Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:22])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][C:20]1[C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:35])([CH3:24])([CH3:25])[CH3:26]
Reactant: Cc1ccccc1Nc1ncccc1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1Nc1ncccc1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.05 mL, 7.53 mmol) was added to a mixture of N2-o-tolylpyridine-2,3-diamine (500 mg, 2.51 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (520 mg, 2.76 mmol), HOAt (380 mg, 2.76 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (530 mg, 2.76 mmol) in anhydrous DCM (20 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min and then slowly warmed to RT. Stirring at RT was continued for 16 h. The resulting mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method J): RT 2.19 min [M+H]+ 371.1.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:43])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])[C:26]3[C:21](=[CH:22][C:23]([CH3:42])=[C:24]([CH3:41])[CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:43])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([OH:33])=[O:32])[C:26]3[C:21](=[CH:22][C:23]([CH3:42])=[C:24]([CH3:41])[CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3cc(C)c(C)cc3n2)CC1
Solvent: CCO
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)O)c3cc(C)c(C)cc3n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 290 mg 4-{2-[(4-Benzyloxycarbonylmethoxy-6,7-dimethyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 10 ml ethanol were added under argon 50 mg Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (5 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethanol and DMF. The crude product was obtained after evaporation of the solvent. Yield: 270 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22](OC(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:60]1[CH2:65][CH2:64][CH2:63][CH:62]([NH:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:61]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([N:60]3[CH2:65][CH2:64][CH2:63][CH:62]([NH:66][C:67](=[O:74])[C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)[CH2:61]3)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: O=C(NC1CCCNC1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](C(=O)N1CCCC(NC(=O)c2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
A solution of tert-butyl (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.025 g) in DCM (1 ml) was treated with trifluoroacetic acid (1 ml) and stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give an oil which was subsequently treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.013 g), HOBT (0.009 g) and triethylamine (0.023 ml). After stirring at room temperature for 1 h, N-piperidin-3-ylbenzamide (0.015 g) was added and stirring was continued for 48 h. The reaction mixture was partitioned between DCM and water. The organic extract was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1, 3:1, 1:1, 1:3 and ethyl acetate) to give the title compound (0.012 g) as a colourless gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:21]>>[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([Cl:21])[N:6]=[C:7]3[C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c3c([nH]c(=O)c2cc1Br)CCCC3
Product: COc1cc2c3c(nc(Cl)c2cc1Br)CCCC3
Temperature: 80 °C

Procedure:
To the product from Step 3, 8-bromo-9-methoxy-1,3,4,5-tetrahydrophenanthridin-6(2H)-one (880 mg, 2.86 mmol) was added POCl3 (6 mL, 64.4 mmol) and the mixture was heated to 80° C. for 3 h. The excess POCl3 was then removed in vacuo, the residue was dissolved in DCM and the pH was adjusted to 5 with 1N NaOH. The organic layer was then dried over Na2SO4 and the solvent was removed in vacuo. The resulting solid was tritrated with ether to yield the title compound as a light yellow solid. LRMS (M+H)+=325.8.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:28]=[CH:27][C:22]5[O:23][CH2:24][CH2:25][O:26][C:21]=5[CH:20]=4)[CH2:15][CH2:14]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:28]=[CH:27][C:22]5[O:23][CH2:24][CH2:25][O:26][C:21]=5[CH:20]=4)[CH2:15][CH2:14]3)[CH:7]=[N:8][C:4]=2[CH:3]=1)(=[O:33])[CH3:32]
Reactant: Nc1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1

Procedure:
Analogously to Example 7, reaction of 6-[4-(4-(5-aminobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane ("E") with acetyl chloride gives 6-[4-(4-(5-acetamidobenzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH:4]1[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5]1.[H][H]>[Pd].CO>[CH3:1][N:2]([CH3:16])[CH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: CN(C)CC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1CCNC1
Yield: 96.8 %

Procedure:
A mixture of 1.25 g (5.72 mmol) of N,N-dimethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 100 ml of methyl alcohol, 0.2 g of 20% palladium on carbon and hydrogen were shaken at a pressure of 55.1 psi. After 16.8 hours the catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was bulb to bulb distilled yielding 0.71 g (97%) N,N-dimethyl-3-pyrrolidinemethanamine as a clear yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:8]=[C:9]2[CH:12]([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH2:11][C:10]2=[CH:21][CH:22]=1.[OH-].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:8]=[C:9]2[CH:12]([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[CH2:11][C:10]2=[CH:21][CH:22]=1
Reactant: ClCCCBr
Reactant: O=C(C1Cc2ccc(O)cc21)N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(C1Cc2ccc(OCCCCl)cc21)N1CCCCC1
Reaction time: 1 h

Procedure:
Tetrabutylammonium chloride (4.48 g) and 1-bromo-3-chloropropane (127.8 ml) are added to a stirred solution of 5-hydroxy-1-(1-piperidinylcarbonyl)benzocyclobutene (31.8 g) in methylene chloride (250 ml) and potassium hydroxide (18.85 g, 45% in H2O) which has been stirred vigorously under nitrogen for one hour. The reaction mixture is stirred at RT overnight, diluted with methylene chloride, extracted with H2O, sat'd aqueous NaCl and the organic layer dried over sodium sulfate. The solution is filtered, evaporated in vacuo and chromatographed (silica gel: ethyl acetate/hexane) yielding the desired product as an oil which is identified by NMR.
Reaction SMILES: O=O.[CH3:3][CH:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pt].O>[CH3:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(C)O
Agent: [Pt]
Agent: O=O
Solvent: O
Product: CCCCCCC(C)=O
Yield: 85.3 %

Procedure:
In an ambient pressure oxygen atmosphere, 26.9 mg of 2-octanol and 35.3 mg of the platinum catalyst obtained in Example 1 were agitated for fifteen hours at 60° C. in 2 ml of water. The reaction mixture was subsequently extracted using ethyl acetate, and the organic layer was dried using magnesium sulfate, filtered and concentrated to obtain 22.6 mg (85% yield) of 2-octanone. The reaction equation and the analytical results of the product are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CNCc2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate XXII) was taken up in THF and an excess of the 2,4-dimethoxy-benzylamine (20 equiv.) was added. The reaction was allowed to stir overnight at room temperature. The volatiles were removed in vacuo. Resulting oil triturated with water to give a gooey solid. Water was decanted off and resulting residue was purified by column chromatography (DCM, 0-8% MeOH saturated with NH3). 1H NMR (400 MHz, CDCl3): 7.32 (d, 1H), 7.19 (br s, 1H), 7.01 (br d, 1H), 6.96 (d, 1H), 6.60 (s, 1H), 6.40-6.33 (m, 2H), 4.11 (br s, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 3.69 (br s, 2H), 3.55 (br s, 3H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8](S(O)(=O)=O)=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[CH2:5]([CH:15]1[O:4][CH2:1][CH2:2][O:3]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:7][CH2:6][CH2:5][CH2:10][CH3:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC1OCCO1
Yield: 226213.09 %

Procedure:
Following example I, 45.56 g (0.25 mole) of dodecyl aldehyde, 17.85 g (0.288 mole) of ethylene glycol, 0.02 g of para-toluenesulfonic acid in 140 ml toluene are reacted to obtain 30 g (55%) of a colorless product; b.p. 112°-116°/1.5 mm. nD20 =1.9999.
Reaction SMILES: C(C1C=NC=CC=1)(=O)C.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])[CH3:11]>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C@H:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1ccccn1
Agent: CC(=O)c1cccnc1
Product: C[C@@H](O)c1ccccn1

Procedure:
Example 1 was repeated except that 3-acetylpyridine used in Example 1 was replaced by 2-acetylpyridine to obtain (R)-1-(2-pyridyl)ethanol. According to a high-speed liquid chromatography using an optical resolution column (CHIRAL CEL OB made by Daicel K. K.), its optical purity was 95% ee or higher.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[CH:16][C:15]([O:26]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(O)ccc2c1=O
Reaction time: 2 h
Yield: 94.1 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.98 g, 7.5 mmol) and 5% palladium carbon (1.5 g) in ethanol (50 mL) was stirred under a hydrogen atmosphere at room temperatures for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl[4-(2-fluorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.11 g, 94.2%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[OH:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:23][CH:24]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:18])[CH:24]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2cccc(O)c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-hydroxyphenyl-boronic acid pinacol ester gives “A70”; method 1: HPLC/MS: 1.12 min, [M+H]=307.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:25]([CH3:30])([C:26]([NH:28]N)=[O:27])[C:24](=[O:31])[NH:23][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:9]=2)[N:7]=1.FC(F)(F)C(O)=O.N(OC(C)(C)C)=O.N[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>C1COCC1>[NH2:1][C:2]1[C:3]2[C:25]([CH3:30])([C:26]([NH:28][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[O:27])[C:24](=[O:31])[NH:23][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:22])([F:20])[F:21])[N:9]=2)[N:7]=1
Reactant: Nc1cccnc1
Reactant: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)F)c4ncccc34)nc(N)c21
Agent: CC(C)(C)ON=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C(=O)Nc2cccnc2)C(=O)Nc2nc(-c3nn(CCC(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a THF solution (2 mL) of the intermediate from Step A (227 mg, 0.521 mmol) at 0° C. was added trifluoroacetic acid (0.044 mL, 0.574 mmol) and tert-butyl nitrite (0.186 mL, 1.564 mmol). After stirring at 0° C. for 30 minutes, the mixture was concentrated in vacuo, ensuring that the temperature was maintained below 40° C. The residue was suspended in acetonitrile (3 mL), cooled to 0° C., and 3-aminopyridine (245 mg, 2.61 mmol) was added in one portion. The resultant mixture was heated to 40° C. for one hour, and then stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo, suspended in EtOAc and washed sequentially with water (4×), saturated aqueous ammonium chloride solution (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using DCM/MeOH (with 0.5% NH4OH) gradient provided the title compound. Chiral separation using SFC on a Chiralpak IC column provided both enantiomers of the title compound, 1H NMR (500 MHz, DMSO-d6): δ 9.53 (1H, s), 9.05 (1H, dd, J=8.08, 1.58 Hz), 8.77 (1H, d, J=2.48 Hz), 8.63 (1H, dd, J=4.47, 1.58 Hz), 8.28 (1H, d, J=4.69 Hz), 8.00 (1H, d, J=8.47 Hz), 7.36 (2H, ddd, J=21.65, 8.21, 4.57 Hz), 6.86 (2H, s), 4.85-4.77 (2H, m), 3.06-2.95 (2H, m), 1.72 (3H, s). m/z=498.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16](O)=[O:17])[CH:5]=[CH:4][C:3]1=2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:35])=O>ClCCl>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([Cl:35])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)O)ccc21
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Reaction time: 1 h

Procedure:
A solution of 2.6 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acrylic acid in 50 ml of anhydrous dichloromethane is introduced into a round-bottomed flask, 2 ml (10 mmol) of dicyclohexylamine are added and the mixture is stirred for one hour. 800 μl (10 mmol) of thionyl chloride are then added and the mixture is stirred for one hour. The mixture is evaporated to dryness, the residue is taken up in anhydrous ethyl ether, the dicyclohexylamine salt is filtered off and the filtrate is evaporated. 2.8 g (100%) of the crude acid chloride are collected, which product will be used subsequently in the synthesis without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:12][C:11](Br)=[CH:10][C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].[C:14]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:3]1[C:4]2[S:12][C:11]([C:21]3[CH:22]=[CH:23][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=3)=[CH:10][C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: N#Cc1c[nH]c(=O)c2cc(Br)sc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(-c2cc3c(=O)[nH]cc(C#N)c3s2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To a solution of 7-cyano-2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine (2.0 g, 7.84 mmol) in DMF (40 mL) and water (15 mL) was added 4-t-butylphenyl boronic acid (2.1 g, 11.8 mmol), potassium carbonate (1.4 g, 10.1 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.192 g, 0.23 mmol). The resulting mixture was stirred under nitrogen for 4 h at 80° C. After this time the mixture was diluted with DMF (20 mL), filtered through celite to remove palladium residues and water (100 mL) added. The precipitated solid was filtered, washed thoroughly with water and dried in air by suction at room temperature providing 1.4 g of 100 which was used without further analysis or purification.
Reaction SMILES: O1[C:3]23[C@:16]([CH3:21])([CH:17]=[CH:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:22])[CH2:9][CH2:8]2)[CH2:5][C:4]3=[CH2:23].[ClH:24]>C(O)(=O)C>[Cl:24][C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[C:4](=[CH2:23])[CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: Cl
Reactant: C=C1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C=CC(=O)C3OC132
Solvent: CC(=O)O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C(Cl)=C12

Procedure:
A solution of 4,5-epoxy-6-methylenandrost-1-ene-3,17-dione (1.0 g) in glacial acetic acid (10 ml) was treated with gaseous hydrogen chloride for 30 min at room temperature The precipitate was filtered off, washed with diethyl ether, dried and chromatographed on silica gel using hexane/ethyl acetate to yield 0.8 g of pure 4-chloro-6-methylenandrosta-1,4-diene-3,17-dione. Found: C 72.40, H 6.91, Cl 10.53; C20H23ClO2 requires: C 72.61, H 7.01, Cl 10.72. N.M.R. δp.p.m.: 0.84 (3H, s); 1.24 (3H, s); 5.13 (1H, s); 5.43 (1H, s); 6.37 (1H, d); 7.08 (1H, d). MS (m/z): 330.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:8](=[C:9]([C:19]([OH:21])=[O:20])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[N:16]=3)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>S(Cl)(Cl)=O>[CH:1]1[C:18]2[C:17]3[C:8](=[C:9]([C:19]([O:21][C:1]4[CH:18]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:20])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[N:16]=3)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c2ccccc2nc2c1ccc1ccccc12
Solvent: O=S(Cl)Cl
Product: O=C(Oc1ccccc1)c1c2ccccc2nc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
Benz[c]acridine-7-carboxylic acid (6.0 g) was suspended in 75 mL thionyl chloride (3-10 mL) and reaction mixture was refluxed for 4 h. The solvent was removed under reduced pressure and the product dissolved in 75 mL of CH2Cl2. Pyridine (8.9 mL) and phenol (2.27 g) were added and the solution was stirred for 3 days at room temperature under Ar. Purification was effected by chromatography on silica gel (50% CH2Cl2 /hexane) to yield 3.05 g of the pure product as a light brown solid. 1H NMR (CDCl3) δ 7.40 (t, 1H), 7.48-7.59 (m, 4H), 7.71-8.01 (m, 7H), 8.259 (d, 1H, J=7.8 Hz), 8.465 (d, 1H, J=7.8 Hz), 9.54-9.57 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:22]([F:23])=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:24]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:4]1[CH:3]=[C:2]([F:1])[C:22]([F:23])=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(F)c(F)cc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)c(F)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4,5-difluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4,5-difluoroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[CH:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][CH:12]1[OH:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC

Procedure:
A 740 mg quantity of 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (2-b)) and 120 mg of sodium borohydride are dissolved in 100 ml of methanol, and the solution is refluxed for one hour. On completion of the reaction, 2 ml of acetic acid is added to the reaction mixture. The resulting mixture is concentrated in a vacuum. The residue is distilled in a vacuum, giving 2-tert-butoxycarbonyl-3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol (compound (1-b), R1 =t-Bu, R2 =CH3) in a yield of 98.5%, b.p. 75°-79° C./0.005 mm Hg.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.Br>C(OCC)C>[F:29][C:21]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=1[O:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Agent: Br
Solvent: CCOCC
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (2.75 g, 6.54 mmol) was added slowly in portion into hydrobromic acid solution (33% in acetic acid, 45 ml). The mixture was stirred at room temperature for 2 hours, then poured into diethyl ether (300 ml). The precipitate was filtered and washed with diethyl ether. The solid hydrobromide salt was stirred in the mixture of sodium acetate aqueous solution (10%, 60 ml) and ethyl acetate (15 ml) for 1 day. The precipitate was filtered, washed with water and dried to give 1.82 g of product [G]. Yield: 86%