Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl.COC>[N:10]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:6]2[CH:5]=[CH:4][N+:3]([O-:26])=[CH:2][C:7]=2[CH:8]=[CH:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Agent: COC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1ccc2c[n+]([O-])ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A stirred suspension of benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1 g, 3.9 mmol, Step a)) in a mixture of dichloromethane and dimethyl ether (10:1 mL) was treated portion wise with 3-chloroperoxybenzoic acid (0.85 g, 4.9 mmol) followed by stirring at room temperature for 4 hours. The reaction was neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield benzyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (1 g, 99%).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[Cl:25][C:26]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[F:2][C:3]([F:24])([F:23])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[C:17]([O:35][C:32]3[CH:33]=[CH:34][C:29]([O:28][C:27]4[CH:36]=[CH:37][C:38]([N+:40]([O-:42])=[O:41])=[CH:39][C:26]=4[Cl:25])=[CH:30][CH:31]=3)=[O:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)c(Cl)c1
Agent: Cl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2Cl)cc1

Procedure:
In Example 1-13, by using 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride hydrochloride instead of 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride hydrochloride, and 4-(2-chloro-4-nitrophenoxy)phenol instead of 4-(4-nitrophenoxy)phenol, 4-(2-chloro-4-nitrophenoxy)phenyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy)propionate was obtained.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ncccn1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ncccn3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-N-methylpyrimidine-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH:15]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cccc(-c2nnn[nH]2)c1
Yield: 58 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 3-chloro-2-methylbenzenesulfonyl chloride (12.4 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 58% yield (10.1 mg). MS (ESI+) calcd mass for C14H12ClN5O2S 349.040023, found 349.040413.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][CH:9]2[C:16]([NH:34][CH2:35][CH:36]([OH:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)COc1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1CC(C(=O)NCC(O)COc2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, staring from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=488.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[CH2:30]([NH:37][S:15]([CH2:14][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:16])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol 1.0 eq.) in DCM (1.0 mL) was combined with benzylamine (47.7 μL, 4.0 eq.) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (7.3 mg). MS m/z: [M+H]+ calcd for C20H23F3N2O3S, 429.14. found 429.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[OH:23]O.Cl>O.C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[O:23][C:8]32[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]3=[O:18])=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccncc2)CCc2ccccc21
Reactant: OO
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1c2ccccc2CCC12OC2c1ccncc1

Procedure:
To a mixture of 10 g. of 2-(4-pyridylmethylene)-3,4-dihydro-1(2H)-naphthalenone in 100 ml of water and 200 ml of ethanol is added sufficient chloroform to dissolve the reactants. The pH is adjusted to between 7 and 9 and a 3 molar excess of 30% hydrogen peroxide in water is added dropwise at room temperature. The reactants are stirred for 5 hours after which sufficient ferrous sulfate is added to neutralize the excess peroxide. The mixture is then acidified with hydrochloric acid and the organic solvent evaporated off. The water solution remaining is made basic and extracted with chloroform. The chloroform is evaporated off yielding 3'-(4-pyridyl)-spiro[1,2,3,4-tetrahydronaphthalene-2,2'-oxirane]-1-one.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:8]=1.[B:22](OC)([O:25]C)[O:23]C.Cl>C1COCC1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([B:22]([OH:25])[OH:23])=[CH:8][CH:9]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
n-Butyllithium (23 ml, 2.5M in hexane, 0.058 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 26 (15.00 g, 0.053 mol) in dry THF (168 ml) under dry nitrogen. The reaction mixture was maintained under these conditions for 2.5 h and then a solution of trimethyl borate (10.98 g, 0.106 mol) in dry THF (50 ml) was added dropwise at -78° C. The reaction mixture was allowed to warm to room temperature overnight and then stirred for 1 h with 10% hydrochloric acid (120 ml). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield an off white solid.
Reaction SMILES: C([NH:3][CH:4]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)=O.S(=O)(=O)(O)O>C(O)C.O1CCCC1.O>[NH2:3][CH:4]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C=Cc1ccc(CC(NC=O)c2cccnc2)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1ccc(CC(N)c2cccnc2)cc1
Temperature: 65 °C
Reaction time: 17 h
Yield: 95.8 %

Procedure:
Ethyl 4-[2-formamido-2-(3-pyridyl)ethyl]cinnamate (0.40 g) was dissolved in a mixed solvent of 10 ml of ethanol, 10 ml of tetrahydrofuran and 8 ml of water, followed by addition of 0.40 ml of concentrated sulfuric acid and heating to 65 ° C., and stirred for 17 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, followed by addition of CH2Cl2 and water and subsequent gradual addition of saturated aqueous solution of sodium hydrogencarbonate to adjust the mixture to weak alkalinity. The organic phase was separated and extracted from aqueous phase with methanol-methylene chloride (5:95 v/v), followed by washing in saturated aqueous sodium chloride solution, drying over magnesium sulfate and evaporation of the solvent, to produce 0.35 g of ethyl 4-[2-amino-2-(3-pyridyl)ethyl]cinnamate.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH:8]=[CH:7][C:6]([CH:9]=O)=[CH:5]1.[N+:11]([CH3:14])([O-:13])=[O:12].CCOCC>CO>[N+:11]([CH:14]=[CH:9][C:6]1[CH:7]=[CH:8][O:4][CH:5]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccoc1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccoc1
Temperature: 0 °C
Yield: 69 %

Procedure:
A freshly prepared solution of sodium methoxide (prepared by dissolving sodium (0.46 g, 20 mmol) in MeOH (5 mL)) was added very slowly via a double ended needle to a solution of 3-furaldehyde (1.73 mL, 20 mM) and nitromethane (1.08 mL, 20 mmol) in MeOH (4 mL) cooled to 0° C. The mixture was stirred at 0° C. an addition 5 min, then Et2O (10 mL) was added. The resultant salt was collected via filtration, thoroughly washed with Et2O, taken up in a minimum amount of water then the solution was added to an ice cold solution of 25% HCl (80 mL). The solid that formed was collected by filtration and washed with water, then the moist product was taken up in CHCl3/MeOH and solvents removed to give 3-(2-nitrovinyl) furan (69%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.O>CN(C)C=O>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]2)[S:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(-c2ccccn2)ns1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccn3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 2-(5-chloro-1,2,4-thiadiazol-3-yl)pyridine (3.96 g, 20.0 mmol) and 1-tert-butoxycarbonyl-piperazine (3.73 g, 20.0 mmol) in dimethylformamide (40 ml) was added triethylamine (11.2 ml, 80.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 6.35 g (91.2%) of tert-butyl 4-(3-pyridin-2-yl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxylate as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([N:26]1[CH2:27][CH2:28][C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[C@H:24]([OH:29])[CH2:25]1)(=[O:40])[CH3:39]
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCNC[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@@H](n2cnc3c(cc(Cc4ccc(Cl)nc4)c4ccccc43)c2=O)[C@H](O)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4R)-3-hydroxypiperidin-4-yl]benzo[h]quinazolin-4(3H)-one (Example 35, 0.050 g, 0.11 mmol) in 2 mL of dichloromethane at 0° C. was added triethylamine (0.023 mL, 0.16 mmol) and acetic anhydride (0.013 mL, 0.14 mmol). The reaction was stirred at 0° C. for 5 h, quenched with water, and concentrated in vacuo. The resultant residue was subjected to purification via reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 462.9 for M+H+: 1H NMR (400 MHz, CDCl3) p9.01-9.00 (m, 1H), 8.37 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=7.1 Hz, 1H), 7.88 (s, 1H), 7.72-7.68 (m, 2H), 7.41 (d, 8.7 Hz, 1H), 7.22-7.20 (m, 1H), 5.07-5.01 (m, 1H), 4.92-4.67 (m, 2H), 4.44 (s, 2H), 4.23-3.98 (m, 3H), 3.34-3.24 (m, 1H), 3.20-3.11 (m, 1H), 2.22 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=[CH:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:20][C:18]1[C:19]2[N:11]([CH2:10][CH2:9][OH:8])[CH:12]=[CH:13][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc2ncnc(Cl)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCCn1ccc2ncnc(Cl)c21
Reaction time: 4 h
Yield: 110.2 %

Procedure:
To a solution of 5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (560 mg) in tetrahydrofuran (1.7 mL), was added tetrabutylammonium fluoride (1M tetrahydrofuran solution) (2.69 mL) under ice-cooling, and the mixture was stirred for 4 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:ethyl acetate/methanol=10/0→9/1). The object fraction was concentrated under reduced pressure and dried to give the title compound (391 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.[ClH:37]>CCO.CC#N.CCOCC>[ClH:37].[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])=[CH:15][CH:16]=2)[NH:11][N:10]=1
Reactant: Cn1ccnc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CCO
Product: Cn1ccnc1/C=C/c1n[nH]c2cc(C=C3C(=O)Nc4ccccc43)ccc12
Temperature: 77.5 °C
Reaction time: 8 h

Procedure:
A sealed, degassed mixture of (E)-3-((3-((E)-2-(1-methyl-1H-imidazol-2-yl)vinyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (35.4 mg, 0.071 mmol) in EtOH (4 mL) and aq HCl (4 M, 1 mL) was heated at 75-80° C. under Ar for 1 d. The reaction mixture was cooled to rt, diluted with MeCN (10 mL) and Et2O (5 mL) and stored at −20° C. overnight. The precipitate was collected by filtration, washed with MeCN to provide the title compound as a 1.5:1.0 (E:Z) mixture of isomers: a yellow solid (14.5 mg, 51%). 1H NMR (400 MHz, CD3OD) δ ppm 8.93 (s, 0.44H), 8.25 (d, J=8.28 Hz, 1.00H), 8.13 (d, J=8.53 Hz, 0.65H), 8.02-8.06 (m, 0.45H), 8.02 (s, 1.78H), 7.92-8.00 (m, 1.78H), 7.86-7.91 (m, 1.47H), 7.58-7.71 (m, 5.0H), 7.53 (d, J=16.81 Hz, 1.29H), 7.25 (t, J=7.65 Hz, 1.52H), 7.05 (t, J=7.78 Hz, 0.66H), 6.94 (d, J=7.78 Hz, 1.01H), 6.83-6.91 (m, 1.73H), 4.04 (s, 2.46H), 4.03 (s, 1.41H); MS ESI 368.1 [M+H]+, calcd for [C22H17N5O+H]+ 368.4.
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>O>[CH2:41]([O:40][C:38]([CH2:37][CH2:36][CH2:35][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:39])[CH3:42]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCCOc1cc2c(cc1[Se]c1ccc(C(=O)OCC)cn1)C(C)(C)CCC2(C)C
Temperature: 80 °C

Procedure:
432 mg (102.0 mmol) of ethyl 6-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro 2-naphthylselanyl)nicotinate, 276 mg (2 mmol) of potassium carbonate and 390 mg (2 mmol) of ethyl 4-bromobutanoate are introduced into a three-necked flask. The mixture is heated at 80° C. for 12 h. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out by settling, washed with water, dried over magnesium sulphate and evaporated. After purification by flash chromatography (9 heptane/1 EtOAc), 467 mg (85%) of the expected compound are collected in the form of an orange-coloured oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnn[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nnn[nH]2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 185.4 %

Procedure:
In THF (6.7 ml)/methanol (6.7 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.25 g). To the solution was added 1N sodium hydroxide solution (6.7 ml), and the mixture was stirred at 50° C. for 4 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (2/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(tetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.45 g).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25]([CH2:28]O)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25]([CH2:28][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:26][CH:27]=2)=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(CO)nc3)nc3ccccc3c2=O)cc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)c1ccc(-n2c(-c3ccc(CN4CCOCC4)nc3)nc3ccccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 984 %

Procedure:
3-(4-sec-butylphenyl)-2-(6-(hydroxymethyl)pyridin-3-yl)quinazolin-4(3H)-one (0.176 g, 0.46 mmol) was dissolved in CH2Cl2 (30 mL) under nitrogen and cooled to 0° C. Hünig's base (0.160 mL, 0.92 mmol) was added, followed by MsCl (0.042 mL, 0.55 mmol), and the mixture was stirred for 15 min at 0° C. Morpholine (0.400 mL) was added, the reaction was warmed to room temperature, and stirred for 2 hours, before concentration and purification by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% methanol/ethyl acetate, afforded the title compound (0.175 g, 984%). 1H-NMR (300 MHz, DMSO-6): δ8.48 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.90-7.95 (m, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.60-7.68 (m, 2H), 7.22-7.27 (m, 3H), 7.10-7.16 (m, 2H), 3.49-3.54 (m, 6H), 2.55-2.63 (m, 1H), 2.19-2.29 (m, 4H), 1.33-1.56 (m, 2H), 1.13 (d, J=6.8 Hz, 3H), 0.62 (t, J=7.2 Hz, 3H). MS (APCI) m/z: 455 (M+H)+.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:4]/[CH:3]=[CH:2]/[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C/C=C/C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)/C=C/CBr
Temperature: 25 °C

Procedure:
To the mixture of (E)-tert-butyl but-2-enoate (10.0 g, 70.4 mmol) and NBS (12.5 g, 70.4 mmol) in CCl4 (150 mL) was added benzoyl peroxide (510 mg, 2.11 mmol), and the reaction was refluxed for 12 h. The mixture was cooled to room temperature, and the solid was filtered off. The filtrate was concentrated in vacuo, and purified by column chromatography to afford (E)-tert-butyl 4-bromobut-2-enoate (I-2a). 1H-NMR (400 MHz, CDCl3) δ 7.02-6.76 (m, 1H), 6.05-5.89 (m, 1H), 4.06-3.95 (m, 2H), 1.56-1.40 (m, 9H). MS calculated for C8H14BrO2 (M+H+) 221.01. found: 221.0.