Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:7])=O.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:5][NH2:7]
Reactant: COc1ccc(C(N)=O)cc1F
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN)cc1F
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 3-fluoro-4-(methyloxy)benzamide (100 mg, 0.60 mmol) in tetrahydrofuran (5 mL) was added sodium borohydride (115 mg, 3.0 mmol) followed by the drop-wise addition of a solution of borontrifluoride etherate (48% BF3 ca., 475 μl, 3.8 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at reflux for 15 hours, then was cooled to room temperature and diluted with ethyl acetate. The organic portion was extracted with 20% aqueous citric acid. The aqueous portion was brought to pH 8 using solid sodium bicarbonate, then was extracted several times using ethyl acetate. The combined organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded a yellow residue, which was purified by silica gel column chromatography using 10% methanol in dichloromethane as eluent. Purified fractions were pooled and concentrated to afford 56 mg, 0.36 mmol (61%) of 3-fluoro-4-methoxybenzylamine as a colorless residue. MS (EI) for C8H10FNO: 156 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.BrC1C(OCC)=[CH:31][CH:30]=[CH:29]N=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:30]([CH3:31])[CH3:29])[C:15]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cccnc1Br
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: CC(C)N(c1ncccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 70, and making non-critical variations but substituting 1-benzyl-4-(1-methylethylamino)piperidine (EXAMPLE 99) for 1-benzyl-4-(methylamino)piperidine and 2-chloro-3-nitropyridine for 2-bromo-3-ethoxypyridine and using a reaction time of 2 hrs, the title compound is obtained, NMR (CDCl3) 8.24, 7.90, 7.31-7.23, 6.62, 3.61, 3.49, 2.97, 2.27, 1.96, 1.77 and 1.39δ.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:24]=[C:23](I)[CH:22]=[CH:21][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>[Cu]I.C(Cl)Cl.O>[F:10][C:11]1[CH:24]=[C:23]([N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]2=[O:9])[CH:22]=[CH:21][C:12]=1[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1
Reactant: Cc1c[nH]c(=O)c(C)c1
Reactant: CN1CCN(Cc2ccc(I)cc2F)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(=O)n(-c2ccc(CN3CCN(C)CC3)c(F)c2)c1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A mixture of 3,5-dimethylpyridin-2(1H)-one (0.07 g, 0.57 mmol), 1-(2-fluoro-4-iodobenzyl)-4-methylpiperazine (0.19 g, 0.57 mmol), K2CO3 (0.08 g, 0.58 mmol), CuI (0.005 g, 0.026 mmol) and DMF (1 mL) was refluxed under N2. The reaction process was monitored by TLC. After the reaction was completed, the mixture was cooled to rt. To the resulting mixture was added H2O (5 mL) and CH2Cl2 (10 mL×3). The organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (0.07 g, 37%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH2:12][CH:11]([CH2:15][CH3:16])[C:10]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:24])[CH:18]=3)=[N:9]2)=[CH:5][CH:4]=1)#N.[OH-:27].[Na+].S(=O)(=O)(O)[OH:30]>O>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH2:12][CH:11]([CH2:15][CH3:16])[C:10]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:24])[CH:18]=3)=[N:9]2)=[CH:5][CH:4]=1)([OH:30])=[O:27]
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Reactant: CCC1CC(=O)N(Cc2ccc(C#N)cc2)N=C1c1ccc(O)c(O)c1
Agent: [Na+]
Solvent: O
Product: CCC1CC(=O)N(Cc2ccc(C(=O)O)cc2)N=C1c1ccc(O)c(O)c1
Reaction time: 10 h

Procedure:
10 g of 2-(4-cyanobenzyl)-6-(3,4-dihydroxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one are added with stirring to a cooled solution of 1.2 g of NaOH in 100 ml of water and the mixture is subsequently stirred for 10 hours. It is warmed cautiously and a stream of air is passed through the solution. Cooled sulfuric acid and water are then added. The mixture is worked up in the customary manner and 2-(4-carboxybenzyl)-6-(3,4-dihydroxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][NH:13][CH3:14].C1COCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
Into a 20 mL scintillation vial were added 3-Bromobenzenesulfonyl chloride (0.301 g, 1.179 mmol) and anhydrous pyridine (5 mL). A 2M solution of dimethylamine in THF (1.0 mL, 2.0 mmol) was added dropwise, and the reaction mixture was stirred at rt under N2 for 5 h after which it was concentrated under vacuum. The crude residue was partitioned between EtOAc and IM citric acid. The layers were separated, and the organic phase was washed 3× with 1M citric acid, then treated with brine, dried (Na2SO4), filtered and concentrated. Trituration with Et2O provided 3-Bromo-N,N-dimethyl-benzenesulfonamide as a white powder (0.297 g, 96%). MS: m/z 263.9/265.9 [MH+].
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:18])(Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.N[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(O)C>O>[CH3:1][C:2]1[N:3]=[C:4]([NH:18][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CC1=Nc2scc(-c3ccccc3)c2C(N)(Cl)N1
Reactant: NCc1ccccn1
Solvent: CCO
Solvent: O
Product: Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 842.3 %

Procedure:
In a 10 ml glass tube were placed 2-methyl-4-chloro-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.076 g, 0.293 mmol), 2-(aminomethyl)pyridine (0.0364 g, 0.03 mmol) and ethanol (2.5 ml). The vessel was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 150° C. Once 150° C. was reached, the reaction mixture was held at this temperature for 10 minutes. After cooling to ambient temperature, water (4 ml) was added and the mixture stirred for 2.5 hours. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 2-methyl-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.084 g) as an off white solid, m.pt. 110-112° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][N:15]=[CH:14]1>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:20][CH2:19][CH2:18][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCn1ccnc1
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)NCCCn1ccnc1
Temperature: 90 °C

Procedure:
A mixture of 2.39 of isatoic anhydride, 2.50 g of 1H-imidazol-1-propanamine and 30 ml of toluene was heated at 90° C. for 45 minutes and cooled. The toluene layer was decanted and the residue was dissolved in methylene chloride, washed with dilute sodium hydroxide solution, water and dried over magnesium sulfate. The organic layer was concentrated to obtain the desired product, mp 107°-110° C.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([CH3:30])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O.[NH2:2]N.FC(F)(F)C1C=C[C:9]2[N:15]3C(CON4C(=O)C5=CC=CC=C5C4=O)=NN=C3CN=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3Cl)[C:10]=2C=1>C(O)C>[NH:2]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:11]=[CH:10][CH:9]=[N:15]1
Reactant: NN
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Solvent: CCO
Solvent: O
Product: C1=Cc2ccccc2NN=C1

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]1,4]benzodiazepine.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([N:13]2[CH2:18][CH2:17][NH:16][C@H:15]([CH3:19])[CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH2:2]1.CS(O[CH2:25][CH2:26][C@H:27]1[C:32]2[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[O:38])=[CH:36][C:31]=2[CH2:30][CH2:29][O:28]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][C@H:27]4[C:32]5[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[O:38])=[CH:36][C:31]=5[CH2:30][CH2:29][O:28]4)[C@H:15]([CH3:19])[CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1CC[C@@H]1OCCc2cc(C(N)=O)ccc21
Temperature: 25 °C

Procedure:
(3R)-1-(1,2-Dihydro-5-acenaphthylenyl)-3-methylpiperazine (0.138 g, 0.55 mmol), 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate (0.15 g, 0.50 mmol), potassium carbonate (0.138 g, 1.0 mmol), potassium iodide (0.083 g, 1.0 mmol) and acetonitrile (50 mL) were heated under reflux for 1 day with stirring under nitrogen. After cooling to room temperature, the inorganics were filtered off and the solvent evaporated in vacuo. The crude product was purified by preparative LC-MS to give the title compound. M+H=456.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Li+].[OH-].OP(O)(O)=O>CO.O>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2)[C:12]([OH:14])=[O:13])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)c1cccc2cnccc12
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC(C(=O)O)c1cccc2cnccc12

Procedure:
4-Tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate (1.00 g, 3.04 mmol) and LiOH (0.29 g) were stirred in MeOH:H2O (3:1, 20 mL) at room temperature for 5 hours. The solution was poured into aqueous H3PO4 (0.1M, 30 mL) and extracted with CHCl3:IPA (3:1, 30 mL×3). The extracts were combined, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 302 (M+H)+; MS (ESI−) m/z 300 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.28 (s, 9H), 2.74 (dd, J1 16.7, J2 6.1, 1H), 3.10 (dd, J1 9.5, J2 6.1, 1H), 4.68 (dd, J1 16.7, J2 9.5, 1H), 7.70 (m, 2H), 8.05 (m, 2H), 8.57 (d, J 6.1, 1H), 9.33 (s, 1H); Anal. Calcd for C17H19NO4+1.25 H2O: C, 63.05; H, 6.69. Found: C, 63.27; H, 6.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
To a cold (0° C.) solution of 4-chloro-2-picoline (5.0 g, 39 mmol) and ethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran (100 mL) was added lithium bis(trimethylsilyl)amide (80 mL, 1.0 M in tetrahydrofuran, 80 mmol) dropwise via a pressure equalizing funnel over 30 minutes. Upon complete addition, the cold bath was removed and the resulting solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and methanol was added to the reaction, resulting in the formation of a white precipitate. The precipitate was collected by filtration and dried to give 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 99%) as a white solid. 1H-NMR (DMSO-d6): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56 (s, 1H), 5.67 (s, 1H), 4.14 (m, 2H); 19F-NMR (DMSO-d6): δ−115.67; MS m/z 250 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])O
Reactant: Brc1cccc2cccnc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Br)c2ncccc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
8-Bromoquinoline (25.00 g, 120.2 mmol) was dissolved in sulfuric acid (82.5 mL) at rt and then cooled to 0° C. HNO3 (fuming, 32.5 mL) was then slowly added over a 10 minute period. The reaction was then warmed to rt and then to 65° C. After 48 h at 65° C., the reaction was cooled to rt and poured onto 500 g of ice. This solution was extracted with methylene chloride (5×200 mL). The organic layers were washed once with brine and dried over anhydrous sodium sulfate. Concentration gave the crude compound 464A as a light yellow solid (28.6 g, 94%). HPLC: 98% at 2.717 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[NH:14][CH:13]=[N:12][N:11]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[N:19]=[CH:18][N:17]=1>>[Cl:8][C:7]1[C:2]([O:26][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:9][C:10]2[NH:14][CH:13]=[N:12][N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Nc1nnc[nH]1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Clc1cccnc1Oc1ccc2ncnc(Nc3nnc[nH]3)c2c1

Procedure:
The compound of Example 118 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-dichloropyridine, 3-amino-4H-[1,2,4]triazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.OO.C([O-])([O-])=[O:12].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccnc(Cl)c1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])c(Cl)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
2-chloro-4-methylpyridine (10 g, 80 mmol) was dissolved in acetic acid (100 ml). Hydrogen peroxide (31%, 86.8 g, 80.7 ml, 790 mmol)) was added in 4 portions and the solution stirred under nitrogen at 65° C. for 18 hours. The mixture was poured into ice water (300 ml), and solid Na2CO3 added until the solution was alkaline. The mixture was extracted with DCM (3×300 ml), the organic fractions combined, washed with sodium thiosulfate (1M, 100 ml), brine, dried over Na2SO4, and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:35])([F:34])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19](/[CH:20]=[C:21](\[C:27](=O)[CH3:28])/[C:22](OCC)=[O:23])=[C:18]([O:32][CH3:33])[CH:17]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(=O)(O)O.[NH2:40][C:41]([NH2:43])=[NH:42]>CO.O.CCOC(C)=O>[NH2:43][C:41]1[N:42]=[C:22]([OH:23])[C:21]([CH2:20][C:19]2[CH:30]=[CH:31][C:16]([O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]([P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2])([F:35])[F:34])=[CH:17][C:18]=2[O:32][CH3:33])=[C:27]([CH3:28])[N:40]=1
Reactant: CCOC(=O)/C(=C/c1ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc1OC)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOc1ccc(Cc2c(C)nc(N)nc2O)c(OC)c1
Temperature: 80 °C
Yield: 15 %

Procedure:
To a solution of (E)-ethyl 2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methoxybenzylidene)-3-oxobutanoate (1 equiv.) in MeOH (0.20 M) was added guanidine carbonate (1.1 equiv.) and the reaction mixture was heated to 80° C. for 3 h. At this point the reaction mixture was allowed to cool to room temperature and it was then diluted with water and EtOAc. The resulting mixture was transferred to a separatory funnel and washed with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound (15%) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:18][C:19]2=[O:22])=[CH:14][CH:13]=1)=[O:10].[OH-].[Na+]>CN(C=O)C>[N:1]1([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:18][C:19]3=[O:22])=[CH:14][CH:13]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)Nc1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
0.042 ml (0.47 mmol) of morpholine was added to a DMF solution containing 50 mg (0.16 mmol) of the 2-chloro-N-(1-oxo-3-phenyl-1,2-dihydroisoquinolin-7-yl)acetamide obtained in Example 57, and the obtained mixture was then stirred at 100° C. for 30 minutes. Thereafter, 30 ml of a 1 N sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate (50 ml×2). The extract was washed with 30 ml of water, and was then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The precipitated solid was collected by filtration, and the filtrate was then washed with a suitable amount of ether and hexane, so as to obtain 44 mg (76%) of 2-morpholin-4-yl-N-(1-oxo-3-phenyl-1,2-dihydroisoquinolin-7-yl)acetamide in the form of a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].C(N(CC)C(C)C)(C)C.CO.[C:46]([O:49][CH2:50]C)(=[O:48])C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:50][O:49][C:46]([C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])=[O:48]
Reactant: CCOC(C)=O
Reactant: Cc1c(-c2c(Br)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cnn(-c2ccc(C#N)cc2)c1-c1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (50.4 mg) in 1,4-dioxane (1.0 ml) were added bis(tri-tert-butylphosphine)palladium (4.9 mg), N,N-diisopropylethylamine (32.0 L) and methanol (1.0 mL), and the resulting mixture was stirred at 10° C. under carbon monoxide atmosphere for four hours. To the reaction mixture was added ethyl acetate (100 ml) and the resulting mixture was washed with water (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford methyl-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylate (9.4 mg) as white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])=[N:7][CH:8]=1)=O.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].N1CCCCC1.C(O)C>O>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][CH2:10][O:9][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[C:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:8][N:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cn1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)cn1
Yield: 29.3 %

Procedure:
A mixture of 5-formyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]pyridine (0.6 g), 2,4-thiazolidinedione (0.235 g), piperidine (0.066 ml) and ethanol (20 ml) was heated for 9 hours while refluxing. The reaction mixture was poured into water; the separating crystal, collected by filtration, was then recrystallized from ethanol-chloroform to yield 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methylidene]-2,4-thiazolidinedione (0.232 g, 29%) as a yellow crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Nc1ccc(Br)cc1N
Solvent: CO
Product: Brc1ccc2nccnc2c1
Yield: 51 %

Procedure:
In a round bottom flask under nitrogen was combined 4-bromo-benzene-1,2-diamine (2.01 g, 10.7 mmol), methanol (50 mL), and glyoxal (40% by wt. 3.1 mL, 26.9 mmol) and the resulting solution stirred overnight. The reaction was then concentrated in vacuo and purified by flash column chromatography on silica gel using 5-10% ethyl acetate in dichloromethane as eluant to yield 1.14 g (50% yield) of 6-Bromo-quinoxaline as a yellow-orange solid. 1H NMR (DMSO-d6): 9.00 (d,2H,J=2.8 Hz), 8.36 (d,1H,J=2.2 Hz), 8.07 (d,1H,J=9.0 Hz), 8.02 (dd,1H,J=8.8,2.1 Hz). CHN for C8H5BrN2: calc. C 45.97, H 2.41, N 13.4; found C 45.99, H 2.09, N 13.09. LC/MS (Method A): r.t.=1.10 min., purity=99%, calculated mass=208, [M+H]+=209/211. HPLC (Method B): r.t.=7.4 min., purity=98.52% at 210-370 and 98.8% at 322 nm.