Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:25]=[CH:24][C:13]2[N:14]([CH3:23])[C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:16][C:12]=2[CH:11]=1)=[O:9])=[O:4].Br.C(S[C:30](=[NH:32])[NH2:31])C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:30]([N:20]1[CH2:21][CH2:22][CH:17]([C:15]2[N:14]([CH3:23])[C:13]3[CH:24]=[CH:25][C:10]([C:8]([NH:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:9])=[CH:11][C:12]=3[N:16]=2)[CH2:18][CH2:19]1)(=[NH:31])[NH2:32]
Reactant: CCSC(=N)N
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(C1CCNCC1)n2C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(C1CCN(C(=N)N)CC1)n2C

Procedure:
Prepared from 5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-2-(4-piperidinyl)-benzimidazole and S-ethylisothiourea-hydrobromide by heating to 100° C. for 4 hours in dimethylformamide in the presence of sodium carbonate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:17])=[N:13][CH:14]=1)[CH3:8].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:3][O:4][CH2:5][O:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[N:13][CH:14]=1)[CH3:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COCOC(C)c1ccc(CCO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOC(C)c1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Yield: 71.3 %

Procedure:
Sodium hydride in oil (60%, 1.6 g) was added in small portions with ice-cooling to a solution of 2-[5-(1-methoxymethoxyethyl)-2-pyridyl]ethanol (7.5 g) and 4-fluoronitrobenzene (5.0 g) in N,N-dimethylformamide (50 ml). The reaction mixture was stirred with ice-cooling for additional 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (40:1, v/v) gave 5-(1-methoxymethoxyethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine (8.4 g, yield: 71%) as oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]([CH2:14][CH3:15])=[C:12]([O:16][CH2:17][O:18][CH3:19])[CH:11]=[C:10]([O:20][CH2:21][O:22][CH3:23])[C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=[O:2].[C:24](OC(=O)C)(=O)C.O.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:14]([C:13]1[C:5]([CH2:4][C:1]([O:3][CH3:24])=[O:2])=[C:6]([C:10]([O:20][CH2:21][O:22][CH3:23])=[CH:11][C:12]=1[O:16][CH2:17][O:18][CH3:19])[C:7]([OH:9])=[O:8])[CH3:15]
Reactant: CCc1c(OCOC)cc(OCOC)c(C(=O)O)c1CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c(OCOC)cc(OCOC)c(C(=O)O)c1CC(=O)OC
Temperature: 100 °C
Reaction time: 4 h
Yield: 126.6 %

Procedure:
The above-obtained 2-(carboxymethyl)-3-ethyl-4,6-bis(methoxymethoxy)benzoic acid (0.38 g, 1.2 mmol) was dissolved in toluene (20 mL) and the obtained solution was added with acetic anhydride (0.20 mL, 2.1 mmol), followed by stirring at 100° C. for 4 hours. The reaction mixture was added with water and then extracted with diethylether 3 times. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (20 mL). The obtained solution was added with sodium methoxide (0.22 g, 4.2 mmol) and stirred at a room temperature for 7 hours. After adding water, the reaction mixture was extracted with ethyl acetate 3 times. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure to obtain 3-ethyl-2-(methoxycarbonylmethyl)-4,6-bis(methoxymethoxy)benzoic acid (0.52 g, 100%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[N:15][C:16]2[CH:17]([S:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:12][C:13]1[CH:14]=[N:15][C:16]2[CH:17]([S:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:9])=[O:24])[CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc2c(c1)CCCC2S(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc2c(c1)CCCC2S(=O)(=O)c1ccccc1

Procedure:
A solution of m-chloroperbenzoic acid (1.4g) in dichloromethane (25ml) was added to a stirred solution of 5,6,7,8-tetrahydro-3-methyl-8-phenylsulphinylquinoline (1.87g) and trifluoroacetic acid (1.2ml) in dichloromethane (25ml). After stirring at ambient temperature for 1h, the reaction mixture was washed with 2M sodium hydroxide, dried over magnesium sulphate and evaporated to a solid. After chromatography on silica eluting with ether the product was recrystallised from diisopropylether affording white crystals, mp 84°-86° C.
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:16]([CH3:20])[C:17](O)=[O:18])[C:12]2=[O:21])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:29])=O>CN(C)C=O.ClCCl>[F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:16]([CH3:20])[C:17]([Cl:29])=[O:18])[C:12]2=[O:21])=[CH:7][CH:6]=1
Reactant: C[C@H](C(=O)O)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C(=O)Cl)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R) -2-[3-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propanoic acid (1.5 g) and 3.8 ml of oxalyl chloride were added to 30 ml of dichloromethane, to which dimethylformamide (7 drops ) was added dropwise at room temperature. After the reaction solution was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure to give 1.5 g of (2R)-2-[3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propanoyl chloride as a pale yellow oil. This product was used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].O>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C@H:8]2[CH2:7][CH2:5][NH:6][C:15]2=[O:18])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.07 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 5 ml of dimethylsulfoxide, and one g of potassium carbonate and 1.53 g of (R)-3-(p-tosyloxy)-2-pyrrolidone are added thereto. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and then concentrated under reduced pressure to dryness. The residue is crystallized with isopropyl ether, and the crystals are recrystallized from aqueous methanol. 0.86 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetate is obtained. The physico-chemical properties of this product are identical with those of the product obtained in Example 1-(2).
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(=O)([O-])[O-].[Na+].[Na+].CO.Br[CH2:20][CH:21]=[C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:21][CH2:20][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCC=C(c1ccccc1)c1ccccc1
Reactant: O=S([O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)(CC=C(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
15.5 gm of sodium phenyl sulfinate and 1.5 gm of sodium carbonate were introduced into 80 cc of methanol. Then 25.6 gm of 1-bromo-3,3-diphenyl-2-propene were added to the reaction mixture under an atmosphere of nitrogen and at room temperature which was then agitated for 1 hour and 30 minutes. Next, the reaction mixture was poured into cold water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, dried and concentrated to dryness. The residue was partly crystallized. The precipitate formed was isolated by vacuum filtering and dried to obtain 25.48 gm of (3,3-diphenyl-2-propenyl)-phenyl sulfone having a melting point of 104° C. A sample of this product, recrystallized from isopropyl ether, had a melting point of 106° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[N:24]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:32]2[CH2:33][CH2:34][CH:29]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:30][CH2:31]2)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: C1CCN(C2CCNCC2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCc2c(Cl)nc(N3CCC(N4CCCC4)CC3)nc2N1c1c(F)cccc1F
Yield: 80.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (250 mg, 0.70 mmol) in DCM (10 mL) were added 4-(1-pyrrolidinyl)piperidine (323 mg, 2.1 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (253 mg, 81%). LC-MS m/z 449 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[NH:26][CH:25]=[C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:23]=[CH:22][C:21](=[O:20])[NH:26][CH:25]=2)=[CH:35][CH:34]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-c2ccc(=O)[nH]c2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoic acid. MS: 457.3 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:28](=[O:30])[NH2:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>[Pd].CO>[C:28]([C:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:30])[NH2:29]
Reactant: NC(=O)C(CC1CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: NC(=O)C(CC1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
10% Palladium on charcoal (900 mg) was added portionwise over 10 minutes to a stirred, ice-cooled solution of 1-benzyl-4-(2-carbamoyl-2,2-diphenylethyl)piperidine (890 mg, 2.23 mmol) (see Example 17) and formic acid (1.0 ml) in methanol (19 ml) and the mixture stirred at room temperature for 24 hours, filtered and evaporated. The residue was partitioned between dichloromethane and saturated aqueous sodium carbonate solution and the organic layer was dried over magnesium sulphate and evaporated to give the title compound (600 mg, 87%) as a colourless foam which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]([CH2:20][CH:21]=[C:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:22]3([CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:21][CH2:20][CH:14]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(CC=C1CCOCC1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CCOCC2)N1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a solution of ethyl 2-{[(4-nitrophenyl)sulfonyl]amino}-4-(tetrahydro-4H-pyran-4-ylidene)butanoate (164) (1.87 g, 4.7 mmol) in anhydrous chloroform (47 mL) was added trifluoromethanesulfonic acid (0.2 mL, 2.3 mmol) and the reaction stirred at room temperature under nitrogen for 4 h. The reaction was diluted with dichloromethane and washed with saturated NaHCO3 and the organic layer dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-70% hexanes/EtOAc to afford the title compound as a white solid (1.47 g, 79% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.19-8.36 (m, 2H) 8.08 (d, J=8.8 Hz, 2H) 4.52 (dd, J=8.5, 2.1 Hz, 1H) 3.99-4.14 (m, 2H) 3.87-3.99 (m, 2H) 3.21-3.49 (m, 2H) 2.58-2.78 (m, 2H) 2.10-2.30 (m, 2H) 1.89-2.06 (m, 2H) 1.77 (dd, J=13.0, 2.1 Hz, 1H) 1.35 (dd, J=12.9, 1.6 Hz, 1H) 1.22 (t, J=7.1 Hz, 3H). LC-MS ESI (M+H)+=399.47.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>N1C=CC=CC=1>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:22](=[O:23])[O:24][CH2:25][CH3:26])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N(Cc2ccc(Cl)cc2)C(=O)OCC)cc1
Temperature: 100 °C

Procedure:
A stirred solution of ethyl 4-(4-chlorobenzylamino)-benzoate (5.8 g; 0.02 mole) in pyridine (50 ml) was treated dropwise with ethyl chloroformate (2.5 g; 0.023 mole) at room temperature. The mixture was heated to 100° C. for 30 minutes, cooled and added to iced water (100 ml). After neutralisation with dilute hydrochloric acid the product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml), dried (anhydrous MgSO4) and the solvent evaporated. The residual oil was purified by chromatography on silica-gel in dichloromethane to give ethyl N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-carbamate as a colourless oil (4.86 g; 56%) which solidifed on standing. M.p. 43°-6° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)#[N:29]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[C:33]5[CH:37]=[CH:38][C:30]([C:28]#[N:29])=[CH:31][CH:32]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (22.6 mg, 60.2%), MS (ISP) m/z=461.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-cyanobenzoic acid.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>CCOC(C)=O>[CH2:12]([O:15][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2)[C:13]#[CH:14]
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: C#CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOC12CC3CC(CC(C3)C1)C2
Yield: 100.9 %

Procedure:
A mixture of 1-bromoadamantane (10.8 g, 50.2 mmol), propargyl alcohol (30 ml, 515 mmol) and triethylamine (7.0 ml, 50.3 mmol) were heated at reflux for 4 hours. The reaction mixture was diluted with EtOAc (70 ml) and was washed sequentially with water (100 ml) and brine (100 ml). The organic phase was dried over magnesium sulfate and the filtrate was evaporated to give the title compound (9.64 g, 100%). 1H NMR (CDCl3) 4.14 (2H, d, J=2.4 Hz), 2.36 (1H, t, J=2.4), 2.16 (3H, s), 1.80-1.79 (6H, m), 1.67-1.57 (6H, m).
Reaction SMILES: C(OC([NH:11][C@H:12]([CH2:30][CH2:31][CH2:32][NH:33]C(OCC1C=CC=CC=1)=O)[CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19]C(OCC1C=CC=CC=1)=O)=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][C@H:12]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH2:19])=[O:15]
Reactant: [H][H]
Reactant: O=C(C[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NCCC[C@@H](N)CC(=O)NCCN
Yield: 98.9 %

Procedure:
In 180 ml of methanol were suspended 1.41 g (2.39 mmol) of (R)-3,6-bis(benzyloxycarbonylamino)-N-(2-benzyloxycarbonylaminoethyl)hexanamide. To the resulting suspension was added a suspension of 718 mg of 10% palladium-carbon in 20 ml of water. After stirring, hydrogen gas was passed through the resulting mixture at room temperature for 3 hours to effect the reaction. The palladium-corbon was filtered off from the reaction mixture obtained, and the filtrate was concentrated to dryness. The residue obtained was dissolved in 15 ml of water and then subjected to a chromatography on a column of "Amberlite CG-50" (trade name, NH4+ -form, 50 ml). After the column was washed with 200 ml of water, the column was eluted with aqueous ammonia at concentrations gradiently varying from 0.5% to 4.0% (0.5%-increased steps; 200 ml at each concentration). Fractions of the eluate as eluted with 2.5% to 3.5% aqueous ammonia were combined together and concentrated to dryness, to afford 445 mg of (R)-3,6-diamino-N-(2-aminoethyl)hexanamide as a colorless paste.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.[CH3:44][S:45]([NH:48][C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1)(=[O:47])=[O:46].B(O)O>>[CH3:40][C@:18]12[C@@:17]3([CH3:41])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:42])([CH3:43])[C:12]([C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])[CH:50]=3)=[CH:29][CH2:28]4)[CH2:25][CH2:24][C@@H:23]1[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]2
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cccc(NS(C)(=O)=O)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 3-(methylsulfonamido)phenylboronic acid as the reactant boronic acid. The product was isolated as a white solid (46.41 mg, 90%). LCMS: m/e 606.58 (M−H)−, 4.37 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.93 (s, 6H), 0.99 (s, 3H), 1.00 (s, 3H), 1.02 (s, 3H), 1.03-1.74 (m, 17H), 1.71 (s, 3H), 1.84-1.96 (m, 2H), 2.11 (dd, J=16.99, 5.86 Hz, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.30-2.39 (m, 1H), 2.96 (s, 3H), 2.99-3.07 (m, 1H), 4.61 (s., 1H), 4.74 (s, 1H), 5.28 (d, J=4.69 Hz, 1H), 6.87 (d, J=7.62 Hz, 1H), 7.03 (s, 1H), 7.14 (d, J=8.20 Hz, 1H), 7.25 (t, J=7.62 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][CH2:39][OH:40]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:37][CH2:38][CH2:39][OH:40])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)OC(C)(C)C)cc3F)ccnc2cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)OC(C)(C)C)cc3F)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of tert-butyl 3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenylcarbamate (400 mg, 1 mmol) in DMF (4 mL) was added K2CO3 (276 mg, 2 mmol) and 3-bromopropan-1-ol (154 mg, 1.1 mmol). The reaction was stirred at rt overnight. The solvent was removed, and the residue was partitioned between water (10 mL) and CH2Cl2 (20 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAC to 10% methanol in EtOAC) to give the title compound as a light yellow solid (300 mg, 65%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[C:3]#[CH:4].I[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: C#CC(O)c1ccccn1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccccn3)c21

Procedure:
Using Method C above, 3-hydroxy-3-(2-pyridinyl)-1-propyne (133 mg, 1 mmol) (from Example 36 above) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (147 mg, 0.4 mmol) using (Starting Material 2) (Ph3P)2PdCl2 (40 mg) (Aldrich) and CuI (20 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 19 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(2-pyridinyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 84 mg, 56%).