Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][CH2:3][O:4][C:5]([CH2:7][NH2:8])=[O:6].CN(C)[CH:11]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:13]=[N+](C)C.Cl([O-])(=O)(=O)=O>O.CCO>[CH2:3]([O:4][C:5]([C:7]1[NH:8][CH:11]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)CN
Reactant: CN(C)C=C(C=[N+](C)C)c1ccccc1
Agent: [Na]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Reaction time: 0.5 h
Yield: 31.83 %

Procedure:
Sodium metal (119 mg, 5.1 mmol) was added to EtOH (15 mL) and stirred for 30 minutes. Glycine ethyl esater hydrochloride (345 mg, 2.47 mmol) and (3-dimethylamino-2-phenyl-allylidene)-dimethyl-ammonium; perchlorate (500 mg, 1.65 mmol) was then added. The resulting mixture was stirred and heated to reflux for 2 hrs. Evaporated the reaction mixture to get the residue. The residue was diluted with cold water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to get the residue. The residue obtained was purified by column chromatography (using silicagel of 60-120 mesh and 10% EtOAc in Hexane as eluent) to afford 113 mg (31.83% yield) of 4-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester. LCMS Purity: 98.96%. 1H NMR (CDCl3): δ 9.2 (bs, 1H), 7.58 (d, 2H), 7.42 (t, 2H), 7.26 (m, 3H), 4.4 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[CH3:26][O:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:32]3[CH2:33][CH2:34][CH:29]([CH2:28][O:27][CH3:26])[CH2:30][CH2:31]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC1CCNCC1
Agent: Cl
Product: COCC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-(methoxymethyl)piperidine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.10 (qd, J=12.3, 4.0 Hz, 2 H) 1.59 (br. s., 1 H) 1.67 (br. s., 1 H) 1.70-1.85 (m, 1 H) 2.36 (s, 3 H) 2.74 (br. s., 1 H) 3.14 (d, J=6.3 Hz, 2 H) 3.17 (s, 3 H) 3.57 (br. s., 1 H) 4.41 (br. s., 1 H) 7.57 (dd, J=8.0, 1.4 Hz, 1 H) 7.64 (s, 1 H) 7.74 (d, J=8.1 Hz, 1 H) 7.96 (dd, J=8.6, 2.3 Hz, 1 H) 8.03-8.09 (m, 1 H) 8.31 (d, J=8.3 Hz, 1 H) 8.42-8.47 (m, 1 H) 13.03 (br. s., 1 H). MS m/z [M+H]+ 432.5.
Reaction SMILES: [N:1]1([C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][CH:20]=3)[CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:25]=O>CC#N>[CH3:25][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([N:10]2[CH2:11][CH:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][CH:20]=3)[CH2:13]2)=[O:9])[CH2:2][CH2:3]1
Reactant: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCNCC3)C2)cn1
Reactant: C=O
Solvent: CC#N
Product: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCN(C)CC3)C2)cn1
Yield: 20 %

Procedure:
In a similar fashion (Route 1, GP A; except that MeCN was used as solvent), 5-{[1-(1,4-diazepan-1-ylcarbonyl)azetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (25 mg, 0.075 mmol) and formaldehyde (6.1 μl of a 37% aq solution, 0.075 mmol) gave the title compound as colourless oil (5.3 mg, 20%) after purification by preparative HPLC.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13]>>[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH:17][C:8]([C:7]1[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=1[CH:1]=[O:2])=[O:10])[CH3:13]
Reactant: CCN(CC)CCN
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Yield: 94.4 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3.0 g, 19.6 mmol) reacted with N,N-diethylethylenediamine (3.03 mL, 21.5 mmol) to give 4.65 g (94%) of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[O:11][C:12]2[C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1.O.[NH4+:24]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[O:11][C:12]2[C:18]([C:19]([NH2:24])=[O:21])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3cc4ccccc4[nH]3)oc12
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cc4ccccc4[nH]3)oc12
Yield: 51 %

Procedure:
Methyl 2-(1H-indol-2-yl)benzo[d]oxazole-7-carboxylate (70 mg, 0.24 mmol) in ammonium water (10 mL) was stirred at 35° C. overnight. Then the suspension was filtered, and the solid was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 1:1) to obtain 2-(1H-indol-2-yl)benzo[d]oxazole-7-carboxamide as a solid (32 mg, yield 51%). 1H-NMR (400 MHz, DMSO-d6) δ 6.54 (s, 1H), 7.11-7.13 (t, J=8 Hz, 1H), 7.26-7.30 (t, J=8 Hz, 1H), 7.48-7.54 (dd, J1=16 Hz, J2=8 Hz, 2H), 7.70-7.72 (d, J=8 Hz, 1H), 7.84-7.86 (d, 1H), 7.88 (brs, 1H), 7.93-7.95 (d, J=8 Hz, 1H), 8.01 (brs, 1H), 12.47 (brs, 1H); LC-MS (ESI) m/z 278 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:15]([C:25]([OH:27])=[O:26])[CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:7]=2[CH:35]=1.[N+](=[CH2:40])=[N-]>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:15]([C:25]([O:27][CH3:40])=[O:26])[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH3:24])[CH2:10][N:9]=[C:8]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:7]=2[CH:35]=1
Reactant: C=[N+]=[N-]
Reactant: CCCN(CCC)CCC(=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2F)=NC1)C(=O)O
Product: CCCN(CCC)CCC(=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2F)=NC1)C(=O)OC

Procedure:
In the manner given in Example 14, 7-(trifluoromethyl)-2-[[1-carboxy-3-(dipropylamino)propylidene]-hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-(trifluoromethyl)-2-[[1-(methoxycarbonyl)-3-(dipropylamino)propylidene]hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:29])[C@H:6]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16](N3CCNCC3)=[CH:15][CH:14]=2)=[CH:11][S:10][N:9]=1)#[N:2].[C:30](C1C=CC(B(O)O)=CC=1)(=[O:32])[CH3:31]>>[C:30]([C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:8]([NH:7][C@H:6]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:29])[CH2:25][CH:26]([CH3:27])[CH3:28])=[N:9][S:10][CH:11]=2)=[CH:18][CH:17]=1)(=[O:32])[CH3:31]
Reactant: CC(C)C[C@H](Nc1nscc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2csnc2N[C@@H](CC(C)C)C(=O)NCC#N)cc1

Procedure:
N2-(4-bromoisothiazol-3-yl)-N1-(cyanomethyl)leucinamide (100 mg, 0.30 mmol, prepared as described in Example 13) was submitted to a Suzuki coupling with 4-acetylphenylboronic acid (99 mg, 0.60 mmoles) as described in Example 1 to afford N2-[4-(4-acetylphenyl)isothiazol-3-yl]-N1-(cyanomethyl)leucinamide which was purified by flash chromatography (30% to 55% EtOAc/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27]>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([F:17])([F:28])[F:29])=[O:27]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (927 mg, 4.19 mmol) and Et3 N (645 μl, 4.63 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (633 μl, 4.19 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.06 g, 62%) as a white crystalline powder. mp 178–180° C.; 1H-NMR (CDCl3) δ 1.44 (s, 9 H), 2.25 (s, 3 H), 3.51 (s, 2 H), 6.38 (br s, 1 H), 7.12–7.18 (m, 3 H), 7.36–7.37 (m, 1 H), 7.49–7.53 (m, 2 H), 8.13–8.16 (m, 1 H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[N:25]=[CH:24][NH:23][N:22]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[N:25]=[CH:24][NH:23][N:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nc[nH]n1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2nc[nH]n2)=C(c2ccccc2)S1(=O)=O
Yield: 3.1 %

Procedure:
A solution of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.110 g, 0.33 mmol) and 3-amino-1,2,4-triazole (0.083 g, 0.991 mmol) in DMF (0.5 mL) was heated at 140° C. for 25 mins in a microwave reactor. The residue was purified by preparative HPLC (Column Ace C8 (5u), 0.1M NH4OAc/MeCN, gradient) to give the title compound (0.0036 g, 2.2%); 1H-NMR (500 MHz, CD3CN): δ 7.78 (s, 1H), 7.20-7.40 (m, 5H), 3.74 (t, 2H), 1.84-1.76 (m, 2H), 1.51-1.42 (m, 2H), 0.99 (t, 3H); Mass Spectrum: M+H 348.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:54])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24](=[O:37])[N:25]2[CH2:29][CH2:28][CH2:27][C@@H:26]2[C:30]([O:32]C(C)(C)C)=[O:31])[CH:19]=[C:18]([O:38][CH2:39][C:40]([N:42]2[CH2:46][CH2:45][CH2:44][C@@H:43]2[C:47]([O:49]C(C)(C)C)=[O:48])=[O:41])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:47]([C@H:43]1[CH2:44][CH2:45][CH2:46][N:42]1[C:40](=[O:41])[CH2:39][O:38][C:18]1[CH:19]=[C:20]([CH:21]=[C:16]([O:15][CH2:14][C:13](=[O:54])[N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])[CH:17]=1)[O:22][CH2:23][C:24]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30]([OH:32])=[O:31])=[O:37])([OH:49])=[O:48]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of 350 mg (0.47 mmol) (R)-1-[[3,5-bis-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 254 mg (92%) of the title compound as a light brown powder.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.CO.[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>CC(O)=O>[Br:1][CH2:2][CH2:3][C:4](=[N:14][NH:15][C:16]([NH2:18])=[S:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNC(N)=S
Reactant: O=C(CCBr)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: NC(=S)NN=C(CCBr)c1ccccc1
Yield: 42.8 %

Procedure:
(Du, X.; Guo, C.; Hansell, E.; Doyle, P. S.; Caffrey, C. R.; Holler, T. P.; McKerrow, J. H.; Cohen, F. E. J. Med. Chem. 2002, 45, 2695-2707) Into a round bottom flask containing 3-bromopropiophenone (0.508 g, 2.34 mmol), 20 mL of anhydrous methanol were added and the solution was refluxed for 15 minutes. To the warm ketone solution, thiosemicarbazide (0.184 g, 2.04 mmol) and 1% solution of HOAc (0.2 mL) were added. The reaction mixture was refluxed under nitrogen atmosphere for 17 h, at which point, the solvent was evaporated and, the crude reaction mixture was purified by flash chromatography (30% EtOAc/70% hex) to obtain 0.2498 g (0.873 mmol) of the product in a 37% yield.
Reaction SMILES: F[C:2]1[CH:7]=C[C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.CC1[S:43]C(B2OC(C)(C)C(C)(C)O2)=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[S:43][C:2]([CH3:7])=[CH:3][CH:4]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:34])[F:33]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)s1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 5-methylthiophene-2-boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=517, obsd.=517).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:8]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1cc(Cc2ncc[nH]2)c2ccccc21
Yield: 73.6 %

Procedure:
1-Ethoxycarbonylmethyl-3-(1-imidazolylmethyl)indole (0.98 g) was dissolved in ethanol (10 ml) and a solution of sodium hydroxide (0.25 g) in water (2 ml) was added. The mixture was heated under reflux for 2 hours and then evaporated. The residue was dissolved in 5 ml of water and the solution was just acidified with acetic acid. The solution was evaporated to dryness and the residue was stirred with a little water and the mixture was filtered to give 1-carboxymethyl-3-(1-imidazolylmethyl)indole, (0.65 g), m.p. 218°-220° C., raised to 223°-224° C. on crystallisation from water. Found: C, 65.47; H, 5.11; N, 16.19. C14H13N3O2 requires: C, 65.87; H, 5.13; N, 16.46.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)C(OC1CC3N(C(=O)N(C)CCCCC=CC4C(C(O)=O)(NC3=O)C4)C1)=NC=C2.Cl[C:39]1[N:40]=[C:41]([O:51][CH:52]2[CH2:69][CH:68]3[N:54]([C:55](=[O:81])[N:56]([CH3:80])[CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH:62][CH:63]4[C:65]([C:71]([NH:73][S:74]([CH:77]5[CH2:79][CH2:78]5)(=[O:76])=[O:75])=[O:72])([NH:66][C:67]3=[O:70])[CH2:64]4)[CH2:53]2)[C:42]2[C:47]([CH:48]=1)=[CH:46][C:45]([O:49][CH3:50])=[CH:44][CH:43]=2>>[C:3]1([C:39]2[N:40]=[C:41]([O:51][CH:52]3[CH2:69][CH:68]4[N:54]([C:55](=[O:81])[N:56]([CH3:80])[CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH:62][CH:63]5[C:65]([C:71]([NH:73][S:74]([CH:77]6[CH2:79][CH2:78]6)(=[O:75])=[O:76])=[O:72])([NH:66][C:67]4=[O:70])[CH2:64]5)[CH2:53]3)[C:42]3[C:47]([CH:48]=2)=[CH:46][C:45]([O:49][CH3:50])=[CH:44][CH:43]=3)[CH:4]=[CH:5][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccccc3)cc2c1

Procedure:
The title product 56 was prepared from 17-(6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (55) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=688.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21]C(C)C)=[CH:15][CH:14]=2)=[CH:9]1.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21][C:34]([NH:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(C)NCC(C)c1ccc(-c2ccsc2)cc1
Reactant: O=C=NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CNC(=O)NCc1ccccc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl-2-propyl amine trifluoroacetate (prepared in example 1) and benzyl isocyanate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1>C(O)(=O)C>[Br:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:14][CH:4]=[C:3]2[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)CC=O
Reactant: NNc1ccc(Br)cc1
Solvent: CC(=O)O
Product: CC(C)c1c[nH]c2ccc(Br)cc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
3-Methylbutanal (0.921 g, 10.69 mmol) was added to a solution of (4-bromophenyl)hydrazine (2 g, 10.69 mmol) in acetic acid (100 mL) at 80° C., and the mixture was stirred for 3 h at 120° C. The reaction mixture was concentrated to get the residue, and the residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with saturated bicarbonate solution and brine, dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 2% ethyl acetate in pet ether to afford title compound (1.1 g, 38.4%) as an oil. 1H NMR (400 MHz, CDCl3): δ 7.91 (bs, 1H), 7.76 (m, 1H), 7.25-7.20 (m, 2H), 6.95 (d, J=2.4 Hz, 1H), 3.18-3.11 (m, 1H), 1.35 (d, J=6.8 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[CH:5]=1)([O-:3])=[O:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]([CH3:11])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1C
Yield: 102 %

Procedure:
The product was prepared by procedures which are well known in the art, that is, by the alkylation of 4-nitro-2-methylphenol (2.508 g, 0.0164 mol) with ethyl bromoacetate (3.00 g, 0.018 mol) in acetonitrile (50 mL) in the presence of potassium carbonate (2.76 g) to afford ethyl 4-nitro-2-methylphenoxyacetate (4.0 g, 100%); hydrogenation of the latter (4.0 g, 0.0164 mol) in ethanol (250 mL) in the presence of 10% palladium on carbon (1.0 g) to afford ethyl 4-amino-2-methylphenoxyacetate; which was then dissolved in CH2Cl2 (50 mL) and treated with pyridine (4.0 mL), followed by methanesulfonyl chloride (1.88 g) in CH2Cl2 (5.0 mL) to afford 3.27 g (69.4%) of N-[4-(ethoxycarbonylmethoxy)-3-(methyl)phenyl]methanesulfonamide, m.p. 83°-84° C., after purification by column chromatography on silica.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5](OC)=[O:6].O.[NH2:14][NH2:15]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([NH:14][NH2:15])=[O:6]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: NN
Solvent: CC#N
Solvent: O
Product: NNC(=O)c1cc(O)cc(Br)c1
Yield: 80 %

Procedure:
Methyl 3-bromo-5-hydroxybenzoate (1 g, 4.33 mmol) was treated with hydrazine hydrate (1 ml, 20.5 mmol) and acetonitrile (5 ml) as a solvent according the method described in Preparation 226a to obtain 0.8 g (64% yield) of the title compound that was used in the next synthetic step without further purification. Purity 80%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.Br[C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[N:26]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Reactant: Cc1ccnc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccnc(-c2ccc3c(c2)CCC3=O)n1

Procedure:
To a 25 mL flask containing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 50.0 mg, 0.19 mmol) was added 2-bromo-4-methyl pyrimidine (33.6 mg, 0.16 mmol) and sodium carbonate (23 mg, 0.76 mmol). The mixture was dissolved in 2 mL DME and 0.5 mL water. The mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (2.9 mg, 5 mol %) was added and the solution was degassed for an additional 15 minutes. The reaction was heated under reflux for 16 hours. The reaction was concentrated to dryness and was partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate and the combined organic layers were washed twice with water and once with brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The final product was purified by silica chromatography on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) eluting with 0-50% ethyl acetate in heptanes. The product was obtained as a white solid (SM-1e, 8.7 mg, 20%). MS (ES+) 225.2 (M+H+). 1H NMR (CDCl3) δ 2.61 (s, 3H), 2.74-2.78 (m, 2H), 3.20 (t, 2H), 7.15 (d, 1H), 7.85 (d, 1H), 8.53 (d, 1H), 8.59 (s, 1H), 8.75 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[C:10](=O)[O:9][C:8]([CH3:12])=[N:7]1.[CH3:17][NH2:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:12][C:8]1[N:18]([CH3:17])[C:10](=[O:9])[C:6](=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[O:2][CH3:1])[N:7]=1
Reactant: COc1ccccc1C=C1N=C(C)OC1=O
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccccc1C=C1N=C(C)N(C)C1=O
Temperature: 80 °C

Procedure:
4-(2′-Methoxybenzylidene)-2-methyl-4H-oxazol-5-one (5 g) was dissolved in ethanol (100 ml) and aqueous methylamine solution (20 ml) and potassium carbonate (7 g) were added. The mixture was heated at 80° C. for 7 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give the title compound (2 g).
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[NH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl[CH2:33][C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+].ClC(Cl)C>ClCCl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:25]=5)[C:20]([CH3:23])=[CH:21][CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)CCl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)ccc1=O
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a flask containing 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.15 g, 0.35 mmol), methyl chloroacetate (0.19 g, 1.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) was added dichloroethane (7 mL) and the reaction mixture was heated to 100° C. in a sealed tube overnight. The reaction was diluted with dichloromethane (15 mL) and washed with water (10 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane) to give the product (0.13 g, 76%). ESI-MS m/z calc. 497.14. found 498.3 (M+1)+ Retention time 1.73 minutes.