Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[C:8]1([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:28][N:29]=[C:30]([C:34]1[O:35][CH:36]=[CH:37][CH:38]=1)[C:31]([OH:33])=[O:32]>>[C:8]1([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:28][N:29]=[C:30]([C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)[C:31]([O-:33])=[O:32])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=C(O)C(=NO)c1ccco1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC[NH+](CC)CC
Product: O=C([O-])C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccco1
Yield: 79 %

Procedure:
Triethylamine (35 ml, 250 mmole), triphenylchloromethane (35 g, 125 mmole) and 2-hydroxyimino-2-(fur-2-yl)-acetic acid (syn isomer) (15.505 g, 100 mmole) were reacted together essentially as described in Preparation 2(a) to give triethylammonium 2-triphenylmethoxyimino-2-(fur-2-yl) acetate (syn isomer) as a pale-yellow solid (39.5 g, 79 mmole, 79%), m.p. 170° to 172° (dec), λmax 275.5 nm, inflexions at 265 and 271.5 nm (ε 17,900; 15,900 and 17,500 resepectively).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]([CH3:14])(O)[O:11][N:10]=[C:9]2[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.BrC1C=CC(C2C(C3C=CC(SC)=C(F)C=3)C(C)(O)ON=2)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[N:10][O:11][C:12]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C2=NOC(C)(O)C2c2ccc(Br)cc2)cc1
Agent: CSc1ccc(C2C(c3ccc(Br)cc3)=NOC2(C)O)cc1F
Product: CSc1ccc(-c2noc(C)c2-c2ccc(Br)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of step 2 in the Example 168 using 4-(4-bromophenyl)-3-(4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol, instead of 3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][C:13]2[O:14][C:15]3[C:22]([Cl:23])=[CH:21][C:20]([CH2:24][CH2:25][CH3:26])=[C:19]([O:27]C(=O)C)[C:16]=3[C:17]=2[CH3:18])=[CH:10][CH:9]=1)([O:3]CC)=[O:2].O.Cl>CO.[OH-].[Na+]>[C:1]([CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][C:13]2[O:14][C:15]3[C:22]([Cl:23])=[CH:21][C:20]([CH2:24][CH2:25][CH3:26])=[C:19]([OH:27])[C:16]=3[C:17]=2[CH3:18])=[CH:10][CH:9]=1)([OH:3])=[O:2]
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OCC(=O)OCC)cc3)c(C)c2c1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OCC(=O)O)cc3)c(C)c2c1O
Yield: 85.4 %

Procedure:
A solution of 2-(p-carboethoxymethoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (133 mg; 0.28 mmole) in methanol (10 mL) and 10N sodium hydroxide (1 mL) was stirred at room temperature for a period of 30 minutes. Water was then added and the mixture was acidified with 6N hydrochloric acid. The solid was filtered, washed with water, and air-dried to yield 93 mg (82%) of 2-(p-carboxymethoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp. 179°-180° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][C:3]=1[N+:11]([O-])=O>CO.[Pd]>[NH2:11][C:3]1[CH:4]=[C:5]([B:8]([OH:10])[OH:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(B(O)O)cc1N
Yield: 90.8 %

Procedure:
A mixture of 4-methyl-3-nitro-phenyl boronic acid (3.34 g, 18.45 mmol) and 10% Pd/C, (334 mg) in MeOH, (30 ml) was hydrogenated (1 atm.) at 23° C. After 22 h the reaction mixture was filtered through celite and concentrated to give 3-amino-4-methyl phenyl boronic acid (2.53 g, 91%). 1H NMR (300 MHz, DMSO-d6) δ 7.21 (s, 1H), 7.08 (d, 1H, J=7.5 Hz), 6.92 (d, 1H, J=7.46 Hz), 4.81 (bs, 2H), 2.09 (s, 3H). MS (ESI) [M+H]/z Calc'd 152, found 152.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[N:13]=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[N:13]=[CH:14]3)=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc2ccc(OS(=O)(=O)C(F)(F)F)cc2cn1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
A suspension of 700 mg (2.09 mmol) of methyl 7-{[(trifluoromethyl)sulfonyl]oxy}-3-isoquinolinecarboxylate, 715 mg (3.13 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 240 mg (0.21 mmol) of tetrakistriphenylphosphine palladium(0) and 3.70 mL (3.31 mmol) of 2.0 M Na2CO3 (aq) in 10 mL of 1,2-dimethoxyethane was stirred at 90° C. for 20 min. The suspension was filtered through a pad of Celite® and the filter cake was washed with EtOAc. The combined organics were then evaporated and the residue purified by silica gel chromatography (40 g of silica gel eluting with 0-15% acetone in CH2Cl2 over 45 minutes) to give 360 mg (62%) of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 9.38 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.21 (d, J=8 Hz, 1H), 8.15 (d, J=8 Hz, 1H), 7.72 (d, J=9 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 3.91 (s, 3H). ESI-LCMS m/z 280 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: C1CCNC1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CN4CCCC4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with pyrrolidine. 1H-NMR (DMSO-D6) δ: d 1.74 (m, 4H, CH2), 2.58 (m, 4H, CH2), 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.20 (s, 2H, CH2), 7.04 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.55 (d, 2H, J=8.8 Hz, Ph-H), 7.66 (d, 2H, J=8.8 Hz, Ph-H), 8.48 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.55 (s, 1H, NH), 9.58 (s, 1H, NH). MS (ESI+) m/z 406.97 [M+H]+ (C21H24N6OS requires 408.52).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[N:11]O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[H][H]>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)=NO)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1cccc(C(C)N)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of 45 g of 1-(3-methoxy-phenyl)-ethanone oxime in 675 ml of methanol charged 45 g of Raney Ni. The resultant suspension was agitated at about 28° C. under 3 kg/cm2 anhydrous hydrogen gas pressure for about 4 hours. After completion of the reaction, the reaction mass was filtered through celite and washed with 90 ml of methanol. The filterate was distilled under vacuum at about 55° C. To the residue charged 150 ml of methanolic HCL and distilled completely under vacuum at about 50° C. To the residue charged 100 ml of acetone and stirred at about 15° C. for about one hour. Separated solid was filtered and the solid was washed with 30 ml of acetone. The solid obtained was dried at about 50° C. for about 3 hours.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:48])[NH:18][C:19]2([CH2:37][C:38]([NH:40][C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)=[O:39])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[C:20]2=[O:36])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.S(=O)(=O)(O)O.O.C(OCC)(=O)C>C(O)C>[CH2:31]([O:30][CH:29]([O:33][CH2:34][CH3:35])[CH2:28][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=2)=[O:48])([CH2:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)=[O:39])[C:20]1=[O:36])[CH3:32]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c2ccccc21)OCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(CO)cc2)c2ccccc21)OCC
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
3-(N′-(4-t-butyldimethylsilyloxymethylphenyl)ureido)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl) indolin-2-one (308 mg) was dissolved in ethanol (15 mL), concentrated sulfuric acid (10 mg) was added, and the mixture was stirred at 15-30° C. for one hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was dried with anhydrous sodium hydrogensulfate and the solvent was distilled off. The reaction mixture was purified by silica gel column chromatography to obtain 225 mg of the title compound (yield: 88%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16](O)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][OH:51])[CH2:46][CH2:45]1>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:44]2[CH2:49][CH2:48][CH:47]([CH2:50][OH:51])[CH2:46][CH2:45]2)=[O:17])=[CH:4][CH:3]=1
Reactant: OCC1CCNCC1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(CO)CC1
Reaction time: 22 h

Procedure:
The following was added sequentially to DMF (10 mL): 1-(4-fluorobenzyl)-1H-indole-2-carboxylic acid (1.175 g, 4.36 mmol), DIPEA (2.29 mL, 13.09 mmol), EDC (1.00 g, 5.24 mmol), and HOBT (802 mg, 5.24 mmol). This solution was allowed to stir at rt for 1.5 h, at which time 4-piperidinemethanol (754 mg, 6.55 mmol) was added. Stirring continued for 22 h at rt, at which time the solution was partitioned between water and 1:1 solution of ethyl acetate:diethyl ether. The organic extract was then washed with saturated aq. sodium carbonate, dried with magnesium sulfate, and concentrated in vacuo. Purification was accomplished via silica gel flash chromatography (100 g silica, 80% EtOAc/Hexanes.) Resulting residue was crystallized via diethyl ether/hexane trituration to give the title compound as a white solid. (Yield: 1.507 g, 4.11 mmol, 94%) 1H NMR (400 MHz, CDCl3) 7.63, 7.37, 7.28-7.22, 7.14, 7.08, 6.91, 6.60, 5.46, 4.65, 4.13, 3.42, 2.76, 1.76-1.54, 1.05, 0.71
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:16]2[C:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:9]1.[OH-].[Na+]>C1COCC1.CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])[N:9]=[C:10]3[C:16]=2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.1 %

Procedure:
5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid methyl ester (Example 82, 0.009 g) was dissolved in 1 mL of 9:1 THF/MeOH and treated with 2 mL of 1 M NaOH. After stirring at RT for 5 h, the solvent was removed in vacuo. The aqueous residue was acidified with 1 mL of 1 N HCl and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, concentrated, and dried on a vacuum line. The residue was then dissolved in 1 mL of 9:1 CH2Cl2/MeOH and treated with 3 mL of 1 N HCl in Et2O. After 4 h, the volatiles were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.002 g of the title compound. MS (ESI): exact mass calculated for C18H22ClN3O2, 347.14; found, m/z 348.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.55-7.53 (m, 4H), 7.35-7.32 (m, 2H), 3.98 (t, J=7.0 Hz, 2H), 3.38-3.35 (m, 2H), 3.28-3.26 (m, 2H), 3.13-3.10 (m, 2H), 2.77-2.74 (m, 2H), 2.09-2.06 (m, 2H), 1.71-1.66 (m, 2H), 1.41-1.37 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([O:24][CH2:25][C:26]3[C:27]([Cl:48])=[C:28]([S:33]([N:36]4[CH2:40][CH2:39][CH2:38][C@H:37]4[C:41]([NH:43][CH2:44][CH2:45][CH2:46][NH2:47])=[O:42])(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=3[Cl:32])[CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([O:24][CH2:25][C:26]3[C:27]([Cl:48])=[C:28]([S:33]([N:36]4[CH2:40][CH2:39][CH2:38][C@H:37]4[C:41]([NH:43][CH2:44][CH2:45][CH2:46][NH:47][C:7]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)=[O:9])=[O:42])(=[O:34])=[O:35])[CH:29]=[CH:30][C:31]=3[Cl:32])[CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCCCN)c3Cl)c2n1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCCCNC(=O)c4ccc(C#N)cc4)c3Cl)c2n1
Yield: 75 %

Procedure:
By following a procedure analogous to Example 5, starting from 4-cyanobenzoic acid and 1-[[3-[(2-methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-aminopropyl]-2(S)-pyrrolidinecarboxamide hydrochloride, the expected product (yield=75%) is obtained after purification by chromatography on silica gel using a dichloromethane/methanol mixture (98/2; v/v) as the eluent. M.p.=78-80° C. [α]D24 =-39° (c=0.3; CH3OH)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:36][CH2:37][CH2:38][CH2:39][CH:40]([OH:45])[CH2:41][CH2:42][CH2:43][CH3:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:25](=[O:27])[O:45][CH:40]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH2:38][CH2:37][CH3:36]
Reactant: CCCCC(O)CCCC
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(CCCC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Yield: 55.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-nonanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (42 mg, yield 49%).
Reaction SMILES: O[CH:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[C:4](=[O:11])[O:3]1.[CH2:12]([P:16]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].[BrH:25]>C(O)(=O)C>[Br-:25].[CH2:21]([P+:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[CH:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[C:4](=[O:11])[O:3]1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C1OC(O)C2=C1CCCC2
Reactant: CCCCP(CCCC)CCCC
Reactant: Br
Solvent: CC(=O)O
Product: CCCC[P+](CCCC)(CCCC)C1OC(=O)C2=C1CCCC2
Product: [Br-]

Procedure:
A solution of EXAMPLE 1A (3 g) in acetic acid (10 mL) at ambient temperature was treated with tri-n-butyl phosphine (4.81 mL) and 33% hydrobromic acid in acetic acid (3.34 mL), heated at reflux for 21 hours, cooled and concentrated. The concentrate was purified by flash chromatography on silica gel with 10% methanol in dichloromethane.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27][O:28][C:10]=12.C(OC(=O)C)C>N1C=CC=CC=1>[F:23][C:17]1[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[C:9]([NH:8][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])=[C:10]2[O:28][CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]=1[CH3:24]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
Cyclopropane sulfonyl chloride (50 mg, 0.35 mmol) was added to a solution of 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 80 mg, 0.199 mmol) in dry pyridine (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1.5% MeOH in DCM) afforded 3 mg of the product (3% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH3:13][N:14]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]1[CH:22]=O>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[N:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]([CH:1]=[CH:22][C:15]3[N:14]([CH3:13])[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=3)=[N:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: Cc1nnc(-c2ccncc2)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nnc(-c2ccncc2)s1

Procedure:
8.8 g of 2-methyl-5-(4-pyridyl)-1,3,4-thiadiazole and 7.7 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with 0.2 g of ZnCl2 in a mixture of 50 ml of glacial acetic acid and 25 ml of acetic anhydride for 6 hours at reflux temperature. After cooling, the precipitated solid is suction filtered, washed with concentrated ammonia and recrystallized from dimethylformamide. The melting point of the product obtained is 240°-241° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)=[O:5])[CH2:23][CH2:22]1
Reactant: Cc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: Cc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2N2CCC(C)CC2)cc1
Yield: 91.9 %

Procedure:
Proceeding as in example 2, with 0.045 mole (13 g) of 2-chloro-4'-methyl-5-nitro-benzophenone, 0.1 mole (11.3 cm3) of 4-methyl piperidine and 0.045 mole (6.2 g) of calcium carbonate mixed in ethanol, 14 g (Yield: 95%) of the expected product are obtained. M.P. 86° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[NH2:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])/[CH:15]=[CH:14]/[C:9]2[CH:10]=[N:11][N:12]([CH3:13])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:33][CH:32]=1
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c1-c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(CN)cc2)c1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 11.6 %

Procedure:
A mixture of tert-butyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]carbamate (2.0 g) and 4N hydrogenchloride in ethyl acetate (80 mL) was stirred at 70° C. for 15 hrs. The precipitated crystals were collected by filtration and washed with ethyl acetate. A 1N aqueous sodium hydroxide solution (50 mL) was added to the obtained crystals (0.30 g) and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give (2E)-N-[4-(aminomethyl)phenyl]-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide as colorless crystals (0.18 g). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 201-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[C:22]3[C:23]([CH3:35])=[C:24]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:25]([CH3:28])=[C:26]([CH3:27])[C:21]=3[O:20][C:19]2([CH3:37])[CH3:36])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[ClH:8].[ClH:8].[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]2[C:22]3[C:23]([CH3:35])=[C:24]([N:29]4[CH2:30][CH2:31][N:32]([CH2:7][C:6]5[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[CH2:33][CH2:34]4)[C:25]([CH3:28])=[C:26]([CH3:27])[C:21]=3[O:20][C:19]2([CH3:37])[CH3:36])=[CH:14][CH:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(F)nc3)C(C)(C)O4)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-methoxybenzyl chloride (0.16 mL, 1.2 mmol) was added to a mixture of 1-(3-(6-fluoropyridine-3-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (369 mg, one mmol) obtained in Example 127 and potassium carbonate (138 mg, 1 mmol) in DMF (5 ml) and the mixture was stirred at room temperature for 3 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed three times using saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 365 mg (yield 75%) of free salt of title compound. Thereafter, it was treated with 4N hydrogenchloride in ethyl acetate to obtain the title compound as a hydrochloride salt. mp. 218–221° C. (decomposition) (ethyl acetate-ethanol).
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].C(O)=O.[CH3:8][C@H:9]1[CH2:18][NH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=2)[N:10]1[C:29](=[O:31])[CH3:30]>>[C:29]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[N:17]([CH:1]=[O:3])[CH2:18][C@@H:9]1[CH3:8])(=[O:31])[CH3:30]
Reactant: O=C[O-]
Reactant: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2NC[C@@H]1C
Agent: [Na+]
Solvent: O=CO
Product: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2N(C=O)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.6 %

Procedure:
Sodium formate (14 mg, 0.200 mmol) and formic acid (46 mg, 1.0 mmol) were added to (S)-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.2 M in 1,2-dichloroethane, 0.1 mL, 0.02 mmol) and shaken at room temperature for 5 h. The reaction was concentrated and the crude product was purified by mass-triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-4-acetyl-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1 (2H)-carbaldehyde (0.0034 g, 46%). MS (ESI, pos. ion) m/z 373