Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)cc1OC
Yield: 72 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,4-dimethoxyphenylboronic acid (142 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THE, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 171 mg (72%) of the title compound as an amorphous foam. mp 108°-112°. FDMS: m/e=365. α[D]589 =+73.75 (c=0.56, chloroform).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[C@@H:22]1[CH2:24][C@H:23]1[C:25](N(OC)C)=[O:26].C(C1C=C2C(=CC=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2[C@@H]1C[C@H]1C=O)#N>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:7]=[C:6]2[C@@H:22]1[CH2:24][C@H:23]1[CH:25]=[O:26]
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C(F)(F)F)cc12
Agent: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@H]3C=O)c3cc(C#N)ccc32)cc1
Product: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@H]3C=O)c3cc(C(F)(F)F)ccc32)cc1
Yield: 95 %

Procedure:
Racemic [trans-2-[5-trifluoromethyl-1-(p-toluenesulfonyl)indol-3-yl]-cyclo-propane-carboxaldehyde (4.13 g, 95%) was prepared from racemic [trans-2-[5-trifluoromethyl-1-(p-toluenesulfonyl)indol-3-yl]cycloprop-1-yl]-N-methoxy-N-methyl-carboxamide in a similar manner to [trans-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropane-carboxaldehyde in Example 1. 1H NMR (400 MHz, DMSO-d6) 9.06 (1H, d, J=5.7 Hz), 8.11 (2H, d, J=8.9 Hz), 7.89 (3H, m), 7.69 (1H, d, J=8.8 Hz), 7.40 (2H, d, J=8.0 Hz), 2.86 (1H, m), 2.32 (3H, s), 2.12 (1H, m), 1.71 (2H, m); MS m/e 406 (M−H)−. Anal calcd. for C20H16F3NO3S: C, 58.96; H, 3.95; N, 3.43. Found: C, 58.95; H, 3.96; N, 3.28
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8]CCCC#N)=[CH:6][C:5]=1[CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([O-:3])=[O:2].OC1C=CC([N+]([O-])=O)=C(C=1)C=O.N1CCCCC1.[BH4-].[Na+]>C(O)C>[OH:8][C:7]1[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:6]=1)[CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: N#CCCCOc1ccc([N+](=O)[O-])c(CN2CCCCC2)c1
Agent: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(O)cc1CN1CCCCC1

Procedure:
In a similar manner to that described in Example 17 4-(4-nitro-3-piperidinomethylphenoxy)butyronitrile was prepared by the reaction of 5-hydroxy-2-nitrobenzaldehyde (10 g) with piperidine (12.3 ml) and sodium borohydride (2.7 g) in absolute ethanol (68 ml) to give N-(5-hydroxy-2-nitrobenzyl)piperidine which was then reacted with 4-bromobutyronitrile (4.1 ml) to give the above-mentioned product.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(=O)O
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (131 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (30 mg). MS 394.4 (M+H); UV 201.1, 247.4, 297.8, 352.3 nm; t 0.476 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[I:20]C1C=CC2N(C=C(C(OCC)=O)N=2)C=1>>[I:20][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cn2cc(I)ccc2n1
Reactant: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1

Procedure:
By working in the same manner as for the preparation of Intermediate 1, replacing the ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate with ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate, 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide is obtained in the form of a beige-coloured solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][C:5](OC)=[C:4](OCC2CCN(C)CC2)[CH:3]=1.C(O)(=O)C.[CH:28](N)=[NH:29]>COCCO>[N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:10])[NH:29][CH:28]=1
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Reactant: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2ccccc12
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 173.8 %

Procedure:
A solution of ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2 g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4 g, 100 mmol) was added in portions every 30 minutes during 4 hours. Heating was prolonged for 30 minutes after the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100 ml) and methylene chloride (50 ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100 ml. The suspension was cooled to 5° C. and the solid was collected by filtration, washed with cold ethanol followed by ether and dried under vacuum overnight at 60° C. to give 6-methoxy-74(1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (12.7 g, 70%).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:6]=1[O:7][CH2:8][CH:9]1[CH2:12][N:11]([C:13](=[O:18])[C:14]([O:16]C)=[O:15])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:6]=1[O:7][CH2:8][CH:9]1[CH2:10][N:11]([C:13](=[O:18])[C:14]([OH:16])=[O:15])[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)N1CC(COc2ccc(Cl)cc2C(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Cl)ccc1OCC1CN(C(=O)C(=O)O)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a stirred solution of methyl {3-[(2-tert-butyl-4-chlorophenoxy)methyl]azetidin-1-yl}(oxo)acetate (232 mg, 0.68 mmol) obtained in Example 206 in THF (5.0 mL) was added lithium hydroxide (1.0M aqueous solution, 5.0 mL, 5.0 mmol) at 0° C. After stirring at 0° C. for 3 hr, the reaction mixture was adjusted to about pH 1 with 1.0N hydrochloric acid. The obtained solution was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (214 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].CC(C)([O-])C.[Na+].C([O:38][C:39](=[O:42])[CH2:40]Cl)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:40][C:39]([OH:42])=[O:38])(=[O:3])[CH3:2]
Reactant: O=C(CCl)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC(=O)OC[C@H]1OC(OCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 9.62 g (100 mmol) of sodium-t-butoxide in 350 ml of dimethyl sulfoxide is cooled to 0° C. At 0° C., 36.92 g (200 mmol) of chloroacetic acid benzyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for one hour at 10° C. 250 ml of methyl-tert-butyl ether is added, the organic phase is separated, and it is filtered. The solvent is distilled off in a vacuum. The residue is taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Catalyst is filtered out, it is rewashed with a little ethanol and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][C:3]=1[CH3:16].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6][C:5]1[CH:13]=[C:14]([CH3:15])[C:2]([Br:1])=[C:3]([CH3:16])[CH:4]=1)(=[O:27])=[O:26]
Reactant: Cc1cc(OCC(C)(C)CO)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(C)(C)COS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled (0° C.) solution of 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropan-1-ol (251 mg) and triethylamine (160 μL) in dichloromethane (3 mL) is added methanesulfonyl chloride (75 μL). The mixture is stirred for 2 days while warming to room temperature. Then the mixture is diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. Yield: 271 mg; LC (method 7): tR=1.18 min; Mass spectrum (ESI+): m/z=365 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl.O.N1C=CC=CC=1>[Cl:11][C:10]1[C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Temperature: 50 °C
Yield: 89882.8 %

Procedure:
To a stirred solution of 2-amino-3-chloro benzoic acid (10 g, 0.058 mmol) in acetonitrile (60 mL, 1 M), was added pyridine (9.4 mL, 0.117 mmol, 2 equiv), and triphosgene (17.3 g, 0.058 mmol, 1 equiv) in dichloromethane (85 mL, 0.7 M). The orange reaction solution was heated at 50° C. for two hours then cooled to room temperature. The solution was diluted with water (50 mL), and the organic and aqueous layers were separated. The aqueous layer was washed with dichloromethane (3×50 mL), and the combined organic layers were washed once with brine (50 mL), and dried over magnesium sulfate. The solvent was removed in vacuo leaving a yellow solid. The solid was titrated with hexanes to yield 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (10.3 g, 73%) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O>CC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To 15 g of BOC-piperazine (80.6 mmol) dissolved in acetone (50 ml) was added in alternating portions benzylchloroformate (11.5 ml, 80.6 mmol) and 1N NaOH (15 ml) keeping the pH at 8-8.5 and the temperature 0°-5° C. After 2 hours, starting material was still present (tlc) and an additional quantity of benzylchloroformate (5 ml) and 1N NaOH (5 ml) was added. The reaction mixture was aged at 5° C. overnight and at room temperature an additional 7 hours. Water was added and the mixture extracted with ethyl acetate (3×50 ml), dried with Na2SO4 and concentrated to 21 g of an oil. This oil was dissolved in 10 ml of ethyl acetate, passed through 40 ml of silica gel and eluted with 200 ml of ethylacetate. Crystallization was effected by trituration with petroleum ether and the crystals collected, affording 8.28 g (32%) of N-t-butoxycarbonyl-N'-benzyloxycarbonylpiperazine, m.p. 90.5°-91.5° C.
Reaction SMILES: C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[N:21][C:20]=1[CH:34]=[CH:35][C:36]1[CH:48]=[CH:47][C:39](/[CH:40]=[CH:41]/[C:42](OCC)=[O:43])=[CH:38][CH:37]=1.CO>ClCCl.O>[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[N:21][C:20]=1/[CH:34]=[CH:35]/[C:36]1[CH:37]=[CH:38][C:39](/[CH:40]=[CH:41]/[CH2:42][OH:43])=[CH:47][CH:48]=1
Reactant: CCOC(=O)/C=C/c1ccc(C=Cc2nc(-c3ccc4ccccc4c3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1/C=C/c1ccc(/C=C/CO)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A toluene solution of diisobutylaluminum hydride (1.5 M, 17 ml) was added drop by drop to a suspension of ethyl (E)-4-[2-[5-methyl-2-(2-naphthyl)4-oxazolyl]vinyl]cinnamate (4.20 g) in dichloromethane (100 ml) at 0° C. After the mixture was stirred at room temperature for 4 hours, methanol (2 ml) and then water (6 ml) were added at 0° C. After the insoluble substances were filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to yield a crystal of (E,E)-3-[4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]phenyl]-2-propenol from the fraction eluted with ethyl acetate-chloroform (5:95, v/v), which was then recrystallized from chloroform-ethanol to yield light yellow prisms (3.04 g, 81%) having a melting point of 184°-185° C.
Reaction SMILES: C([O:4][CH:5]1[C:6]([O:53][CH:54]([O:56][CH2:57][CH3:58])[CH3:55])([CH3:52])[CH2:7][CH2:8][CH:9]([O:44][Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:43])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:42])[CH2:24][CH:25]2[O:41][CH:26]2[CH:27]([CH3:40])[CH:28]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[C:32]([O:31][CH:28]([CH2:29][CH3:30])[CH:27]([CH3:40])[CH:26]1[O:41][CH:25]1[CH2:24][CH:23]([CH3:42])/[CH:22]=[CH:21]/[CH:20]=[C:19](\[CH3:43])/[CH:14]1[O:13][C:11](=[O:12])[CH2:10][CH:9]([O:44][Si:45]([CH2:48][CH3:49])([CH2:46][CH3:47])[CH2:50][CH3:51])[CH2:8][CH2:7][C:6]([O:53][CH:54]([O:56][CH2:57][CH3:58])[CH3:55])([CH3:52])[CH:5]([OH:4])[CH:17]=[CH:16][CH:15]1[CH3:18])(=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)C=CC1OC(C)=O
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)/C=C/C1O
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)/C=C/C1OC(C)=O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(=O)c2ccccc2)C(C)C=CC1O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
(8E,12E,14E)-7-acetoxy-21-benzoyloxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (89.1 mg, 108 μmol) was dissolved in methanol (3 mL), and the solution was cooled to 0° C. Potassium carbonate (30.2 mg, 219 μmol) was added to the reaction solution. The reaction solution was warmed to room temperature, and stirred at the same temperature for 3.5 hours. Acetic acid (12.3 μL, 215 μmol) was added to the reaction solution, and then the solution was concentrated. The concentrate was suspended in ethyl acetate (30 mL), and the suspension was washed with saturated aqueous solution of sodium hydrogencarbonate (6 mL) twice, purified water (6 mL) twice, and brine (6 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (MERCK Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=5:1→4:1) to obtain the title compound (60.9 mg, 77.6 μmol, 72.1%) as a colorless oil.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[NH2:25]>CN(C=O)C>[C:13]1([C:2]2[N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]3=[N:25][C:3]=2[C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncccn1
Reactant: O=Cc1ccc(C(=O)C(Br)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc3ncccn3c2-c2ccccc2)cc1

Procedure:
4.6 g 4-[bromo(phenyl)acetyl]benzaldehyde and 1.64 g pyrimidin-2-amine are stirred in 140 ml DMF at 90° C. for 4 h. The DMF is evaporated and the residue suspended in ethylacetate over night, collected by filtration.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>C(Cl)Cl.O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:31][CH:30]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(CBr)cc2)cc1
Reaction time: 12 h

Procedure:
A solution of 4-(bromomethyl)benzenesulfonyl chloride (5.6 mmol) in 5 mL of CH2Cl2 at 25° C. is treated with Et3 N (8.4 mmol) followed by bis-(4-methoxy-benzyl)-amine (5.8 mmol). The reaction is stirred for 12 hours, diluted with H2O, extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. The resultant crude material is purified by silica flash chromatography (20% EtOAc/hexanes) to yield 4-bromomethyl-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide: 1H NMR (400 MHz, CDCl3): δ 7.72 (apparent t, J=8.4 Hz, 2H), 7.44 (dd, J1=1.6 Hz, J2=8.4 Hz, 2H), 6.91-6.86 (m, 4H), 6.69 (d, J=8.8 Hz, 4H), 4.5 (s, 2H), 4.19 (s, 4H), 3.71 (s, 3H); LC/MS: (ES+) 490.1 (M+1)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:10]=3[C:9]([NH2:21])=[N:8][C:7]=2[CH:22]=1.C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH:41]2[CH2:46]N[CH2:44][CH2:43][NH:42]2)=[CH:35][CH:34]=1>CN1CCCC1=O.C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:10]=3[C:9]([N:21]3[CH2:44][CH2:43][NH:42][CH:41]([CH2:40][CH2:39][C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)[CH2:46]3)=[N:8][C:7]=2[CH:22]=1
Reactant: NC1=Nc2cc(F)ccc2Nc2ccc(C(F)(F)F)cc21
Reactant: Fc1ccc(CCC2CNCCN2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Fc1ccc(CCC2CN(C3=Nc4cc(F)ccc4Nc4ccc(C(F)(F)F)cc43)CCN2)cc1
Temperature: 195 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
Heat a solution of 8-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.2 g, 0.60 mmol) and diisopropylethylamine (0.086 g, 0.66 mmol) in 1-methyl-2-pyrrolidinone (4 mL) to 60° C. After 30 minutes, add 2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.38 g, 1.81 mmol) and heat the reaction mixture to 195° C. for 16 hours. Cool reaction mixture to ambient temperature. Dilute with of ethyl acetate (50 ml) and wash twice with saturated aqueous sodium chloride then twice with water. Collect the organic layer and dry over sodium sulfate. Remove solvent under reduced pressure. Purification via flash chromatography, eluting with a linear gradient starting with 100% dichloromethane and going to 85% of dichloromethane with 15% 2M ammonia in methanol, gives the free base of the title compound (0.083 g, 0.17 mmol, 28% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 487(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([S:10]([C:13]([CH3:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([C:32]([O:34]CC)=[O:33])=[CH:29][C:30]([CH3:31])=[C:25]2[NH:24][C:23]1=[O:37].O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[C:32]([C:28]1[N:27]=[C:26]2[N:22]([C:3]3[CH:4]=[C:5]([S:10]([C:13]([CH3:14])([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH3:21])(=[O:12])=[O:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])[C:23](=[O:37])[NH:24][C:25]2=[C:30]([CH3:31])[CH:29]=1)([OH:34])=[O:33]
Reactant: CCOC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(S(=O)(=O)C(C)(C)c4ccccc4)c(OC)cc3Cl)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(C)cc(C(=O)O)nc32)cc1S(=O)(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a mixture of 3-[2-chloro-4-methoxy-5-(1-methyl-1-phenylethylsulfonyl)-phenyl]-5-ethoxycarbonyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (36 mg), tetrahydrofuran (2 mL), methanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (56 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (33 mg).