Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:18][N:17]=2)=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cnc(/C=C/c3ccc(F)cc3)cn2)sc1C(=O)NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cnc(CCc3ccc(F)cc3)cn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Part B. To a solution of 2-{5-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (20 mg, 0.05 mmol, 1.0 equiv) in ethyl acetate/ethanol (1:1) was added Pd(OH)2 (10 mg, 20%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 3 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 2-{5-[2-(4-fluoro-phenyl)-ethyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid benzylamide (13 mg, 65%). 1H NMR (400 MHz, CD2Cl2) δ 9.27 (s, 1H), 8.27 (s, 1H), 7.27-7.35 (m, 5H), 7.12-7.15 (m, 2H), 6.92-6.96 (m, 2H), 6.19 (bs, 1H), 4.58 (d, J=4.0 Hz, 2H), 3.05-3.16 (m, 4H), 2.72 (s, 3H); HRMS (M+H)+=433.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]([CH3:18])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.C=O.NCCCN1CCOCC1.ClC1C=C(C=CC=1Cl)C[N:40]([CH3:60])[C:41]([C:43]1[CH2:47][N:46]([CH2:48][CH2:49]C(NCCC(O)=O)=O)[C:45](=O)[C:44]=1[OH:59])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]([CH3:18])[C:7]([C:8]1[CH2:60][N:40]([CH2:41][CH2:43][CH2:47][N:46]2[CH2:48][CH2:49][O:59][CH2:44][CH2:45]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Agent: C=O
Agent: NCCCN1CCOCC1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCN2CCOCC2)C1

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and N-(3-aminopropyl)morpholine as described in the preparation of Compound 37. The title compound was isolated as a white solid (0.1345 g, 61% yield). 1H NMR (500 MHz, DMSO) δ: 1.69 (t, J=6.4 Hz, 2H), 2.25 (s, 2H), 2.32 (s, 4H), 2.97 (s, 3H), 3.40 (t, J=6.4 Hz, 2H), 3.55 (s, 4H), 4.05 (s, 2H), 4.59 (s, 2H), 7.24 (s, 1H), 7.51 (s, 1H), 7.62 (d, J=8.3 Hz, 1H). HRMS (M−H) calcd for C20H25N3Cl2O4: 442.13005. found: 442.1296.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]3=2)[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22]COC(C)=O>>[CH3:22][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]3=2)[CH:3]=[C:2]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2ccc3oc4ccccc4c3c2[nH]1
Reactant: CCOC(C)=O
Product: CCOC(=O)c1cc2ccc3oc4ccccc4c3c2n1C
Yield: 86.3 %

Procedure:
Using the procedure outlined in Example 34A, ethyl 1H-benzofuro[2,3-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 86.3% yield of ethyl 1-methyl-1H-benzofuro[2,3-g]indole-2-carboxylate, mp 114°-116°, (EtOAc), (C,H,N).
Reaction SMILES: [F:1][CH2:2][C:3](=[O:34])[CH:4]([NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([N:20]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[O:11])[CH2:5][C:6]([OH:8])=O.C(Cl)CCl.[CH2:39]([NH2:41])[CH3:40]>C(Cl)Cl.C1COCC1>[CH2:39]([NH:41][C:6](=[O:8])[CH2:5][CH:4]([NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([N:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:27][C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])=[O:11])[C:3](=[O:34])[CH2:2][F:1])[CH3:40]
Reactant: O=C(O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Reactant: CCN
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
To a stirred mixture of [3S/R, (2S)]-5-fluoro-4-oxo-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid (196 mg, 0.4 mmol), prepared as in Example 1, in anhydrous DCM (8 ml), was added Polymer bound EDC (400 mg, 0.8 mmol) and a solution of the ethylamine in THF (0.6 ml of a 2M solution, 12 mmol). The mixture was stirred at room temperature for 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (2.5% methanol in dichloromethane) to afford the title compound as a white solid (22.7 mg, 11%): 1H NMR (400 MHz, CDCl3) δ 1.09-1.39 (3H, m), 1.44-1.66 (6H, m), 2.04-3.66 (7H, m), 4.18-4.76 (6H, m) and 7.10-7.79 (8H, m). 19F NMR (376 MHz, CDC3) δ −223.32, −223.73, −225.92 and −226.76.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH:22]=[CH:23][C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I>[S:21]1[CH:22]=[CH:23][C:19]2[CH:18]=[C:17]([N:12]3[CH2:13][CH2:14][N:10]([C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:4]=4[CH:1]4[CH2:3][CH2:2]4)[C:11]3=[O:15])[CH:25]=[CH:24][C:20]1=2
Reactant: Brc1ccc2sccc2c1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Product: O=C1N(c2ccc3sccc3c2)CCN1c1cnccc1C1CC1
Yield: 13 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 70 mg, 0.344 mmol) was reacted with 5-bromobenzo[b]thiophene (88.1 mg, 0.413 mmol) 1,4-dioxane (5 mL), copper iodide (6.5 mg, 0.034 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (4.8 mg, 0.034 mmol) and potassium phosphate (219 mg, 1.034 mmol) to afford the crude product. Purification by preparative HPLC afforded 15 mg of the product (13% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>O1CCCC1.O.CCOCC>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:29])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccnc4)c3C2=O)C(=O)N1
Yield: 79.3 %

Procedure:
A stirred mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.09 g, 4.0 mmol) and nicotinoyl chloride hydrochloride (1.42 g, 8.0 mmol) in tetrahydrofuran (60 ml) was heated to reflux for 22 h. The suspension was filtered and washed with tetrahydrofuran (20 ml) and ether (10 ml) to yield a white solid. The solid was slurried in pH 7 buffer (40 ml) and ether (30 ml) for 1 h. The suspension was filtered and washed with water (20 ml) and ether (20 ml) to N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-3-pyridylcarboxamide as a white solid (1.2 g, 79% yield): mp, 176–178° C.; 1H NMR (DMSO-d6) δ 2.06–2.10 (m, 1H, CHH), 2.49–2.65 (m, 2H, CH2), 2.83–2.97 (m, 1H, CHH), 5.18 (dd, J=5.3, 12.5 Hz, 1H, NCH), 7.64 (dd, J=4.9, 7.9 Hz, 1H, Ar), 7.71 (d, J=7.3 Hz, 1H, Ar), 7.92 (t, J=7.8 Hz, 1H, Ar), 8.29–8.34 (m, 1H, Ar), 8.45 (d, J=8.2 Hz, 1H, Ar), 8.83 (dd, J=1.2, 4.8 Hz, 1H, Ar), 9.15 (d, J=1.7 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 49.00, 119.06, 119.34, 123.91, 127.36, 129.17, 131.55, 135.24, 135.94, 136.20, 148.47, 152.95, 163.85, 166.59, 167.54, 169.69, 172.72; Anal Calcd for C19H14N4O5+0.13 H2O: C, 59.95; H, 3.78; N, 14.72; H2O, 0.62. Found: C, 59.83; H, 3.66; N, 14.68; H2O, 0.64.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH2:29])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([NH2:29])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: NC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(N)=O)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-benzamide in an analogous manner to Example 1221d. Title compound isolated as an orange solid (29 mg, 21%). LCMS 487.20 (M+H), MP 128-134, HPLC purity 90%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.37 (s, 1H), 9.22 (s, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.52-7.43 (m, 3H), 7.21 (s, 1H), 7.13-7.10 (m, 1H), 6.83-6.80 (m, 1H).
Reaction SMILES: C([CH:8]([CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=3[Cl:27])[C:12]=2[O:11]1)[NH2:9])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>>[Cl:27][C:20]1[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]1[C:12]2[O:11][CH:10]([CH2:8][NH:9][C:38](=[O:39])[O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: NC(Cc1ccccc1)C1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1)OCc1ccccc1
Yield: 86.8 %

Procedure:
Treatment of (±)-benzyl[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.83 g, 8.61 mmol) with diisopropylethylamine (1.67 g, 12.92 mmol) and benzyl chloroformate (1.76 g, 10.33 mmol) generally according to the procedure described for Intermediate 12 provided 3.46 g (87%) of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Br:23]N1C(=O)CCC1=O.CN(C)C=O>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Br:23])[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)c(Br)c1

Procedure:
A mixture of 10.0 g. (0.034 mol.) of 2-n-butyl-3-(4'-hydroxybenzoyl)benzofuran and 6.1 g. (0.034 mol.) of N-bromosuccinimide in 150 ml. of damp dimethylformamide was refluxed for 12 hours. The reaction mixture was poured into water and extracted with chloroform. The extracts were washed repeatedly with water, then dried (Na2SO4) and concentrated to give 2-n-butyl-3-(3'-bromo-4'-hydroxybenzoyl)-benzofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28](O)=[O:29])=[N:9]1.C(N1C=CN=C1)([N:33]1[CH:37]=[CH:36]N=C1)=O.C(N)C.C1COCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([NH:33][CH2:37][CH3:36])=[O:29])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)O)nn3-c3ccccc3Cl)s2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a suspension of 1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole-3-carboxylic acid (92 mg, 0.2 mmol) in DCM (2 mL) was added carbonyldiimidazole (39 mg, 1.2 equiv) and stirring was continued for 2 h at 20° C. A solution of ethylamine in THF (1.8 M, 0.17 mL, 1.5 equiv) was added and the mixture was stirred overnight at 20° C. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to afford 1-(2-chlorophenyl)-N-ethyl-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole-3-carboxamide (84 mg). 1H-NMR (CDCl3): δ 8.03 (m, 1H), 7.83 (m, 1H), 7.74 (m, 1H), 7.62-7.45 (m, 5H), 7.22 (m, 1H), 7.19 (s, 1H), 6.91 (m, 1H), 6.82 (d, 1H), 3.55-3.43 (m, 2H), 3.07 (3 s, H), 1.25 (s, 3H). MS(ES): 486 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:23][O:24][C:25]1[C:26]([CH3:39])=[C:27]([CH:36]=[CH:37][CH:38]=1)[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=O.Cl>C1COCC1>[CH3:23][O:24][C:25]1[C:26]([CH3:39])=[C:27]([CH:36]=[CH:37][CH:38]=1)[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]=[C:30]1[C:9]1[O:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: COc1cccc(CC2CCCCC2=O)c1C
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Temperature: 5 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 4,5-diphenyloxazole (990 mg) in THF (15 ml) was added n-BuLi (1.56M solution in hexane, 2.87 ml) at −60° C. and stirred for 1 hour. To the mixture was added a solution of 2-(3-methoxy-2-methylbenzyl)cyclohexanone (945 mg) in THF (4 ml), warmed to 5° C., and stirred for 2 hours. To the reaction mixture was added 1N HCl and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was dissolved in toluene (45 ml) and p-TsOH.H2O (79 mg) was added. The mixture was refluxed for 48 hours, cooled to room temperature, diluted with EtOAc, washed with saturated sodium hydrogen carbonate, water, and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 15:1 to 10:1) to give 2-[1-(3-methoxy-2-methylbenzyl)-2-cyclohexen-2-yl]-4,5-diphenyloxazole (1.19 g) as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1Cc2cc(N)ccc2CCC1=O
Product: CN1Cc2cc(Nc3ncc(Cl)c(Nc4ccccc4-c4nccn4C)n3)ccc2CCC1=O

Procedure:
Following a procedure analogous to Example 1742a, 8-amino-2-methyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one and (2,5-dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine were converted to 8-{5-chloro-4-[2-(1-methyl-1H-imidazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-2-methyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one. TFA salt: 1H NMR (300 MHz, CDCl3) δ 10.87 (s, 1H), 8.63 (d, 1H), 8.14 (s, 1H), 7.50 (m, 4H), 7.35 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7.11 (s, 2H), 4.53 (s, 2H), 3.87 (s, 3H), 3.22 (t, 2H), 3.11 (s, 3H), 3.01 (t, 2H); MS (m/e) 474 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4]1)[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:9][CH:10]=1
Reactant: CCn1nnc(-c2ccc(C)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1nnc(-c2ccc(CBr)cc2)n1
Reaction time: 1.5 h
Yield: 103.7 %

Procedure:
A solution of 18.8 grams (0.100 mole) of 2-ethyl-5-(4-methylphenyl)-1,2,3,4-tetraazole in 156 mL of carbon tetrachloride was stirred, and 19.6 grams (0.110 mole) of N-bromosuccinimide, followed by 0.24 gram (0.001 mole) of benzoyl peroxide were added. Upon completion of addition, the reaction mixture was heated to reflux where it stirred for 90 minutes. After this time the reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, yielding 27.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl[CH2:26][CH2:27][N:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:29][N:28]([CH3:30])[CH2:27][CH2:26][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[C:2]1=[O:1]
Reactant: CN(C)CCCl
Reactant: COC(=O)c1ccc(-c2ccc[nH]c2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cccn(CCN(C)C)c2=O)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
Methyl 4-(2-oxo-1,2-dihydropyridin-3-yl)benzoate (1.04 g) was dissolved in N,N-dimethylformamide (20 mL), and sodium carbonate (1.88 g) and (2-chloroethyl)dimethylamine hydrochloride (981 mg) were added, followed by stirring at 80° C. for 7 hours. Then, potassium carbonate (628 mg) was added, followed by stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1) to obtain methyl 4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoate (954 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H][H]>O1CCOCC1.[Ni]>[NH2:16][C:4]1[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Oc1ccc(O)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(Cl)cnc1Oc1ccc(O)cc1
Yield: 97.7 %

Procedure:
110.7 g (0.415 mole) of 4-(5-chloro-3-nitropyridin-2-yloxy)phenol are dissolved in 1200 ml of dioxan and, after addition of 22.0 g of Raney nickel catalyst, hydrogenated with hydrogen at 20°-25° C. The catalyst is then removed by filtration, the solution is concentrated and the residue is stirred in hexane and the product is filtered and dried, affording 96.0 g (98% of theory) of 4-(3-amino-5-chloropyridin-2-yloxy)phenol with a melting point of 174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([S:51]([N:60]([CH3:62])[CH3:61])(=[O:59])=[N:52][C:53](=[O:58])[C:54]([F:57])([F:56])[F:55])=[CH:47][CH:46]=1>O1CCOCC1>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([S:51]([N:60]([CH3:62])[CH3:61])(=[O:59])=[N:52][C:53](=[O:58])[C:54]([F:56])([F:55])[F:57])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CN(C)S(=O)(=NC(=O)C(F)(F)F)c1ccc(Br)cc1
Solvent: C1COCCO1
Product: CN(C)S(=O)(=NC(=O)C(F)(F)F)c1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-[(4-bromophenyl)-(dimethylamino)oxo-λ6-sulfanylidene]-2,2,2-trifluoroacetamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.22 min; Mass spectrum (ESI+): m/z=782 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:32][CH:33]5[CH2:37][O:36]C(C)(C)[O:34]5)=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.C(N(CC)CC)C>C(#N)C.CO.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:32][C@H:33]([OH:34])[CH2:37][OH:36])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC1(C)OCC(COc2ccc3c(c2)sc2ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)O1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: OC[C@@H](O)COc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 124.5 %

Procedure:
[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[7-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-amine (0.92 g, 2 mmol) was dissolved in acetonitrile (5 mL) and filtered through a filter paper and filter paper washed with acetonitrile (2 mL). To the clear brown solution at 45° C. was added concentrated hydrochloric acid (37%, 0.14 mL, 2 mmol). To the resultant solid was added acetonitrile (5.0 mL) and then another equivalent of concentrated hydrochloric acid (37%, 0.14 mL, 2 mmol). The mixture was stirred at 45° C. for 1.5 hours when the reaction was judged complete by TLC (3% MeOH/Dichloromethane+one drop of triethylamine). The mixture was cooled to room temperature, filtered, and the solid was washed with acetonitrile (15 mL) and dried under vacuum at 40° C. over P2O5 for 16-18 hours to give ((2R)-3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino) [1]benzothieno[2,3-d]pyrimidin-7-yl]oxy}propane-1,2-diol hydrochloride (0.70 g, 77%).
Reaction SMILES: [CH2:1]([S:5]([OH:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:9][C:10]([N:12]([OH:47])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH2:21][CH2:22][C:23]([N:25]([OH:46])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([CH2:34][CH2:35][C:36]([N:38]([OH:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[O:37])=[O:33])=[O:24])=[O:20])=[O:11]>>[CH2:1]([S:5]([O-:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:9][C:10]([N:12]([OH:47])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH2:21][CH2:22][C:23]([N:25]([OH:46])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([CH2:34][CH2:35][C:36]([N:38]([OH:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[O:37])=[O:33])=[O:24])=[O:20])=[O:11]
Reactant: CCCCS(=O)(=O)O
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Product: CCCCS(=O)(=O)[O-]

Procedure:
Following a procedure analogous to that of Example 1, butane-1-sulphonic acid and desferrioxamine-B are reacted to give the butane-1-sulphonate salt of desferrioxamine-B.