Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([S:11]([CH2:14][CH2:15][CH2:16][O:17][Si](C(C)C)(C(C)C)C(C)C)(=[O:13])=[O:12])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[CH3:34])[N:3]=1.CC1(C)C(C)(C)OB([C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.C(Cl)Cl.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.C(O)C.O.COCCOC.CN(C=O)C>[NH2:47][C:46]1[CH:48]=[CH:49][C:43]([C:2]2[N:7]=[C:6]([C:8]([S:11]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:12])=[O:13])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:3]=2)=[CH:44][CH:45]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)[Si](OCCCS(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(Cl)n1)(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)CCCO)nc(-c2ccc(N)cc2)n1
Temperature: 90 °C
Reaction time: 5 h
Yield: 61.5 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.176 g, 0.25 mmol) was added to 3-[2-[2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]propan-2-ylsulfonyl]propoxy-tri(propan-2-yl)silane (2 g, 3.74 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.107 g, 5.05 mmol) and 2M sodium carbonate solution (3 mL, 6.00 mmol) in a solvent mixture of DMF (5 mL), DME (8 mL), water (2 mL) and ethanol (1.5 mL) and the resulting mixture stirred at 90° C. for 5 hours, under an inert atmosphere. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (2×100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford a residue which was dissolved in DCM (100 mL), and tetrabutylammonium fluoride (18.72 mL, 18.72 mmol) added. The mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with a saturated aqueous solution of ammonium chloride (50 mL) and water (2×100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 100% ethyl acetate in isohexane then 4% methanol in ethyl acetate, to give a material which was further purified by ion exchange chromatography using an SCX column, eluting with 7N ammonia in methanol, to give the desired material as a beige solid (1.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[CH2:9]1[CH2:13]O[CH2:11][CH2:10]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:9]1[C:13]2[C:7](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:11]=[CH:10]1
Reactant: ClCc1ccccn1
Reactant: C1CCOC1
Product: C1=CC(Cc2ccccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium indenyl (3.0 g, 24.6 mmol) was suspended in THF (20 mL) in a 300 cc Schlenk flask and cooled in a dry ice acetone bath. Into this flask was added slowly a THF (15 mL) solution of 2-picolyl chloride (3.13 g, 24.6 mmol). The resulting suspension was warmed to room temperature gradually and stirred overnight. Solvent was removed under vacuum and the resulting residue was extracted with ether (2×30 mL) and filtered, removal of ether via vacuum resulting in a dark-brown oil (yield, 4.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:23]([O-])=O)[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].[H][H]>CO.[C].[Pd]>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: [H][H]
Reactant: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc([N+](=O)[O-])cc4c3c2C1=O
Agent: [Pd]
Solvent: CO
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc(N)cc4c3c2C1=O
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
In 30 ml of methanol was dissolved 60 mg of N-(2-dimethylaminoethyl)-6-nitrocarbazole-3,4-dicarboximide. Thereto was added 30 mg of 5% palladium-carbon. The mixture was subjected to catalytic reduction in a hydrogen atmosphere at room temperature at atmospheric pressure for 5 hours. Thereto was added Celite, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was mixed with diethyl ether, and the mixture was stirred for 10 minutes. The resulting crystals were collected by filtration and dried to obtain 30 mg (yield: 55%) of N-(2-dimethylaminoethyl)-6-aminocarbazole-3,4-dicarboximide as orange crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11]O.C1(C)C=CC=CC=1.O>CC(CC(C)=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)#[N:11]
Reactant: NO
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: CC(=O)CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(O)cc1
Yield: 91 %

Procedure:
503 Milligrams of p-hydroxybenzaldehyde, 323 mg of hydroxylamine hydrochloride and 10 ml of toluene were introduced to a flask of 50 ml, equipped with a Dean-Stark dehydrating apparatus. The reaction mixture was stirred under reflux for 4 hrs. After the reaction finished, water and MIBK were added to the reaction mixture and mixed, followed by separation into two layers. Aqueous layer was extracted again by MIBK and the extract was combined with toluene layer first separated and subjected to the analysis of the products by gaschromatography [5% PEG 20M, 0.5 m, 190° C. (4 minutes retention)→220° C. (5 minutes retention), 2° C./min]. From the results, it was found that the conversion of p-hydroxybenzaldehyde was 100% and 449 mg (91% yield) of p-cyanophenol and 6.1 mg (1.1% yield) of p-hydroxybenzaldoxime were produced.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.Br[C:20]1[C:21]2[C:22]3[CH:36]=[CH:35][S:34][C:23]=3[C:24](=[O:33])[NH:25][C:26]=2[C:27]([CH3:32])=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:31][O:30][C:29]1[CH:28]=[C:27]([CH3:32])[C:26]2[NH:25][C:24](=[O:33])[C:23]3[S:34][CH:35]=[CH:36][C:22]=3[C:21]=2[C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:18])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(Br)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 54.3 %

Procedure:
Following General Procedure E, (R)-tert-butyl 2-(4-bromophenyl)propylcarbamate (60 mg, 0.20 mmol) was reacted with 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (60 mg, 0.20 mmol) to afford the desired product (52 mg, 62%) as a brown solid: ESI MS m/z 479 [C27H30N2O4S]+
Reaction SMILES: [CH2:1]([N:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[N:17]=[C:16]([CH2:18][CH2:19][C:20]2([CH3:28])[O:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][O:21]2)[N:15]=[C:14]2[C:10]=1[N:11]=[C:12](Br)[N:13]2[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:44]1[CH:48]=[CH:47][N:46]=[N:45]1>CN(C=O)C>[CH2:1]([N:8]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]1[N:17]=[C:16]([CH2:18][CH2:19][C:20]2([CH3:28])[O:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][O:21]2)[N:15]=[C:14]2[C:10]=1[N:11]=[C:12]([N:45]1[N:46]=[CH:47][CH:48]=[N:44]1)[N:13]2[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]nn1
Reactant: Cn1c(Br)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(CCC3(C)OCC(C)(C)CO3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(-n2nccn2)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(CCC3(C)OCC(C)(C)CO3)nc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl-{8-bromo-9-methyl-2-[2-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-ethyl]-9H-purin-6-yl}amine (1.9 g, 3.50 mmol) in anhydrous DMF (20 ml) were added K2CO3 (0.72 g, 5.2 mmol) followed by 1H-1,2,3-triazole (362 mg, 5.2 mmol). The mixture was stirred overnight at 100° C. The solvent was evaporated under reduced pressure to give a residue that was purified by flash chromatography (DCM/MeOH: 93/7).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C1(C)C=CC=CC=1.[C:27]1([C@@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([C@@H:33]([NH:35][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][N:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3cnccc32)n1
Reactant: C[C@H](N)c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cnccc32)n1)c1ccccc1
Temperature: 100 °C

Procedure:
To a flask containing 2-methanesulfonyl-4-[5-azabenzimidazol-1-yl]pyrimidine (33.8 mg) was added toluene (0.25 mL) and (S)-1-phenylethylamine (0.25 mL). The mixture was warmed to 100° C. The 2-methanesulfonyl-4-[5-azabenzimidazol-1-yl]pyrimidine did not dissolve so DMF (0.25 mL) was added and the mixture was maintained at 100° C. overnight. The reaction mixture was cooled and the solvents were removed under reduced pressure. The product was purified by preparative thin layer chromatography (eluted with 7% MeOH in CH2Cl2) to give 28 mg of the title compound. 1H NMR (500 MHz, CD2Cl2): δ 1.63 (3H, d, J=7 Hz), 5.18, (1H, br s), 5.96 (1H, br s), 6.78 (1H, d, J=5.5 Hz), 7.28 (1H, t, J=7 Hz), 7.38 (2H, t, J=7 Hz), 7.46 (2H, m), 7.62 (1H, br), 8.43 (1H, d, J=5 Hz), 8.4-8.6 (2H, m), 9.07 (1H, s).
Reaction SMILES: C(N(CCCC)CCCC)CCC.C(O)=O.[Br:17][C:18]1[S:22][C:21]([C:23]([CH2:25][O:26][C:27]2[C:36](I)=[CH:35][C:34]3[C:33]([CH3:39])([CH3:38])[CH2:32][CH2:31][C:30]([CH3:41])([CH3:40])[C:29]=3[CH:28]=2)=[CH2:24])=[CH:20][CH:19]=1>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Br:17][C:18]1[S:22][C:21]([C:23]2([CH3:24])[CH2:25][O:26][C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:36]2=3)[C:33]([CH3:39])([CH3:38])[CH2:32][CH2:31][C:30]4([CH3:41])[CH3:40])=[CH:20][CH:19]=1
Reactant: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: CC#N
Solvent: CCCCN(CCCC)CCCC
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OCC3(C)c1ccc(Br)s1
Temperature: 60 °C

Procedure:
A mixture of tributylamine (2.66 ml, 18.39 mmol), palladium diacetate (53 mg, 0.24 mmol), formic acid (0.205 ml, 5.32 mmol) and 5-bromo-2-[1-(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxymethyl)-vinyl]thiophene (2.57 mg, 4.84 mmol) in acetonitrile (75 ml) was heated at 60° C. for 4 h. The reaction medium was concentrated in a rotary evaporator under vacuum at 40° C. Water and ethyl ether were added. After decantation, the organic phase was washed twice with 20 ml of water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:15][CH2:14][C:13](=[CH2:12])[CH2:5][OH:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=C(CO)COCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Sodium hydride (from 55-60% oil dispersion (0.52 g) washed with pentane (3×3 ml)), dry dimethylformamide (20 ml), and 2-metyylenepropane-1,3-diol (1.0 g) were mixed. After 1 hour when H2 -evolution had ceased 1-chloro-6-(triphenylmethoxy)hexane (4.2 g) was added, and the mixture was stirred for 3 hours at 85° C. After cooling water (20 ml) was carefully added, and the mixture was extracted with ether (2×100 ml). The ether extracts were washed with water (100 ml), dried over magnesium sulfate and evaporated to dryness in vacuo. The product was purified through a column of silica gel 60 (70-230 mesh, 40 g) eluting with ether. Futher purification was achieved by chromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/pentane 1:2 followed by ether/pentane 1:1 as eluent.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([CH2:19]C1C=CC=CC=1)[CH:6]([C:11]1([CH:17]=[O:18])[S:16][CH2:15][CH2:14][CH2:13][S:12]1)[C:7]([F:10])([F:9])[F:8])C.[OH-].[Na+]>>[CH:17]([C:11]1([CH:6]([C:7]([F:8])([F:9])[F:10])[CH:5]([CH3:19])[C:4]([OH:26])=[O:3])[S:12][CH2:13][CH2:14][CH2:15][S:16]1)=[O:18]
Reactant: CCOC(=O)C(Cc1ccccc1)C(C(F)(F)F)C1(C=O)SCCCS1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)C(C(F)(F)F)C1(C=O)SCCCS1

Procedure:
A solution of 3 g of the ethyl ester of Example 2, paragraph 1, in 40 ml ofethanol is treated with 25% aqueous sodium hydroxide for about 15 hours at 25° C. The mixture is then acidified and extracted well with chloroform. The organic phase is dried and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (810 mg, 1.31 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 4 mL). The reaction was stirred at room temperature for 3 h and concentrated. The crude trifluoroacetic acid salt was loaded onto a strong cation exchange cartridge in methanol and washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. The crude amine was dissolved in dichloromethane (5 mL) and treated with di-tert-butyl dicarbonate (572 mg, 2.62 mmol) and triethylamine (0.27 mL, 2.0 mmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (30% ethyl acetate/hexanes) to give 400 mg (63%) as a viscous oil. 1H-NMR (CDCl3, 500 MHz) δ 9.90 (s, 1H), 7.89 (s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.22-7.25 (m, 2H), 7.02-7.06 (m, 2H), 6.96 (d, J=1.8 Hz, 1H, 1H), 4.49 (q, J=6.7 Hz, 1H), 3.62-3.72 (m, 2H), 3.23-3.36 (m, 2H), 2.94-3.06 (m, 2H), 2.05-2.24 (m, 2H), 1.70-1.86 (m, 2H), 1.44 (m, 3H), 1.41 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 171.1, 161.7 (d, J=246.6 Hz), 155.0 135.7, 133.8, 128.7, 127.5, 126.2, 124.8, 124.2, 119.0, 115.7, 79.6, 78.6, 78.2, 60.4, 41.2, 28.5, 22.2, 14.3. Mass spec.: 488.39 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a solution of ethyl 3-(6-chloro-2-pyridyl)-3-oxopropionate (7.6 g, 33.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.34 g, 33.4 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (7.98 g, 33.4 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-(6-chloro-2-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (13.0 g, 100%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=O)[O:21]C3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Product: CN1CCN(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
4-Methyl-piperazine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate M and 4-methyl-piperazine. MS calcd. for C22H24ClN4O2 [(M+H)+] 411.2, obsd. 411.0.
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]([CH2:9]O)C=C[CH:8]=1.[CH3:11][S:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1.C(OC)(=[O:25])C=C>>[CH3:11][S:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]#[N:21])[CH:16]=[CH:17][CH:18]=1.[CH3:11][S:12][C:13]1[CH:14]=[C:15]([C:19]2([C:20]#[N:21])[CH2:9][CH2:5][C:4](=[O:25])[CH2:3][CH2:8]2)[CH:16]=[CH:17][CH:18]=1
Reactant: C=CC(=O)OC
Reactant: CSc1cccc(CO)c1
Agent: CSc1cccc(CC#N)c1
Product: CSc1cccc(C2(C#N)CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared according to the process described in Example 183 via the intermediates (3-methylsulfanylphenyl)methanol (MS (ESI+): 155) and (3-methylsulfanylphenyl)acetonitrile (MS (ESI+): 164). In step c), the reaction mixture was not heated under reflux after the addition of the methyl acrylate, but stirred for 16 h at room temperature. From 2.9 g of (3-methylsulfanylphenyl)acetonitrile, 0.85 g of the title compound was obtained.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[NH2:8][C:9](=[S:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C>[CH:4]([C:3]1[N:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:15][CH:2]=1)([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(N)=S
Reactant: CC(C)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1nc(C(C)C)cs1
Temperature: 25 °C

Procedure:
1-Bromo-3-methylbutan-2-one (3.72 g) in ethanol (15 mL) was added dropwise over 15 minutes to a refluxing solution of ethyl 2-amino-2-thioxoacetate (3 g) in ethanol (120 mL). The mixture was heated at reflux for 2 hours and then cooled to room temperature. The solvent was evaporated down under reduced pressure to a volume of 30 mL, this solution was added to ice/water (200 mL) and the mixture neutralised by dropwise addition of ‘880’ concentrated aqueous ammonia. The mixture was extracted twice with ethyl acetate, the combined organics were washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 20% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 2.2 g.
Reaction SMILES: N[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.Cl.C(O)(=[O:20])C>>[OH:20][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1
Reactant: Cn1c(=O)cc(N)n(-c2ccccc2)c1=O
Reactant: CC(=O)O
Agent: Cl
Product: Cn1c(=O)cc(O)n(-c2ccccc2)c1=O
Temperature: 100 °C
Yield: 68 %

Procedure:
6-Amino-3-methyl-1-phenyluracil as obtained in Reference Example 1 (8.7 g, 40 mM) was dissolved in 80 ml of acetic acid and hydrochloric acid (16 ml) was added, followed by heating at 100° C. for 1 hour. The solvent acetic acid was then distilled off under reduced pressure and water war added to the residue. The pH of the resulting solution was adjusted to 1 by adding hydrochloric acid and a product was extracted with dichloromethane. After the solvent dichloromethane was distilled off under reduced pressure from the dichloromethane layer, crystallization with ethanol was performed to give 6-hydroxy-3-methyl-1-phenyluracil (yield: 5.9 g, or 68% based on 6-amino-3-methyl-1-phenyluracil).
Reaction SMILES: [S:1]([CH2:7][CH2:8][OH:9])([CH2:4][CH2:5][OH:6])(=[O:3])=[O:2].Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12]>N1C=CC=CC=1>[OH:6][CH2:5][CH2:4][S:1]([CH2:7][CH2:8][O:9][C:11]([O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)=[O:12])(=[O:3])=[O:2]
Reactant: O=S(=O)(CCO)CCO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: O=C(OCCS(=O)(=O)CCO)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 2,2′-sulfonyldiethanol (4.85 g, 39.75 mmol) and p-nitrophenyl chloroformate (2.0 g, 9.92 mmol), in 20 ml of dry pyridine, was stirred for 2 h at room temperature and then evaporated to dryness. The residue was dissolved in 350 ml of ethyl acetate and washed with water (4×100 ml). The organic solution was dried over sodium sulfate, filtered and evaporated. The crude product was purified by silica gel chromatography, eluting with ethyl acetate. The pure product fractions were pooled and evaporated affording an oil: 0.68 g (22%) yield.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:10])=[N:6][S:7][C:8]=1N.[NH2:11][C:12]1[C:21]([C:22]([O:24]N2C3C=C(Cl)C=CC=3N=N2)=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1.O>CN1C(=O)CCC1>[NH2:11][C:12]1[C:21]([C:22]([O:24][C:8]2[S:7][N:6]=[C:5]([CH3:10])[C:4]=2[Br:3])=[O:23])=[C:15]2[N:16]=[CH:17][C:18]([F:20])=[CH:19][N:14]2[N:13]=1
Reactant: Cc1nsc(N)c1Br
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nsc(OC(=O)c2c(N)nn3cc(F)cnc23)c1Br
Reaction time: 0.17 h

Procedure:
NaH (210.3 mg, 5.259 mmol) was added to a solution of 4-bromo-3-methyl-isothiazol-5-amine (533 mg, 2.761 mmol) in dry NMP (21.95 mL) at RT. The solution was stirred at RT for 5 min before (6-chlorobenzotriazol-1-yl) 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (914.4 mg, 2.630 mmol) was added. After 10 min, the reaction mixture was treated with water (120 mL) and stirred for 15 mins. The pale brown solid was filtered off and dried in vacuo to afford 4-bromo-3-methylisothiazol-5-yl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate. (801 mg, 82%). MS (ES+) 370.5.