Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:27][CH2:26][CH2:25][C@H:14]1[C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:12])[CH3:10])=[O:7])([OH:3])=[O:2]>C(O)C.[Pd]>[C:1]([CH2:4][CH2:5][C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:27][CH2:26][CH2:25][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH3:10])=[O:7])([OH:3])=[O:2]
Reactant: C[C@H](NC(=O)CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NC(=O)CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 19 h

Procedure:
A solution of the phenylmethyl ester product from part (a) (700 mg., 1.86 mmole) in 95% ethanol (100 ml.) containing 10% palladium on carbon catalyst (100 mg.) is hydrogenated at 25 psi in a Parr apparatus for 19 hours, after which it is filtered and concentrated to give 1-[N-(3-carboxy-1-oxopropyl)-L-alanyl]-L-proline as a colorless oil. This diacid product is dissolved in water, passed through a column of AG 50 W X8 (Li+) and lyophilized to give 1-[N-(3-carboxy-1-oxopropyl)-L-alanyl]-L-proline, dilithium salt as a stable, off white solid which is homogeneous by TLC (Rf 0.6, silica gel, 3:1:1 n-butanol:acetic acid:water). [α]D =-100° (1.5% water).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH2:40]O)([CH3:35])([CH3:34])[CH3:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH2:40][O:12][C:3]1[C:4]([F:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[F:1])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1F
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a solution of 2,6-difluoro-3-nitrophenol (248 mg, 1.416 mmol) and triphenylphosphine (558 mg, 2.127 mmol) in THF (10 mL) was added a solution of (2-hydroxyethyl)carbamic acid tert-butyl ester (274 mg, 1.70 mmol) in THF (2 mL). The mixture was cooled in an ice bath and a solution of diethyl azodicarboxylate (372 mg, 2.127 mmol) in THF (2 mL) was added over 5 min. The reaction was removed from the ice bath after 5 min and stirred at RT for 2 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 30-40% EtOAc in cyclohexane) affording the title compound as a colourless gum (483 mg, quantitative). 1H NMR (CDCl3, 300 MHz): 7.84 (1H, ddd, J=9.5, 7.8, 5.3 Hz), 7.05 (1H, dt, J=9.9, 2.2 Hz), 5.05 (1H, bs), 4.26 (2H, t, J=5.0 Hz), 3.52 (2H, q, J=5.4 Hz), 1.45 (9H, s)
Reaction SMILES: O1CCCC1.CO.[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:21][CH2:22][CH2:23][C@H:24]1[C@@H:32]2[C@@H:27]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:25]1)[C:18]([NH2:20])=[O:19])([O:10]C)=[O:9].[OH-].[Na+]>O>[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:21][CH2:22][CH2:23][C@H:24]1[C@@H:32]2[C@@H:27]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:25]1)[C:18]([NH2:20])=[O:19])([OH:10])=[O:9]
Reactant: COC(=O)CCCCCC(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C(CCCCCC(=O)O)CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 40 °C

Procedure:
To a mixture of 25 mL of tetrahydrofuran and 25 mL of methanol, was dissolved 5-carbomethoxypentyl-D-biotinamide (800 mg, 2.15 mmol) obtained in Production Example 5-2, followed by addition of a solution of sodium hydroxide (2.33 g, 58.3 mmol) in water (12.5 mL) dropwise at room temperature. After the addition was completed, the mixture was heated to 40° C. and reacted for 2 hours.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2.P(=O)(O)(O)O>C(O)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CN1CCCCC1=O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: COc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1

Procedure:
Using the procedure of J. Org. Chem., Vol. 40, No. 17 (1975), p. 2525, 1-methyl-piperidone and 5-methoxy-1H-indole were condensed in refluxing acetic acid in the presence of phosphoric acid to obtain 5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 235° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C.[Pd]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)/C=C/c1ccco1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccco1
Reaction time: 4 h

Procedure:
A cis/trans mixture of ethyl (E)-3-(2-furyl)prop-2-enoate (15.5 g, 93.27 mmol, 1 eq) was stirred in ethanol (120 ml) containing 10% palladium on charcoal (775 mg, 5% by w). The reaction mixture was stirred under hydrogen for 4 h. A further quantity of 10% Pd/C (775 mg, 5% by w) was added. The reaction was stirred under hydrogen for an additional 95 mins. The reaction was filtered and evaporated under reduced pressure. The crude product was purified by silica column chromatography eluting with 20% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure and ethyl 3-(2-furyl)propanoate was obtained as a clear oil (3.69 g, 24% yield).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:37]>ClCCl>[C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@@H:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N+:21]([O-:37])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2cccnc2)cc1)C(=O)NCC#N
Solvent: ClCCl
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2ccc[n+]([O-])c2)cc1)C(=O)NCC#N
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
To a solution of (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamide from example 38 (95 mg, 0.23 mmol) in dichloromethane (10 mL) was added 77% quality 3-chloroperoxybenzoic acid (51.5 mg, 0.23 mmol) at 5° C. The temperature was permitted to gradually rise to r.t. over 1.5 h. The mixture was concentrated and the residue partitioned between ethyl acetate and 1M Na2CO3. The ethyl acetate layer was dried (Na2SO4) and concentrated to yield 100 mg of the title compound. Purification by chromatography on silica gel using 10% methanol in dichloromethane and concentrating with diethyl ether 2 times gave a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[NH:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(Nc1cc(-c2cnccn2)ccc1[N+](=O)[O-])N1CCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2cnccn2)cc1NC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 1 N-(2-nitro-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.11 g, 0.35 mmol) in methanol (6 mL) and THF (6 mL) was added Pd/C (0.04 g, 0.94 mmol, 0.33 equiv.). The reaction mixture was degassed then stirred at room temperature under H2 atmosphere for 1 h. The reaction was filtered through celite and concentrated. The crude solid was washed with ether, and dried under reduced pressure to obtain of pure N-(2-amino-5-(pyrazin-2-yl)phenyl)pyrrolidine-1-carboxamide (0.07 g, 70% yield). ESI+ MS: m/z 284([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.30 (s, 1H), 8.55 (s, 1H), 8.40-8.39 (m, 1H), 7.88 (s, 1H), 7.71-7.69 (m, 1H), 7.53 (s, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.31 (s, 2H), 3.40-3.37 (m, 4H), 1.86 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH3:28]>CC(C)=O>[CH2:25]([O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: COC(=O)CCCCC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(C(=O)CCCCC(=O)O)cc1

Procedure:
A mixture of methyl 5-(4-hydroxybenzoyl)pentanoate (2 g), acetone (50 ml), potassium carbonate (2.34 g), and 1-bromobutane (2.0 ml) is gently refluxed for 4 hours. The reaction mixture is filtered and the filtrate concentrated in vacuo. The resulting brown solid is dissolved in ethanol (25 ml) and 2N sodium hydroxide (25 ml), and then refluxed for 4 hours. After washing with ether (100 ml), the aqueous layer is acidified to pH 1.0 with concentrated hydrochloric acid and the product extracted with ether (1×300 ml). The ether solution is dried over magnesium sulfate, filtered, and concentrated in vacuo. The product is recrystallized from ethanol/water to yield 5-(4-n-butoxybenzoyl)pentanoic acid (1.2 g), m.p. 95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: N
Product: CC(C)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 375) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.051 g, 18%). Yellow oil. 1H NMR (300 MHz, DMSO d6) δ 0.80 (d, J=5 Hz, 6H), 1.47 (m, 3H), 4.42 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.50 (m, 1H), 7.65 (m, 2H), 7.83 (m, 2H), 7.93 (m, 2H), 8.18 (s, 1H), 8.60 (bs, 1H). MS (DCI/NH3) m/z 432 (M+H)+, 449 (M+NH4)+. Anal. calc. for C21H22FN3O4S: C, 58.46; H, 5.14; N, 9.74. Found C, 58.16; H, 5.21; N, 9.57.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].C(O)C>CN(C)C=O>[CH2:19]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:18][CH2:17][CH2:16][C:15]#[CH:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CCCCCCl
Agent: [K]
Solvent: CCO
Solvent: CN(C)C=O
Product: C#CCCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 40.1 %

Procedure:
To potassium phthalimide (37.5 g) in dimethylformamide (400 ml) at 100° C,. was added dropwise 1-chloro-5-hexyne (23.67 g) in dimethylformamide (100 ml). The reaction mixture was stirred at 100° C. for a further hour, cooled and stirred at room temperature overnight. The mixture was poured on to ice/water to give an oil, which on trituration gave as a white solid N-5-hexynyl phthalimide (18.35 g), m.p. 74°-6° C. (recrystallisation from ethanol).
Reaction SMILES: C([O:3][C:4](=O)[C@@:5]([NH:25]C(OC(C)(C)C)=O)([CH3:24])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.[BH4-].[Li+].C(OCC)(=O)C>C(OCC)C>[NH2:25][C@:5]([CH3:24])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH2:4][OH:3]
Reactant: CCCCc1ccc(-c2ccc(CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)OCC)cc2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCc1ccc(-c2ccc(CC[C@@](C)(N)CO)cc2)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-4-(4′-butyl-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester (22 mg) in diethylether is added lithium borohydride (20 mg). After stirring the suspension for 9 h at RT, ethyl acetate (5 ml) is added and the mixture is washed with water (2 ml), 1M citric acid (2×2 ml) and water (2 ml). The organic phase is dried over MgSO4, the solvent removed and the crude material purified by chromatography using diethyl ether/hexane (1/1) (Rf=0.31, MS: (ES+): 412.6 (M+H)+). The purified product is dissolved in dioxane containing 4M HCl and left at room temperature for 16 h. After lyophilisation, the desired compound is obtained as a white solid in the hydrochloride salt form (Rf=0.48 in DCM/methanol 100/15, MS: (ES+): 312.5 (M+H)+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N:30]1[N:31]=[CH:32][N:33]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][N:41]([C:38]3[CH:37]=[CH:36][C:35]([N:33]4[CH:34]=[N:30][N:31]=[CH:32]4)=[CH:40][CH:39]=3)[C:42](=[O:44])[CH3:43])[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: CC(=O)Nc1ccc(-n2cnnc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(-n2cnnc2)cc1
Temperature: 50 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (60 mg, 0.14 mmol) from Example 5 step 1 and N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide (30.6 mg, 0.15 mmol) were added in DMF (0.7 mL), then cesium carbonate (224 mg, 0.69 mmol) was added and the reaction was heated to 50° C. overnight. The reaction was cooled to room temperature, water (10 mL) was added and extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™silica gel cartridge eluting with 50% acetone/hexanes to give the title compound as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:32]=[CH:31][C:30](I)=[C:29]([CH3:34])[N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:32]3[C:27]([CH3:26])=[N:28][C:29]([CH3:34])=[CH:30][CH:31]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1ccc(I)c(C)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c(C)n1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 105 mg (0.26 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 134 mg (0.58 mmol) of 2,6-dimethyl-5-iodo-pyridine in 1 mL THF with 0.30 mL 2M isopropylmagnesium chloride. Yield: 19 mg of a white powder. LC-MSD, m/z for C23H18BrN3O2 [M+H]+=448.0, 450.0; HPLC retention time: 1.2 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Br[CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[O:12][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[CH3:2]
Reactant: CCOc1cc(O)cc(CO)c1
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(CO)cc(OCC(C)(C)CO)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 3-ethoxy-5-hydroxymethyl-phenol (0.3 g, 1.78 mmol, 1.0 equiv) in DMF (2 mL) was added cesium carbonate (2.32 g, 7.14 mmol, 4.0 equiv), potassium iodide (0.59 g, 3.57 mmol, 2.0 equiv) and 3-bromo-2,2-dimethyl-propan-1-ol (0.66 mL, 0.89 g, 5.35 mmol, 3.0 equiv) and the reaction mixture stirred under Ar at 100° C. for 24 h. The reaction mixture was filtered, the solid material washed with DMF and the organic filtrate evaporated to dryness under reduced pressure. The crude reaction mixture was suspended in water (20 mL), extracted with dichloromethane (3×50 mL), the combined organic phases washed with a sat. solution of sodium chloride (1×20 ml) and dried over Na2SO4 providing 0.15 g (33%) of the title compound in sufficient purity for the next reaction step. MS (ISP): 255.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][S:6][CH:7]1[C:11]2[C:12]([O:21][CH3:22])=[C:13]3[C:18](=[C:19]([OH:20])[C:10]=2[C:9](=[O:23])[N:8]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[N:17]=[CH:16][CH:15]=[CH:14]3.O.CO.[Li+].[OH-]>C1COCC1>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:8]2[C:9](=[O:23])[C:10]3[C:19]([OH:20])=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([O:21][CH3:22])[C:11]=3[CH:7]2[S:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:30][CH:29]=1
Reactant: COC(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2SCCC(=O)O

Procedure:
A solution of 23 (150 mg, 0.329 mmol) in 3.29 mL of a 1:2:3 solution of H2O:MeOH:THF was stirred with LiOH. H2O (69 mg, 1.65 mmol) for 1 hour when LCMS demonstrated complete conversion of starting materials to product. The reaction mixture was dried under reduced pressure and the residue was suspended in water and the pH was adjusted to 11 with aqueous 1N NaOH solution. The aqueous layer was washed with EtOAc twice. The pH of the aqueous layer was then adjusted to 5 using 1N HCl and the product was extracted with CH2Cl2 under continuous extraction conditions. The organic layer was dried in vacuo to yield the product 24 as an orange solid. 1H NMR (300 MHz, CDCl3) δ 2.1 (s, 1H), 2.25-2.45 (m, 4H), 4.04 (s, 3H), 4.43 (d, 1H, J=15 Hz), 5.32 (dd, 1H, J=3, 14 Hz), 5.49 (s, 1H), 7.03 (t, 2H, J=9 Hz), 7.35 (dd, 2H, J=5, 8 Hz), 7.57 (dd, 1H, J=4, 8 Hz), 8.52 (dd, 1H, J=2, 8 Hz), 8.98 (dd, 1H, J=2, 5 H); 13C NMR (75 MHz, CD3OD) δ 21.4, 33.6, 41.9, 61.8, 61.9, 112.3, 115.7, 116.0, 123.1, 125.0, 126.5, 130.4, 130.5, 131.8, 131.8, 139.3, 142.6, 148.3, 149.6, 162.4 (d, J=245 Hz), 167.2, 175.3; 19F NMR (282.6 MHz, CDCl3) δ 62.6; EI MS (m/z) 441.4 [M−H]−, 883.1 [2M−2H]−.
Reaction SMILES: [CH:1]([O:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].S(O)(O)(=O)=O.Cl[C:24]1[NH:25][CH2:26][CH2:27][N:28]=1>ClCCl>[CH:1]([O:4][C:5]1[S:9][C:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:24]3[NH:28][CH2:27][CH2:26][N:25]=3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: ClC1=NCCN1
Reactant: CC(C)Oc1ccc(Cc2ccc(N)cc2)s1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(Cc2ccc(NC3=NCCN3)cc2)s1
Temperature: 80 °C
Yield: 89.7 %

Procedure:
To a solution of 4-(5-isopropoxythien-2-ylmethyl)-phenylamine (131 mg, 0.53 mmol) in aceonitrile (8 ml) was added 2-chloro-2-imidazoline sulfate (121 mg, 0.59 mmol) at 20-25° C. under argon. The mixture was heated at 80° C. for 1.5 hours. The mixture was diluted with dichloromethane and washed with sodium hydroxide, water, dried (Na2SO4) and concentrated to dryness. Purification by preparative TLC, eluting with ethyl acetate/methyl alcohol/isopropylamine, gave 2-[4-(5-isopropoxythien-2-ylmethyl)phenyl]amino-imidazoline (150 mg, 90%) as a thick yellow oil; 1H NMR (300 Mhz, CDCl3 δ 7.13 (d,J=8.4 Hz, 2H) 6.93 (d,J=8.4 Hz, 2H), 6.37 (dt, J=3.7, 1.0 Hz, 1H), 6.02 (d, J=3.7 Hz, 1H), 4.28 (quintet, J=6.2 Hz, 1H), 3.93 (bs, 2H), 3.52 (5, 4H), 3.24-3.5 (broad, 2H), 1.32 (d, J=6.2 Hz, 6H). MS m/e (%):316 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](=[O:13])([O:10][CH2:11][CH3:12])N>C(O)C>[CH2:11]([O:10][C:8](=[O:13])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCOC(N)=O
Reactant: Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 75.6 %

Procedure:
1024 g aniline, 980 g ethyl carbamate and 1060 g ethanol (approximately 96%) were reacted in the apparatus described in Example 1 for 6.0 hours at 200° C. When the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and distilled to remove the excess ethanol. The product was then fractionally distilled at 0.4 m bar. 1373 g N-phenyl-carbamic acid ethyl ester (75.5% of the theoretical yield), were collected and crystallized. The product had a melting point of 51° to 52° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.[CH3:11][O:12][CH2:13][C:14](OCC)=[O:15].Cl>C1C=CC=CC=1.O>[CH3:11][O:12][CH2:13][C:14]([CH:6]1[CH2:5][CH:4]([CH3:3])[CH2:9][CH2:8][C:7]1=[O:10])=[O:15]
Reactant: CC1CCC(=O)CC1
Reactant: CCOC(=O)COC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COCC(=O)C1CC(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
In 50 ml of benzene was suspended 2.5 g of 60% sodium hydride. While cooling the suspension, a mixture of 5.6 g of 4-methylcyclohexanone and 5.4 g of ethyl methoxyacetate was dropwise added thereto. After stirring at room temperature for 2 hours, 20 ml of water was added thereto and the pH was rendered 3 with concentrated hyrochloric acid. The benzene phase was separated and the aqueous phase was extracted with ether. The benzene solution and the ether solution were combined with each other followed by washing with a sodium chloride aqueous solution. After drying, the mixture was concentrated to give 7.4 g of crude 2-methoxyacetyl-4-methylcyclohexanone. The crude product was used at the following step. (2) 4-Cyano-2,3,5,6,7,8-hexahydro-1-methoxymethyl-7-methyl-3-oxoisoquinoline
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH2:20][C:21]#[CH:22]>O1CCCC1>[CH3:18][N:19]([CH2:20][C:21]#[CH:22])[C:15]([C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)=[O:16]
Reactant: C#CCNC
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Solvent: C1CCOC1
Product: C#CCN(C)C(=O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of 20.8 g of 9-anthroyl chloride in 100 ml of tetrahydrofuran is added at 10°-15° to a solution of 14.2 g of N-methylpropargylamine in 50 ml of tetrahydrofuran. After stirring at room temperature for 3 hours, the solvent is removed and the residue is stirred with methylene chloride and 5% aqueous sodium bicarbonate solution. The methylene chloride layer is dried and concentrated to give 23.3 g of crude N-methyl-N-propargyl-9-anthramide as an oil. H nmr spectrum: τ 1.7-2.9 (m, 9); 5.4 (d, 2.5 Hz, 1.3); 6.4 (d, 2.5 Hz, 0.7); 6.7 (s, 0.9); 7.4 (s, 2.1); 7.7 (t, 2.5 Hz, 0.7) and 8.0 (t, 0.3). The spectrum shows the presence of two rotamers.