]4[CH:23]=[CH:24][C:19]([O:9][CH2:8][C:5]5[CH:4]=[C:3]([C:2]([F:10])([F:1])[F:11])[S:7][CH:6]=5)=[CH:20][C:21]4=[O:38])=[CH:26]3)=[N:30]2)[CH2:36][CH2:35]1
Reactant: Cc1c2cc(-n3ccc(Cl)cc3=O)ccc2nn1C1CC1
Reactant: OCc1csc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)ccc2nn1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of [5-(trifluoromethyl)thiophen-3-yl]methanol (100 g) in DMA (1363 ml) was added potassium tert-butoxide (61.3 g) at 5° C., and the mixture was stirred at the same temperature for 30 min. To the obtained mixture was added 4-chloro-1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)pyridin-2(1H)-one (136.5 g), and the mixture was stirred at an inside temperature of 70° C. for 1.5 hr. The reaction mixture was cooled to room temperature, water (1.4 L) was added, and the obtained suspension was stirred overnight. The precipitated solid was collected by filtration, and washed with water (2.8 L), ethanol (540 ml) and diisopropyl ether (500 ml) to give the title compound (168.6 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[CH:20]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH2:21].Cl>CS(C)=O>[O:11]=[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]([CH2:21][CH2:20][P:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:29])([O:2][CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Reactant: C=CP(=O)(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOP(=O)(CCC(OC)(C(=O)c1ccccc1)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
16.4 g (0.1 mole) of benzoin methyl ether are dissolved in 100 ml of dimethyl sulphoxide. While passing in nitrogen, 3ml of 4 normal sodium hydroxide solution are added dropwise. Then 18 g (0.11 mole) of diethyl vinylphosphonate are added dropwise in the course of 10 minutes. The reaction mixture is stirred for 16 hours at room temperature under nitrogen and subsequently neutralised with 2 normal hydrochloric acid. After the reaction mixture has been completely concentrated under reduced pressure, the oily residue is taken up in toluene, washed twice with water and again completely concentrated by rotory evaporation to yield 1-oxo-2-(2-diethylphosphonoethyl)-2-methoxy-1,2-diphenylethane as a slightly viscous yellowish oil which crystallises on standing; m.p. 60°-62° C (initiator 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=1.[CH2:16]([OH:19])[CH2:17][CH3:18].CS(O)(=O)=O>C1(C)C=CC=C(C)C=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:16][CH2:17][CH3:18])[N:10]=[C:11]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:12]=[CH:13][NH:14]1
Reactant: Cc1ccc(-c2ncnc(Cl)n2)c(C)c1
Reactant: CCCO
Agent: CS(=O)(=O)O
Solvent: Cc1cccc(C)c1
Product: CCCOC1(c2ccc(C)cc2C)N=C(c2ccc(C)cc2C)N=CN1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A 500 mL round-bottomed flask fitted with a condenser, a magnetic stirrer and a nitrogen atmosphere is charged with 5.48 g (0.0169 mol) of 4,6-bis-(2,4-dimethylphenyl-2-chloro-s-triazine, 10.2 g (0.169 mol) of n-propanol, 2,37 g (0.0246 mol) of methane-sulfonic acid and 25 mL of m-xylene. The mixture is stirred at 90° C. for one hour. The mixture is then allowed to cool to room temperature and vacuum filtered through a plug of silica gel which is subsequently washed with 95:5 heptane:ethyl acetate. The combined organic layers are vacuum filtered through another plug of silica gel. The solvent is removed under reduced pressure to afford 3.31 g of the title compound as off-white crystals melting at 86-88° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:66][CH2:67][CH2:68][CH:69]([O:73][CH2:74][CH3:75])[O:70][CH2:71][CH3:72]>CN(C=O)C.O>[CH2:71]([O:70][CH:69]([O:73][CH2:74][CH3:75])[CH2:68][CH2:67][NH:66][C:28]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[C:17]([O:16][C:15]3[CH:31]=[CH:32][C:12]([NH:11][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[O:10])=[CH:13][CH:14]=3)[CH:22]=[CH:21][N:20]=2)[NH:27][CH:26]=1)=[O:29])[CH3:72]
Reactant: CCOC(CCN)OCC
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)cc3)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (Example 115) (700 mg, 1.64 mmol) in 10 ml of anhydrous DMF were added HATU (684 mg, 1.84 mmol) and N,N-diisopropylethylamine (426 mg, 3.3 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (294 mg, 2.0 mmol). The mixture was stirred at room temperature for another 10 minutes and poured into 150 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 910 mg, 100%.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N-:53]=[N+:54]=[N-:55].[Li+]>CN(C)C=O>[CH2:1]([O:19][CH2:20][CH:21]([N:53]=[N+:54]=[N-:55])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(COCCCCCCCC/C=C\CCCCCCCC)OS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COCCCCCCCC/C=C\CCCCCCCC)N=[N+]=[N-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A mixture of 150 mg (80%) of the above 1,3-O-dioleyl-2-O-(p-toluenesulfonyl)glycerol, 30 mg (0.6 mmol) of lithium azide, and 5 ml of N,N-dimethylformamide was stirred at 100° C. for 2 hours. After cooling, the solvent was distilled off and the residue was diluted with water and extracted with ether. The extract was washed with water, dried, and concentrated to provide 125 mg (99%) of 1,3-dioleyloxy-2-propyl azide as light-brown oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:16])=[O:15])[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-])=O>CO.[Pd]>[NH2:19][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:3]=1[NH:2][CH3:1])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:16])=[O:15])[CH:9]=1
Reactant: CNc1ccc(Oc2ccnc(C(N)=O)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(C(N)=O)c2)cc1N

Procedure:
The mixture containing 4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxamide in methanol with catalytic amount of 10% Pd/C was hydrogenated to yield 4-(3-amino-4-(methylamino)phenoxy]pyridine-2-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[NH:42])[O:39][CH2:40][CH3:41])=[CH:34][CH:33]=1>CN(C)C=O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([C:8]([N:10]([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:16])[CH3:15])=[O:9])[CH:6]=[CH:7][C:2]=1[O:1][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](=[NH:42])[O:39][CH2:40][CH3:41])=[CH:36][CH:37]=1
Reactant: CCOC(=N)c1ccc(OCCCCCBr)cc1
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=N)c1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)cc2OC)cc1
Temperature: 70 °C

Procedure:
A stirred solution of 4-hydroxy-3-methoxy-N,N-bis(1-methylethyl)benzenecarboxamide (319 mg, 1.27 mmol) in 3.5 mL anhydrous N,N-dimethylformamide is treated with cesium carbonate (435 mg, 1.33 mmol) and ethyl 4-[5-bromopentoxy]benzenecarboximidoate (400 mg, 1.27 mmol) and heated at 70° C. for 1.0 hours. After cooling to room temperature, the reaction is partitioned between ethyl acetate and water and the organics washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a yellow oil. This material is purified by chromatography on silica gel (22 g) with 30-75% ethyl acetate/hexanes as the eluent to afford ethyl 4-[5-[2-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentoxy]benzenecarboximidoate as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:34])(=[O:33])[NH2:32])=[CH:21][CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4].[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:33])(=[O:34])[NH:32][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:21][CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Solvent: ClCCl
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
By the procedure of Example 13, Step C, 5-n-butyl-2-(2-chlorophenyl)-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Example 13, Step B) was reacted with 4-fluorobenzoyl chloride. Column chromatography on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) afforded an 80% yield of the title compound as cream-colored crystals, mp 118°-120° C., satisfactory purity by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 619 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:14])[N:3]=1.[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][NH2:19]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(NCCC(C)(C)C)cc(C)nc1Cl
Yield: 79.9 %

Procedure:
A solution of ethyl 2,4-dichloro-6-methyl-3-pyridinecarboxylate (1.00 g, 4.27 mmol) in ethanol (20.0 mL) was treated with (3,3-dimethylbutyl)amine (0.570 mL, 4.27 mmol). The mixture was refluxed for 2 days, and upon cooling, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash column chromatography (20-60% ethyl acetate in hexanes) to afford the title compound as an amber oil (1.02 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.94 (t, J=4.4 Hz, 1H), 6.18 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 2.82-3.17 (m, 2H), 2.25 (s, 3H), 1.35-1.54 (m, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.84 (s, 9H). MS(ES+) m/e 299 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:32])([CH3:31])[C:18]([NH:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:3][CH2:2]1.F[C:39](F)(F)[C:40](O)=[O:41]>>[NH2:23][CH2:22][CH2:21][N:20]([CH2:39][CH2:40][OH:41])[C:18](=[O:19])[C:17]([S:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[N:7][C:8]=2[CH:13]=1)(=[O:15])=[O:16])([CH3:32])[CH3:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)NCCNC(=O)OC(C)(C)C)ccc2n1CC1CC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)N(CCN)CCO)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 1,1-dimethylethyl {2-[(2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoyl)amino]ethyl}carbamate (Step A, 217 mg, 0.406 mmol) and trifluoroacetic acid (4 mL) was stirred at room temperature for 1 h. After the mixture was concentrated under reduced pressure, the residue was diluted with dichloromethane. The mixture was washed with 2 mol/L sodium hydroxide aqueous solution and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by HPLC (ODS, gradient elution with acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (127 mg, 71%) as an amorphous.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].[Sn](Cl)Cl>Cl>[NH:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12])[NH2:1]
Reactant: Cc1ccncc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Cc1ccncc1NN

Procedure:
2.55 ml of a 2.5 M aqueous sodium nitrite solution are added to a solution of 4.0 g (37 mmol) of 3-amino-4-methylpyridine in 19 ml of 6 N hydrochloric acid while cooling in an ice/salt bath. The resulting diazonium salt solution is slowly added dropwise at −10° C. to −15° C. to a solution of 21 g (111 mmol) of tin(II) chloride in 26 ml of hydrochloric acid. The solution is left to stand in a refrigerator overnight in order to complete the reaction. The precipitated solid is filtered off with suction, suspended in 26 ml of water, made basic with concentrated sodium hydroxide solution and filtered. The filtrate is extracted ten times with 20 ml of dichloromethane each time, and the combined organic phases are dried over sodium sulphate and concentrated. Drying under high vacuum results in 1.45 g (31% of theory) of the desired product as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[O:10].[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[OH:10]
Reactant: COc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reaction time: 24 h
Yield: 64.3 %

Procedure:
To 3.66 g of (2-amino-5-chlorophenyl)(3-methoxyphenyl)methanone dissolved in 15 ml of ethanol are added, at 20° C., 1.59 g of sodium borohydride. After 24 hours at 20° C., the reaction medium is concentrated, taken up in ethyl acetate and washed twice with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is solidified with dichloromethane to give 2.37 g of the expected product.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)CC(C)C.[C:35]([O:39][C@H]1CC[C@H](N)CC1)([CH3:38])([CH3:37])[CH3:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[C:35]([O:39][C@H:4]1[CH2:5][CH2:6][C@H:1]([N:7]([CH2:21][CH2:22][CH:23]([CH3:28])[CH3:24])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:2][CH2:3]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CC(C)(C)O[C@H]1CC[C@H](N)CC1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](OC(C)(C)C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, trans-4-tert-butoxy-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]=1[CH:15]([OH:21])[C:16](=[NH:20])[O:17]CC.[O:22]1CCC[CH2:23]1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]=1[CH:15]1[O:21][C:23](=[O:22])[NH:17][C:16]1=[O:20]
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1c(OC)ccc2cc(OC)ccc12
Product: COc1ccc2c(C3OC(=O)NC3=O)c(OC)ccc2c1

Procedure:
By the procedure of Example 12, Method A, ethyl 1-(2,6-dimethoxy-1-naphthyl)-1-hydroxymethanecarboximidate (3.0 g.) in 125 ml. of tetrahydrofuran converted to the desired product. To isolate, the reaction mixture was quenched by pouring slowly into 200 ml. of crushed ice and extracted with two 100 ml. portions of ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, evaporated to semi-solids (2.6 g.) and crystallized by trituration with ether, affording 5-(2,6-dimethoxy-1-naphthyl)oxazolidine-2,4-dione (0.43 g.; m.p. 175°-180° C.; m/e 287).