Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21]C(C)(C)[O:23][C@@H:19]2[C@@H:18]([CH2:26][N:27]([CH:37]([CH3:39])[CH3:38])[CH:28]2[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]2)[CH2:17]1.C(N(CC)C(C)C)(C)C.[C:55]([C:59]1[CH:60]=[C:61]([NH2:66])[C:62]([NH2:65])=[CH:63][CH:64]=1)([CH3:58])([CH3:57])[CH3:56].C([O-])(O)=O.[Na+]>CN(C)C=O>[NH2:66][C:61]1[CH:60]=[C:59]([C:55]([CH3:57])([CH3:56])[CH3:58])[CH:64]=[CH:63][C:62]=1[NH:65][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:31][CH:28]([N:27]([CH2:26][C@H:18]2[CH2:17][C@@H:16]([N:11]3[CH:10]=[N:9][C:8]4[C:12]3=[N:13][CH:14]=[N:15][C:7]=4[NH:6][CH2:5][C:4]3[CH:40]=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:3]=3[O:2][CH3:1])[C@H:20]([OH:21])[C@@H:19]2[OH:23])[CH:37]([CH3:38])[CH3:39])[CH2:29]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@@H](O)[C@H]2O)c(OC)c1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (1.19 g, 3.13 mmol) added to a solution of 3-{3-[{[(3aR,4R,6R,6aS)-6-{6-[(2,4-dimethoxybenzyl)amino]-9H-purin-9-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl}{isopropyl)amino]cyclobutyl}propanoic acid (1.30 g, 2.09 mmol) and N,N-Diisopropylethylamine (1.20 ml, 6.89 mmol) and 4-tert-butylbenzene-1,2-diamine (0.411 g, 2.50 mmol) in N,N-Dimethylformamide (12.9 ml). The reaction was stirred for 2 hours, NaHCO3 (saturated) was added and the mixture extracted with EtOAc (3×) and the combined organics was dried over MgSO4 filtered and concentrated. The residue was purified by flash chromatography (DCM→DCM/7N NH3 in MeOH 95:5) to yield the desired amide (1.4 g) as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1>O1CCCC1>[N:17]1[N:16]=[C:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[NH:19][CH:18]=1
Reactant: Nc1nc[nH]n1
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: O=C(Nc1nnc[nH]1)c1ccc2ccccc2c1
Yield: 63 %

Procedure:
A mixture of 2-naphthyl carboxylic acid (3.0 g, 17 mmol) and N,N'-carbonyldiimidazole (3.1 g, 19 mmol) in dry tetrahydrofuran (75 ml) was stirred at reflux temperature for 1 h. To the cooled reaction mixture was added 3-amino-1,2,4-triazole (1.5 g, 17 mmol) and the resulting mixture was refluxed for 2.5 h. The cooled reaction mixture was quenched with water (150 ml) and the precipitate was filtered off and washed with water (2×20 ml), heptane (2×20 ml) and diethyl ether (2×20 ml), dried in vacuo at 50° C. affording 2.55 g (61%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]2[NH:30][N:29]=[N:28][N:26]=2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCCCCc1ccc(OCCCc2nnn[nH]2)cc1)OCc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A mixture of {4-[4-(3-cyanopropoxy)phenyl]butyl}carbamic acid benzyl ester 2 (0.90 g, 2.5 mmol), sodium azide (0.50 g, 7.5 mmol), and ammonium chloride (0.40 g, 7.5 mmol) in DMF (7 mL), was stirred at 120° C. for 16 h. Inorganics were removed by vacuum filtration. The filtrate was diluted with ethyl acetate, and washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated. The residue was taken up in ethyl acetate (5 mL) and diluted with hexanes (10 mL). Solid precipitates were collected by suction filtration and purified by flash silica gel column chromatography eluting with methanol/dichloromethane (1:50, v/v) to give the desired product 3 as a white solid (0.78 g, 76% yield). 1H NMR (300 MHz, CD3OD) δ 1.51 (m, 4H), 2.20 (m, 2H), 2.50 (m, 2H), 3.10 (m, 4H), 4.00 (m, 2H), 5.00 (s, 2H), 6.75 (d, 2H), 7.05 (d, 2H), 7.30 (m, 5H). m/z (ESI): 410 [C22H27N5O3+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)C1CCCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)C3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(cyclopentylsulfonyl)benzene MS (ESI): mass calcd. for C21H20FN3O2S, 397.13; m/z found, 398.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.65 (d, J=1.3, 1H), 8.30 (d, J=1.3, 1H), 8.19 (dd, J=7.9, 1.2, 1H), 8.14 (m, 1H), 7.79 (m, 1H), 7.71 (m, 1H), 7.48 (dd, J=7.5, 1.2, 1H), 7.42 (s, 1H), 7.41-7.38 (m, 1H), 3.23-3.15 (m, 1H), 1.92-1.81 (m, 2H), 1.77-1.63 (m, 4H), 1.60-1.51 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:20])[CH2:11][CH:10]2[CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:33][NH:34][CH3:35]>CN(C)C=O>[CH3:33][N:34]([CH2:21][CH:10]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[CH2:11]1)[CH3:35]
Reactant: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2c2ccccc2)c1
Reactant: CNC
Solvent: CN(C)C=O
Product: COc1cccc(C2C(CN(C)C)CC(=O)N2c2ccccc2)c1
Reaction time: 3 h

Procedure:
To. 22.0 gm. of 5-(3-methoxyphenyl)-1-phenyl-4-(p-toluenesulfonyloxymethyl)pyrrolidin-2-one in 150 ml. of dimethylformamide was added 21 ml. of 40% aqueous dimethylamine, the solution refluxed for 3 hours and then 21 ml. more of 40% aqueous dimethylamine added and reflux continued for an additional 3 hours. After cooling the reaction was decanted into ice water and acidified. Extraction with ether followed by basification of the aqueous phase with potassium carbonate yielded a semi-solid which was extracted with chloroform, dried (Na2SO4), filtered and concentrated in vacuo to a solid. Recrystallization from acetonitrile provided 7.0 gm. of beige crystals, m.p. 88°-92°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C=O)C>[Si:12]([O:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cn[nH]c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cn[nH]c1
Reaction time: 17 h
Yield: 94.3 %

Procedure:
4-Hydroxypyrazole (1.16 g, 13.8 mmol) and imidazole (1.13 g, 16.6 mmol) were suspended in DMF (50 ml) under nitrogen and t-butyldimethylsilylchloride (2.3 g, 15.2 mmol) was added. After stirring 17 hours, the solvent was removed in vacuo and the residue treated with water containing 4.5 g of potassium carbonate. The mixture was extracted with two portions of chloroform and the organic layer dried over sodium sulfate. The solvent was removed in vacuo to yield product (2.58 g, 94%). NMR
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH3:15]>N1CCCCC1>[CH2:14]([O:16][C:17](=[O:21])[C:18]([C:19]#[N:20])=[CH:6][C:5]1[CH:8]=[C:9]([O:10][CH3:11])[C:2]([NH2:1])=[C:3]([O:12][CH3:13])[CH:4]=1)[CH3:15]
Reactant: CCOC(=O)CC#N
Reactant: COc1cc(C=O)cc(OC)c1N
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1cc(OC)c(N)c(OC)c1

Procedure:
A mixture of 18.1 g. of 4-amino-3,5-dimethoxy-benzaldehyde, 11.3 g. of cyanoacetic acid ethyl ester and 3 drops of piperidine was heated at 120° C. for 1 hour in an open vessel, whereby the formed water evaporated. The residue was recrystallized from ethyl acetate/petroleum ether and there was obtained 4-amino-α-cyano-3,5-dimethoxy-cinnamic acid ethyl ester having a melting point of 134°-136° C.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]([NH:35][S@@](C(C)(C)C)=O)[CH3:34])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2>CO>[F:8][C:9]1[CH:10]=[C:11]([C@@H:33]([NH2:35])[CH3:34])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrogen chloride, 4.0 M solution in 1,4-dioxane (0.63 mL, 2.5 mmol) was added to a suspension of (R)-N-((S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide. (0.413 g, 0.84 mmol)) in methanol (60.00 mL). The yellow reaction mixture was allowed to stir at ambient temperature for 4 h. The crude reaction mixture was concentrated in vacuo and purified by silica gel chromatography to afford (S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanamine. MS (ESI) m/z: calculated: 389.1; Observed: 390.1 (M++1).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[CH3:27]>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][C:19]=1[CH3:27]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Product: CCC(=O)NC1CCCc2c(-c3ccc(F)c(C)c3)cncc21
Yield: 82 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 4-fluoro-3-methylphenylboronic acid to give the title compound as light yellow foam in 82% yield. MS: 313.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[N:6][OH:7])[CH3:5])[CH3:2].C(O[K])(C)(C)C.[CH2:14]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1F)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[N:6][O:7][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:30])[CH3:5])[CH3:2]
Reactant: CCOC(C)=NO
Reactant: O=C(OCc1ccccc1)c1ccccc1F
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(C)=NOc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a stirring solution of ethyl-N-hydroxyacetimidate (2.06 g, 20.0 mmol) in anhydrous DMF (60 mL) under Ar was added tBuOK (2.21 g, 19.7 mmol) all at once. After 30 min benzyl-2-fluorobenzoate 16 (4.13 g, 17.9 mmol) was added as a solution in DMF (20 mL) and the reaction was stirred at room temperature. After 3 h the reaction was diluted with H2O (400 mL), extracted with EtOAc (3×100 mL), and the combined organics were washed with H2O (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatographic purification over silica (5-10% gradient EtOAc in hexanes) afforded 18 as a clear syrup (3.61 g, 64%). 1H-NMR (500 MHz, CDCl3) δ 1.34 (t, J=7.0 Hz, 3H), 2.00 (s, 3H), 4.18 (q, J=7.0 Hz, 2H), 5.34 (s, 2H), 6.96 (dt, J=1.1, 7.7 Hz, 1H), 7.30-7.35 (m, 1H), 7.35-7.39 (m, 2H), 7.42-7.48 (m, 3H), 7.55 (dd, J=1.1, 8.4 Hz, 1H), 7.90 (dd, J=1.8, 7.7 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 14.4, 14.5, 63.1, 66.6, 114.5, 117.0, 120.4, 128.2, 128.4, 128.5, 131.7, 133.8, 136.1, 159.5, 165.8, 166.7; GC-MS 313 m/z[M]+, C18H19NO4 requires 313, 228 m/z [M-85]+, benzyl-2-hydroxybenzoate C14H12O3 requires 228.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:26])([CH2:15][N:16]1[CH:25]=[C:19]2[N:20]=[CH:21][C:22]([Br:24])=[CH:23][C:18]2=[N:17]1)[C:13]#[N:14]>C1COCC1>[Br:24][C:22]1[CH:21]=[N:20][C:19]2=[CH:25][N:16]([CH2:15][C:12]([NH:11][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=3)([C:13]#[N:14])[CH3:26])[N:17]=[C:18]2[CH:23]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(I)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-iodobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 182) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (8.3 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=510, RT=0.59 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:26]I>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH3:26])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: COC(=O)CCCNS(=O)(=O)c1ccc(-c2ccc(C#N)cc2)cc1
Product: COC(=O)CCCN(C)S(=O)(=O)c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
(prepared from 4-cyano-4'-[(3-methoxycarbonylpropyl)-aminosulphonyl]biphenyl by methylation with methyl iodide)
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26](C#N)=[C:25]([O:31][CH3:32])[CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[C:6]([CH:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[C:25]([O:31][CH3:32])[CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1C
Reactant: COc1cc(OCCOCc2ccccc2)ccc1C#N
Product: COc1cc(OCCOCc2ccccc2)ccc1-c1cc2ccccc2c(=O)[nH]1
Yield: 10.3 %

Procedure:
According to Example 36-1, N-methyl-o-toluamide (1.70 g) and 4-(2-benzyloxyethoxy)-2-methoxybenzonitrile (3.30 g) were reacted, to give 3-[4-(2-benzyloxyethoxy)-2-methoxyphenyl]isoquinolin-1-one (0.47 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([F:14])[CH:8]=1.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][NH2:26]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([F:14])[CH:8]=2)[N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])[N:26]=1)=[O:16]
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)c(F)c1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
4-(4-bromo-3-fluoro-phenyl)-2-oxo-3-butenoic acid methyl ester (665.0 mg, 2.3 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (455.0 mg, 2.6 mmol) were added to acetic acid (10.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 835.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1.O.CN([CH:21]=[O:22])C>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[O:16][CH2:15][O:14][C:11]2=[CH:12][C:13]=1[CH:21]=[O:22]
Reactant: COc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1C=O)OCO2
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of phosphorous oxychloride (3.0 ml, 0.033 mol) in DMF (10 ml) was added a solution of 1-methoxy-3,4-methylenedioxybenzene (2.0 g, 0.013 mol) in DMF (2 ml) at 0° C. After stirring at 60° C. for 18 h the mixture was cooled to 0° C. and then poured into water (500 ml). The precipitate was filtered and dried. The title compound was collected as a yellow solid (2.20 g, 92%).
Reaction SMILES: CO[C:3](=[O:32])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:31])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([Br:30])[CH:17]=1)[CH3:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2([CH3:15])[C:3](=[O:32])[C:4]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=3[Cl:10])[NH:12][C:13]2=[O:31])=[CH:17][C:18]=1[Br:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OCc2ccccc2)c(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(OCc3ccccc3)c(Br)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 67.3 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 2-[2-(4-benzyloxy-3-bromo-phenyl)-propionylamino]-4,6-dichloro-benzoic acid methyl ester (0.80 g, 1.50 mmol) and LiHMDS (3.20 mmol, 1M THF solution). After normal workup, the objective compound (0.51 g, 67%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.71 (s, 3H, CH3), 5.09 (s, 2H, CH2Ph), 6.78 (d, J=2.0 Hz, 1H, ArH), 6.85 (d, J=9.0 Hz, 1H, ArH), 7.04 (dd, J=8.6, 2.4 Hz, 1H, ArH), 7.11 (d, J=2.4 Hz, 1H, ArH), 7.33-7.43 (m, 5H, ArH); m.p. 189-190° C.; MS(EI) m/e 503 [M+], 91; HRMS m/e cacld. for C23H16NO3Br1Cl2 502.9691, found 502.9696.
Reaction SMILES: [OH:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C1(CC#[N:21])C=CC=CC=1>O1CCOCC1>[OH:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: N#CCc1ccccc1
Reactant: O=C(Cl)c1cc(I)cc(I)c1O
Solvent: C1COCCO1
Product: NC(=O)c1cc(I)cc(I)c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.9 parts of 2-hydroxy-3,5-diiodobenzoyl chloride and 3.7 parts of 4-amino-2-(trifluoromethyl)-α-[3-trifluoromethyl)phenyl]benzeneacetonitrile in 60 parts of 1,4-dioxane is stirred and refluxed for 10 minutes. The reaction mixture is evaporated. The residue is boiled in methylbenzene for 10 minutes. After cooling to room temperature, the precipitated product is filtered off, yielding N-[4-{α-cyano-α-[3-trifluoromethyl)phenyl]methyl-}3-(trifluoromethyl)phenyl]-2-hydroxy-3,5-diiodobenzamide; mp. 206.3° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][C:13](=O)[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(OP([CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])(OCC)=O)C.[H-].[Na+]>COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14]/[C:13](=[CH:25]\[CH:26]=[CH:27]\[C:28]([O:30][CH2:31][CH3:32])=[O:29])/[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCN(Cc2ccc3c(c2)OCO3)C1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)/C=C/C=C1\CCN(Cc2ccc3c(c2)OCO3)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
To a solution of ketone 274 (0.65 g, 2.96 mmol) and (E)-ethyl 4-(diethoxyphosphoryl)but-2-enoate (1.0 mL, 4.33 mmol) in ethyleneglycol dimethylether (50 mL) at 0° C. was added NaH (0.26 g, 6.58 mmol) and the mixture was stirred at 0° C. for 30 min then at room temperature for 2 h. The reaction mixture was quenched with acetone (2 mL) then diluted with DCM and washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent: 50% AcOEt in DCM) to provide title compound 275 (0.15 g, 16% yield) as a mixture of cis/trans isomers.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=2)[CH:3]=1
Reactant: COc1ccc(Br)cc1C
Reactant: Clc1ccnc2ccccc12
Product: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1C

Procedure:
The title compound, m. p. 90-92° C., MS: m/e=283 (M+), was prepared from 4-chloro-quinoline and 4-bromo-1-methoxy-2-methyl-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CON
Reactant: O=CCCc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CON=CCCc1ccc(Cl)c(Cl)c1
Yield: 91 %

Procedure:
Reaction of 3-(3,4-dichlorophenyl)-propionaldehyde (Heck, J. Amer. Chem. Soc., 90, 1968, 5526) with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (91% yield), bp 80-90° C./0.5 torr (bulb to bulb distillation, air bath temperature). 1HNMR indicated a 55:45 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.63 and 2.76 (2H, 2 m, CH2), 2.9 (2H, m, CH2), 3.96 and 4.01 (3H, 2 s, OCH3), 6.77 (t, J=5.5 Hz, CH), 7.16-7.5 (3H, m, aromatics and CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[F:13][C:14]([F:24])([F:23])[C:15](=O)[CH2:16][C:17](OCC)=[O:18]>>[OH:18][C:17]1[C:8]2[C:6](=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[N:7]=[C:15]([C:14]([F:24])([F:23])[F:13])[CH:16]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1cc([N+](=O)[O-])c2nc(C(F)(F)F)cc(O)c2c1
Yield: 27 %

Procedure:
The reaction of 4-methoxy-2-nitroaniline with ethyl trifluoroacetoacetate in polyphosphoric acid at 130°-140° gave 4-hydroxy-6-methoxy-8-nitro-2-trifluoromethylquinoline. The pure compound (tan crystals, mp 138°-140° ) was obtained in 27% yield following several crystallizations of the crude product from ligroin.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[O-:25][C:26]#[N:27].[Na+]>O>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:26]([NH2:27])=[O:25])[CH:4]=2)[NH:8][CH:7]=1
Reactant: N#C[O-]
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A solution of 2-[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3-(2H)-dione, hemisulphate, hydrate (1.01 g) in hot water (27 ml) was treated with a solution of sodium cyanate (0.25 g) in water (9 ml) and heated on a steam bath for 1.5 h. The reaction mixture was cooled and filtered, affording the title urea as a white crystalline solid (0.82 g) m.p. 230°-2°.