Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].COCCO[Al+]O[CH2:9][CH2:10]OC.[Na+].[OH-].COC1C=C([CH2:23][NH:24][CH2:25]CCNCCCCNCCCNCC2C=CC(O)=C(OC)C=2)C=CC=1O.CN(CC([C:55]1[C:66]2[CH:65]3[CH2:67][CH:60]([NH:61][CH2:62][C:63]4[CH:71]=[CH:70][CH:69]=[CH:68][C:64]=43)[C:59]=2[CH:58]=[CH:57][CH:56]=1)=O)C>C1C=CC=CC=1>[CH3:23][N:24]([CH3:25])[CH2:9][CH2:10][N:61]1[CH2:62][C:63]2[CH:64]=[CH:68][CH:69]=[CH:70][C:71]=2[CH:58]2[CH2:59][CH:60]1[C:67]1[CH:65]=[CH:66][CH:55]=[CH:56][C:57]=12
Reactant: COCCO[Al+]OCCOC
Reactant: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Reactant: CN(C)CC(=O)c1cccc2c1C1CC2NCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CN(C)CCN1Cc2ccccc2C2CC1c1ccccc12
Temperature: 25 °C

Procedure:
Add a 1M benzene solution of sodium bis(2-methoxyethoxy)aluminum hydroxide (Red-Al®)(5.3 ml.) dropwise with stirring at room temperature to a solution of dl-6-(dimethylaminoacetyl)-5,6,7,12-tetrahydro-5,12-methanodibenz[c,f]azocine (2.8 g. of the free base) in benzene (27 ml.) over 0.5 hours. Reflux for 2 hours, cool, stir at room temperature then quench by careful addition of saturated aqueous ammonium chloride solution (1.85 ml.) dropwise with stirring. Filter and evaporate the filtrate in vacuo. Dissolve the residue in methylene chloride, wash with water, brine then dry and evaporate the solvent in vacuo to obtain 2.79 g. of the free base of the title product as a viscous oil. Treat the free base with two equivalents of fumaric acid in acetone to obtain the title product as the difumarate salt, m.p. 169°-171.5° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:5]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(=O)c1nn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(3-acetyl-1H-indazol-1-yl)acetate (4 g, 12.4 mmol) in CH2Cl2 (45 mL) was added TFA (15 mL, 195.0 mmol), and the reaction mixture was stirred at RT overnight. Then was then diluted with CH2Cl2 and MeOH, and volatiles were evaporated under reduced pressure to afford the title compound: MS: 219 [M+H]+; tR (HPLC conditions d): 2.78 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11](O)[CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].C(N(CC)CC)C.CS([Cl:30])(=O)=O.[F:31][C:32]1[CH:45]=[CH:44][C:35]([C:36]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])=[CH:34][CH:33]=1>ClCCl.O1CCOCC1>[ClH:30].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([N:41]1[CH2:42][CH2:43][CH:38]([C:36](=[O:37])[C:35]2[CH:34]=[CH:33][C:32]([F:31])=[CH:45][CH:44]=2)[CH2:39][CH2:40]1)[CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC(O)c1ccc2ccccc2c1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CC(c1ccc2ccccc2c1)N1CCC(C(=O)c2ccc(F)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1.4 g of 1-(2-naphthyl)-2-diethylaminoethanol was dissolved in 20 ml of dichloromethane. 2.4 ml of triethylamine and 0.9 ml of methanesulfonyl chloride were added to the solution under cooling with ice and the mixture was stirred at room temperature for 4.5 h. A solution of 1.2 g of 4-(p-fluorobenzoyl)piperidine in 25 ml of dioxane was added to the reaction mixture and the obtained mixture was refluxed for 2 h. After completion of the reaction, the product was purified according to silica gel column chromatography and then converted into its hydrochloride.
Reaction SMILES: [CH:1]1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:15]=1)[CH:13]=O.CCCCCC.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])[CH3:26]>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:13]=[C:26]([CH3:1])[C:25]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=1
Reactant: c1ccccc1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(C)=Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To 200 ml of benzene, 10.0 g (53.8 mmol) of 5-chloro-2-nitrobenzaldehyde (manufactured by Aldrich Chemical Co., Inc.) and 18.1 g (50.0 mmol) of Wittig reagent (carbethoxyethylidene triphenylphosphorane, manufactured by Aldrich Chemical Co., Inc.) were added, and the mixture m was stirred at room temperature for one night. After the completion of the reaction was verified by TLC, the reaction liquid was concentrated, whereby a crude product was obtained. This crude product was refined by a column chromatography (aminopropyl-modified silica gel (Fuji Silysia Chem. Co., NH-DM); developing agent: hexane/ethyl acetate=1/1), whereby 13.3 g of the aimed compound were obtained as a crystal (yield: 98%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][C:16]2([CH3:37])[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.[NH2:38][CH2:39][CH2:40][CH2:41][OH:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:42][CH2:41][CH2:40][CH2:39][NH:38][C:34]([C:16]1([CH3:37])[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17]1)=[O:35]
Reactant: NCCCO
Reactant: CC(C)(C)CC1NC(C)(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C)(C(=O)NCCCO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 59.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 33c (0.4 g, 0.7 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.4 g, 5.3 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1 g, 7.7 mmol) in CH2Cl2 (30 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide as a white solid (0.21 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1>C(#N)C>[OH:29][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[N:15]([CH3:18])[C:16]3[C:12]([N:13]=2)=[C:11]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:10]=[C:9]([N:8]2[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH:1][C:41]2=[O:42])[N:17]=3)[CH2:25][CH2:24]1)([CH3:28])[CH3:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Solvent: CC#N
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(=O)[nH]c4ccccc43)nc21
Yield: 15.9 %

Procedure:
A mixture of 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (40 mg, 0.083 mmol) and N,N-carbonyldiimidazole (17 mg, 0.108 mmol) in acetonitrile (2 mL) was stirred at reflux for 15 hours. The reaction mixture was then filtered through paper and purified by RP-HPLC to give 156 (6.7 mg, 16%). LCMS: M+H+=507.2. 1H-NMR (400 MHz, DMSO-d6): δ 11.0 (s, 1H), 7.55 (d, 1H), 7.04 (m, 3H), 4.21 (s, br, 4H), 4.02 (s, 1H), 3.78 (s, 3H), 3.74 (m, 6H), 2.88 (m, 2H), 2.00 (m, 2H), 1.66 (m, 2H), 1.20 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4](C)[C:3]=1[CH2:10][OH:11].[H-].[Na+].I[CH2:15][C:16]([O-:18])=[O:17].[Na+]>C1COCC1>[CH2:10]([O:11][CH2:15][C:16]([OH:18])=[O:17])[C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(C)c(CO)c(C)c1
Reactant: O=C([O-])CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COCc1ccccc1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
(2,4,6-Trimethyl-phenyl)-methanol (4.50 g, 30 mmol) was introduced to the suspension of sodium hydride (95%, 0.84 g, 35 mmol) in dry THF (100 ml), under a nitrogen blanket and the reaction mixture was heated to reflux for one hour. After the reaction mixture cooled down to 25° C., sodium iodoacetate (7.28 g, 35 mmol) was added in one portion, and the reaction was heated to reflux for another two hours. The resulting precipitate was collected by filtration, and then dissolved into water (60 ml). This aqueous solution was acidified to pH 2 at 5° C. by 6N HCl to generate precipitate, which was then isolated by filtration to give pure benzyloxy acetic acid as white powder (3.2 g, 51.2%), mp 81-83°. Microanalysis for C12H16O3 (208.26): C, 69.21, H, 7.74. found: C, 68.83, H, 7.66. 1H-NMR (d6-DMSO): 6.82 (s, 2 arom. H); 4.50 (s, OCH2CO2H); 4.01, 4.02 (2s, CH2O); 2.29 (s, 2 ortho-CH3); 2.20 (s, para-CH3).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[CH2:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:25]([C:24]1[C:23]([CH3:27])=[C:22]2[C:18]([C:19](=[O:28])[O:20][CH2:21]2)=[C:17]([OH:29])[C:16]=1[CH2:15][CH:14]=[C:13]([CH3:36])[CH2:12][NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])[CH3:26]
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1c(C)c2c(c(O)c1CC=C(C)CNCCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Yield: 72.6 %

Procedure:
(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (27.7 mg, 0.051 mmol) was dissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (78.3 mg, 0.512 mmol) was added and the reaction was stirred at room temperature. After 20 hrs the reaction was quenched with MeOH (0.3 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 14.2 mg (57%) of the free phosphonic acid [MS: 484 M++1].
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][C:8](O)=[O:9])[S:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[NH:32][C:31]2=[O:39])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC#N>[O:1]=[C:2]1[CH:6]([CH2:7][C:8]([N:24]2[CH2:25][CH2:26][CH:27]([N:30]3[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[NH:32][C:31]3=[O:39])[CH2:28][CH2:29]2)=[O:9])[S:5][CH:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CC1SC(c2ccccc2)N(Cc2ccncc2)C1=O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(CC1SC(c2ccccc2)N(Cc2ccncc2)C1=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-oxo-2-phenyl-3-((pyridin-4-yl)methyl)thiazolidin-5-yl)acetic acid (0.15 mmol, 49 mg), 1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (0.15 mmol, 33 mg) and DIPEA (0.375 mmol, 65.3 μl) in 4:1 CH3CN:DMF (0.5 ml) was added HATU (0.18 mmol, 68 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%/99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=528.1; tR=2.28. H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.60 (d, J=6.3 Hz, 2H), 7.40-7.38 (m, 2H), 7.33-7.29 (m, 5H), 7.06-6.92 (m, 4H), 5.55-5.53 (m, 1H), 4.55 (d, J=4.4 Hz, 2H), 4.45-4.42 (m, 3H), 4.07 (d, m, 2H), 3.42-3.41 (m, 1H), 3.20-3.15 (m, 1H), 3.01-2.90 (m, 1H), 2.66 (m, 2H), 1.88 (m, 2H) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[OH:15].[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30]OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O>CN(C=O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[O:15][CH2:30][CH:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:29][CH2:28]1
Reactant: COc1ccc2nccc(O)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2nccc(OCC3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C

Procedure:
NaH dispersion (55% in mineral oil, 88 mg, 2 mmol) was added to a suspension of 6-methoxy-4-hydroxyquinoline (350 mg, 2 mmol) in DMF (4 ml) and stirred at room temperature until a solution formed. trans-Methanesulphonic acid 4-tert-butoxycarbonylaminocyclohexylmethyl ester (635 mg, 2 mmol) was added and the reaction mixture was stirred overnight at 80° C. Water was added to the mixture and extraction was carried out with ethyl acetate. Organic extracts washed with water, dried over Na2SO4 and concentrated. The crude product was purified by chromatography on silica gel (DCM/MeOH 9:1).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[CH2:7]([NH:11][C:12]#[N:13])[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C>CCOCC>[C:12]([N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[C:3](=[O:4])[CH:2]([Br:1])[CH3:6])#[N:13]
Reactant: CCCCNC#N
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCN(C#N)C(=O)C(C)Br
Reaction time: 3 h
Yield: 70.8 %

Procedure:
29.5 g (0.137 mole) of 2-bromopropionyl bromide are added dropwise at 15° C. to 13.4 g (0.137 mole) of butyl cyanamide and 13.8 g (0.137 mole) of triethylamine in 150 ml of ether. The mixture is stirred for 3 hours at 20° to 25° C., then filtered to remove the precipitated salt. The filtrate is extracted with dilute hydrochloric acid and the extract is dried over sodium sulfate and concentrated by evaporation. The oily residue is distilled under high vacuum, affording 22.6 g (70.8% of theory) of 2-bromopropionic acid N-cyano-N-butylamide with a boiling point of 53°-54° C. at 0.0052 mbar.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:19][CH3:20])[CH:9]=2)[N:4]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC.[F-].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH2:17]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:19][CH3:20])[C:11]=1[C:8]1[CH:9]=[C:10]2[C:2]([CH:30]=[CH2:31])=[CH:3][N:4]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:23][CH:22]=3)[C:5]2=[CH:6][N:7]=1)[CH3:18]
Reactant: CCc1cccc(CC)c1-c1cc2c(Br)cn(-c3ccc(C(C)C)cc3)c2cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (440 mg, 0.98 mmol), tributyl-vinyl-stannane (620 mg, 1.96 mmol), Pd(PPh3)4 (113 mg, 0.098 mmol), and DMF (5 mL) is heated to 100° C. for 3 h under nitrogen. The mixture is poured to a saturated aqueous KF solution (20 mL), and the resultant mixture is stirred for three hours at room temperature. The product is extracted with EtOAc (70 mL×3). The combined organic extracts are washed with water (100 mL×3) and brine (100 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 10:1) to afford 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-3-vinyl-1H-pyrrolo[2,3-c]pyridine as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(O)C>[OH:15][C:8]1[CH:9]=[CH:10][C:11]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)CC1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccc(Nc2ccccc2)cc1
Yield: 27 %

Procedure:
0.93 g of aniline, 2.24 g of 1,4-cyclohexanedione and 1.4 ml of triethylamine were heated with stirring in 15 ml of ethanol at 50° C. to 60° C. and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After concentrating the reaction mixture under reduced pressure, the resultant was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and 0.50 g of N-(4-hydroxyphenyl)aniline was obtained (yield 27.4%).
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:13]N)[CH:4]=1.O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:21]1[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C:16]=1[NH:13]2
Reactant: Cc1cc(C(=O)O)c(NN)cc1Br
Reactant: CCOC(=O)C1CCCC(=O)C1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(C)c(Br)c23)C1
Temperature: 117 °C
Yield: 54.6 %

Procedure:
A mixture of 4-bromo-2-hydrazinyl-5-methylbenzoic acid hydrochloride (2.17 g, 7.71 mmol), ethyl 3-oxocyclohexanecarboxylate (1.44 g, 8.48 mmol) and acetic acid (1.32 mL, 23.1 mmol) in toluene (40 mL) was heated in an oil bath at 117° C. for 5 h. The mixture was concentrated and dried under vacuum, and the residue was diluted with toluene (18 mL) and TFA (4.5 mL). The mixture was heated at 90° C. overnight. The cooled mixture was diluted with EtOAc, sonicated, and the precipitate was collected by filtration and washed with EtOAc to give a yellow solid. The filtrate was concentrated and the residue was suspended in EtOAc with sonication. The precipitate was collected by filtration and combined with the first precipitate. The solid was triturated with MeOH to give 5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a pale yellow solid (1.60 g, 55% yield). Mass spectrum m/z 380, 382 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][N:8]3[CH:21]=[CH:22][N:23]=[C:7]3[C:6]=2[CH:24]=1.ClC1C=CC2OCCC3N(C=C(C([O:42][CH3:43])=O)N=3)C=2N=1.CCCC[N+:48](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:15])[CH3:16])[CH2:9][N:8]3[CH:21]=[C:22]([C:43]([NH2:48])=[O:42])[N:23]=[C:7]3[C:6]=2[CH:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OCC1Cn2ccnc2-c2cc(Br)ccc2O1
Reactant: COC(=O)c1cn2c(n1)CCOc1ccc(Cl)nc1-2
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1Cn2cc(C(N)=O)nc2-c2cc(Br)ccc2O1

Procedure:
10-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was prepared from 10-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine using the same procedures as outlined for the synthesis of methyl 2-chloro-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-9 carboxylate. TBAF (1.7 g, 6.50 mmol, 2.00 equiv) was added in several batches to a stirred solution of this intermediate (1.6 g, 3.54 mmol, 1.00 equiv) in tetrahydrofuran (7 mL) at room temperature. After 1 h the resulting solution was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:21]([C:20]2[CH:24]=[CH:25][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=2)=[O:22])=[CH:29]1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(c1ccc(C(F)(F)F)cc1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-(4-trifluoromethyl-phenyl)-methanone was prepared from phenanthridine, 4-trifluoromethylbenzoyl chloride, and indole according to GP 2. Yield, 12%. 1H-NMR (CD3OD): δ=6.19 (s, 1H), 6.28 (s, br., 1H), 6.75 (t, br., J≈6.8 Hz, 1H), 7.03-7.11 (m, 2H), 7.14 (t, J=7.6 Hz, 1H), 7.20-7.25 (m, 1H), 7.33-7.51 (m, 5H), 7.52-7.60 (m, 1H), 7.57 (d, J=7.6 Hz, 2H), 7.92 (d, J=7.8 Hz, 1H), 7.99 (s, br., 1H), 8.07 (d, J=7.8 Hz, 1H); (+)-ESI-MS: m/z=469 [M+H]+, 352 [M-indole+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14](Cl)=[O:15])[S:13][C:6]=12.Cl.[C:25]([N:32](C)[CH2:33][CH2:34][NH2:35])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:35][CH2:34][CH2:33][NH:32][C:25](=[O:26])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:15])[S:13][C:6]=12
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 40 (shown in the scheme 7, 100 mg, 0.26 mmol), N-Boc-N-methylethylenediamine hydrochloride (50 mg, 0.26 mmol) and Et3N (36 μL, 0.52 mmol) in DCM (2 mL) was stirred for 4 h at room temperature and diluted with EtOAc (10 mL). The combined mixture was washed with brine and phases were separated. The aqueous phase was extracted with EtOAc, and the extract was combined with the organic phase, dried over anhydrous Na2SO4 and concentrated to afford title compound 292 (119 mg, 96%, crude) as yellowish solid. MS (m/z): 477.1 (M+H) (found).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].Cl.[OH-:28].[Li+]>>[CH3:1][C:2]1[C:7]([C:8]([OH:9])=[O:28])=[C:6]([O:17][C:16]2[C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]([O:21][CH3:22])=[C:12]([CH3:23])[C:11]=2[OH:10])[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Product: COc1cc(C(=O)O)c(Oc2c(C=O)c(O)cc(C)c2C(=O)O)c(O)c1C
Reaction time: 8 h

Procedure:
Psoromic acid (35 mg, 1 mmol) was dissolved in 1 mol/L of aqueous lithium hydroxide (3 ml), and the reaction is allowed to stand overnight. The solution was acidified to a pH of 4 with 1 mol/L dilute HCl, filtered, and collected to give a white solid product.