Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH3:19][C:17]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=[C:13]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:18]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a solution of 1,2,4-triazole (4.0 g, 58 mmol) in dry DMF (20 mL) was added potassium carbonate (12.0 g, 87 mmol) and 2-chloro-4-methyl-5-nitropyridine (10 g, 58 mmol) and the mixture stirred at ambient temperature under nitrogen for 24 hours. Ethyl acetate (500 mL) and water (250 mL) were added to the mixture and the resulting precipitate was collected by filtration to give the title compound (5.08 g, 43%) as a pale brown solid. The filtrate was separated and the organic phase was washed with water (250 mL) and brine (250 mL), dried (MgSO4) and evaporated. The residue was triturated with ethyl acetate and the precipitate collected by filtration to give the title compound as a brown solid (4.11 g, 35%, overall yield 78%). mp 198°-200° C. 1H NMR (360 MHz, CDCl3) δ 2.72 (3H, s), 7.86 (1H, s), 8.07 (1H, s), 9.03 (1H, s) and 9.15 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])[O:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccccc1F
Reactant: COC(=O)CCCNC(=O)c1cc(-c2ccc(N)cc2)no1
Product: COC(=O)CCCNC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Yield: 73 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and methyl 4-(3-(4-aminophenyl)isoxazole-5-carboxamido)butanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 73% of the title compound. MS (ES+): m/z 441 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.3 (s, 1H), 9.0 (t, 1H), 8.62 (s, 1H), 8.12 (m, 1H), 7.85 (d, 2H), 7.61 (d, 2H), 7.53 (s, 1H), 7.24 (m, 1H), 7.1 (m, 1H), 7.02 (m, 1H), 3.57 (s, 3H), 3.26 (q, 2H), 2.36 (t, 2H), 1.77 (m, 2H).
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH:14]=[C:13](Cl)[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:3]([O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH:14]=[C:13]([C:20]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc2cc(Cl)nc(OCc3ccccc3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2cc(-c3cccnc3)nc(OCc3ccccc3)c2c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
1-(Benzyloxy)-7-methoxy-3-(pyridin-3-yl)isoquinoline was prepared using Method N2. 1-(Benzyloxy)-3-chloro-7-methoxyisoquinoline (93 mg, 0.5 mmol, 1.0 eq.), potassium carbonate (357 mg, 2.5 mmol, 5.0 eq.), and Pd(PPh3)2Cl2 (18 mg, 0.026 mmol, 0.05 eq.) was dissolved in the mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). The resulting mixture was stirred at 120° C. for 30 min under the microwave condition. The solid was filtrated off and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1:10) to afford 100 mg of xxxviii-a as a yellow solid (84.7%).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C([Si](C)(C)[O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])[CH:25]=[CH:26][CH:27]=1)(C)(C)C.[OH-].[Na+]>C1COCC1>[OH:4][C:3]1[CH2:5][C:30]([CH2:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:31][C:1](=[O:6])[CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CCC(=O)c2ccccc2)c1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2cccc(O)c2)(c2ccccc2)O1
Temperature: 25 °C

Procedure:
The title compound was prepared as described in General Methods 6 and 7 using 2.4 mL (22.2 mmol) of methyl acetoacetate, 1.02 g (25.5 mmol) of 60% sodium hydride, 16 mL (25.6 mmol) of 1.6 M n-butyllithium, 6.2 g (18.2 mmol) of 3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-phenyl-propan-1-one from Example Q and 180 mL of THF. After standard work-up, the crude aldol product was dissolved in THF (60 mL), treated with 0.2N NaOH (500 mL), and stirred at room temperature. The title compound was isolated via the normal procedure. 1H NMR (CDCl3) δ 2.21 (m, 2 H), 2.38 (m, 1 H), 2.61 (m, 1 H), 2.93 (dd, 2 H), 3.28 (dd, 2 H), 6.54-6.65 (m, 3 H), 7.06 (m, 1 H), 7.28-7.40 (m, 6 H).
Reaction SMILES: [CH:1]([C:3]1(O)[CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C[O:10][C:11]([CH3:13])=[CH2:12].P(=O)(O)(O)O.C(N(CC)CC)C>CC(OC)(C)C>[C:3]1(=[CH:1][CH2:2][CH2:12][C:11](=[O:10])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=CC1(O)CCCC1
Reactant: C=C(C)OC
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)CCC=C1CCCC1
Temperature: 130 °C
Yield: 72.1 %

Procedure:
In an autoclave under N2, a mixture of 1-vinylcyclopentanol (65 g, 0.58 mol), 2-methoxypropene (108 ml, 1.15 mol), 85% phosphoric acid (0.29 ml), triethylamine (0.63 ml) was heated at 130° C. for 15 h. The reaction mixture was cooled to 20° C., diluted with MTBE (500 ml), washed three times with water (25 ml), once with a saturated aqueous solution of NaCl (25 ml), dried (MgSO4) and concentrated. Widmer-Distillation (0.13 mbar, head temp. 58° C.) of the crude product gave 5-cyclopentylidenepentan-2-one (63.67 g, 72%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([C:9](O)=[O:10])[N:5]([CH3:8])[C:6]=1[Br:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>>[Br:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([C:9]([NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[O:10])[N:5]([CH3:8])[C:6]=1[Br:7]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)Oc1c(Br)c(Br)n(C)c1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)Oc1c(Br)c(Br)n(C)c1C(=O)Nc1nnn[nH]1
Yield: 51.5 %

Procedure:
Prepared by the method described in Example 115 from 4,5-dibromo-3-(1-methylethoxy)-1-methyl-1H-pyrrole-2-carboxylic acid (3.5 g, 0.01 moles), 1,1'-carbonyldiimidazole (1.7 g, 0.01 moles), and 5-aminotetrazole (0.87 g, 0.01 moles). Recrystallization from ethyl acetate gave the product (2.1 g); mp 218°-220° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=3)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]
Reactant: CC(C)C(O)(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)cc1OC
Yield: 85.6 %

Procedure:
By the reaction in the same manner as in Example 29-(i) using 1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.50 g), 3,4-dimethoxyphenylboronic acid (762 mg), 2M aqueous sodium carbonate solution (2.79 ml) and tetrakis(triphenylphosphine)palladium(0) (96.7 mg), the colorless amorphous title compound (1.42 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH2:26])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].Br.CC1C([C:35]2[NH:36][CH2:37][CH2:38][N:39]=2)=C(C)NN=1>CO>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:35]3[NH:39][CH2:38][CH2:37][N:36]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1n[nH]c(C)c1C1=NCCN1
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCON)ccc21
Agent: Br
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC3=NCCN3)ccc21
Reaction time: 120 h
Yield: 99 %

Procedure:
3-[5-(2-aminooxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethyl ester (208 mg, 0.56 mmol) and 2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidazole hydrobromide (125 mg, 0.90 mmol) were dissolved in methanol (3 mL) and stirred for 5 days. The solvent was evaporated under vacuum and the crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol in dichloromethane to afford the title compound (99% yield). 1H NMR (CDCl3) δ 7.16–7.29 (m, 7H), 7.07 (d, 1H, J=2.3 Hz), 6.80 (dd, 1H, J=2.3, 8.8 Hz), 6.47 (d, 1H, J=3.2 Hz), 6.00 (t, 1H, J=7.0 Hz), 4.24 (m, 2H), 4.17 (m, 2H), 4.03 (c, 2H, J=7.2 Hz), 3.51 (br s, 4H), 3.26 (m, 2H), 1.09 (t, 3H, J=7.2 Hz).
Reaction SMILES: C([O:5][C:6](=[O:25])[C@H:7]([CH2:21][C:22](=[O:24])[NH2:23])[NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10])(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[C:9]([NH:8][C@H:7]([C:6]([OH:25])=[O:5])[CH2:21][C:22](=[O:24])[NH2:23])=[O:10]
Reactant: CC(C)(C)OC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under a nitrogen atmosphere, 4.0 g (11.6 mmol) of quinoline-2-carbonyl-(L)-asparagine tert-butyl ester are dissolved in 40 ml of dioxane, and 40 ml of 4N HCl/dioxane are added. On stirring for 17 h at RT, the product is precipitated in the form of a solid. Filtration and washing with DIPE yields the pure title compound: 1H-NMR (200 MHz, CD3OD): 3.02 (d, J=6 Hz, 2H), 5.09 (t, J=6 Hz, 1H), 7.92 (m, 1H), 8.12 (m, 1H), 8.26 (m, 1H), 8.4 (m, 2H), 9.03 (m, 1H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[C:17](=[O:19])[CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[NH4+].[Cl-].[OH-].[K+]>O1CCCC1.CCOCC>[CH2:1]([NH:4][C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]([OH:19])[CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: CCCNc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCNc1c2c(nc3ccccc13)CCCC2O
Yield: 74.9 %

Procedure:
In 50 ml of dry tetrahydrofuran was suspended 2.49 g of 3,4-dihydro-9-(n-propylamino)acridin-1(2H)-one. The mechanically stirred suspension was cooled in ice and 4.50 ml (0.5 eq) of 1.1M LiAlH4 solution in ether was added dropwise, whereupon a solution formed. After the addition, the reaction appeared complete based on thin layer chromatography analysis. The excess hydride was neutralized with 0.5 ml of saturated NH4Cl solution and thereafter 30% potassium hydroxide was added to dissolve the salts. The supernatant tetrahydrofuran solution was separated and evaporated to a solid. The solid was recrystallized from 1:4 dichloromethane/EtOAc to yield 1.88 g (75%) of needles, melting point 164° C.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#N)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C[OH:35].O>C1COCC1>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:35])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C#N)c2)c1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)c1cccc(OCc2cccc(C=O)c2)c1
Yield: 30 %

Procedure:
To a solution of 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzonitrile (10.0 g). in THF was added diisobutylaluminum hydride (15 g.) and the reaction was refluxed overnight. Methanol (10.2 ml) was slowly added followed by water (5.7 ml). The mixture was filtered and the filtrate was concentrated to an oil. The oil was dissolved in chloroform. The solution was washed with 5% aqueous hydrochloride acid (4 times), dried (MgSO4) and concentrated to an oil (3.0 g., 30% yield). In like manner as above, using appropriate starting materials, the following intermediate was prepared:
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]([C:7]12[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:13][C:12](=NN)[CH:11]1[CH2:10][N:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8]2)=[O:6].O.C(OCC)(=O)C>O1CCCC1.C(N(CC)CC)C>[CH3:3][O:4][C:5]([C:7]12[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH:13]=[C:12]([I:1])[CH:11]1[CH2:10][N:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8]2)=[O:6]
Reactant: II
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Temperature: 25 °C
Yield: 47 %

Procedure:
52.07 g of iodine, in solution in 250 cm3 of tetrahydrofuran, were added dropwise to a solution of 37.75 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-phenyloctahydroisoindole-3a-carboxylate in 200 cm3 of tetrahydrofuran and 43 cm3 of triethylamine. Stirring was maintained at room temperature for one hour after the end of the addition. 1 dm3 of water and 1 dm3 of ethyl acetate were then added. The organic phase was separated by settling, washed successively with a saturated sodium hydrosulphite solution and then with a saturated sodium chloride solution, and dried over magnesium sulphate. After concentrating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (95/5 by volume). 22.25 g (47%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4, 5 ,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a yellow pasty solid, the characteristics of which were as follows:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C(O)C>[NH2:1][C:2]1[S:3][C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:5][N:6]=1
Reactant: Nc1nnc(Br)s1
Reactant: C1COCCN1
Solvent: CCO
Product: Nc1nnc(N2CCOCC2)s1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A mixture of 9 g of 2-amino-5-bromo-1,3,4-thiadiazole (0.05 mole), 9.1 g of morpholine (0.105 mole) and 150 ml ethanol was refluxed for 6 hours. After standing overnight at room temperature the precipitate was filtered off, suspended in water, again filtered off and then dried. Thus 2-amino-5-morpholino-1,3,4-thiadiazole is obtained in a yield of 43.6% of the theoretical yield. Melting point: 186°-188° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[CH:24]=[C:23]([CH3:35])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([CH3:35])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.54 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a white solid (0.175, 37%). MS (ISP) 471.2 [(M+H)+]; mp 202.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25](OCC)=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[O:8][N:7]=[C:4]4[CH2:3][CH2:2][O:1][CH2:6][C:5]=34)[CH2:20][CH2:21]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(F)cc2)CC1
Reactant: ON=C1CCOCC1
Product: Fc1ccc(N2CCN(CCCc3onc4c3COCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using tetrahydro-4H-pyran-4-one oxime and ethyl 4-(4-(4-fluorophenyl)piperazin-1-yl)-n-butyrate, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-6,7-dihydro-4H-pyrano[4,3-c]isoxazole is obtained.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4].[OH-].[Na+].[CH:25]([O:27][CH2:28][CH2:29][O:30][NH2:31])=[CH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C>[CH:25]([O:27][CH2:28][CH2:29][O:30][NH:31][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4])=[CH2:26]
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
To a solution of 8-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (200 mg, 0.49 mmol) in IMS (10 mL) was added a 1.0 M aqueous solution of sodium hydroxide (1.0 mL, 1.0 mmol). The reaction mixture was heated at 65° C. for 2 hours and then cooled to room temperature and concentrated in vacuo. The resulting residue was azeotroped with toluene, and then suspended in THF (10 mL). O-(2-Vinyloxy-ethyl)-hydroxylamine (103 mg, 1.0 mmol), N-N-diisopropylethylamine (0.34 mL, 1.96 mmol), EDCI (192 mg, 1.0 mmol) and HOBt (135 mg, 1.0 mmol) were then added sequentially before the reaction mixture was stirred 18 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in dichloromethane) to afford the title compound as a pale yellow oil (151 mg, 64%). LCMS (method B): RT=3.05 min, [M+H]+=483.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[C:3]1[C:12]([O:14]CC)=O.C(O[C:20](OCC)([CH3:23])[C:21]#[N:22])C.CC1C=CC(S(O)(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[N:1][N:2]2[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[C:3]2[C:12]=1[OH:14])#[N:22]
Reactant: CCOC(C)(C#N)OCC
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(O)c(C#N)cnn2c1
Temperature: 125 °C
Yield: 50 %

Procedure:
To a round bottom flask was added diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate (40 g, 177 mmol), diethoxypropionitrile (53 mL) and p-TSA (10 g, 0.052 mmol). The reaction was heated at 125° C. for 3 hours and the EtOH was removed. The reaction was cooled to room temperature before DBU (30 g, 340 mmol) was added. The reaction was then heated at 80° C. for 2 hours. The reaction was cooled to room temperature and diluted with CH2Cl2. The mixture was washed with 5% citric acid solution (2×), water and brine solution. The organic layer was concentrated and the residue was purified by flash silica gel column chromatography (10% MeOH in CHCl3) to yield 20 g (50%) of the title compound as a brown oil. LCMS (condition A): m/z=230.2 −ve. 1H NMR (400 MHz, CDCl3) δ ppm: 9.53 (1H, br s), 8.32 (1H, s), 7.75 (1H, s), 6.75 (1H, s), 4.25 (2H, q), 1.28 (3H, t).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1([O:19][CH2:20][CH2:21][CH3:22])[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]1([O:19][CH2:20][CH2:21][CH3:22])[CH2:9][NH:10][CH2:11]1
Reactant: CCCOC1(C2CCCCC2C)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOC1(C2CCCCC2C)CNC1
Reaction time: 1 h

Procedure:
91 mg (0.29 mmol) of tert-butyl 3-(2-methylcyclohexyl)-3-propoxyazetidine-1-carboxylate are dissolved in 8 mL of dichloromethane. The reaction medium is immersed in an ice bath. 2 mL of trifluoroacetic acid are added. After 1 hour, the solvents are evaporated off. 113 mg in the form of a brown oil are used in the following step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([F:38])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.C(O)C>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:30][C:31]=1[F:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 5-cyclopropyl-6-(N-(3-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (230 mg, 0.43 mmol) and stannous chloride (291 mg, 1.29 mmol) in ethyl acetate (5 mL) and ethanol (5 mL) was maintained at reflux for 3 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-amino-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.39 mmol, 90% yield) as a yellow powder. LCMS (m/z, ES+)=512 (M+H+)