Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=2)[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:19]=2)=[O:17])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Cc1ccc(C(Cc2cccc(C(=O)c3c[nH]c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(CC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 20 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A mixture of 3-[3-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl]indole (442 mg), ethyl 4-bromobutyrate (185 mg) and potassium carbonate (360 mg) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 4 hours. Ethyl 4-bromobutyrate (185 mg) and potassium carbonate (120 mg) were added, and resulting mixture was stirred at 20° C. for 16 hours. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of hexane and ethyl acetate (10:1) to give ethyl 4-[3-[3-[2,2-bis(4isobutylphenyl)ethyl]benzoyl]indol-1-yl]butyrate (480 mg) as an oil.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(-c3ccccc3F)c2O1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (681 mg) obtained in Example 12, steps 1-4, (2-fluorophenyl)boronic acid (356 mg), dichlorobis(triphenylphosphine)palladium (68 mg) and potassium carbonate (809 mg) in DME-water (1:1, 20 mL) was stirred at 85° C. for 4 hr under a nitrogen stream. The reaction solution was cooled to room temperature, and water was added. The mixture was filtered through celite, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (694 mg, 98%) as a colorless oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[NH2:56][C:57]1[C:58]([OH:68])=[C:59]([S:64]([OH:67])(=[O:66])=[O:65])[CH:60]=[C:61]([Cl:63])[CH:62]=1>CN(C=O)C.C(O)(C(F)(F)F)=O.N1C=CC=CC=1>[NH2:1][C@@H:2]([CH2:3][CH2:4][C:5](=[O:6])[NH:56][C:57]1[CH:62]=[C:61]([Cl:63])[CH:60]=[C:59]([S:64]([OH:67])(=[O:66])=[O:65])[C:58]=1[OH:68])[C:8]([OH:10])=[O:9]
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: N[C@@H](CCC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
101 mg (0.33 mmol) of Boc-Glu-OtBu, 130 mg (0.33 mmol) of HATU, 45 mg (0.33 mmol) of HOAt and 77 mg (0.33 mmol) of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid were suspended in 2.0 ml of DMF, to which 0.5 ml of pyridine was added and stirred at room temperature overnight. After distilling the solvent away, purification step A was used to obtain an intermediate. This crude product was dissolved in 2.0 ml of TFA and stirred at room temperature for 90 minutes. After distilling the solvent away, purification step A was used to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.OS(O)(=O)=O>O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2ccc(F)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1ccc(COCC2CCNCC2)cc1
Reaction time: 2 h

Procedure:
To a solution of 0.89 g (2.35 mmol) of 1-t-butoxycarbonyl-4-(4-fluorobenzyloxymethyl)piperidine in 8 mL of H2O at rt was added 2 mL of TFA and the reaction mixture was stirred for 2 h. To the reaction mixture was added 50 mL of 0.5N H2SO4. After stirring vigorously for 5 min, the mixture was was washed with CH2Cl2. The aqueous fraction was made basic with solid K2CO3 and extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4 and filtered. The filtrate was concentrated to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][O:7][C:8]1[CH:12]=[C:11]([N:13]2[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[N:15]=[CH:14]2)[S:10][C:9]=1[C:22]([O:24]C)=O.[NH3:31]>CO>[F:30][CH:2]([F:1])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][O:7][C:8]1[CH:12]=[C:11]([N:13]2[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[N:15]=[CH:14]2)[S:10][C:9]=1[C:22]([NH2:31])=[O:24]
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 37.5 mg of methyl 3-{[2-(difluoromethoxy)benzyl]oxy}-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness, the resulting residue is dissolved in a mixture of acetonitrile and methanol (9:1 (v/v)) and purified by preparative HPLC (water/acetonitrile, elution gradient 9/1 to 1/9 (v/v)) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11])[C:5]#[N:6].[OH-:26].[NH4+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11])[C:5]([NH2:6])=[O:26]
Reactant: [OH-]
Reactant: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Concentrated sulfuric acid (70 ml) was added to 3-chloro-4-(5H,11H-pyrrolo-[2,1-c][1.4]benzodiazepine-10-carbonyl)-benzonitrile (12.85 g). The mixture was stirred at 60° C. for 3 hours, followed by stirring at room temperature for 18 hours. The reaction mixture was poured over ice and neutralized at 0° C., with 30% ammonium hydroxide (184 ml). The resulting suspension was extracted with ethyl acetate. The aqueous mixture was filtered, and reextracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and the solvent removed in vacuo. The residue was triturated with a mixture of diethyl ether (50-60 ml) and a small quantity of ethyl acetate. Filtration of the precipitate afforded the title compound as a crystalline solid (10.44 g), m.p. 211-212° C.; MS (EI), m/z: 365 (M)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:23]Br>C(Cl)Cl.ClC1C=CC=CC=1>[Br:23][C:18]1[CH:17]=[C:16]([CH:13]2[CH2:14][CH2:15][CH:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: BrBr
Reactant: CCCC1CCC(C2CCC(c3ccc(O)cc3)CC2)CC1
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CCCC1CCC(C2CCC(c3ccc(O)c(Br)c3)CC2)CC1
Temperature: 0 °C
Yield: 39.6 %

Procedure:
4-(4-(4-Propylcyclohexyl)cyclohexyl)phenol (0.5 g) was dissolved in a mixed solvent of methylene chloride (5 ml) and chlorobenzene (1 ml), to which was then added dropwise a solution of bromine (0.28 g) in methylene chloride (2 ml) under ice cooling while stirring. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 minutes, added in ice water, and then extracted with methylene chloride. An organic layer was washed with water, rinsed with a sodium thiosulfate aqueous solution, and then dried over anhydrous magnesium sulfate. The methylene chloride solution was concentrated in vacuo and then subjected to isolation and purification by silica gel column chromatography, thereby obtaining a white crystal (0.25 g) of 2-bromo-4-(4-(4-propylcyclohexyl)cyclohexyl)phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].OS(O)(=O)=O.[N:23]([O-])=O.[Na+].Cl[Sn]Cl>O.Cl>[NH:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:13])=[O:14])[CH:6]=[CH:5]2)[NH2:23]
Reactant: O=N[O-]
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: NNc1ccc2cc(S(=O)(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
To a solution of 6-aminonaphthalene-2-sulfonic acid (2.23 g, 10 mmol) in 15 ml of H2O was added 2N NaOH (0.75 ml). The mixture was stirred for 5 min at RT and conc. H2SO4 (0.68 g, 6.9 mmol) was added to it dropwise at 0° C. 2 ml of iced H2O was added, followed by a solution of NaNO2 (1.04 g, 15 mmol) in 2 ml of H2O. After the solution was stirred at 0° C. for 2 h, the diazonium salt was removed by filtration and washed with cold water. The salt was then added in portions to a cold (<0° C.) solution of SnCl2 (4.9 g, 22 mmol) in 3.2 ml of conc. HCl and 1.8 ml of H2O. The mixture was stirred overnight. The solid was filtered and washed twice with water, dried under vacuum to give 1.84 g of 6-hydrazinylnaphthalene-2-sulfonic acid (77%), which was used directly for next step.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[C:9]([F:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:5]=1[Cl:15].[OH-].[Na+]>C(O)C>[Cl:15][C:5]1[C:6]([O:13][CH3:14])=[CH:7][C:8]([O:11][CH3:12])=[C:9]([F:10])[C:4]=1[C:3]([OH:16])=[O:2]
Reactant: COC(=O)c1c(F)c(OC)cc(OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(C(=O)O)c1F

Procedure:
A suspension of 2-chloro-6-fluoro-3,5-dimethoxy-benzoic acid methyl ester (7.9 g, 31.9 mmol) and sodium hydroxide (3.2 g, 79.6 mmol) in 96 mL of anhydrous ethanol is refluxed for 24 hours. The ethanol is concentrated in vacuo and solid residue is dissolved in water and extracted twice with ether. The aqueous layer is acidified with Conc. HCl and a white precipitate is filtered, washed with cold water and dried in vacuo to afford 2-chloro-6-fluoro-3,5-dimethoxy-benzoic acid (21); 1H NMR 400 MHz (CDCl3) δ 6.61 (d, 1H), 3.87 (s, 3H), 3.84 (s, 3H); MS m/z 235.0 (M+1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.[BH4-].[Na+]>>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][CH:5]([CH2:3][OH:2])[CH2:9][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CC(CO)CN1c1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to Example 33a) from (RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and sodium borohydride. Yield: 82% of a colorless solid. MS: m/e=316.3 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH2:13][CH3:14])[C:5]=1[NH:15][C:16]([NH:18][C:19](=[NH:22])[NH:20][CH3:21])=[O:17])[CH3:3].Cl>C(O)C>[ClH:1].[ClH:1].[NH2:10][C:8]1[CH:9]=[C:4]([CH2:2][CH3:3])[C:5]([NH:15][C:16]([NH:18][C:19](=[NH:22])[NH:20][CH3:21])=[O:17])=[C:6]([CH2:13][CH3:14])[CH:7]=1
Reactant: CCc1cc([N+](=O)[O-])cc(CC)c1NC(=O)NC(=N)NC
Agent: Cl
Solvent: CCO
Product: CCc1cc(N)cc(CC)c1NC(=O)NC(=N)NC

Procedure:
A mixture of 5.0 g (15.2 mmol) of 1-(2,6-diethyl-4-nitrophenyl)-3-methylamidinourea hydrochloride and 5% paladium on carbon (500 mg) in absolute ethanol (175 ml) containing concentrated hydrochloric acid (2 ml) is shaken under an atmosphere of hydrogen (50 psi) for thirty minutes. The mixture is filtered through a Celite pad. To the filtrate is added HCl/MeOH and the alcohol is removed under vacuum to give a yellow foam which is crystallized from methanol-ethyl acetate to give 1-(4-amino-2,6-diethylphenyl)-3-methylamidinourea dihydrochloride, m.p. 218°-222° C. (dec).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:34])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (48 mg, 0.21 mmol), (4-benzyloxy-phenyl)-acetic acid (50 mg, 0.21 mmol), ethyldimethylpropylcarbodiimide hydrochloride (47 mg g, 0.25 mmol), N-hydroxybenzotriazole (33 mg, 0.25 mmol), N-methyl morpholine (50 mg, 0.50 mmol) in 2 mL of DMF was shaken for 6 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.82 (t, 2H, J=6.78), 3.60 (s, 2H), 4.38 (t, 2H, J=6.78), 5.09 (s, 2H), 6.97 (m, 2H), 7.11–7.45 (m, 8H), 7.65 (m, 1H), 7.93 (m, 1H), 8.12 (s, 1H), 10.27 (s, 1H); MS (DCI/NH3) m/z 455 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=O)[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:27][C:28]([F:33])([F:32])[CH2:29][CH2:30][NH2:31].C([BH3-])#N.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH:18]([NH:31][CH2:30][CH2:29][C:28]([F:33])([F:32])[F:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: NCCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1c(Cl)cc(C(/C=C/c2ccc3c(c2)CCC3NCCC(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3-dihydro-1H-inden-1-one (0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine (0.048 g, 0.42 mmol) and sodium cyanoborohydride (0.055 g, 0.875 mmol) in cooling and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCE, was washed with water and brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a colorless gummy material (0.042 g, 24%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 6.62 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 2H), 1.82 (m, 1H), 1.42 (m, 1H); ESIMS m/z 497.98 ([M−H]−); IR (thin film) 3027, 1654, 815 cm−1.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5]([O:7]CC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1[CH2:21][CH2:20][CH2:19][CH2:18]1.O.[OH-].[Na+].O1CC[CH2:27][CH2:26]1>C(OCC)C>[CH3:10][CH:2]([CH3:1])[CH:3]([C:18]1[CH:27]=[CH:26][CH:21]=[CH:20][CH:19]=1)[CH2:4][CH2:5][OH:7]
Reactant: CCOC(=O)CCC(C)C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)C(CCO)c1ccccc1
Reaction time: 1.5 h
Yield: 42 %

Procedure:
Under a nitrogen atmosphere, ethyl 4-methylpentanoate (350 mg) was dissolved in tetrahydrofuran (10 mL) at −78° C., a lithium aluminum hydride/tetrahydrofuran solution (1.0 M, 1.58 mL) was added, and the mixture was stirred. While the temperature of the mixture was naturally returned to room temperature, the mixture was stirred, and after 1.5 hours, water (0.05 mL), a 2N aqueous sodium hydroxide (0.05 mL) and water (0.15 mL) were successively added thereto, and the mixture was stirred. Further, diethyl ether was added thereto, and then the resulting insoluble matters were filtered off and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate system), to give the title compound as a colorless oil (257 mg, 42%: 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:17]=1[CH2:16][CH2:15][NH:14][C:13]2=[O:12]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(F)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-fluoro-1,3-dihydro-indol-2-one (30.2 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:27]2[CH:26]=[CH:25][C:24]([CH:28]=O)=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2.N1CCCCC1>C(O)C>[I-:1].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](/[CH:13]=[CH:28]/[C:24]2[CH:25]=[CH:26][C:27]3[N:15]([CH3:14])[C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Reactant: Cc1cc[n+](C)c2ccccc12
Agent: [I-]
Solvent: C1CCNCC1
Solvent: CCO
Product: Cn1c2ccccc2c2cc(/C=C/c3cc[n+](C)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A solution mixture of 1,4-dimethylquinolinium iodide (0.14 g, 0.5 mmol), 3b (0.13 g, 0.6 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford Me-SLM (0.14 g) in 62% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=6.4 Hz, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 8.49 (d, J=6.4 Hz, 1H), 8.45-8.23 (m, 5H), 8.15 (d, J=8.8 Hz, 1H), 8.06 (t, J=7.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 4.51 (s, 3H), 3.95 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 152.9, 147.3, 144.8, 142.2, 141.2, 138.7, 134.8, 128.8, 127.4, 126.6, 126.4, 126.3, 126.0, 122.6, 122.0, 121.8, 120.4, 119.7, 119.1, 116.0, 115.0, 109.8, 109.7, 44.3, 29.3. HRMS (MALDI-TOF) m/z Calcd for C25H21N2 349.1699. Found 349.1694 [M]+.
Reaction SMILES: CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O.[OH:26][C@H:27]([C@H:32]([NH:36][C:37](=[O:77])[C@H:38]([NH:40][C:41](=[O:76])[C@H:42]([NH:46][C:47](=[O:75])[CH2:48][C@H:49]([OH:74])/[CH:50]=[CH:51]/[CH2:52][CH2:53][S:54][C:55]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH:43]([CH3:45])[CH3:44])[CH3:39])[CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C1COCC1.CN(C=O)C>[OH:26][C@H:27]1[CH2:28][C:29](=[O:31])[O:30][O:74][C@H:49](/[CH:50]=[CH:51]/[CH2:52][CH2:53][S:54][C:55]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:48][C:47](=[O:75])[NH:46][C@H:42]([CH:43]([CH3:44])[CH3:45])[C:41](=[O:76])[NH:40][C@H:38]([CH3:39])[C:37](=[O:77])[NH:36][C@@H:32]1[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)[C@@H](NC(=O)[C@@H](C)NC(=O)[C@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C)[C@@H](O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H]1NC(=O)[C@@H](C)NC(=O)[C@@H](C(C)C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OOC(=O)C[C@@H]1O
Yield: 19.4 %

Procedure:
To a solution of MNBA (73.5 mg, 0.21 mmol) and DMAP (51.9 mg, 0.42 mmol) in CH2Cl2/THF (33 mL, 2:1) was added dropwise a solution of acid 8 (129 mg, 0.18 mmol) in CH2Cl2/THF (134.5 mL, 2:1) with 3 drops of DMF over 4 h. After a further 16 h the reaction mixture were concentrated in vacuo. Purification by flash column chromatography on silica (eluent 1:0-98:2-96:4-94:6-92.8 CH2Cl2/MeOH) gave 9 (24.7 mg, 0.035 mmol, 17%) as a white solid: Rf 0.43 CH2Cl2/MeOH (90:10); IR (thin film) 3293 (b), 2963 (m), 1732 (m), 1660 (s), 1536 (m) cm−1.