Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[N:26]=[C:25]([O:27]C)[C:24]([O:29]C)=[CH:23][N:22]=1>C1COCC1.[Pd]>[OH:29][C:24]1[C:25](=[O:27])[NH:26][C:21]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:22][CH:23]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cnc(Cl)nc1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)ncc1O
Temperature: 150 °C
Yield: 3.9 %

Procedure:
To a mixture of 0.05 g (0.26 mmol) 4-trifluoromethylphenylboronic acid, 0.02 g (0.009 mmol Pd EN Cat™ 30, and 0.65 mL 1 M aq Cs2CO3, was added a solution of 0.005 g (0.009 mmol) 1,1′-(bisdiphenylphosphino)ferrocene and 0.03 g (0.17 mmol) 2-chloro-4,5-dimethoxy-pyrimidine in 1 mL THF, The resulting mixture was heated by microwave to 150° C. for 10 minutes. After cooling, the aq layer was removed and the organic phase was filtered and concentrated. To the resulting residue was added 1 mL 33% HBr in AcOH, and the resulting mixture was heated by microwave to 160° C. for 5 min. The resulting solution was diluted with water (2 mL) and loaded onto an SCX column. After washing with MeOH (5 mL), the crude product was eluted off with 2 M ammonia in MeOH. Purification by automated mass-guided HPLC afforded 1.7 mg (4%) 5-hydroxy-2-(4-trifluoromethyl-phenyl)-3H-pyrimidin -4-one. NMR (499 MHz, DMSO-d6): δ 9.85 (br s, 1 H); 8.22 (d, J=7.93 Hz, 2 H); 7.85 (d, J=8.12 Hz, 2 H); 7.63 (br s, 1 H). High resolution mass spec (FT/ICR) calc (M+H)+=257.0533 found 257.0532.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[O:12]1[CH2:17][CH2:16][N:15]([CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[C:19]([CH3:21])([CH3:20])[C:10]2=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)=CN1CCOCC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: CC1(C)C(=O)N(c2ccc(Cl)c(Cl)c2)C1N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1.88 g. portion of 3,4-dichlorophenylisocyanate was added to 2.82 g. of 1-morpholino-1-isobutene. The mixture was stirred at room temperature for 48 hours. At the end of that time, the excess enamine was removed under vacuum, and the remaining oil, 3.0 g., was found by nuclear magnetic resonance analysis to be 1-(3,4-dichlorophenyl)-3,3-dimethyl-4-morpholino-2-azetidinone, a liquid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)[NH2:24]>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:14][N:22]=[C:23]([C:25]3[CH:33]=[CH:32][C:28]4[NH:29][CH:30]=[N:31][C:27]=4[CH:26]=3)[N:24]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:18])[F:20]
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 1 starting from Intermediate 11 (143 mg; 0.50 mmol) Intermediate 1 (88 mg; 0.50 mmol). Reaction mixture was filtered over a SPE-NH2 column, washed with THF followed by evaporation of the solvent under reduced pressure. Evaporation of the solvent gave a yellow oil which was recrystallized in a DCM/n-pentane mixture to give the title compound as an off-white solid. 1H NMR (DMSO, d6) δ 12.77 (s, 1H), 8.46 (dd, J=8.4, 2.1 Hz, 1H), 8.40 (m, 2H), 8.34 (s, 1H), 7.97 (dd, J=8.5, 1.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 3.20-3.14 (m, 1H), 2.99-2.94 (m, 1H), 2.67-2.57 (m, 1H), 1.79 (m, 2H), 1.68-1.27 (m, 4H), 0.76 (d, 6 Hz, 3H). HPLC (Method A) Rt 4.51 min (Purity: 99.4%). LC/MS (method B): 428.3 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1(Br)[CH2:11][CH2:10][CH2:9][CH2:8]1.[O:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[C:17]([OH:18])[CH:16]=1>CN(C)C=O.O>[CH:7]1([O:18][C:17]2[CH:16]=[C:15]([CH:23]=[CH:22][C:19]=2[O:20][CH3:21])[CH:14]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Potassium carbonate (27.6 g, 0.20 mole) was added to a solution of cyclopentyl bromide (26.4 g, 0.18 mole) and isovanillin (25.8 g, 0.17 mole) in N,N-dimethyl formamide (80 mL). The resulting suspension was stirred at ambient temperature for 1 week, then diluted with water (about 500 mL) and extracted with diethyl ether (2×300 mL). The combined ether extracts were washed with water (5×150 mL), 10% sodium hydroxide (3×50 mL), and water (2×100 mL), then dried over magnesium sulfate and concentrated under vacuum to provide 27.5 g of 3-cyclopentyloxy-4-methoxybenzaldehyde as a viscous yellow oil.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Cl[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:8]=1>>[CH3:1][NH:2][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=[CH:11][N:12]=1
Reactant: CN
Reactant: FC(F)(F)c1cccc(Nc2cc(Cl)ncn2)c1
Solvent: CCO
Product: CNc1cc(Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A solution of methylamine in ethanol (32 mL, 256 mmol) is added to (6-chloro-pyrimidin-4-yl)-(3-trifluoromethyl-phenyl)-amine (3.49 g, 12.8 mmol) and the mixture is stirred for 5 h at 100° C. in a pressure bottle. The reaction mixture is concentrated in vacuo, the residue diluted with CH3OH and basified using conc. aqueous ammonia solution. The product is filtered off, washed with H2O and CH3OH and dried in vacuo.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=O)[C:9]2=O)([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc2c1NC(=O)C2=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cccc2cc[nH]c12
Temperature: 90 °C

Procedure:
To a solution of 7-isopropyl-1H-indole-2,3-dione (2.97 g, 15.7 mmol) in tetrahydrofuran (20 mL) was dropped 2.0 M solution of lithium borohydride in tetrahydrofuran (15 mL, 30 mmol). The mixture was heated at 90° C. for 4 hours. It was quenched with 5% HCl, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness to provide a crude 7-isopropyl-1H-indole. To a solution of the crude 7-isopropyl-1H-indole in diethyl ether (40 mL) was dropped 2.0 M solution of oxalyl chloride in dichloromethane (15 mL, 30 mmol). After stirring at room temperature for 5 hours, it was evaporated to dryness. Ethanol was added to the residue and it was stirred at room temperature overnight. After the ethanol was evaporated, flash chromatography on silica gel provided 0.972 g (24%) of the title compound as solid. ESI (−) MS m/e=258 (MH−).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1

Procedure:
Intermediate B-11 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 1-BOC-piperazine as starting materials. LCMS (ESI) calcd for [M+1]+ 279.2. found 279.2.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1[CH:36]=[CH:37][C:38]([N+:45]([O-:47])=[O:46])=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:36]=[CH:37][C:38]([N+:45]([O-:47])=[O:46])=[C:39]([CH:44]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanol (15 ml) and a 4 N hydrochloric acid/ethyl acetate solution (30 mL) were added to tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (40a) (1.5 g, 4.12 mmol), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, azeotropically dehydrated by adding toluene, and dissolved in DMF (10 ml). Methyl 5-chloro-2-nitrobenzoate (900 mg, 4.17 mmol) and potassium carbonate (2.1 g, 15.2 mmol) were added, and the mixture was stirred at 175° C. for 24 hours. The reaction solution was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to obtain the title compound. The total resulting compound was used for the next reaction.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:30]C)=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:32])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:2]1=2.[Si](I)(C)(C)C>C(#N)C.ClCCl>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][CH:24]=5)[N:22]=4)=[O:15])[CH2:12][CH2:13]3)[CH:9]=[CH:10][C:2]1=2
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCCO5)CC3)ccc2C)cc1C
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCCO4)CC2)nc1-c1c[nH]c(=O)c(C)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (16 mg, 0.037 mmol) in acetonitrile (1 mL) was added TMS-Iodide (21.10 μL, 0.148 mmol). The reaction was stirred at 50° C. for 20 minutes. The reaction solution was diluted with dichloromethane and washed with saturated NaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (10-99% CH3CN in water). ESI-MS m/z calc. 417.5. found 418.3 (M+1)+. Retention time 1.40 minutes.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1>CN(C=O)C.O>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:33][CH2:34]2)[S:6]1(=[O:22])=[O:21]
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC1
Temperature: 70 °C
Yield: 57.2 %

Procedure:
1-(3-bromopropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.61 g, 1.56 mmol) was dissolved in 5 mL of DMF along with 430 mg (3.1 mmol) of potassium carbonate and 0.32 g (1.56 mol) of tert-butyl piperidin-4-ylcarbamate. The solution was heated to 70° C. for 16 hours then poured in water. The solution was extracted 2× with ethyl acetate and the water layer discarded. The combined organic phase was washed 3 times with brine, then dried (MgSO4) and concentrated. The residue was subjected to Biotage chromatography (10-50% ethyl acetate-hexane) to afford 0.45 g (55%) of tert-butyl (1-{3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperidin-4-yl)carbamate. MS (ES) m/z 505.1; HPLC purity 97.9% at 210-370 nm, 10.5 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Bicarb Buff.Ph=9.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:15]=2[C:16]([OH:18])=O)=[C:11]([CH3:29])[CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:67]=[CH:66][C:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:57][CH:56]=1>CN(C=O)C>[F:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:15]=2[C:16]([NH:54][C:55]2[CH:67]=[CH:66][C:58]([C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])=[CH:57][CH:56]=2)=[O:18])=[C:11]([CH3:29])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Triethylamine (177.4 ml, 1.27 mmol) was added to a solution of 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoic acid (100 mg, 0.32 mmol), HATU (121 mg, 0.32 mmol) and tert-butyl 4-aminobenzoate (61.49 mg, 0.32 mmol) in DMF (1 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and purified by reverse phase LC-MS using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield tert-butyl 4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)benzoate (43.8 mg, 28%). ESI-MS m/z calc. 489.16, found 490.3 (M+1)+; Retention time: 2.46 minutes (3 minutes run).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH2:19])[CH:13]=1.C(N(CC)CC)C.Br[CH:28]([CH3:32])[C:29](Br)=[O:30]>O1CCCC1>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH:28]([CH3:32])[C:29](=[O:30])[NH:19][C:14]=2[CH:13]=1
Reactant: Cc1ccn2c(C)c(-c3ccc(O)c(N)c3)nc2c1
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccn2c(C)c(-c3ccc4c(c3)NC(=O)C(C)O4)nc2c1
Yield: 32.4 %

Procedure:
A solution of 3,7-dimethyl-2-(3-amino-4-hydroxyphenyl)imidazo[1,2-a]pyridine (1.27 g) and triethylamine (1.0 g) in tetrahydrofuran (100 ml) was added to 2-bromopropionyl bromide (1.3 g) at ambient temperature. The resultant mixture was stirred at ambient temperature for 2 hours and at 60° to 70° C. for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in a mixture of ethyl acetate and water. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1). The fractions containing the desired compound were combined and evaporated in vacuo to afford a crystalline residue, which was recrystallized from ethyl acetate to give 6-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.5 g). mp. 254°-256° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:4]([OH:6])[C:3]3[C:2](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:1]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1cc(-c2ccc(Cl)cc2)nc2ccccc12
Temperature: 60 °C
Yield: 87.4 %

Procedure:
To a stirred mixture of 16.52 g (0.1 mol) of ethyl o-aminobenzoate, 15.46 g (0.1 mol) of p-choroacetophenone, and 250 ml of diphenyl ether was carefully added 18.67 g of aluminum chloride. This mixture was heated under reflux for 2 hr and then let cool to 60° C. The solids were collected and washed with 2×100 ml of toluene. These solids were triturated twice with a mixture of 500 ml of 6N hydrochloric acid and 50 ml of acetone. Each time the solids were collected they were washed with 100 ml of 6N hydrochloric acid, 3×100 ml of water, and 2×50 ml of acetone. There was obtained 22.34 g of the above-named product, mp 327-330.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:16]2[C:15](=[O:17])[NH:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[NH:11][C:10]=2[C:9]([CH3:22])=[CH:8]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[NH:14][C:15](=[O:17])[C:16]2[N:7]([CH3:6])[CH:8]=[C:9]([CH3:22])[C:10]1=2)=[O:4]
Reactant: Cc1cn(C)c2c1Nc1ccccc1NC2=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Yield: 68.9 %

Procedure:
A solution of 1.47 g of chloroacetyl chloride in 20 ml of dioxane is added dropwise with stirring to 1.9 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one, 5.5 g of powdered anhydrous potassium carbonate and 50 ml of dioxane in the course of 10 minutes at 50° C. The obtained mixture is stirred for several hours; precipitate is then filtered off, and the filtrate is concentrated to dryness. 1.75 g (69%) of the title compound of m.p. 267° to 269° C. (from acetonitrile) are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]2=[O:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:23][S:24]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:7]2=[O:22])(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CN)cc2C1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CNS(C)(=O)=O)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 2-(5-(aminomethyl)-1,3-dioxoisoindolin-2-yl)acetate hydrochloride (0.409 g, 1.252 mmol) in dry pyridine (10 ml) cooled to 0° C., methanesulfonyl chloride (0.117 ml, 1.502 mmol) was added. The reaction was warmed to room temperature and stirred overnight. Additional methanesulfonyl chloride (0.148 ml, 1.878 mmol) was added over 24 hours cooling at 0° C. and stirring at room temperature. The solvent was removed under vacuum and the residue was portioned between ethyl acetate and 1N HCl. The organic phase was washed with brine and dried over sodium sulfate. The solvent was evaporated to dryness affording tert-butyl 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetate (0.461 g, 1.251 mmol, MS/ESI+ 390.9 [MNa]+). This crude was used in the following steps without purification.
Reaction SMILES: Cl[P:2]1(Cl)[N:7]=[P:6](Cl)(Cl)[N:5]=[P:4](Cl)(Cl)[N:3]=1.[C:13]1([CH3:19])[CH:18]=CC=C[CH:14]=1>>[CH2:14]([P:2]1([CH2:19][C:13](=[CH2:14])[CH3:18])[N:7]=[P:6]([CH2:14][C:13](=[CH2:19])[CH3:18])([CH2:14][C:13](=[CH2:19])[CH3:18])[N:5]=[P:4]([CH2:18][C:13](=[CH2:14])[CH3:19])([CH2:14][C:13](=[CH2:19])[CH3:18])[N:3]=1)[C:13](=[CH2:19])[CH3:18]
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Reactant: Cc1ccccc1
Product: C=C(C)CP1(CC(=C)C)=NP(CC(=C)C)(CC(=C)C)=NP(CC(=C)C)(CC(=C)C)=N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Furthermore, into the 5-liter flask as described above is put a solution of hexachlorocyclotriphosphazene in toluene (700 g (6.0 unit mol) of hexachlorocyclotriphosphazene, 3,500 mL of toluene). The slurry solution of 2-methyl-2-proper-1-ol sodium salt is added dropwise thereto at 5° C. or lower over 6 hours, followed by warming to 25° C. and stirring for 4 hours, to obtain a solution of hexamethallylcyclotriphosphazene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](=[O:11])(=[O:10])[NH:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCN
Solvent: c1ccncc1
Product: CCCCCCCCCCNS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
Commercially available 4-methoxybenzenesulfonylchloride (Aldrich; 25 g, 0.12 moles) is added portionwise to a solution of decylamine (Kodak; 19 g, 0.12 moles) in pyridine (75 mL). The heterogeneous reaction mixture is stirred overnight at room temperature and poured into dilute HCl/ice water (1.5 L). After stirring 30 minutes, the light orange solid is isolated by filtration, washed with water and air dried. Recrystallization from ethanol (Norite) affords 26.3 g (66% yield) of the desired product as golden platelets, mp 53°-54.5° C. NMR (CDCl3) d 0.8-0.95 (t, 3H's); 1.1-1.6 (m, 16H's); 2.8-3.0 (t, 2H's); 3.9 (s, 3H's); 6.95-7.0 (d, 2H's); 7.75-7.85 (d, 2H's).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:24]([CH3:30])=[N:25][CH:26]=[N:27][C:28]=3[CH3:29])=[O:22])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[O:39]([NH2:41])[CH3:40].CC([O-])=O.[Na+]>CO>[CH3:40][O:39][N:41]=[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:24]([CH3:30])=[N:25][CH:26]=[N:27][C:28]=3[CH3:29])=[O:22])[CH2:13][CH2:12]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(C)c1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of COMPOUND 293 in MeOH (3 mL) were added methoxylamine hydrochloride (15 mg, 0.18 mmol) followed by NaOAc (14 mg, 0.17 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 294 as a clear oil (31 mg, 82%) after work-up and purification. 1H NMR (CDCl3) δ 0.95-1.17 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.58 (m, 1H), 1.74-1.79 (m, 3H), 2.14 (s, 3H), 2.17 (t, 1H, J=11.7 Hz), 2.52 (s, 6H), 2.57 (t, 1H, J=11.4 Hz), 2.73-2.89 (m, 3H), 3.28-3.36 (m, 1H), 3.59-3.68 (m, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 6.60 (d, 2H, J=9.0 Hz), 6.98-7.03 (m, 2H), 7.28 (dd, 1H, J=4.8, 3.0 Hz), 7.45 (d, 2H, J=9.0 Hz), 8.71 (br s, 1H), 8.89 (s, 1H). ES-MS m/z 549 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[CH:23]=[CH:24][S:20][CH:21]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccsc1
Product: COc1ccc2c(-c3ccsc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-thiophene boronic acid to give (6-methoxy-1-thiophen-3-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 323(MH+).