Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:3]([NH:5][C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=O)[CH3:4].P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:2]2([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:3]([CH3:4])[NH:5][C:6]([C:8]3[CH:13]=[N:12][CH:11]=[CH:10][N:9]=3)=[N:1]2)=[CH:15][CH:16]=1
Reactant: CC(NC(=O)c1cnccn1)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC1NC(c2cnccn2)=NC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
To a solution of the above-mentioned amide compound (157 mg) in benzene (4 mL) was added phosphorus pentachloride (266 mg), and the mixture was stirred at 50° C. for 3 days. After cooling to room temperature, to the reaction mixture was added 2N sodium hydroxide aqueous solution (4 ml), and the reaction mixture was stirred for an additional 30 minutes. The obtained mixture was extracted with chloroform thrice, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=1:1→1:2) to give the objective compound (100 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][CH:25]1[CH2:30][N:29]([CH3:31])[C:28](=[O:32])[CH2:27][CH2:26]1.Cl>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:24][CH:25]1[CH2:26][CH2:27][C:28](=[O:32])[N:29]([CH3:31])[CH2:30]1)=[O:5])[CH3:2]
Reactant: CN1CC(N)CCC1=O
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(NC1CCC(=O)N(C)C1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 5-amino-1-methylpiperidin-2-one (ChemBridge, free base was made from the purchased HCl salt) as starting materials. The crude reaction mixture was diluted with EtOAc and washed with aqueous NaHCO3 solution and brine. tr: 1.07 min (LC-MS 2); ESI-MS: 511.1 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.42 (m, 2H), 7.30 (m, 2H), 6.28 (NH, br, 1H), 4.85-5.00 (m, 1 H), 4.25 (quin, 2 H), 3.15-3.05 (m, 2H), 2.84-2.75 (m, 1H), 2.72 (d, 3H), 2.38-1.85 (m, 4H), 1.75-1.58 (m, 1), 1.45 (d, 3 H), 1.24 (t, 3 H), 0.83 (t, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH3:20])[C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=2[CH:8]=O)[CH2:3][CH2:2]1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH3:20])[C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=2[CH:8]=[N:22][OH:23])[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To ethanol (30 ml) are added 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (6.8 g), hydroxylamine hydrochloride (1.66 g) and sodium acetate (1.95 g) and the mixture is stirred at room temperature overnight. Ethanol is removed by evaporating under reduced pressure and thereto is added chloroform and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1→2:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde oxime (5.78 g). MS (m/z): 301 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][C:10]([O-:13])(C)[CH3:11].[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([N:6]2[C:9]3[CH:7]=[CH:2][CH:3]=[CH:11][C:10]=3[O:13][CH2:4][CH2:5]2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CC(C)(C)[O-]
Agent: [Fe+2]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCOc3ccccc32)cn1
Temperature: 80 °C

Procedure:
A nitrogen stream was bubbled through a mixture of 5-bromo-2-methylpyridine (3.818 g, 22.195 mmol) in toluene (28 ml), then, tBuONa (6.186 g, 64.365 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.615 g, 1.11 mmol), bis(dibenzylideneacetonato)palladium (0.383 g, 0.666 mmol) and 3,4-dihydro-2H-1,4-benzoxazino [CA.S. 5735-53-5] (1.77 g, 13.097 mmol) were added. The reaction mixture was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; eluent:DCM/EtOAc from 100/0 to 80/10 as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound D29 (3.812 g, 75%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[S:10]([Cl:14])(=O)(=[O:12])[OH:11]>O>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[S:10]([Cl:14])(=[O:12])=[O:11]
Reactant: Cc1c(F)cccc1F
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: Cc1c(F)ccc(S(=O)(=O)Cl)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
To 1,3-difluoro-2-methylbenzene (5.00 g, 39.0 mmol), chlorosulfuric acid (10.5 mL, 158 mmol) was added with cooling on ice, and the mixture was stirred at room temperature for 5 hours. To the reaction solution, water (100 mL) was added with cooling on ice, followed by extraction with dichloromethane (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (8.65 g, 98%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>[NH4+].[OH-].C(OCC)(=O)C>[CH3:1][CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][N:3]1[C:17](=[O:19])[CH3:18]
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3C
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Reaction time: 0.33 h

Procedure:
To a solution of 700 mg (3.24 mmol) 1-methyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline, and 5 drops NH4OH in ethyl acetate was added 0.4 mL (3.88 mmol) acetic anhydride under N2 gas. The reaction was stirred for 20 min. and then washed with water. The organic layer collected was dried over MgSO4, filtered, and concentrated in vacuo to a dark oil. The oil was dissolved in methanol and chromatographed on reverse phase C-18 using methanol and water. The product was collected and concentrated to a white solid, which showed characteristic peaks: NMR (CDCl3) δ: 1.45 ppm (d, 3H), 2.25 ppm (s, 3H), 3.85 ppm (s, 3H).
Reaction SMILES: COCC(O)C.[Br:7][C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]4[CH2:30][CH2:29][O:28][CH2:27]4)=[O:24])[CH2:19][CH2:18]3)=[N:13][C:12]=12>>[Br:7][C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][CH:26]([CH3:30])[CH2:27][O:28][CH3:29])=[O:24])[CH2:21][CH2:22]3)=[N:13][C:12]=12
Reactant: O=C(O[C@@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Solvent: COCC(C)O
Product: COCC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1

Procedure:
This was made by using 1-methoxypropan-2-ol and following the Part B in the procedure described above for making (R)-tetrahydrofuran-3-yl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:14]([OH:17])(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][C:4]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Biphenyl (46.3 g, 0.3 mol) was dissolved in 500 ml of chloroform. The solution was cooled in an ice/water bath. Chlorosulfonic acid (19.9 ml, 1 eq) was added dropwise over 30 min. The ice/water bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the solid was washed with CHCl3 to provide 41.2 g of biphenyl-4-sulfonic acid as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][N:31]3[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=2)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[CH3:7][N:6]([CH3:8])[C:5]1[CH:9]=[CH:10][C:2]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][N:31]3[CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:39])[CH3:40])=[CH:27][CH:26]=2)=[CH:3][CH:4]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CN(C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(N(C)C)cc3)ccc12
Yield: 17.3 %

Procedure:
785 mg of 4-bromo-N,N-dimethylaniline, 646 mg of sodium carbonate, 10 cm3 of water and 196 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 56, in 50 cm3 of dioxane. The medium is then refluxed for 18 hours, the resulting mixture is then allowed to return to room temperature and 75 cm3 of ethyl acetate and 75 cm3 of water are added. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.) to give 1.6 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 170 mg of N-[6-[4-(dimethylamino)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:8][C:9](=[O:29])[CH:10]([NH:19][C:20](OC1C=CC=CC=1)=[O:21])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:5]([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[CH:4]([N:8]1[C:9](=[O:29])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:19][C:20]1=[O:21])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)C(NC(=O)C(CCc1ccccc1)NC(=O)Oc1ccccc1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C(C)C)N1C(=O)NC(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of the compound obtained in step c above (1140 mg) in DMF (14 mL) was added DIEA (0.6 mL, 3.30 mmol). After stirring overnight at room temperature, the solvent was removed. The residue was diluted with EtOAc and washed with water. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a colourless oil (672 mg, 77%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C:15]([OH:20])(=[O:19])[CH:16]([CH3:18])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH:16]([C:15]([OH:20])=[O:19])[CH3:18])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=CCNc1ccc(CC(=O)OC(C)C(=O)O)cc1

Procedure:
A flask containing 10.0 g. 4-(allylamino)phenylacetic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 4-(allylamino)phenylacetate separates as off-white crystals.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.ClC1C=CC(C2C(C3C=CC(Cl)=CC=3)NC(C3C=CC(OC)=CC=3OC)=N2)=CC=1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(=O)(O)[O-].[Na+]>C1COCC1.C(Cl)Cl>[CH3:41][N:42]1[CH2:47][CH2:46][N:45]([CH:1]=[O:2])[CH2:44][CH2:43]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)Cl
Agent: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C=O)CC1
Reaction time: 2.5 h

Procedure:
Phosgene (1.31 mL, 2.53 mmol, 1.93 M in toluene) was added dropwise to a cooled (0° C.) mixture of triethylamine (0.37 mL, 2.64 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy phenyl)-4,5-dihydro-1H-imidazole (225 mg, 0.53 mmol, example 1) in THF (5 mL). The reaction mixture was stirred for 2.5 h and evaporated. The residue was kept under high vacuum for 30 min and was redissovled in methylene chloride (10 mL). The slurry was added dropwise to a solution of N-methylpiperazine (1.05 g, 10.48 mmol) in methylene chloride (5 mL). After 1 h, the reaction was worked up with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with water and brine, and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 1-4% methanol in methylene chloride gave 4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C29H31N4O3Cl2[(M+H)+]553.1768, observed 553.1773.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[C:25]3=[N:26][C:27](S(C)(=O)=O)=[N:28][CH:29]=[C:24]3[CH2:23][N:22]([C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])C2=O)[CH:15]=1)([CH2:12][CH3:13])[CH2:10][CH3:11])(C)(C)C.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>ClCCl>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[NH2:7][CH2:8][C:9]([C:14]1[CH:15]=[C:16]([N:20]2[C:25]3=[N:26][C:27]([NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[N:28][CH:29]=[C:24]3[CH2:23][N:22]([C:34]3[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=3[Cl:40])[C:53]2=[O:55])[CH:17]=[CH:18][CH:19]=1)([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: Nc1ccccc1
Reactant: CCC(CC)(CNC(=O)OC(C)(C)C)c1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(CN)c1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 140 °C
Yield: 19 %

Procedure:
A mixture of 400 mg (0.62 mmol) of (2-[3-[3-(2,6-dichlorophenyl)-7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-2-ethyl-butyl)-carbamic acid tert-butyl ester and 600 mg (6.5 mmol) of aniline was heated at 140° C. for 45 minutes and cooled. The residue was dissolved in 20 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid. After 10 minutes the mixture was evaporated and the product purified by flash chromatography on silica gel using a gradient elution from dichloromethane/methanol 98:2 to dichloromethane/methanol 95:5. Product-containing fractions were evaporated and the residue dissolved in 4 ml of dichloromethane. The product was precipitated by the addition of pentane and subsequently filtered and dried to give 65 mg (19%) of 1-[3-(1-aminomethyl-1-ethyl-propyl)-phenyl]-3-(2,6-dichloro-phenyl)-7-phenylamino-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one trifluoroacetate as a white solid of melting point 232° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.[C:16](=[O:19])([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.ICI>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:19][CH2:16][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH2:15])=[N:12][O:13][N:14]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccc(F)cc1
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ICI
Product: Nc1nonc1-c1nc2ccccc2n1COc1ccc(F)cc1

Procedure:
To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g, 0.497 mmol) is added potassium carbonate (0.172 g, 1.24 mmol) followed by 4-fluorophenol (0.0557 g, 0.497 mmol) and diiodomethane (0.133 g, 0.497 mmol). The mixture is stirred over night. Evaporation of the solvent under reduced pressure and partitioning of the resulting residue between water and ethyl acetate followed by drying of the organic solution over sodium sulphate and chromatography of the residue gives the title compound as a colorless solid, m.p. 155-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: COc1cccc(C(=O)O)n1
Reactant: Nc1nnn[nH]1
Product: COc1cccc(C(=O)Nc2nnn[nH]2)n1
Yield: 46.4 %

Procedure:
0.48 g of 6-methoxy-2-pyridinecarboxylic acid, 0.51 g of N,N'-carbonyldiimidazole and 0.29 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide, water and ethanol, whereby 0.32 g of N-(5-tetrazolyl)-6-methoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]>Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N1CCOCC1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: CC1COCCN1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A solution of 4-chloro-N-[5-chloro-2-(3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (40 mg) in 3 mL HCl (4M in dioxane) and water (1 mL) was refluxed for 2 h. Upon Cooling to room temperature, the mixture was concentrated and the residue was purified via preparative TLC (50% EtOAc in hexane) to afford 21 mg of 4-chloro-N-[5-chloro-2-(3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS m/z: 498.0 (M+H).
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH:41]=O)=[CH:28][CH:27]=1.[CH3:43][C:44]1[O:48][N:47]=[CH:46][N:45]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH2:41][C:46]2[N:45]=[C:44]([CH3:43])[O:48][N:47]=2)=[CH:30][CH:31]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cc1ncno1
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cc1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 5-methyl-1,2,4-oxadiazole. M/e+ 325 for C17H14ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=6.9 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.23 (m, 1H), 6.88 (t, J=6.9 Hz, 1H), 4.42 (d, J=0.7 Hz, 2H), 2.56 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[C:7]3[N:8]([C:11]([CH2:14][CH3:15])=[N:12][N:13]=3)C=[N:10][C:5]=2[S:4][CH:3]=1.CNCCN>CO.[Cl-].[NH4+]>[Cl:1][C:2]1[C:6]([C:7]2[NH:13][N:12]=[C:11]([CH2:14][CH3:15])[N:8]=2)=[C:5]([NH2:10])[S:4][CH:3]=1
Reactant: CCc1nnc2c3c(Cl)csc3ncn12
Agent: CNCCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCc1n[nH]c(-c2c(Cl)csc2N)n1
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
9-Chloro-3-ethylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (20 mg, 83.8 umol) and N-methylethane-1,2-diamine (0.05 ml, 5.67 umol) in methanol (2 ml) was placed into a preheated oil bath at 60° C. After stirring for 15 min, the solution was diluted with saturated ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 18 mg (94% yield) of 4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine as a brown solid. Method [8] Retention time 2.63 min by HPLC (M+229 and 231).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][C@H:21](OS(C)(=O)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1>>[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[CH:21]1[CH2:22][CH2:23][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([N:3]3[CH2:4][CH2:5][C:6]4([CH2:7][CH2:8][O:9][CH2:10][CH2:11]4)[C:2]3=[O:1])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Reactant: C[C@H]1CCCCN1
Product: C[C@H]1CCCCN1C1CCC(c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 9 by condensing cis-methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and (S)-2-methyl-piperidine.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][C:17]([CH:19]([C:31]([F:34])([F:33])[F:32])[CH2:20][NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])=O>CN(C=O)C>[C:25]1([N:24]2[C:17](=[O:16])[CH:19]([C:31]([F:34])([F:33])[F:32])[CH2:20][NH:21][C:22]2=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NCC(C(=O)O)C(F)(F)F)Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1c1ccccc1
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A solution of DCC (206 mg; 1.0 mmole) in DMF (0.5 ml) was added dropwise to a solution of 1-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)-3-phenylurea (276 mg; 1.0 mmole) obtained above in DMF (1 ml), and the mixture was stirred for 1 hour. The precipitated solid was filtered off, and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel (ethyl acetate:chloroform=1:3) to give 120 mg (yield: 47%) of 3-phenyl-5-trifluoromethyl-5,6-dihydrouracil. m.p.: 215°-216° C.