Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[C:23]([C:24]([N:11]2[CH2:10][CH2:9][C:7]3[N:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[N:4]=[CH:5][C:6]=3[CH2:12]2)=[O:25])[CH:27]=1)(=[O:18])=[O:17]
Reactant: FC(F)(F)c1ncc2c(n1)CCNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ncc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (CA [74737-17-7]; WO2004069162) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): 498.4 (M+H+).
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:16].BrBr>C(O)(=O)C>[Br:16][CH:8]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: O=C(Cc1ccncc1)c1ccccc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)c1ccncc1
Temperature: 60 °C

Procedure:
To a solution of 36 g (182 mmol) of 1-phenyl-2-pyrid-4-ylethanone in 350 mL of acetic acid are successively added at room temperature 28 ml (210 mmol) of a solution containing 30% by weight of hydrobromic acid in acetic acid and 10.1 ml (197 mmol) of bromine dissolved in 50 mL of acetic acid. The solution is heated at 60° C. for one hour and then cooled. The product is precipitated by adding diethyl ether, and 63 g of a yellow solid are isolated after drying.
Reaction SMILES: [Na+].[I-:2].CNCCNC.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]2)=[C:12]([CH3:26])[CH:11]=1>O1CCOCC1.CCOC(C)=O.[Cu]I>[I:2][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]2)=[C:12]([CH3:26])[CH:11]=1
Reactant: Cc1cc(Br)ccc1NCCN1CCC(C)CC1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(I)ccc1NCCN1CCC(C)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
73 mg (0.386 mmol) of CuI, 1.16 g (7.71 mmol) of NaI, and N,N′-dimethylethane-1,2-diamine were added under argon to a solution of 1.20 g (3.86 mmol) of (4-bromo-2-methylphenyl)-[2-(4-methylpiperidin-1-yl)ethyl]amine in 3.9 mL of 1,4-dioxane and the mixture was stirred for 20 hours at 110° C. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with 10% aqueous ammonia, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 1.22 g (88% of theoretical); C15H23IN2 (M=358.261); calc.: molpeak (M+H)+: 359; found: molpeak (M+H)+: 359; HPLC-MS: 6.24 minutes (method A).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:21])[C:13](=[O:20])[N:14]([CH2:15][C@@H:16]([O:18][CH3:19])[CH3:17])[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:33]=[N:34][CH:35]=2)O1.C(OCC)(=O)C.[Na].O1CCOCC1>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:19][O:18][C@@H:16]([CH3:17])[CH2:15][N:14]1[C:5]2[C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[C:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:33]=[N:34][CH:35]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:12]([CH3:21])[C:13]1=[O:20]
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CO[C@@H](C)Cn1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cncc(-c2ccc3ncc4c(c3c2)n(C[C@H](C)OC)c(=O)n4C)c1
Temperature: 85 °C
Reaction time: 10 h
Yield: 79.9 %

Procedure:
To a three-necked flask containing 8-bromo-1-[(2S)-2-methoxypropyl]-3-methyl-imidazo[4,5-c]quinolin-2-one (35 g, 100 mmol), ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (29.1 g, 105 mmol), sodium ethyl acetate (28.7 g, 350 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.817 g, 1.0 mmol) add 1,4-dioxane (200 mL) and water (200 mL) under N2. Then heat the reaction mixture to 85° C. and continue stirring for 10 hours. Cool the reaction mixture to room temperature. Filter the mixture with Kieselguhr® Silica-Thiol to remove the catalyst. Add water (400 mL) drop wise and solid precipitates. Filter the mixture and wash the solid with water (400 mL). Stir the solid in ethyl acetate (70 mL) at room temperature for one hour; filter, wash with ethyl acetate (70 mL), and dry under vacuum below 65° C. to give the title compound (33.6 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 9.25 (d, 1H, J=2 Hz), 9.15 (d, 1H, J=2.4 Hz), 8.75 (s, 1H), 8.73 (d, 1H, J=1.6 Hz), 8.65 (t, 1H), 8.24 (d, 1H, J=8.8 Hz), 7.89 (dt, 1H, J=8.8, 1.6 Hz), 4.47 (q, 2H), 4.38 (m, 2H), 3.90 (m, 1H), 3.64 (s, 3H), 3.26 (s, 3H), 1.45 (t, 3H), 1.37 (d, 3H, J=6 Hz).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[CH:9]=1)(C)(C)C.F>C1COCC1>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(C#N)s2)c1
Agent: F
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(CO)ccn2)s1
Reaction time: 0.33 h

Procedure:
2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile (1.30 g, 3.75 mmol) was dissolved in 10 mL anh THF. Hydrogen-fluoride (Aldrich, 5.0 mL) was added and the reaction was stirred for 20 minutes. The bulk of the solvent was removed in vacuo and the resulting residue was diluted with half-saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford the titled compound. 1H NMR (DMSO-d6) δ12.23 (bs, 1H), 8.30 (d, 1H, J=5.3 Hz), 8.26 (s, 1H), 7.15 (s, 1H), 6.99 (d, 1H, J=5.3 Hz), 5.49 (t, 1H, J=5.7 Hz) 4.54 (d, 2H, J=5.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:20](O)[CH2:21][CH2:22][OH:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Yield: 96.1 %

Procedure:
To a cooled (0° C.) solution of 0.815 g (2.37 mmol) 3-(3-bromophenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 0.51 mL (7.12 mmol) of 1,3-propanediol and 1.20 g (4.75 mmol) of 1,1'-(azodicarbonyl)dipiperidine in 15 mL of anhydrous tetrahydrofuran was added 1.18 mL (4.75 mmol) of tri-n-butylphosphine dropwise over 8 min. Dichloromethane (10 mL) was added to aid stirring. After stirring at ambient temperature for 5.5 h, the reaction mixture was diluted with 100 mL of diethyl ether. The resulting mixture was stirred for 30 min, filtered and the filtrate concentrated to give a pale yellow semisolid. This residue was flash chromatographed on 80 g of silica gel with 25-50% ethyl acetate-hexane to afford 0.914 g (96% yield) of the title compound as a colorless resin: 1H-NMR (300 MHz; CDCl3) δ 8.01 (t, 1H, J=1.8 Hz), 7.79 (m, 2H), 7.42 (t, 1H, J=8.0 Hz), 6.64 (s, 1H), 6.41 (s, 1H), 6.37 (t, 1H, J=2.2 Hz), 4.01 (t, 2H, J=6.0 Hz), 3.83 (t, 2H, J=5.6 Hz), 2.26 (s, 3H) and 2.00 (m, 2H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 61.3 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.13 g of sodium ethoxide was added thereto. A solution of 4.7 g of tetradecyl bromide in 20 ml of ethanol was added to the mixed solution while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. Then, the mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 3.5 g of diethyl 2-acetamido-2-tetradecylmalonate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:13]3)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:13]3)[N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC(c1ccc2ncc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2ncc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A flask containing crude (3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methanol (153 mg, ˜0.44 mmol) was flashed with Ar and charged with phthalimide (71 mg, 0.48 mmol) and triphenylphosphine (130 mg, 0.48 mmol) and anh. THF (10 mL). DIAD (0.1 mL, 0.48 mmol) was added slowly dropwise at rt and then the reaction was stirred at rt for 16 h. The reaction was concentrated under reduced pressure and purified by flash chromatography (silica gel, 5% EtOAc in DCM to 10%) affording 2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione compound as a creamy solid. To stirred solution of the crude 2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione (147 mg, 0.31 mmol) in anh. EtOH (12 mL) and anh. DCM (2 mL) under Ar was added anh. hydrazine (0.03 mL, 0.9 mmol). The reaction mixture was stirred at rt for 22 h. The 1:1 mixture of the product and a partially cleaved phthalimide was concentrated under reduced pressure at rt and dried under high vacuum overnight. The light yellow, solid residue was dissolved in anh. i-PrOH (6 mL) and anh. CHCl3 (3 mL) and heated under Ar at 50° C. for 16 h. Later the reaction was cooled to rt, evaporated to dryness and triturated with DCM. The DCM aliquots were filtered through a pad of Celite affording the title compound as a light yellow solid; 1H NMR (400 MHz, CD3OD/CDCl3) δ 9.37 (s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.23 (d, J=6.8 Hz, 2H), 8.12 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.88 (dd, J=0.8 Hz, 8.8 Hz, 1H), 7.62-7.52 (m, 3H), 5.81 (s, 1H). MS (ES+): m/z 348.0 (40) [MH+]; HPLC: tR=2.08 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[CH2:29](Br)[CH:30]1[O:34][CH2:33][CH2:32][CH2:31]1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33][O:34]3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: BrCC1CCCO1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CCCO3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and tetrahydrofurfuryl bromide in the same manner as in Example 32.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[C:15]([C@:20]2([CH2:31][F:32])[CH2:25][C@@H:24]([C:26]([F:29])([F:28])[F:27])[O:23][C:22]([NH2:30])=[N:21]2)[C:16]([F:19])=[N:17][CH:18]=1>>[NH2:30][C:22]1[O:23][C@H:24]([C:26]([F:27])([F:29])[F:28])[CH2:25][C@:20]([C:15]2[CH:14]=[C:13]([NH:12][C:9](=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:18]=[N:17][C:16]=2[F:19])([CH2:31][F:32])[N:21]=1
Reactant: NC1=N[C@](CF)(c2cc(N)cnc2F)C[C@@H](C(F)(F)F)O1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2cnc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1

Procedure:
The title compound was synthesized using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-cyano-picolinic acid and (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (12k, as described in Example 138, method S). MS m/z=441.0 [M+H]+. Calculated for C18H13F5N6O2: 440.3
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[C:13]([CH3:20])=[C:12]([CH3:21])[N:11]=1>>[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[C:13]([CH3:20])=[C:12]([CH3:21])[N:11]=1
Reactant: NCCCCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCCO)c1C
Yield: 36.1 %

Procedure:
Using the general method of Example 89 Part A, 6-aminohexan-1-ol (15.91 g, 135.7 mmol) was reacted with 2,4-dichloro-5,6-dimethyl-3-nitropyridine (30 g, 136 mmol) to provide 14.79 g of 6-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]hexan-1-ol as a yellow solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:10])=[NH:9].[CH2:11]([O:13][C:14](=[O:23])[C:15](=[CH:19]N(C)C)[C:16](=O)[CH3:17])[CH3:12]>CCO>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)=[N:10][CH:19]=1)=[O:23])[CH3:12]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: N=C(N)c1ccccn1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccn2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Na0 (31.7 mmol) is added to anhydrous EtOH (100 mL) and stirred at rt for 15 min. Pyridine-2-carboxamidine hydrochloride (31.7 mmol) is added and the solution is stirred for 15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid ethyl ester (31.7 mmol) is added and the reaction mixture is heated at reflux under N2 for 1 h. The reaction is cooled to rt and concentrated in vacuo. The residue is dissolved in EtOAc (200 mL), washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid ethyl ester (6.77 g, 88%). MS: 261 (M+H); 1H 1H NMR (300 MHz, CDCl3): δ 1.44 (t, 3H), 2.97 (s, 3H), 4.44 (q, 2H), 7.44 (m, 1H), 7.91 (m, 1H), 8.60 (m, 1H), 8.90 (m, 1H), 9.31 (s, 1H).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:45])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:42])=[O:34])=[C:28]([O:43][CH3:44])[CH:27]=2)[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO>[CH3:44][O:43][C:28]1[CH:27]=[C:26]([CH2:25][C:24]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[CH2:18][NH:17][C@@H:14]2[CH2:15][CH2:16][C@H:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]2)=[O:45])[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])=[O:34]
Reactant: COc1cc(CC(=O)N2CCCC2CN[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)ccc1NC(=O)Nc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)N2CCCC2CN[C@H]2CC[C@@H](C(=O)O)CC2)ccc1NC(=O)Nc1ccccc1C
Temperature: 70 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
To a stirred solution of benzylcis-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetyl]-2-pyrrolidinyl]methylamino]cyclohexanecarboxylate (1.5 g, 2.45 mmol) in THF (10.0 ml) and MeOH (5.0 ml) was added 1N NaOH (3.68 ml, 3.68 mmol). The mixture was stirred at 70° C. for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with 1N HCl. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH—CH2Cl2 (1:5, v/v) as eluent to give cis-4-[[1-[3-methoxy-4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]cyclohexanecarboxylic acid 171 (940 mg, 73%) as an amorphous solid. MW 522.64 IR (KBr) 3283, 2945, 2860, 1534, 1453, 1415 cm−1; 1H-NMR (DMSO-d6) δ1.38-2.00 (m, 12H), 2.45 (s, 3H), 2.30-3.95 (m, 4H), 3.22-3.75 (m, 2H), 3.58 (s, 2H), 3.86 (s, 3H), 4.12 (m, 1H), 6.73-7.16 (m, 5H), 7.77-7.79 (m, 1H), 7.98-8.02 (m, 1H), 8.51-8.52 (m, 1H), 8.57-8.59 (m, 1H); MS (FAB) m/z 523 (M++1); Anal. Calcd. for C29H38N4O5.0.5NaCl.2.2H2O: C, 58.89; H, 7.23; N, 9.47. Found: C, 59.21; H, 7.11; N, 9.11.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.Br[C:30]1[S:31][C:32]([CH3:40])=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=1>>[CH2:12]([O:11][C:10]([NH:9][C@H:8]1[CH2:7][CH2:6][N:5]([C:30]2[S:31][C:32]([CH3:40])=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=2)[CH2:4][C@H:3]1[O:2][CH3:1])=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nc(Br)sc1C
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)sc1C
Yield: 47.8 %

Procedure:
The same operation as in Example (38b) was performed using benzyl cis(±)-(3-methoxypiperidin-4-yl)-carbamate obtained in Example (40b) (0.2 g, 0.76 mmol), diisopropylethylamine (0.25 mL, 1.44 mmol) and ethyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate obtained in Example (40c) (0.2 g, 0.80 mmol), to obtain 157.6 mg of the title compound as a yellow oily substance (48%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH2:5][CH:4]([CH3:12])[CH:3]1[C:13](OC)=O.[CH:17](=[C:21]([CH2:24]CCl)[CH2:22]Cl)[CH:18]([CH3:20])[CH3:19]>>[CH:17](=[C:18]1[CH2:20][CH2:13][C:3]2([CH:4]([CH3:12])[CH2:5][C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:7][C:2]2=[O:1])[CH2:19]1)[CH:21]([CH3:24])[CH3:22]
Reactant: CC(C)C=C(CCl)CCCl
Reactant: COC(=O)C1C(=O)C=C(OC(C)C)CC1C
Product: CC(C)C=C1CCC2(C1)C(=O)C=C(OC(C)C)CC2C

Procedure:
Methyl 2-oxo-4-isopropoxy-6-methyl-3-cyclohexene carboxylate was reacted with 2-isobutylidene-1,4-dichlorobutane and the resultant alkylated carboxylate cyclized by the same method described in Example 2 to yield 2-isobutylidene-8-isopropoxy-10-methylspiro[4.5]dec-7-en-6-one having the structure: ##STR29## which was crystallized from petroleum ether, mp 88°-91° C.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH:7]1[CH2:12][CH2:11][C:10](=[N:13][S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH:22]1([Mg]Br)[CH2:24][CH2:23]1>C(OCC)C>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH:7]1[CH2:8][CH2:9][C:10]([NH:13][S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])([CH:22]2[CH2:24][CH2:23]2)[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(=O)N=C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: Br[Mg]C1CC1
Solvent: CCOCC
Product: CC(C)(C)S(=O)NC1(C2CC2)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 3.00 g (9.05 mmol) of 2-methyl-propane-2-sulfinic acid [4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylidene]-amide (25) in 15 mL of diethyl ether was added dropwise to 54.3 mL (27.1 mmol) of a 0.5 M solution of cyclopropylmagnesium bromide in diethyl ether precooled to −78° C. The reaction solution was stirred at −78° C. for 1 h and was allowed to warm to room temperature overnight. The reaction was quenched by dropwise addition of saturated aqueous Na2SO4, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography to yield 800 mg of the title compound (26) as diastereomeric mixture. Rt=2.22 min, 2.25 min (Method C). Detected mass: 374.3 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[N:6][C:7]1[CH:8]=[C:9]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].CS(N1C2C(=CC=C(N)C=2)[CH:26]=[CH:25]1)(=O)=O.[ClH:34].CCOCC>CO.C(O)(C)C>[ClH:34].[CH3:17][S:14]([N:13]1[C:9]2[C:10](=[CH:11][CH:12]=[C:7]([N:6]=[C:2]3[NH:3][CH2:4][CH2:5][NH:1]3)[CH:8]=2)[CH:26]=[CH:25]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Nc1cccc(N=C2NCCN2)c1
Reactant: CS(=O)(=O)n1ccc2ccc(N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)n1ccc2ccc(N=C3NCCN3)cc21

Procedure:
3.82 g of 2-chloroimidazoline hydrogen sulfate (see Example 6A) was treated with 50 ml of 1M NaOH solution and immediately extracted with CH2Cl2 (3×20 ml). The extracts were dried (K2CO3) and the solution decanted. 10 ml of isopropanol was added and the CH2Cl2 was removed at reduced pressure. The resultant isopropanol solution was added to a refluxing solution of the N-methanesulfonyl-6-aminoindole (2.02 g, 9.61 mmol) in isopropanol (10 mmol). The mixture was refluxed for 3 hr, cooled, and concentrated under vacuum. A portion (800 mg) of the crude product was dissolved in MeOH:H2O (5:1) then 10 g of silica gel was added. The mixture was dried under vacuum and the resulting powder was applied to a silica gel column and eluted with ethyl acetate:MeOH:iPrNH2 (93:5:2) (iPr=isopropyl). The white solid obtained was suspended in MeOH (4 ml) and treated with 3 ml of 1.0M HCl/ether. The solid dissolved then a precipitate formed which was filtered off after chilling the mixture in an ice bath. 590 mg of N-methanesulfonyl-6-(imidazolidin-2-ylideneamino)indole hydrochloride were obtained (mp 167.6-170.6° C.).
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][NH:7][C:8](=[O:26])[C@H:9]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:10](C(OC(C)(C)C)=O)[CH3:11])[CH2:2][CH3:3].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)(Cl)Cl.CO.C(O)(=O)C.O>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH2:1]([S:4][CH2:5][CH2:6][NH:7][C:8](=[O:26])[C@H:9]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:10][CH3:11])[CH2:2][CH3:3]
Reactant: CCCSCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCSCCNC(=O)[C@H](Cc1ccccc1)NC

Procedure:
The protected amide from (a)(1.4 g) was deprotected with aqueous trifluoroacetic acid (10 ml) as in Example 7(b). Chromatography on silica in chloroform:methanol:acetic acid: water 120:36:2:3 gave a gum (1.1 g). Rf3A=0.61, Rf7B=0.71
Reaction SMILES: C[O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([CH:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[BrH:24]>>[BrH:24].[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([CH:7]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CNCc3c2ccc(OC)c3C)cc1OC
Agent: Br
Product: Cc1c(O)ccc2c1CNCC2c1ccc(O)c(O)c1

Procedure:
To 410 mg of 7-methoxy-4-(3,4-dimethoxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline, was added 8.2 ml of 48% hydrobromic acid, and the mixture was heated under reflux under an argon gas stream for 3 hours. The reaction mixture was cooled, and the crystals which separated out were collected by filtration, giving 410 mg of 7-hydroxy-4-(3,4-dihydroxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide.