Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:10][C:9]=2[N+:26]([O-])=O)=[CH:4][CH:3]=1.[OH2:31].O.[Sn](Cl)Cl.[CH2:36]([OH:38])[CH3:37]>>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:10][C:9]=3[N:26]=[C:5]2[C@H:4]2[CH2:3][CH2:2][CH2:30][CH2:29][C@H:37]2[C:36]([OH:31])=[O:38])=[CH:4][CH:3]=1
Reactant: O
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(Br)cc1
Agent: Cl[Sn]Cl
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
To a 1 L round-bottomed flask were added a stir bar, N-(4-bromobenzyl)-2-nitro-4-(quinolin-2-ylmethoxy)aniline (6.1 g, 13 mmol), tin(II) chloride dihydrate (12.5 g, 55.4 mmol) and ethanol (250 mL). The resulting mixture was heated to 80° C. After 24 h, the mixture was cooled and partitioned between water (100 mL) and EtOAc (300 mL). The mixture was stirred vigorously while the pH was adjusted to 8 using 2 M sodium carbonate. The organic layer was separated and washed with brine (100 mL), dried with magnesium sulfate, filtered, and concentrated to dryness to afford the title compound (3.1 mg, 54%). The residue was kept under vacuum until use.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:20]=1
Reactant: CS(=O)(=O)NCc1ccc(N)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CS(=O)(=O)NCc1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
5.309 g N-(4-Amino-benzyl)-methanesulfonamide (obtained in Step 2, 26.5 mmol) and 4.739 g 4,6-dichloropyrimidine (31.81 mmol) was dissolved in 120 cm3 of isopropyl-alcohol, 6.93 cm3 N,N-diisopropyl-ethylamine (5.140 g, 39.76 mmol) was added and the mixture was refluxed for four days. The reaction mixture was cooled to room temperature and the precipitated compound was filtered off. The light yellow product was washed well with diethyl-ether and air-dried. 3.813 g N-[4-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide was obtained above 98% purity in 46% overall yield. For analitical results and compound identification see Table 1. The compound was used as a starting material in the preparation of Example 34-58 and 76.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:20]([F:19])([F:29])[O:21][C:22]1[CH:23]=[C:24]([S:28][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)Oc1cccc(S)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2cccc(OC(F)(F)F)c2)CC1
Yield: 74.1 %

Procedure:
A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.34 g, 4.79 mmol), 3-(trifluoromethoxy)benzenethiol (1.12 g, 5.75 mmol) and potassium carbonate (1.99 g, 14.4 mmol) in N,N-dimethylformamide (50 mL) at 90° C. for 20 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (20:1) to give 1.34 g (74%) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3=[C:15]([OH:32])[C:16]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5[O:30][CH3:31])[C:20](=[O:21])[C:17]=4[C:18]([OH:19])=[C:13]3[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:38])[C@@H:3]1[OH:39].C(N([CH2:45][CH3:46])CC)C.C[C@@H]1O[C@@H]([O:54][C@@H:55]2[C:60]3=[C:61]([OH:78])[C:62]4[C:74](=O)[C:73]5C(=CC=C[C:72]=5[O:76]C)C(=O)[C:63]=4C(O)=[C:59]3[CH2:58][C@@:57](O)([C:79](CO)=[O:80])[CH2:56]2)C[C@H](N)[C@@H]1O.Cl.[C:87](O)(C(F)(F)F)=O>CN(C=O)C.C(#N)C.O>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3=[C:15]([OH:32])[C:16]4[C:28](=[O:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][C:26]=5[O:30][CH3:31])[C:20](=[O:21])[C:17]=4[C:18]([OH:19])=[C:13]3[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:38])[C@@H:3]1[OH:39].[CH3:87][C@@:23]12[C@H:74]3[CH2:73][C@@H:72]([OH:76])[C@:45]4([CH3:46])[C@@H:58]([C:57]5[CH2:79][O:80][C:55](=[O:54])[CH:56]=5)[CH2:59][CH2:60][C@:61]4([OH:78])[C@@H:62]3[CH2:63][CH2:20][C@@H:22]1[CH2:27][C@@H:26]([OH:30])[CH2:25][CH2:24]2
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@@H](O)[C@]2(C)[C@@H](C3=CC(=O)OC3)CC[C@]12O
Reaction time: 2 h

Procedure:
Doxorubicin was obtained from Sigma-Aldrich. To couple digoxygenin to doxorubicin, we performed the following procedure: To a solution of Digoxigenin-3-O-methylcarbonyl-epsilon-aminocaproic acid-N-hydroxysuccinimide ester (20 mg, 30.4 μmol) in DMF (500 μL) was added triethylamine (8.4 μL, 60.8 μmol) and the resulting mixture was transferred immediately to a solution of Doxorubicin-HCl (16.6 mg, 30.4 μmol) in DMF (500 μL). The reaction mixture was tumbled for 2 h at ambient temperature, filtered, and the target compound was isolated by preparative reversed phase HPLC employing an acetonitrile/water gradient containing 0.1% TFA (Merck Cromolith prep RP-18e column, 100×25 mm). After lyophilization the Doxorubicin-Digoxigenin conjugate was obtained as a colorless solid (25.2 mg, 76%). Analytical HPLC: tR=13.9 min (Merck Chromolith Performance RP-18e, 100×4.6 mm, water+0.1% TFA acetonitrile/water+0.1% TFA 80:20, 25 min); ESI-MS (positive ion mode): m/z: calcd for C58H75N2O18: 1087.5; found: 1087.6 [M+H]+. The molecular weight of doxorubicin is 579.98 Da. The molecular weight of the resulting Doxorubicin-Dig conjugate is 1087.24 Da. Until the point of complexation to the antibody, we stored the conjugate in aliquots in DMSO at −20° C. FIG. 18 shows the structure of Doxorubicin-digoxygenin conjugate.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=O)[CH3:7].Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=[N:11][OH:12])[CH3:7]
Reactant: CC(=O)CCCN(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(CCCN(C)C)=NO
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of 20 gm (167 mMol) N,N-dimethyl-5-amino-2-pentanone, 14.5 gm (208 mMol) hydroxylamine hydrochloride, and 8.8 gm (83 mMol) sodium carbonate in 50 mL water was heated at reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The residual oil crystallized on standing at room temperature. The solid was washed with hexane to provide 12.8 gm (54%) of the desired oxime as a colorless solid in two crops.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Mg].[CH3:11][N:12]([CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#N)[CH3:13].CC[O:25]CC>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([CH2:14][N:12]([CH3:13])[CH3:11])[CH:16]=2)=[O:25])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)Cc1cccc(C#N)c1
Reactant: Clc1cccc(CBr)c1
Reactant: CCOCC
Agent: [Mg]
Product: CN(C)Cc1cccc(C(=O)Cc2cccc(Cl)c2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.50 g of 3-chlorobenzyl bromide in 100 ml of dry ether was added slowly to 0.98 g of magnesium in 150 ml of dry ether under nitrogen. The Grignard reagent was stirred at ambient temperature for one hour and then added to a solution of 2.86 g of 3-[(dimethylamino)methyl]benzonitrile in 150 ml of dry ether. The resulting slurry was stirred at room temperature overnight and then quenched with the dropwise addition of saturated ammonium chloride solution. This was diluted with water and the layers separated. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography (silica gel; ethyl acetate) and then treated with ethereal HCl until acidic to wet litmus paper. The precipitate was collected and recrystallized from ethanol-ether to give 2.2 g of 2-(3-chlorophenyl)-1-[3-[(dimethylamino)methyl]phenyl]ethanone hydrochloride, m.p. 187°-189° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(O)CCC.[OH-].[NH4+:25]>>[NH2:25][C:6]1[C:7]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: [NH4+]
Reactant: CN(C(=O)c1ccccc1)c1c(Cl)ncnc1Cl
Agent: [OH-]
Solvent: CCCCO
Product: CN(C(=O)c1ccccc1)c1c(N)ncnc1Cl

Procedure:
To a solution of N-(4,6-dichloropyrimidin-5-yl)-N-methylbenzamide (0.455 g, 0.00161 mol) in 1-butanol (5 mL, 0.05 mol) was added ammonium hydroxide (0.50 mL, 0.013 mol) and the mixture was refluxed for 24 h. To the reaction was added ammonium hydroxide (1.0 mL, 0.026 mol) and the mixture was refluxed for 24 h, cooled, extracted with a mixture of ethyl acetate:isopropanol, washed with saturated aqueous sodium bicarbonate, brine, dried (Na2SO4), filtered, concentrated and triturated in diethyl ether to obtain 284 mg (67.1%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:7]=[CH:8][C:9]=1[NH2:10])(=[O:3])[CH3:2].[Li+:17].[OH-]>C1COCC1.O>[C:1]([C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][C:13]([O-:15])=[O:14])[CH:7]=[CH:8][C:9]=1[NH2:10])(=[O:3])[CH3:2].[Li+:17]
Reactant: COC(=O)CCc1ccc(N)c(C(C)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(CCC(=O)[O-])ccc1N

Procedure:
Methyl 3-(3-acetyl-4-aminophenyl)propanoate (221 mg) and 4 M LiOH (0.275 mL) were added to 3 mL THF/water(v/v=3/1). The solvent was removed under reduced pressure after the reaction completed, affording lithium 3-(3-acetyl-4-aminophenyl)propanoate (X3547-1). 1H NMR (400 MHz, MeOD): δ 7.62 (d, J=2.0 Hz, 1H), 7.17 (dd, J=8.4 Hz, J′=2.0 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 2.80 (dd, J=7.6 Hz, J′=9.0 Hz, 2H), 2.55 (s, 3H), 2.41 (dd, J=7.6 Hz, J′=9.0 Hz, 2H); MS-ESI+ 207.22 (MH+).
Reaction SMILES: [CH2:1]([O:5]C(=O)C=C)[CH2:2]CC.[C:10]([OH:18])(=[O:17])[C:11]([CH2:13]C(O)=O)=[CH2:12].C(OS([O-])(=O)=O)CCCCCCCCCCC.[Na+]>>[CH3:13][C:11]([C:10]([O:18][CH2:2][CH2:1][OH:5])=[O:17])=[CH2:12]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: C=CC(=O)OCCCC
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: C=C(C)C(=O)OCCO

Procedure:
To the solution is added 19 g butylacrylate, 3 g itaconic acid and 1 g 30% sodium laurylsulfate solution. Polymerization is carried out as described before to obtain a stable latex with essentially no coagulum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)C(C)C)(C)C.[CH3:38][C:39]([CH3:59])=[CH:40][CH2:41][CH2:42]/[C:43](/[CH3:58])=[CH:44]/[CH2:45][CH2:46]/[C:47](/[CH3:57])=[CH:48]/[CH2:49][S:50][CH2:51][C@H:52]([NH2:56])[C:53]([OH:55])=[O:54]>C(Cl)Cl.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([NH:56][C@@H:52]([CH2:51][S:50][CH2:49]/[CH:48]=[C:47](\[CH3:57])/[CH2:46][CH2:45]/[CH:44]=[C:43](\[CH3:58])/[CH2:42][CH2:41][CH:40]=[C:39]([CH3:59])[CH3:38])[C:53]([OH:55])=[O:54])=[O:10]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C(O)CCc1cccs1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CCc1cccs1)C(=O)O
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2-thienyl) propanoic acid (187 mg, 1.2 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 332 mg, 1.2 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol). After stirring for 5 min, S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added slowly. The solution was stirred at room temperature for 4 h and then diluted with ethyl acetate (60 mL). The solution was washed sequentially with an NH4Cl saturated solution (15 mL×2), H2O (10 mL×1) and brine (15 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (310 mg, 67%) to yield Compound N-31. 1H-NMR (500 MHz, CD3OD): δ 1.50 (s, 6H), 1.57 (s, 3H), 1.59 (s, 3H), 1.86-1.89 (m, 2H), 1.96-2.06 (m, 6H), 2.54 (t, J=7.5 Hz, 2H), 2.56-2.61 (m, 1H), 2.87 (dd, J=4.5, 14.0 Hz, 1H), 3.00-3.06 (m, 3H), 3.11-3.15 (m, 1H), 4.49 (dd, J=5.0, 8.5 Hz, 1H), 5.00-5.01 (m, 2H), 5.12 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.16, 16.25, 17.81, 25.96, 26.74, 27.40, 27.79, 30.13, 33.42, 38.74, 40.79, 40.89, 53.32, 121.62, 124.36, 125.14, 125.47, 125.75, 127.81, 132.11, 136.27, 140.47, 144.46, 174.98, 174.64; ES-MS: mass calcd for Chemical Formula: C25H37NO3S2 463.70. Found (M+23) m/z 486.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:13].[Na+].OO.Cl>O>[NH2:9][C:10]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:13]
Reactant: [OH-]
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(F)cccc1C(=O)O
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A mixture of 19.27 g of the product of Step B and 197 ml of 10N sodium hydroxide solution was heated to 70° C. with stirring and heating was ceased to add 36.5 ml of 30% hydrogen peroxide over 20 minutues during which the temperature rose to 80° C. and descended to 70° C. At the end of the addition, the mixture was heated to 80° C. and held there for 10 minutes and then was cooled during which a mass formed. The latter was added to 200 ml of water with stirring and the pH was adjusted to 1 by addition of concentrated hydrochloric acid at a temperature less than 20° C. The mixture was stirred for 90 minutes and was vacuum filtered. The product was empasted twice with iced water and dried under reduced pressure at 70° C. The product was crystallized from 100 ml of a 1-1 ethanol-water mixture and 3 ml of acetic acid. The mixture was iced for one hour and was vacuum filtered. The product was empasted with a 1-1 ethanol-water mixture and dried at 70° C. under reduced pressure to obtain 14.8 g of 2-amino-3-fluoro-benzoic acid melting at 188° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:8]([CH:9]1[CH2:10][O:19]1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(CCC2CO2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 1820.8 %

Procedure:
A modified procedure of Woodward was used (Bernier, D. et al., The Journal of Organic Chemistry 2008, 73, 4229). A stirred solution of 4-phenyl-1-butene 62 (500 mg, 568 μl, 3.78 mmol) in CH2Cl2 (20 ml) was cooled to 0° C. m-CPBA (816 mg, 4.73 mmol) was added as a solid and the reaction mixture was stirred at 0° C. for 1.5 h, then r.t. for 24 h. The reaction mixture was poured into saturated K2CO3 solution (50 ml) and extracted with CH2Cl2 (2×50 ml). The combined organic phases were washed with saturated K2CO3 solution (50 ml) before being dried (MgSO4), filtered and concentrated to give a clear colourless liquid. This material was purified by column chromatography, eluting with petrol/EtOAc (9:1), to give the epoxide 61 (10.2 g, 91%) as a clear colourless liquid. The 1H, 13C, and IR data were consistent with the literature (Mitchell, J. M. et al., Journal of the American Chemical Society 2001, 123, 862; Elings, J. A. et al., European Journal of Organic Chemistry 1999, 1999, 837).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:12]1[S:25][C:15]2[C:16]3[CH:24]=[N:23][CH:22]=[CH:21][C:17]=3[O:18][CH2:19][CH2:20][C:14]=2[CH:13]=1)=[N:10][NH2:11].C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>CN(C)C=O>[S:25]1[C:15]2[C:16]3[CH:24]=[N:23][CH:22]=[CH:21][C:17]=3[O:18][CH2:19][CH2:20][C:14]=2[CH:13]=[C:12]1[C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:31](=[O:32])[NH:11][N:10]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=c1[nH]nc(-c2cc3c(s2)-c2cnccc2OCC3)n1-c1ccccc1Cl
Temperature: 65 °C
Yield: 32.1 %

Procedure:
A mixture of N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine-2-carbohydrazonamide (42 mg, 0.11 mmol) from Example 230 and 92 mg (0.57 mmol) of N,N-carbonyldiimidazole in 3 ml of dimethylformamide was heated at 65° C. for 18 hours. The mixture was concentrated in vacuum and triturated with diethylether. The precipitate was collected, washed with ethyl ether and purified by flash chromatography eluting with 5% of methanol in methylene chloride to give 321 (14 mg, 31%). MS: (ESI+) 397.0
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH3:14].C[Si]([C:19]#[N:20])(C)C>CO.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[NH2:14][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])[C:19]#[N:20]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Product: N#CC(N)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of 4-fluoro-2-(trifluoromethyl)benzaldehyde (5.0 g) in methanol (20 ml) were added sequentially ammonia solution (28.9 ml, 7 M solution in methanol) and tetraisopropyl orthotitanate (9.0 ml) and the resulting mixture was stirred at r.t. for 1 h. Trimethylsilylcyanide (3.3 ml) was then added dropwise and stirring continued at r.t. overnight. The reaction mixture was poured onto ice-water (400 ml) and the mixture was then extracted twice with ethyl acetate. The combined organic phases were washed with brine and then dried over sodium sulphate and concentrated in vacuo to afford (RS)-amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetonitrile (4.48 g, 81%) as an orange viscous oil. MS (ISP): 219.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[ClH:13].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:10][CH:9]1[CH2:8][N:7]([CH3:11])[CH2:6][C:5]2[O:12][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Cc1cc2c(o1)CN(C)CC2O
Reactant: Fc1cccc(Cl)c1Cl
Product: Cc1cc2c(o1)CN(C)CC2Oc1cccc(Cl)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][Br:16])[O:8][C:7]=1[C:12]([F:15])([F:13])[F:14])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(C)oc1C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(CBr)oc1C(F)(F)F
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (0.95 g, 4.5 mmol) in CCl4 (12 mL) was added N-bromosuccinimide (0.84 g, 4.8 mmol) followed by AIBN (0.004 g, 0.01 mmol). After refluxing for 2 h, analytical HPLC analysis confirmed the reaction was complete. The reaction was cooled to rt, then CH2Cl2 and sat'd NaHCO3 (aq.) were added. The organic portion was separated and dried to provide the crude residue as a yellow oil. This material was purified by RP HPLC to provide the title compound (510 mg, 38%). MS (ESI): mass calcd. for C9H8BrF3O3, 300.0; m/z found, 302.9 [M+H]+. 1H NMR (CDCl3): 6.84 (s, 1H), 4.44 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH:33]([C:35]1[CH:39]=[CH:38][O:37][C:36]=1B(O)O)=[O:34]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:36]2[O:37][CH:38]=[CH:39][C:35]=2[CH:33]=[O:34])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=Cc1ccoc1B(O)O
Product: COc1cc(-c2csc3c(-c4occc4C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.120 g, 0.217 mmol), 3-formyl-2-furylboronic acid (0.247 mmol) and the procedure described in General Procedure A. 1H NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H), 7.96 (d, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.57 (m, 2H), 7.51 (s, 1H), 7.33 (s, 1H), 7.29 (m, 1H), 7.26 (d, 1H), 7.17 (m, 1H), 7.13 (t, 1H), 7.05 (m, 1H), 4.04 (s, 3H), 3.91 (s, 3H); MS: (M−H)− 521.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[N:45]1([CH2:51][CH2:52][NH2:53])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:53][CH2:52][CH2:51][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:43])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCN1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN4CCCCC4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-piperidino-1-ethanamine (56 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (79 mg, yield 55%).