Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:22][OH:23])=[O:16])=[CH:10][C:9]=1[O:24][CH3:25].N1C=CC=CC=1.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH:14][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[C:11]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:22][OH:23])=[O:16])=[CH:10][C:9]=1[O:24][CH3:25]
Reactant: COC(=O)CCCOc1cc(N)c(C(=O)N2CCCC2CO)cc1OC
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1cc(OCCCC(=O)OC)c(OC)cc1C(=O)N1CCCC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A batch of the amine 15 (22.5 g, 61.5 mmol) was dissolved in anhydrous DCM (300 mL) in the presence of anhydrous pyridine (10.9 mL, 134 mmol) at 0° C. Allyl chloroformate (7.17 mL, 67.5 mmol) diluted in anhydrous DCM (200 mL) was added dropwise at 0° C. The resulting solution was allowed to stir overnight at room temperature. It was then washed with cold 1N aqueous HCl (200 ml), water (200 mL), saturated aqueous NaHCO3 (200 mL), and brine (200 mL). The solution was then dried (MgSO4), and the solvent was removed in vacuo to provide 16, slightly contaminated by the product of diacylation (27 g, quantitative yield). A sample was columned (EtOAc/Hexane) to provide the analytical data. 1H NMR (CDCl3) δ 8.78 (1H, bs), 7.75 (1H, s), 6.82 (1H, s), 5.97 (1H, m), 5.38-5.34 (1H, dd, J=1.5, 17.2 Hz), 5.27-5.24 (1H, dd, J=1.3, 10.4 Hz, 1H), 4.63 (2H, m), 4.40 (2H, bs), 4.11 (2H, t, J=6.3 Hz), 3.82 (3H, s), 3.69 (4H, m), 3.61-3.49 (2H, m), 2.54 (2H, t, J=7.4 Hz), 2.18 (2H, p, J=6.7 Hz), 1.92-1.70 (4H, m); 13C NMR (CDCl3) δ 173.4, 170.9, 153.6, 150.5, 144.0, 132.5, 132.0, 118.1, 115.4, 111.6, 105.6, 67.7, 66.6, 65.8, 61.1, 60.4, 56.6, 51.7, 30.5, 28.3, 25.1, 24.3; MS (FAB+) m/z 50 (451, M+H); IR (golden gate) vmax 2949, 2359, 1728, 1596, 1521, 1433, 1202, 1173, 1119, 998, 844, 652 cm−1; [α]26D=−67° (c=0.45, CHCl3).
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].C([Li])CCC.C(C([O:19][N+:20]([O-])=[O:21])=O)(F)(F)F>O1CCCC1.[N+]([O-])([O-])=O.[K+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N+:20]([O-:21])=[O:19])=[O:2]
Reactant: O=Cn1ccnc1
Reactant: O=C(O[N+](=O)[O-])C(F)(F)F
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=Cn1ccnc1[N+](=O)[O-]
Reaction time: 0.03 h
Yield: 62 %

Procedure:
1-formyl-imidazole (about 0.100 grams) was dissolved in 1 mL of tetrahydrofuran at room temperature. Immediately, 1 equivalent (eq.) of n-butyl lithium in about 1.6 M (molar) hexanes was added to the reaction mixture, followed by 1.2 eq. of freshly prepared 1:1 molar mixture of potassium nitrate (KNO3) and trifluoroacetic anhydride (TFAA) in tetrahydrofuran as solvent at about 0° C. to about 4° C. The active nitrating species (CF3C(O)ONO2), thus, was generated in situ and the reaction mixture was stirred further for about 1.5 minutes. The 1-formyl-2-nitro-1H-imidazole product was isolated and purified by flash column chromatography to yield the pure product (i.e., about 95% purity) in about 62% yield. The structure of the 1-formyl-2-nitro-1H-imidazole product was confirmed by 1H NMR spectroscopy. 1H NMR (CDCl3): δ 2.8 (s, 3H), 7.20 (d, 1H), 7.74 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyloxycarbonyl chloride (12.4 ml) was added dropwise to a mixture of 10 g of trans-4-aminocyclohexanol, 13.3 ml of triethylamine and 300 ml of dichloromethane under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction mixture was washed and dried, and the solvent was removed under reduced pressure. The residue was recrystallized from an ethyl acetate solution to give 5.80 g of N-benzyloxycarbonyl-trans-4-aminocyclohexanol (yield: 27%, melting point: 148°-151° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]([CH3:20])[C:11]2=O)[CH:7]=[N:8][CH:9]=1)=[O:4].B.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]([CH3:20])[CH2:11]2)[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1C1C(=O)N(C)Cc2ccccc21
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CN(C)Cc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 3-(2-methyl-3-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (90 mg, 0.316 mmol) in THF (2 mL) is added a 1 M solution of borane in THF (1.6 mL, 1.6 mmol). The reaction is permitted to stir for 1 hour, at which time it is quenched with 1 M aqueous HCl. The acidified reaction is permitted to stir for one hour and then is treated with 1 N aqueous NaOH until the pH is >7. The mixture is then extracted with dichloromethane. The organic extract is dried over Na2SO4, filtered, and concentrated. The resulting residue is purified by semi-preparative reverse phase HPLC (5 to 100% acetonitrile/water w/0.1% NH4OH) to furnish 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 272.2 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester; 1H NMR (400 MHz, CDCl3) δ ppm 2.39 (s, 3 H), 2.80 (dd, J=12.4, 3.8 Hz, 1 H), 2.94-3.02 (m, 1 H), 3.40 (d, J=15.2 Hz, 1 H), 3.91 (s, 3 H), 3.90-3.96 (m, 1 H), 6.35 (m, 1 H), 7.11-7.23 (m, 3 H), 7.24-7.32 (m, 1 H), 7.50 (s, 1 H), 7.77 (s, 1 H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[N:7][CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:10]=1.[NH4+:22].[OH-]>>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:9]2[CH:10]=[C:5]([CH2:4][C:3]([NH2:22])=[O:2])[C:6]([N+:18]([O-:20])=[O:19])=[N:7][CH:8]=2)[CH2:12][CH2:13]1
Reactant: [NH4+]
Reactant: COC(=O)Cc1cc(N2CCN(C)CC2)cnc1[N+](=O)[O-]
Agent: [OH-]
Product: CN1CCN(c2cnc([N+](=O)[O-])c(CC(N)=O)c2)CC1

Procedure:
A solution of [5-(4-Methyl-piperazin-1-yl)-2-nitro-pyridin-3-yl]-acetic acid methyl ester (222 mg, 0.75 mmol) in 33% aq. NH4OH (100 mL) is stirred for 16 h at 50° C. in a sealed autoclave. TLC analysis indicated complete consumption of starting material. The solvent is evaporated at reduced pressure to afford the title compound as a yellow solid in a 3:2 mixture with the corresponding carboxylic acid. 1H NMR (d6-DMSO 400 MHz): δ 2.18 (s, 3H), 2.36-2.44 (m, 4H), 3.36-3.44 (m, 4H), 3.77 (s, 2H), 6.92 (bs, 1H), 7.34 (d, J=2 Hz, 1H), 7.44 (bs, 1H), 8.07 (d, J=2 Hz, 1H). ES+−MS: 280.4 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1>C(O)C>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:19][NH:18][C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:23])[F:22])=[CH:21][CH:20]=2)[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CC(=NNC(=O)c1ccc(C(F)(F)F)cc1)c1ccncc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A mixture of 2.97 gm (0.0245 mole) of 4-acetylpyridine, 5.0 gm (0.0245 mole) of 4-trifluoromethylbenzhydrazide and 100 ml of absolute ethanol is refluxed for 6 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point, cooled to room temperature and chilled. The crystals which separate are collected, washed with water and dried to yield 6.29 gm (84%) of the title compound having a melting point of 198.4° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:7](=[O:24])[C:6]=12.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[OH:33][CH2:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([N:3]2[C:2]([NH:1][C:34](=[O:36])[CH3:35])=[C:6]3[C:7](=[O:24])[N:8]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]3=[N:4]2)=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1
Product: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-[4-(2-hydroxyethyl)phenyl]-5-(4-methoxybenzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.2 g) and acetic anhydride (2 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added thereto, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and concentrated after drying. To the obtained crystal was added methanol (20 ml) and an 1N aqueous sodium hydroxide solution (0.5 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, a 1N hydrochloric acid (0.5 ml) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution, water and saturated brine, dried and concentrated to obtain the target compound (0.2 g).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:13])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:12])[CH2:9][CH2:10][CH3:11].[CH2:14]1[O:18][C:17]2[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:16]=2[O:15]1>>[CH3:13][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:12])[CH2:9][CH2:10][CH3:11])=[CH:3][CH2:2][O:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][O:18][C:17]=2[CH:19]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCC(C)=CCCC(C)=CCBr
Product: CCCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCO2

Procedure:
By the procedure of Example 1, 1-bromo-3,7-dimethyl-2,6-decadien is reacted with sesamol to obtain 4-[(3,7-dimethyl-2,6-decadienyl)-oxy]-1,2-(methylenedioxy)-benzene of boiling point (bulb tube) 140° C./0.025 mm Hg.; nD23 = 1.5237.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([NH2:39])=[O:38].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:39][C:37]([C:36]1[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=1[NH:34][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1)=[O:9])=[O:38]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(O)c1csc(Br)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 144 h
Yield: 89.9 %

Procedure:
2-Bromo-4-thiazolecarboxylic acid (1 g), HATU (2.01 g) and 2-aminobenzamide (0.65 g) are introduced into N,N-dimethylformamide (DMF) (20 ml). The mixture is cooled with an ice bath, and N,N-diisopropylethylamine (0.90 ml) is added. The reaction mixture is stirred at room temperature for 6 days, poured into ice-water and allowed to thaw with stirring, and the precipitated solid is filtered off with suction, washed twice with water, twice with diethyl ether and dried in vacuo. Intermediate VI.1 is obtained as a solid (1.4 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:28]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:5][CH2:6]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(Cc4ccccc4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and benzaldehyde (0.05 g) dissolved in 1,2-dichloroethane (10 ml) was added under ice cooling sodium triacetoxyborohydride (0.12 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and then was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-benzylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 58) (0.17 g) as colorless prisms.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([Cl:31])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pt]=O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:22]2[C:17]3[CH:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:25][C:26]=1[Cl:31]
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(O)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Yield: 48.9 %

Procedure:
After dissolving 255 mg of the 4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl amine synthesized in Production Example 153-5 in 10 ml of ethanol and 3 ml of tetrahydrofuran, 100 mg of platinum oxide was added and the mixture was stirred overnight at room temperature under normal pressure in a hydrogen atmosphere. After filtering with celite, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 105 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]([NH:24][NH:25][C:26](=O)[C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[O:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:26]([C:27]5[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=5)=[N:25][N:24]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1
Reactant: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)NNC(=O)c4ccc(Cl)cc4)cc3[nH]2)c(C)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(C)c1
Reaction time: 0.33 h

Procedure:
To a 5 mL microwave vial was added 0.2010 g (0.369 mmol) of (4-{6-[N′-(4-Chloro-benzoyl)-hydrazinocarbonyl]-1H-benzoimidazol-2-yl}-3,5-dimethyl-phenoxy)-acetic acid methyl ester, 5 mL of THF, and 0.1890 g (0.793 mmol) of burgess reagent. The suspension was placed in the microwave at 150° C. for 20 min. The brownish solution was concentrated and the residue was purified by silica gel (ACN/DCM, 1:9 to 5:5) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 6H) 3.72 (s, 4H) 4.86 (s, 2H) 6.81 (s, 2H) 7.68-7.74 (m, 2.5H) 7.87 (d, J=8.46 Hz, 0.5H) 7.97-8.04 (m, 1H) 8.15-8.24 (m, 2.5H) 8.45 (s, 0.5H) 12.93 (d, J=15.66 Hz, 1H). MS (m/z) 489.1 M (+1), tR=1.40, Meth 10
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:13][O:14][C:15]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:16]=1[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29].C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6]([N:18]([CH2:17][C:16]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:15]=2[O:14][CH3:13])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])(=[O:8])=[O:7])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2OC)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2OC)S(=O)(=O)Cc2cccc(Br)c2)c(OC)c1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
While cooling with ice, 4.94 g of 3-bromobenzylsulfonyl chloride were initially charged in 60 ml of dichloromethane and, within 15 minutes, a solution of 5.64 g of bis(2,4-dimethoxybenzyl)amine in 30 ml of dichloromethane and then a solution of 3.82 ml of N,N-diisopropylethylamine in 5 ml of dichloromethane were added dropwise. The reaction mixture was allowed to come to room temperature and stirred for 1 hour. Subsequently, the mixture was washed with 50 ml of water, with 50 ml of 1 N aqueous hydrochloric acid, with 50 ml of saturated aqueous sodium hydrogencarbonate solution and finally with 50 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (9.23 g) with a molecular weight of 550.5 g/mol (C25H28BrNO6S).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][O:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)/[CH3:24]>C(Cl)Cl>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[O:28][CH2:27][C:26]1[N:5]([C:4]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cc(F)cc(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2cc(F)cc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.81 g, 4.13 mmol) in DCM (15 mL) was added trimethylaluminium (6.2 mL, 12.4 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-(3,5-difluorophenoxy)acetamido)but-2-enoate (1.18 g, 4.14 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred at rt for 12 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale brown solid (1.08 g, 61%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH2:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1.[CH:42]1([S:45](Cl)(=[O:47])=[O:46])[CH2:44][CH2:43]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH:38][S:45]([CH:42]4[CH2:44][CH2:43]4)(=[O:47])=[O:46])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(N)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NS(=O)(=O)C3CC3)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of compound 9D (4.0 g, 7.02 mmol) in anhydrous CH2Cl2 (100 mL) were added cyclopropanesulfonyl chloride (16D, (1.97 g, 14.03 mmol) and triethylamine (3.91 mL, 28.07 mmol), successively. The reaction mixture was stirred at rt overnight. It was concentrated to small volume and purified with silica column chromatography eluting with dichloromethane/EtOAc to give the title compound (17D) which was recrystallized from hexanes/acetone to provide compound 17D as white powder in ˜60% yield. 1H NMR (CDCl3, 500 MHz) δ 10.66 (s, 1H), 8.67 (s, 1H), 8.18 (s, 1H), 7.67 (d, 2H, J=8.0 Hz), 7.62 (s, 1H), 7.54 (d, 2H, J=8.0 Hz), 7.43 (s, 5H), 7.20 (d, 1H, J=8.5 Hz), 6.97 (d, 1H, J=9.0 Hz), 5.82 (d, 1H, J=8.0 Hz), 5.42 (d, 1H, J=9.0 Hz), 5.20 (s, 1H), 4.67 (d, 1H, J=11.5 Hz), 3.96 (s, 3H), 3.76 (d, 1H, J=11.5 Hz), 3.61 (br s, 2H), 3.44 (dd, 1H, J=12.0, 3.0 Hz), 2.93 (m, 1H), 2.41 (m, 1H), 1.15 (s, 2H), 0.94 (d, 2H, J=5.5 Hz). LCMS (ESI) m/z 696.19 (MNa+), 674.22 (MH+), 351.10 (100). HPLC: tR=4.95 min.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Br[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1ccccc1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 54.5 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), (2-bromoethyl)benzene (0.136 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.128 g (55%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[NH:3]1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCCl>[CH3:1][C:2]1([CH3:13])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[NH+:3]1[O-:19]
Reactant: Cc1ccc2c(c1)C=CC(C)(C)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: Cc1ccc2c(c1)C=CC(C)(C)[NH+]2[O-]
Temperature: 40 °C

Procedure:
To a stirring solution of 2,6-Dimethylquinaldine (1) (5 g, 0.0318 mol) in 1,2 dichloroethane (130 ml) was added 3-CPBA (3-chloro-peroxybenzoic acid) (7.43 g of 72% activity, 0.0310 mol). The reaction was then heated to 40° C. for 24 hours. The completed reaction mixture was allowed to cool to room temperature, concentrated, and 10% K2CO3 and a minimal amount of ethyl acetate was to produce a two phase mixture. A precipitate then formed in both layers and was filtered, washed with water to remove traces of K2CO3 and dried to afford 4.67 g (85%). H1 NMR (CDCl3): δ 2.52_(s, 3H), 2.66 (s, 3H), 7.28-7.56 (m, 4H), 8.70-8.79 (m, 1H).