Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[CH3:32][O-:33].[Na+].O>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[C:7]([C:8]#[N:9])=[C:2]([O:33][CH3:32])[N:3]=3)[N:21]=2)=[CH:26][CH:27]=1
Reactant: C[O-]
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(N2CCCCC2)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100.0 mg (0.21 mmol) of the compound from Example 4A are initially charged in 2 ml of dry methanol. 12.2 mg (0.23 mmol) of sodium methoxide are added to this solution, and the mixture is stirred at +65° C. for 20 h. After cooling to RT the reaction mixture is stirred into 2 ml of water and stirred at RT for 1 h. The precipitate that is formed is filtered off with suction and washed with 1 ml of cold water. Purification is carried out by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:22][CH2:23][C:24]([NH2:26])=[NH:25])[C:5]([C:7]1[NH:8][CH:9]=[C:10]([N:12]([CH3:21])[C:13]([C:15]2[NH:16][CH:17]=[C:18]([NH2:20])[CH:19]=2)=[O:14])[CH:11]=1)=[O:6].C(N(C(C)C)CC)(C)C.[Cl:36]C1C=C(Cl)C(Cl)=CC=1[CH2:45][N:46]([N:50]=[O:51])[C:47](=O)[O-:48]>CN(C=O)C>[ClH:36].[CH3:3][N:4]([CH2:22][CH2:23][C:24]([NH2:26])=[NH:25])[C:5]([C:7]1[NH:8][CH:9]=[C:10]([N:12]([CH3:21])[C:13]([C:15]2[NH:16][CH:17]=[C:18]([NH:20][C:47]([N:46]([CH3:45])[N:50]=[O:51])=[O:48])[CH:19]=2)=[O:14])[CH:11]=1)=[O:6]
Reactant: CN(CCC(=N)N)C(=O)c1cc(N(C)C(=O)c2cc(N)c[nH]2)c[nH]1
Reactant: O=NN(Cc1cc(Cl)c(Cl)cc1Cl)C(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC(=N)N)C(=O)c1cc(N(C)C(=O)c2cc(NC(=O)N(C)N=O)c[nH]2)c[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To an ice-cooled solution of β-[N-methyl-4-(N-methyl-4-aminopyrrole-2-carboxamido)pyrrole-2-carboxamido]propionamidine dihydrochloride (0.404 g) in 5 ml of DMF and 320 mg of 2,4,5-trichlorophenyl-N-methyl-N-nitrosocarbamate [prepared according to J. Med. Chem. 25, 178 (1982)], a solution of diisopropylethylamine (0.164 ml) in 8 ml of DMF was added dropwise. The resulting solution was stirred 1 hour at 0° C. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography to yield 251 mg of β-[N-methyl-4-[N-methyl-4-(3 -methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[Mg]Br>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:28]3[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=3[CH3:26])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(C)c([Mg]Br)c1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 2,5-dimethylphenylmagnesium bromide. Yield: 57 mg of a white solid. LC-MSD, m/z for C24H19BrN2O2 [M+H]+=447.0, 449.0; HPLC retention time: 2.7 min.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].O.[NH2:14][NH2:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:7])[NH:14][NH:15][C:5]2=[O:6]
Reactant: NN
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c(Cl)cccc12
Temperature: 125 °C

Procedure:
3-Chloro-phthalic anhydride (5a, purchased from TCI) (10 g, 54.95 mmol) was dissolved in glacial acetic acid (100 mL), and hydrazine hydrate (20 mL) was added dropwise at 0° C., and then refluxed for two hours at 125° C. When the reaction was completed, the solution was cooled down to room temperature, filtrated, and washed with water until the filtrate pH 6.0, and then dried to give 5-chloro-2,3-dihydrophthalazin-1,4-dione (5b), 10.08 g white solid (yield 93%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[CH2:14]=O.CO.[BH4-].[Na+]>O>[CH3:14][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
In a dried reaction flask, (R)-tert-butyl pyrrolidin-3-ylcarbamate (5.774 g, 31.0 mmol) and formaldehyde solution (37%, 6.82 mL) were dissolved into methanol (124 mL) under a nitrogen protection. The mixture was stirred at room temperature for 1 hr. Sodium borohydride (3.518 g, 93.0 mmol) was added in portion under an ice bath. The mixture was stirred at room temperature for 3 hr. Water was added and the solution was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to produce a white solid (3.685 g) in 59.4% yield.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:14]([NH2:22])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=C[CH:16]=1.Cl.C(Cl)C1C=CC=NC=1>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:16]([C:15]3[CH:14]=[N:22][CH:18]=[CH:19][CH:20]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Agent: Cl
Agent: ClCc1cccnc1
Product: COc1ccc2c(O)nc(-c3cccnc3)nc2c1C
Yield: 92 %

Procedure:
The general procedure described in Example 10 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative and nicotinyl chloride hydrochloride as acid chloride, which gave the title compound (2.5 g, 92%), [M+H]=268.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].O1CCOCC1.[Br:18]N1C(=O)CCC1=O>O>[Br:18][C:3]1[C:2]([OH:1])=[C:9]([O:10][CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C=O)cc1O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C=O)c(Br)c1O
Reaction time: 0.5 h
Yield: 75 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (200 g, 1.31 mol), dioxane (1000 ml) and water (400 ml) were mixed, and N-bromosuccinimide (245.7 g, 1.38 mol) was added over 10 minutes. After 60 and 70 minutes, N-bromosuccinimide was further added in an amount of 16.4 g (92.1 mmol) and 7.02 g (39.4 mmol), respectively, and the mixture was further stirred for 30 minutes. Water (1600 ml) was added, and the precipitated crystals were collected by filtration. The crystals were washed with water (1000 ml) to give 2-bromo-3-hydroxy-4-methoxybenzaldehyde (227.1 g, 74.8%) as pale-red crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C.C(N(C(C)C)C(C)C)C.O>O1CCCC1>[C:35]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:34])[CH2:36][OH:37]
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CO)Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[4-(trifluoromethyl)phenyl]benzamide (215 mg, 0.50 mmol) produced in Example A25(v), 2-chloro-2-oxoethyl acetate (273 mg, 2.00 mmol) and N-ethyl-N-isopropylpropane-2-amine (518 mg, 4.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (140 mg, 57%) as a pale-yellow solid.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C1COCC1.Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>CCN(CC)CC>[CH:34]([O:33][C:31]([N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[S:15][CH:16]=[C:12]([CH2:11][O:10][C:9]3[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:24][CH:23]=3)[N:13]=2)[CH2:18][CH2:19]1)=[O:32])([CH3:36])[CH3:35]
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3CCNCC3)n2)cc1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the HCl salt (Intermediate 3, 43 mg, ˜0.12 mmol) of 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine was added 3 mL of THF, followed by isopropyl chloroformate (1.0 M solution in toluene, 0.15 mL, 0.15 mmol) and Et3N (0.05 mL). The resulting mixture was stirred at room temperature for 2 hours, and then partitioned between EtOAc and H2O. After concentration of the organic layer in vacuo, the residue was purified by silica gel column chromatography with EtOAc/hexanes (40-70%) to give the desired product. 1H NMR (CDCl3): δ 7.86 (2H, d, J=9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J=9.0 Hz), 5.22 (2H, s), 4.92 (1H, m), 4.24 (2H, m), 3.17 (1H, m), 3.03 (3H, s), 2.90 (2H, m), 2.10 (2H, m), 1.72 (2H, m), 1.23 (6H, d, J=6.4 Hz).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].NC1C(Br)=[N:12][CH:11]=[C:10](Br)[N:9]=1.[CH2:16]([N:18](CC)CC)[CH3:17]>O1CCCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]1[C:6]([NH:18][C:16]#[CH:17])=[N:12][CH:11]=[C:10]([Si:2]([CH3:4])([CH3:3])[CH3:1])[N:9]=1
Reactant: CCN(CC)CC
Reactant: C#C[Si](C)(C)C
Reactant: Nc1nc(Br)cnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CNc1ncc([Si](C)(C)C)nc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 64 h
Yield: 82.7 %

Procedure:
Trimethylsilylacetylene (11.1 mL, 80 mmol) was added to a solution of 2-amino-3,6-dibromopyrazine (5.06 g, 20 mmol), Pd(PPh3)2Cl2 (0.140 g, 0.20 mmol), triethylamine (11.4 mL, 80 mmol) and copper(I) iodide (0.114 g, 0.60 mmol) in 50 mL of tetrahydrofuran at 0-5° C. The reaction mixture was allowed to warm to RT and stirred for 64 h. Additional trimethylsilylacetylene (5.6 mL, 40 mmol), Pd(PPh3)2Cl2 (0.140 g, 0.20 mmol) and copper(I) iodide (0.114 g, 0.60 mmol) were added, and the mixture was stirred at 50° C. for 22 h then allowed to cool to RT. The mixture was diluted with 200 mL of ethyl acetate and 200 mL of hexanes, then sequentially washed with three 200 mL portions of water and 200 mL of a sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated to a residue. Silica gel chromatography (0->25% EtOAc/hexanes) afforded 4.36 g (76%) of 3,5-bis-trimethylsilanylethynyl-pyrazin-2-ylamine as a brown oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:30][CH:31]1[CH2:45][C:34]2[C:35]3[NH:36][C:37](=[O:44])[C:38](=[O:43])[NH:39][C:40]=3[CH:41]=[CH:42][C:33]=2[CH2:32]1>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:30][CH:31]2[CH2:45][C:34]3[C:35]4[NH:36][C:37](=[O:44])[C:38](=[O:43])[NH:39][C:40]=4[CH:41]=[CH:42][C:33]=3[CH2:32]2)[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC2Cc3ccc4[nH]c(=O)c(=O)[nH]c4c3C2)CC1
Temperature: 80 °C
Yield: 70 %

Procedure:
A mixture of N-Boc-piperidine-4-carboxylic acid (0.23 g, 1 mmol) and 1,1'-carbonyldiimidazole (0.16 g, 1 mmol) in tetrahydrofuran (5 mL) was heated at 80° C. for 15 min. After cooling, it was added to a solution of 8-amino-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione hydrochloride (0.11 g, 0.5 mmol) and the mixture was heated at 70° C. for 2 days. After filtration to remove precipitate, the filtrate was evaporated and the residue suspended in water. The resulting solid was collected by filtration, washed with diethyl and dried in vacuo (0.15 g, 70% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:19]1([C:25]#[C:26][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:10]#[C:8][C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)=[CH:14][CH:13]=3)=[O:11])=[O:9])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(C(=O)c1ccc(C#Cc2ccccc2)cc1)c1ccc(C#Cc2ccccc2)cc1

Procedure:
A solution of 4,4'-dibromobenzil (15.8 g, 0.0431 mol), phenylacetylene (5.06 g, 0.0495 mol), (PPh3)2PdCl2 (0.151 g, 0.0002 mol) and CuI (0.820 g, 0.0043 mol) in diethylamine (150 mL) is heated at reflux overnight. The reaction mixture is concentrated to dryness, then taken up in CH2Cl2 (150 mL), washed with 1 M HCl, 10 percent Na2CO3 /H2O, brine and dried (Na2SO4), then concentrated. Crystallization from 2-propanol gives 7.92 g (45 percent) as a light tan solid, mp 168° C. to 170° C. 1H NMR (CDCl3) δ 7.97 (d, J=8.2 Hz, 4H), 7.64 (d, J=8.2 Hz, 4H), 7.55 (m, 4H), 7.37 (m, 6H); 13C NMR (CDCl3) δ193.03, 132.46, 132.03, 131.82, 130.21, 129.84, 129.06, 128.47, 122.37, 94.28, 88.55.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22]>C(#N)C.O.Cl>[CH2:19]([N:23]([C:6]1[C:5]([CH2:9][CH3:10])=[C:4]([Cl:11])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22]
Reactant: CCc1c(Cl)nc(C)nc1Cl
Reactant: CCCCNCC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCN(CC)c1nc(C)nc(Cl)c1CC
Yield: 88.3 %

Procedure:
A mixture of 2-methyl-5-ethyl-4,6-dichloro-pyrimidine (1.009 g, 5.28 mmol) in 5 ml of acetonitrile was treated with triethylamine (0.571 g, 5.65 mmol) and N-butyl-ethyl-amine (0.540 g, 5.31 mmol) and heated at reflux overnight. The mixture was diluted with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate and washed with brine, dried and concentrated to give 1.193 g of yellow oil which was purified through silica gel column chromatography to give 1.157 g (86%) of title compound as a yellow oil. 1H NMR (CDCl3) δ 0.90 (t, 3H), 1.13 (t, 3H), 1.18 (t, 3H), 1.1–1.33 (m, 2H), 1.4–1.6 (m, 2h), 2.41 (s, 3H), 2.62 (q, 2H), 3.25–3.48 (m, 4H) ppm.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]I)C.C(OC(=O)CCCCCCI)C.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(Cl)(=O)C1C=CC=CC=1.[NH2:44][OH:45].Cl>C(N(CC)CC)C>[OH:45][NH:44][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCCCCI
Reactant: NO
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CCOC(=O)CCCCCCI
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc(C(=O)CCCCCC(=O)NO)cc1
Yield: 54 %

Procedure:
Following the procedure described in Example 18, step 1, 2, 3, but substituting respectively ethyl-6-iodohexanoate for ethyl-7-iodoheptanoate and 4-methoxybenzoyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 110 in 54% yield. 1H NMR (300 MHz, 20% CD3OD in CDCl3): δ 7.86 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.87 (t, J=6.6 Hz, 2H), 2.07 (br t, 2H), 1.62 (m, 4H), 1.34 (m, 2H). 13C NMR (75 MHz, 20% CD3OD in CDCl3): δ 23.68, 24.96, 28.32, 32.28, 37.63, 55.14, 113.49, 129.48, 130.13, 163.35, 171.06, 199.81.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:16]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:11])=[O:10].ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[N:16]=2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:11])(=[O:36])=[O:10]
Reactant: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1S(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)cs2)ccc1S(C)(=O)=O
Reaction time: 1 h
Yield: 16.6 %

Procedure:
In 100 ml of chloroform-ethanol was suspended 2.9 g of 2-(3-methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole. Under ice-cooling, 1.72 g of m-chloroperbenzoic acid (80%) was added in small portions and the mixture was stirred for 1 hour. Then, the mixture was returned to room temperature and stirred overnight. The resulting crystals were collected by filtration, washed with ethanol and diethyl ether, and dried. Recrystallization from dimethylformamide-water to obtain 0.50 g of 2-(3-methoxy-4-methylsulfonylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as a white powder.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[N:8]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCO)CCC2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2RS,5RS)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyric acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and purification by column chromatography yielded the title compound as a colorless oil, MS: m/e=392.2 (M+H+).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:31])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=4)[N:23]=[C:17]3[N:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:31])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:27]=[CH:28][CH:29]=4)[N:23]=[C:17]3[N:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(Br)c3)nc2n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(-c4ccccc4)c3)nc2n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of argon, in a 25 mL round-bottomed flask, 4-(azetidine-1-carbonyl)-N-(2-(3-bromophenyl)imidazo[1,2-a]pyrimidin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (85 mg, 177 μmol, Eq: 1.00, example 117), phenylboronic acid (43.2 mg, 354 μmol, Eq: 2), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (14.5 mg, 17.7 μmol, Eq: 0.1) and potassium carbonate (73.4 mg, 531 μmol, Eq: 3) were combined with DMF (2 ml) and water (0.2 ml) to give a brown solution. The reaction was stirred for 1 h at 100° C. The HPLC-MS showed complete conversion. The reaction mixture was poured into 20 mL water and extracted with EtOAc (2×25 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. After the addition of 2 ml Methanol the desired product crystallized. The suspension was filtered off and washed with 0.5 ml MeOH. The residual solvent was removed under vacuum. The title compound was obtained as a light brown solid (42 mg, 49.7%). 4-(Azetidine-1-carbonyl)-N-(2-(3-bromophenyl)imidazo[1,2-a]pyrimidin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide was prepared in analogy to example 29, using 2-(3-bromo-phenyl)-imidazo[1,2-a]pyrimidin-7-ylamine in the first step. 2-(3-Bromo-phenyl)-imidazo[1,2-a]pyrimidin-7-ylamine can be prepared in analogy to example 1, step 1, from 2-bromo-1-(3-bromo-phenyl)-ethanone.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:17]1[CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:13]([CH3:12])[CH2:18]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CNc1ccc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 2-methyl-4-(methylamino)benzaldehyde (D93) (0.397 g) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (0.533 g, 2.66 mmol) in 1,2-DCE (35 mL) was added sodium tri(acetoxy)borohydride (0.847 g, 4.00 mmol) and the reaction stirred at room temperature overnight. Saturated aqueous NaHCO3 (30 mL) was added and the mixture was stirred for 4 h. The reaction mixture was extracted with DCM and the organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with ether/petroleum ether gave the title compound as a colourless oil (0.328 g).