Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1.O.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
To a solution of 0.58 g (2.5 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 30 mL anhydrous pyridine was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring for 6 hours in a heat flux condition. After cooling to room temperature, cold water (100 mL) containing HCl (10 mL) was added to the solution, which was then allowed to stand for 30 min to form precipitates. These were separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.70 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 75%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.Br[C:36]1[N:37]=[C:38]([CH3:41])[S:39][CH:40]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[CH3:24][CH:23]1[CH2:22][C:21]2[C:16](=[CH:17][C:18]([C:36]3[N:37]=[C:38]([CH3:41])[S:39][CH:40]=3)=[CH:19][CH:20]=2)[CH2:15][N:14]1[C:12]1[CH:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:9]=[C:10]([NH2:34])[N:11]=1
Reactant: Cc1nc(Br)cs1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cs1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (0.0464 g, 0.100 mmol), 4-bromo-2-methyl-1,3-thiazole (0.0231 g, 0.130 mmol, Frontier, Cat. No. B4559) in 1,4-dioxane (1.0 mL) was stirred at r.t. for 10 min. Potassium carbonate (63.0 mg, 0.456 mmol) in water (0.50 mL) was added to give a deep red solution. The mixture was degassed and refilled with nitrogen three times. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.0 mg, 0.0061 mmol) was added and the mixture was degassed and refilled with nitrogen three times and then heated at 120° C.) (oil bath temperature) for 3 h. After cooling, the mixture was diluted with methanol, and filtered. The filtrate was purified on RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=436.1.
Reaction SMILES: [H-].[Na+].I[CH3:4].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([CH3:4])[C:19]2=[O:27])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Reaction time: 12 h

Procedure:
A mixture of 0.060 g of sodium hydride, 60% oil dispersion, 10 mL of DMF, 0.086 mL of iodomethane, and 0.4 g of 1,3-dihydro-1-(1-tert-butyloxycarbonylpiperidin-4-yl)-2H-benzimidazol-2-one was stirred for 12 h, then partitioned between 100 mL of chloroform and 50 mL of water. The chloroform extracts dried over MgSO4, and concentrated under reduced pressure. Trituration with hexane gave 0.38 g of 1,3-dihydro-1-(1-tert-butyloxycarbonylpiperidin-4-yl)-3-methyl-2H-benzimidazol-2-one as a crystalline solid: 1H NMR (300 MHz, CDCl3) 7.13-7.03 (m, 3H), 6.98 (d, 1H), 4.5 (m, 1H), 4.3 (br m, 2H), 3.4 (s, 3H), 2.85 (m, 4H), 2.3 (m, 2H), 1.8 (d, 2H), 1.5 (s, 91H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26]Br)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][N:3]2[C:4]3=[N:9][C:8]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[CH:7][C:6](=[O:16])[N:5]3[CH2:17][C:2]2([CH3:18])[CH3:1])=[CH:23][CH:22]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CC1(C)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(CCN2c3nc(N4CCOCC4)cc(=O)n3CC2(C)C)cc1

Procedure:
The product is prepared according to the procedure described in Example 1, using 100 mg of 2,2-dimethyl-7-morpholin-4-yl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one and 0.94 ml of 4-methoxyphenethyl bromide, replacing the sodium hydride with caesium carbonate. After purification by silica column chromatography (eluent: dichloromethane/methanol: 98/02), 39 mg of 1-[2-(4-methoxyphenyl)ethyl]-2,2-dimethyl-7-morpholin-4-yl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are obtained, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH:5]([NH2:8])[CH2:6][NH2:7])[CH3:2].[C:15](O)(=O)C.C(N)=N>C(O)C>[N:7]1[CH2:6][CH:5]([CH2:4][N:3]([CH2:1][CH3:2])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:8][CH:15]=1
Reactant: CC(=O)O
Reactant: CCN(CC(N)CN)c1ccccc1
Agent: N=CN
Solvent: CCO
Product: CCN(CC1CN=CN1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
To a solution of rac-N1-ethyl-N1-phenyl-propane-1,2,3-triamine (0.19 g, 1.0 mmol) in ethanol (5 ml) was added formamidine acetate (0.11 g, 1.08 mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated, water (5 ml) was added and the mixture was extracted 3 times with dichloromethane (10 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield an off-white amorphous solid (0.042 g, 21%); MS (ISP): 204.1 ((M+H)+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[C:24]([CH2:25]O)=[CH:23][CH:22]=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:25][C:24]2[C:19]([CH3:18])=[N:20][C:21]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)ccc1C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(C)(C)Oc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1C

Procedure:
In analogy to the procedures described in examples 70B] and 26C], 2-(5-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 70A]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M]) in the presence of triphenylphosphine and di-tert.-butyl azodicarboxylate to give 2-methyl-2-{2-methyl-5-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: Cl.[CH:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][NH:4][N:3]=1.[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12].C(N(C(C)C)CC)(C)C>CO.O>[CH2:11]([NH:13][C:14]([N:3]1[N:4]=[CH:5][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:2]1)=[S:15])[CH3:12]
Reactant: C1=NNCC12CCCC2
Reactant: CCN=C=S
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=S)N1CC2(C=N1)CCCC2
Temperature: 30 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
2,3-Diaza-spiro[4.4]non-1-ene hydrochloride (15.4 g, 95.9 mmol; isolated from reaction of 2,3-diaza-spiro[4.4]non-2-ene, synthesized as described in WO 2008/034863, with HCl in isopropanol/toluene) was taken up in a mixture of 70 mL methanol and 30 mL water. Ethyl isothiocyanate (10.09 g, 115.1 mmol) was added using an addition funnel, and the funnel was rinsed with 40 mL methanol. At 30° C., diisopropylethylamine (14.8 g, 114.5 mmol) was added dropwise over a period of 10 minutes, and the addition funnel was rinsed with 7 mL water. After stirring the reaction mixture for 1 hour at 30° C., the mixture was cooled to 10° C. over a period of 1 hour and subsequently stirred at this temperature for another 2 hours. The precipitate was isolated by filtration, washed twice with 20 mL of a cold 3:1 mixture of methanol and water and dried at 50° C. under reduced pressure to give 16.8 g (83%) of 2,3-diaza-spiro[4.4]non-3-ene-2-carbothioic acid ethylamide as a white to off-white solid. 1H NMR identical to spectrum obtained from material prepared on small scale (vide supra).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11](C2OC=CC=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1.[S:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1>>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11]([C:39]2[CH:40]=[CH:41][S:37][CH:38]=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1
Reactant: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccco1
Reactant: OB(O)c1ccsc1
Product: COc1c(-c2ccsc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 33 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with thiophen-3-yl boronic acid (8.1 mg, 0.063 mmol) as described in Example 63, Part B to give the title compound as an off-solid (8.6 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1H) 7.93 (d, J=2.94 Hz, 1H) 7.87 (d, J=7.72 Hz, 1H) 7.53-7.75 (m, 6H) 7.49 (t, J=6.25 Hz, 1H) 7.39 (d, J=2.57 Hz, 1H) 6.57 (s, 1H) 5.68 (dd, J=7.91, 2.02 Hz, 1H) 4.19 (d, J=5.15 Hz, 2H) 3.47 (s, 2H) 3.21 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[O:16])=[CH:10][CH:9]=1>C(Cl)Cl.C1(N=C=N)CCCCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:23]([C:20]1[S:19][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:4](=[O:6])[CH2:3][O:2][CH3:1])=[CH:13][CH:12]=2)=[N:22][CH:21]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cnc(NC(=O)Cc2ccc(N)cc2)s1
Reactant: COCC(=O)O
Agent: CN(C)c1ccncc1
Agent: N=C=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCC(=O)Nc1ccc(CC(=O)Nc2ncc(C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methoxyacetic acid (41 μl, 0.53 mmol) in CH2Cl2 (1.5 ml), N-cyclohexylcarbodiimide, N′-methyl polystyrene (0.53 g, loading 2 mmol/g, 1.064 mmol), previously washed with CH2Cl2 (5 ml×3), 4-DMAP (0.032 g, 0.266 mmol) and a solution of 2-(4-aminophenyl)-N-(5-isopropyl-1,3-thiazol-2-yl)acetamide (0.076 g, 0.266 mmol) in CH2Cl2/DMF (0.4 ml/10.6 ml) were added. The reaction mixture was maintained under stirring at room temperature for about 72 hours the resin was filtered, washed with CH2Cl2 (10 ml×3), the filtrated combined, washed with water, 5% hydrochloric acid, water, saturated sodium bicarbonate and water, dried and evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][CH2:8][C:9](=O)C(O)=O>C(O)C>[NH:3]1[C:2]2=[N:1][CH:7]=[CH:8][CH:9]=[C:6]2[CH:5]=[N:4]1
Reactant: Nc1cc[nH]n1
Reactant: CCC(=O)C(=O)O
Solvent: CCO
Product: c1cnc2[nH]ncc2c1
Temperature: 80 °C

Procedure:
In an alternative route, R2-aldehyde (II), 3-aminopyrazole (III) and R3-containing methyl pyruvic acid (V) are mixed in ethanol and heated to 50-120° C., preferably 60-100° C. Subsequent oxidization, preferably by exposure to air yields the 1H-Pyrazolo[3,4-b]pyridine acid derivative (VII).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH2:9]>>[Br:8][C:4]1[N:3]=[C:2]([N:3]([CH3:4])[CH2:2][CH2:7][OH:9])[CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: Brc1cccc(Br)n1
Product: CN(CCO)c1cccc(Br)n1

Procedure:
7.45 g of 2,6-dibromopyridine and 12 mL of N-methylethanol were stirred overnight at 140° C. Water was added to the reaction liquid, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. After concentrated under reduced pressure, the residue was purified through silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 3.98 g of the entitled compound as a colorless oily substance.
Reaction SMILES: [O:1]1[CH:3]([C:4]([F:7])([F:6])[F:5])[CH2:2]1.Cl.[CH3:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][N:30]([CH:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[CH:31]=4)=[CH:23][N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:12]=[N:11]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:5][C:4]([F:7])([F:6])[CH:3]([OH:1])[CH2:2][N:35]1[CH2:34][CH2:33][CH:32]([N:30]2[CH:31]=[C:27]([C:24]3[CH:25]=[N:26][C:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([C:13]5[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=5)[CH:16]=4)=[N:22][CH:23]=3)[CH:28]=[N:29]2)[CH2:37][CH2:36]1
Reactant: FC(F)(F)C1CO1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(CC(O)C(F)(F)F)CC5)c4)cn3)c2)cn1
Temperature: 50 °C
Yield: 36.3 %

Procedure:
1,2-Epoxy-3,3,3-trifluoropropane(84 mg; 0.72 mmol; 2.4 eq.) was added to a solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidine (example 1, 200 mg; 0.31 mmol; 1.0 eq.) and DIEA (53 μl; 0.31 mmol; 1.0 eq.) in DMF (4 mL). The reaction mixture was stirred at 50° C. O/N. It was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:EtOAc, gradient from 40:60 to 0:100) afforded the title compound as a beige powder (56 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.59-8.49 (m, 2H), 8.27 (s, 1H), 8.25-8.18 (m, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.75-7.67 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 6.24-6.13 (m, 1H), 4.28-4.08 (m, 2H), 3.90 (s, 3H), 3.12-2.97 (m, 2H), 2.66-2.53 (m, 2H), 2.36-2.17 (m, 2H), 2.12-1.86 (m, 4H). HPLC (Condition A): Rt 2.85 min (purity 98.4%). MS (ESI+): 498.4.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C:13]1[N:14]([CH3:26])[C:15](=[O:25])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:18]=1)C1C=CC=CC=1.[BrH:28]>C(O)(=O)C>[BrH:28].[NH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH3:26])[C:15](=[O:25])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:18]=1
Reactant: Cn1c(CCNC(=O)OCc2ccccc2)nc(-c2ccncn2)cc1=O
Agent: Br
Solvent: CC(=O)O
Product: Cn1c(CCN)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
0.085 g (0.23 mmol) of [2-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-carbamic acid benzyl ester was dissolved in 0.164 g (1.16 mmol) of hydrobromide acid in acetic acid. The resulting mixture was stirred at room temperature for 2 h. The resulting precipitate was filtered, washed with diethyl ether and dried to afford 0.07 g of a yellow compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1>C(#N)C>[Br:25][C:13]1[C:14]([NH2:17])=[N:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[N:12]=1
Reactant: Nc1cnc(C2CCC3(CC2)OCCO3)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(C2CCC3(CC2)OCCO3)nc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-amine (620 mg, 2.64 mmol) was added Acetonitrile (20 mL) and then was added NBS (469 mg, 2.64 mmol) in portions over 2 min. The reaction was stirred at room temperature for 20 min and quenched with saturated sodium bicarbonate solution, and 250 mL of ethyl acetate was added. The aqueous was extracted and the organic layer was washed with saturated sodium bicarbonate, water (2×), saturated salt solution, then dried with sodium sulfate, filtered and concentrated to residue to give 650 mg of the desired product, used as is, (79% yield). LCMS (m/z): 314.1/316.1 (MH+), 0.61 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Ni].C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:9]=1
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CCC(=O)c2ccccc2)cc1

Procedure:
A mixture of 3-(4-nitro-phenyl)-1-phenyl-prop-2-en-1-one (24.9 g, 98.3 mmol), Raney nickel (7.0 g), MeOH (100 mL), and THF (400 mL) was shaken in a hydrogen atmosphere of 51 psi at 20° C. for 18.5 hours. The catalyst was filtered, and the filtrate was concentrated. The residue was recrystallized from 95% EtOH, to give the title compound, m.p. 76-78° C. 1H NMR (CDCl3) δ 2.98 (t, 2 H), 3.25 (t, 2 H), 3.62 (bs, 2 H), 6.65 (d, 2 H), 7.05 (d, 2 H), 7.40-7.61 (m, 3 H), 7.96 (d, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].[F:17][CH:18]([F:25])[CH2:19]OS(C)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:19][CH:18]([F:25])[F:17]
Reactant: CS(=O)(=O)OCC(F)F
Reactant: Oc1c(Cl)cc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)COc1c(Cl)cc(Cl)cc1Br
Yield: 78.6 %

Procedure:
To a solution of 2-bromo-4,6-dichloro-phenol (14.6 g, 60.3 mmol) (intermediate B-1 [A]) in DMF (10 ml) were added K2CO3 (16.53 g, 120.6 mmol) and methanesulfonic acid 2,2-difluoro-ethyl ester (10.7 g, 66.4 mmol) (intermediate B-1 [B]) and the mixture was heated to reflux for 16 h. The DMF was then evaporated in vacuo and the resulting residue was dissolved in EtOAc (300 ml). This solution was washed two times with water, with brine, dried with Na2SO4 and evaporated. The remaining crude product was purified by chromatography (silica gel; hexane) and the title compound (14.5 g, 79%) was obtained as white solid. MS: 304 (M+, 1Br).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26]>CN1CCCC1=O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:27])([NH2:28])[CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(N)CN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.6 mL, 47 mmol) was added slowly to a solution of 2,4-dichloro-3-nitroquinoline (10.0 g, 41.1 mmol) in anhydrous 1-methyl-2-pyrrolidinone (40 mL). The reaction mixture was cooled to 0° C. with an ice bath. A solution of 1,2-diamino-2-methylpropane (4.1 g, 47.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (5 mL) was added dropwise over a period of 15 minutes while maintaining the temperature of the reaction mixture below 4° C. After the addition was completed the ice bath was removed and the reaction mixture was allowed to stir at ambient temperature for 4 hours. The reaction mixture was slowly poured into vigorously stirred warm water (300 mL). The resulting suspension was stirred for 1 hour and then cooled to 13° C. by adding ice. The solid was isolated by filtration and then washed with cold water until the filtrate was clear to provide 12.1 g of N1-(2-chloro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine as a damp yellow solid.
Reaction SMILES: [O:1]([CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[C:9]([Cl:12])([Cl:11])[Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]=[C:25]=[O:26].O>CC(C)=O.C(N(CC)CC)C>[O:1]([CH:8]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:25](=[O:26])[NH:24][CH3:23])[C:9]([Cl:10])([Cl:11])[Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(Oc1ccccc1)C(Cl)(Cl)Cl)c1ccccc1O
Reactant: CN=C=O
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccccc1C(=O)NC(Oc1ccccc1)C(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 36.3 %

Procedure:
10 g of N-(1'-phenoxy-2',2',2'-trichloroethyl)-2-hydroxybenzamide and 1.8 g of methyl isocyanate were dissolved in 150 mml of acetone. Two or three drops of triethylamine were added to the solution under stirring. After allowing to stand overnight, the reaction mixture was poured into water and the crystals which thus resulted were recrystallized from methanol to obtain 4.2 g of N-(1'-phenoxy-2',2',2'-trichloroethyl)-2-methylcarbamoyloxybenzamide as white crystals. Melting point: 138°-141° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12]/[C:13](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)/[CH2:14][CH2:15][CH2:16][OH:17].C(OCC)C>ClCCl>[CH3:12]/[C:13](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)/[CH2:14][CH2:15][CH:16]=[O:17]
Reactant: C/C(=C\c1ccc(C)cc1)CCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(=C\c1ccc(C)cc1)CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
Solid pyridinium chlorochromate (13.2 g, 0.06 mol) was added in one portion to a pre-cooled (−10° C.) solution of (4E)-4-Methyl-5-(4-methylphenyl)-4-penten-1-ol (9.88 g, 0.052 mol) in dry dichloromethane (250 ml) under nitrogen. After 30 minutes, the reaction was warmed up to room temperature. After 1 hour, diethyl ether (700 ml) was added to the reaction. After stirring for 10 minutes, the reaction was filtered through silica gel, rinsing with diethyl ether. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 10:1) followed by bulb-to-bulb distillation (100° C./0.001 mbar). 3.55 g (yield=36%) of the desired product were obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([NH:23][S:24]([CH2:27][CH2:28][NH2:29])(=[O:26])=[O:25])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([NH:23][S:24]([CH2:27][CH2:28][NH:29][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:26])=[O:25])[CH2:21][CH2:22]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NCCS(=O)(=O)NN1CCN(Cc2ccccc2)CC1
Product: O=C(NCCS(=O)(=O)NN1CCN(Cc2ccccc2)CC1)c1ccc(Cl)s1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [2-(4-benzyl-piperazin-1-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 5 iii) starting from 100 mg (1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 183 mg (0.61 mmol) 2-amino-ethanesulfonic acid (4-benzyl-piperazin-1-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [2-(4-benzyl-piperazin-1-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material. Yield: 41 mg