Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OC(C)C)(C)C>[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:26])=[O:25])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of tert-butyl 5-aminopentylcarbamate 30a (20 g, 99 mmoles) and 2-nitrobenzene-1-sulfonyl chloride 30b (23 g, 1.05 eq) in DCM (200 mL) was added dropwise diisopropyl ethyl amine (19.2 g, 1.5 eq) at 0° C. After stirring at RT overnight, the RM was successively washed with an aqueous solution of citric acid, then brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 32.61 g (85% yield) of tert-butyl 5-(2-nitrophenylsulfonamido)pentylcarbamate 30c as a white solid; m/z 388 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([OH:30])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.[ClH:32].[CH3:33]CO>>[CH2:1]([O:2][C:3](=[O:31])[C@H:4]([OH:30])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:18][CH:17]=1)[NH2:7])[CH3:33].[ClH:32]
Reactant: CCO
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1

Procedure:
A solution of (R)-3-[N′-t-butoxycarbonyl-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid methyl ester (20 g, 16 mmol) in HCl/EtOH (1.1 M, 200 mL) was stirred overnight and then concentrated in vacuo. The residue was dispersed in EtOAc (2×40 mL), and the precipitate was collected by filtration to give the title compound as an off-white solid HCl salt (8.8 g). LC-MS: 367 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (t, J=7.2 Hz, 3 H), 3.05-3.03 (q, J=7.2 Hz, 2 H), 4.06-3.95 (m, 4 H), 4.42 (br, 1 H), 6.46 (br, 1 H), 7.62-7.40 (m, 7 H), 9.42 (s, 3 H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@@H:10]1Br)(=[O:7])[CH3:6]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:10]1[N:3]=[C:2]=[S:1])(=[O:7])[CH3:6]
Reactant: N#C[S-]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 76 %

Procedure:
Potassium thiocyanate (2.81 g, 28.7 mmol), tetrabutylammonium hydrogen sulphate (1.22 g, 3.59 mmol) and molecular sieves (6.00 g) were stirred in absolute acetonitrile (500 ml) for 30 minutes. 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 37 (5.90 g, 14.4 mmol) was then dissolved in acetonitrile, added to the reaction flask and refluxed for 90 minutes. The solution was then allowed to cool, filtered through a celite pad and concentrated. Purification by column chromatography in hexane:ethyl acetate 2:1 (v/v) to give 52 (4.26 g, 76%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][CH2:32][CH3:33])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.Cl[C:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:45].C(N(CC)CC)C.Cl>C(Cl)Cl.C(OCC)(=O)C>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:42])[F:41])[CH:36]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:32][CH3:33])[C:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:45])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reactant: CCOC(=O)CCCCCC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (164 mg) is dissolved in methylene chloride (5 ml), and thereto are added ethyl 6-(chloroformyl)hexanoate (67 mg) and triethylamine (26 μl), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=17:3→7:3) to give ethyl 6-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamoyl]-hexanoate (147 mg). MS (m/z): 778 [M+H]+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:11]=[C:12]2[C:18]3=[CH:19][C:20]4[N:21]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:22]5[C:27]([C:28]=4[CH:29]=[C:17]3[N:16]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:13]2=[CH:14][CH:15]=1)=[CH:26][C:25](Br)=[CH:24][CH:23]=5.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:18]3=[CH:19][C:20]4[N:21]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:22]5[C:27]([C:28]=4[CH:29]=[C:17]3[N:16]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:13]2=[CH:14][CH:15]=1)=[CH:26][C:25]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[CH:24][CH:23]=5
Reactant: CCCCCCCCCCCCn1c2ccc(Br)cc2c2cc3c(cc21)c1cc(Br)ccc1n3CCCCCCCCCCCC
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCn1c2ccc(-c3cccs3)cc2c2cc3c(cc21)c1cc(-c2cccs2)ccc1n3CCCCCCCCCCCC

Procedure:
ALIQUAT™336 (0.6 g), 2-thiopheneboronic acid (0.921 g, 7.2 mmol), 2,8-dibromo-5,11-didodecylindolo[3,2-b]carbazole (2.252 g, 3 mmol), 2M Na2CO3 solution (7.5 mL, 15 mmol), Pd(PPh3)4 (72 mg, 0.06 mmol) and toluene (10 mL) were added into a 50 mL flask. The mixture was heated to gentle reflux and maintained for 48 h. The reaction mixture was cooled down, organic layer separated, dried, and filtered. The toluene solution was passed through a silica gel column and the solvent was removed. Recrystallization from toluene gave the title compound as a yellow solid. Yield: 1.476 g (61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:16])([F:17])[F:18])[CH:7]=1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Reactant: CC(C)NNC(=O)c1ccco1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)N(NC(=O)c1ccco1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 44 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (174 mg, 0.52 mmol) and furan-2-carboxylic acid N′-isopropyl-hydrazide (90 mg, 0.53 mmol) in DMF (5 ml) was treated with diisopropyl amine (0.235 ml, 1.32 mmol) and PyBroP (370 mg, 0.79 mmol) at room temperature overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-80% ethyl acetate in hexanes gradient to afford the product as a white solid (110 mg, 44%). MS m/e 481.38 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5](C(OCC)=O)[N:6]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[NH:5][N:6]=1
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Reagent 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate, E1(I), (10.97 g, 33.9 mmol) was dissolved in MeOH (200 mL) after which NaOH (5 eq, 169 mmol) was added. After stirring the mixture at room temperature for 3 h, the starting material disappeared. After removal of MeOH, add H2O and AcOEt was added, and the product was extracted with AcOEt and dried over Na2SO2 followed by concentration to afford E1(II).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([CH3:34])[C:28]([C:35]([O:37]CC)=[O:36])=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([CH3:34])[C:28]([C:35]([OH:37])=[O:36])=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2cc1C(=O)O
Temperature: 90 °C
Yield: 98.8 %

Procedure:
A 1 N solution of sodium hydroxide (92.8 μL, 92.8 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-methyl-3-quinolinecarboxylate (26.7 mg, 46.4 μmol) in tetrahydrofuran and methanol (1:1, 927.9 μL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (92.8 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 25.1 mg (99%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-methyl-3-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.31 (br s, 1H), 8.86 (s, 1H), 8.29 (d, J=2 Hz, 1H), 8.09 (dd, J=9, 2 Hz, 1H), 7.98 (d, J=9 Hz, 1H), 7.69 (d, J=9 Hz, 2H), 7.66-7.60 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.93 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.47 (septet, J=7 Hz, 1H), 2.86 (s, 3H), 1.34 (d, J=7 Hz, 6H). HRMS C30H24Cl2N2O4 m/z 547.1191 (M+H)+Cal; 547.1191 (M+H)+Obs.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])[S:2]1.[OH:17]O>CC(C)=O>[O:17]=[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])[S:2]1
Reactant: OO
Reactant: CS(=O)(=O)NC(=O)CCCCC1CCSS1
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=O)CCCCC1CCS(=O)S1
Reaction time: 8 h

Procedure:
500 mg of N-[5-(1,2-dithiolan-3-yl)pentanoyl]methanesulfonamide (prepared as described in Example 2) were dissolved in 10 ml of acetone, and 0.44 ml of a 31% w/v aqueous solution of hydrogen peroxide was added to the solution, whilst ice-cooling. The mixture was stirred and then left to stand at room temperature overnight. At the end of this time, a further 0.2 ml of a 31% w/v aqueous solution of hydrogen peroxide was added to the reaction mixture, and then the mixture was stirred at room temperature for 30 minutes, and then stirred on an oil bath at 50° C. for 1 hour. The mixture was then left to stand at room temperature for 3 days, after which it was stirred on an oil bath at 50° C. for 10 hours; it was then left to stand at room temperature overnight. The solvent was then removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue thus obtained, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by reverse phase preparative silica gel column chromatography, using 1:3 and 2:3 by volume mixtures of acetonitrile and water as the eluent. The solvent was evaporated from the eluted fraction thus obtained under reduced pressure, and the fraction was lyophilised, to obtain 0.15 g of the title compound (diastereomer mixture) as a colorless oil having an Rf value of 0.43 (silica gel thin layer chromatography, using a 10:1 by volume mixture of ethyl acetate and methanol as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:26])[C:5]([C:8](=[N:23][O:24][CH3:25])[CH2:9][NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:26])[C:5]([C:8](=[N:23][O:24][CH3:25])[CH2:9][NH:10][C:11](=[S:36])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CON=C(CNC(=S)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To 222 mg of the N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(methoxyimino)ethyl]-2-(trifluoromethyl)benzamide prepared in Step 4 in Synthetic Example 20 in 5 ml of 1,4-dioxane, 200 mg of Lawesson's Reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) was added, and the mixture was stirred at 80° C. for 3 hours and then at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 40 ml of 0.05M aqueous sodium hydroxide and extracted with a mixture of ethyl acetate-diethyl ether (2:1) (30 ml×1), the resulting organic layer was washed with 40 ml of 0.2M aqueous sodium hydroxide and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 2:8) as the eluent to obtain 133 mg of the desired product as a brown resinous substance.
Reaction SMILES: COC([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:9][CH2:8][C:7]([CH2:15][O:16][CH2:17][O:18][CH3:19])([CH2:10][O:11][CH2:12][O:13][CH3:14])[C:6]1=[O:20])=O.[OH-].[Na+].O>C(O)(C)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH:5]2[C:6](=[O:20])[C:7]([CH2:10][O:11][CH2:12][O:13][CH3:14])([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:8][CH2:9]2)=[CH:27][CH:26]=1
Reactant: COCOCC1(COCOC)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: COCOCC1(COCOC)CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
In isopropanol (5.5 mL), 1-(4-chlorobenzyl)-3,3-bis((methoxymethoxy)methyl)-2-oxocyclopentane carboxylic acid methyl ester (2.2895 g, 5.52 mmol) was dissolved, and a 2 M sodium hydroxide solution (5.5 mL) was added thereto. The mixture was stirred at 90° C. for 2 hours. Following the completion of the reaction, water was added, and the mixture was subjected to extraction using ethyl acetate. The organic layer was washed with saturated brine solution and water, and dried using anhydrous sodium sulfate. The solvent was distilled out, and the residue was purified using silica gel to obtain a target product.
Reaction SMILES: O[C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C>[Si:13]([C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C=O)c(O)c1Br
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c([Si](C)(C)C(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Diiospropylethylamine(3.0 ml ) was added to a stirred solution (under argon) of 2-hydroxy-3-bromo--4-methoxybenzaldehyde(1.96, 8.5 mmole) in DMF (15 ml) followed by t-butyldimethlsilyl chloride(TBSCl, 1.91 g, 12.8 mmole). The reaction mixture was stirred at room temperature for 30 min and Ice (20 g) was added to the mixture. The mixture was then extracted with ether (3×25 ml). The ethereal solution was washed with water (25 ml) and saturated NaHCO3 solution (2×15 ml). The solvent evaporated to yield 2-(t-butyldimethylsilyl)-3-bromo-4-methoxy benzaldehyde as an oil (2.54 g, 7.06 mmole, 83.1%).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]2[C:19]3[CH:20]=[C:21]([O:26][CH3:27])[C:22]([O:24][CH3:25])=[CH:23][C:18]=3[CH2:17][C:16]([CH3:28])=[N:15][N:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[C:1]1([CH:11]=[CH:12][C:13]2[C:19]3[CH:20]=[C:21]([O:26][CH3:27])[C:22]([O:24][CH3:25])=[CH:23][C:18]=3[CH2:17][CH:16]([CH3:28])[NH:15][N:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2c(cc1OC)C(C=Cc1cccc3ccccc13)=NN=C(C)C2
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1OC)C(C=Cc1cccc3ccccc13)=NNC(C)C2
Yield: 70.4 %

Procedure:
To a solution of 5.35 g (14.3 mmoles) of 1-[2-(1-naphtyl)-vinyl]-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine in 30 ml of glacial acetic acid a solution of 1.76 g (46.3 mmoles) of sodium borohydride in 10 ml of water is dropped at 50° C., under stirring, and the reaction mixture is stirred further for 2 hours. The product is then stirred with 250 ml of water, made alkaline with ammonium hydroxide solution, the separated yellow precipitate is filtered, washed with water and recrystallized from isopropanol. Thus 3.75 g (70.5%) of the desired compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:33])[C:23]=1[O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH:19]=O.II.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:33][C:22]1[CH:21]=[C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:17]=[C:16]([CH3:15])[C:23]=1[O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCOCC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCOCC4)c(C)c3)nc2c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (451 mg, 2.3 mmol) and 3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-benzaldehyde (550 mg, 2.09 mmol) in N,N-dimethyl formamide (20 mL), iodine (636 mg, 2.5 mmol) and potassium carbonate (288 mg, 2.09 mmol) were added and the reaction mixture was stirred at 70° C. for 48 h. The reaction mixture was poured into ice. The mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product was purified by column chromatography and converted to the hydrochloride salt of 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (40 mg, 4%) as an off-white solid. Selected data: MS (ES) m/z: 440.1; MP 185-187° C. (HCl salt).
Reaction SMILES: C(O/C=[CH:5]/[C:6]1[C:7]([C:38]2[N:39]([C:48](OC(C)(C)C)=O)[C:40]3[C:45]([C:46]=2[CH3:47])=[CH:44][CH:43]=[CH:42][CH:41]=3)=[N:8][C:9]([C:12]2[C:13]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[CH:31]=2)=[CH:10][CH:11]=1)C.Cl>O1CCOCC1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[O:19][C:15]3[CH:14]=[C:13]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:34])=[O:35])[C:12]([C:9]4[CH:10]=[CH:11][C:6]5[CH:5]=[CH:48][N:39]6[C:40]7[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=7[C:46]([CH3:47])=[C:38]6[C:7]=5[N:8]=4)=[CH:31][C:16]=3[C:17]=2[C:27]([NH:28][CH3:29])=[O:30])=[CH:25][CH:24]=1
Reactant: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1c(C)c2ccccc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4ccn5c6ccccc6c(C)c5c4n3)cc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (E)-tert-butyl 2-(3-(2-ethoxyvinyl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)pyridin-2-yl)-3-methyl-1H-indole-1-carboxylate (60 mg, 0.080 mmol) in 1,4-Dioxane (2 mL) was added 4 M HCl in dioxane (1 mL, 4.00 mmol). The resultant bright orange mixture was stirred at ambient temperature for 45 minutes then was heated at 60° C. for 1.75 h. The mixture was concentrated in vacuo, azeotroping from CH3CN, and the residue was diluted with saturated NaHCO3 (aq) solution and extracted into EtOAc. The organic layer was washed with brine (1×), dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography using a gradient of 0-70% EtOAc/Hexanes as eluent. Lyophilization from CH3CN/H2O provided the title compound. 1H NMR δ (ppm) (CHCl3-d): 8.27 (1H, s), 8.14 (1H, d, J=7.34 Hz), 8.09˜8.05 (2H, m), 7.91˜7.84 (3H, m), 7.71˜7.68 (2H, m), 7.46˜7.43 (2H, m), 7.24 (2H, t, J=8.65 Hz), 6.61 (1H, d, J=7.33 Hz), 5.96 (1H, br s), 3.35 (3H, s), 3.06 (6H, m), 2.73 (3H, s). MS (M+H): 607.