Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH2:44]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:44][CH3:43])=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and methylamine, 2M in THF.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([CH:11]2[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]2)[OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]([C:28]2[C:33]([F:34])=[CH:32][C:31]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:30][C:29]=2[F:39])=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26]>>[F:39][C:29]1[CH:30]=[C:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH:32]=[C:33]([F:34])[C:28]=1[C:22]1[S:21][C:20]([NH:19][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH:9]([CH:11]3[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]3)[OH:10])[N:7]=2)=[C:24]([C:25]([NH2:27])=[O:26])[CH:23]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=S1(=O)CCC(C(O)Cc2cccc(Br)n2)CC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CC(O)C4CCS(=O)(=O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-(6-bromopyridin-2-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethanol (0.11 g, 0.32 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.10 g, 0.32 mmol) as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[OH-].[Na+].Cl>ClCCl.O>[CH3:17][N:13]1[C:14]2[C:10](=[CH:9][C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH:7]=[N:6][CH:5]=3)=[CH:16][CH:15]=2)[CH2:11][C:12]1=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)Cc2cc(-c3cncc(N)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(-c3cncc(NS(C)(=O)=O)c3)ccc21
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-amino-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one, prepared as described in Example 3, (35 mg, 0.146 mmol), in dichloromethane (2.0 mL) was added diisopropylethylamine (75 pt, 0.44 mmol). The reaction was cooled to −10° C. and methanesulfonyl chloride (22 μL, 0.28 mmol) was added. After 15 minutes the reaction was quenched with saturated aqueous sodium bicarbonate and diluted with dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methanol (5 mL) and treated with 2 M aqueous sodium hydroxide (0.5 mL, 1 mmol) and permitted to stir at room temperature for 10 minutes. The reaction was then diluted with dichloromethane and water and the pH of the solution was brought to ca. 7 via the careful addition of 1M aqueous HCl. The layers were separated and the aqueous layer was extracted four additional times with dichloromethane and one time with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7%) to furnish N-[5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridin-3-yl]-methanesulfonamide; HRMS: (ES+) m/z 318.0912 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.11 (s, 3H), 3.28 (s, 3H), 3.62 (s, 2H), 6.94 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.51-7.59 (m, 1H), 7.91 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)(=[O:36])=[O:35])(=[O:27])=[O:26])[CH:5]=[C:6]([CH:23]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11]C1C=CC=C2C(NC(=O)C=12)=O.C[NH2:45]>O1CCCC1.C(O)C.C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)(=[O:36])=[O:35])(=[O:27])=[O:26])[CH:5]=[C:6]([CH:23]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH2:45]
Reactant: CN
Reactant: Cc1cc(OCCCOc2cccc3c2C(=O)NC3=O)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(C)CC2)c1
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture 3-[5-methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide (156 mg, 0.25 mmol), as prepared in the previous step, and 40% aqueous methylamine (1.50 mL, 21.5 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 4 hours. The solution was concentrated and the residue was purified by flash chromatography (10% methanol in dichloromethane) giving a slurry that was twice dissolved in diethyl ether, filtered, and concentrated giving the title compound as a clear oil (113 mg, 91%). 1H NMR (300 MHz, CDCl3/CD3OD) δ8.22 (dd, 1H, J=7.9, 1.3 Hz), 8.18 (dd, 1H, J=7.9, 1.4 Hz), 7.83 (td, 1H, J=7.7, 1.4 Hz), 7.70 (td, 1H, J=7.7, 1.3 Hz), 6.60 (br s, 1H), 6.56 (br s, 1H), 6.53 (t, 1H, J=2.1 Hz), 3.93 (t, 2H, J=6.3 Hz), 3.80 (t, 2H, J=6.2 Hz), 3.41 (m, 5H), 2.50 (br t, 4H, J=4.9 Hz), 2.30 (s, 3H), 2.24 (s, 3H), 2.00 (pentet, 2H, J=6.2 Hz).
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH:16]([N:19]([CH2:23][CH2:24][CH2:25][O:26][NH2:27])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].C(O)(=O)/C=C/C([O-])=O>>[CH:16]([N:19]([CH2:23][CH2:24][CH2:25][O:26][N:27]=[C:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:20]([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: O=C1CCCCCCCCCCC1
Reactant: CC(C)N(CCCON)C(C)C
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)O
Product: CC(C)N(CCCON=C1CCCCCCCCCCC1)C(C)C

Procedure:
Starting from 18.23 g. (0.1 moles) of cyclododecanone and 30.16 g. (0.12 moles) of diisopropylaminopropoxyamine dihydrochloride the title compound is prepared as in Example 13. Yield: 24.2 g. (71.6%). Hydrogen fumarate, m.p.: 119°-121° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][C:30](=[O:31])[N:26]([CH3:25])[C:27]4=[O:32])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CN1C(=O)CNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)cc3F)CC2)c(C)c1
Yield: 23.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 3-methylimidazolidine-2,4-dione (46 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (40 mg) was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:10][CH2:11][CH2:12][CH:13]([CH3:17])[CH2:14][CH:15]=O)(=[O:9])[CH3:8].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC>[C:7]([O:10][CH2:11][CH2:12][CH:13]([CH3:17])[CH2:14]/[CH:15]=[CH:22]\[CH2:18][CH2:19][CH3:20])(=[O:9])[CH3:8]
Reactant: CC(=O)OCCC(C)CC=O
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCC/C=C\CC(C)CCOC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under an atmosphere of nitrogen, a solution of 46.3 g (413 mmol) of potassium tert-butoxide in 250 mL of dry THF was a added between −15° C. and −10° C. to a stirred mixture of 150 g (376 mmol) butyl triphenylphosphonium bromide in 500 mL of dry THF. After complete addition, stirring was continued at −10° C. for 30 min, prior to the dropwise addition of 65.3 g (413 mmol) of 3-methyl-5-oxopentyl acetate in 250 mL of dry THF within a period of 30 min. Stirring was continued a further 15 min at −10° C., before the cooling bath was removed and the reaction mixture was allowed to warm to room temp. After 3 h of stirring at room temp., the reaction mixture was poured into 1 L of water, the organic layer separated and aqueous one extracted twice with 1 L of ether each. The combined organic extracts were washed with water and brine, dried with sodium sulphate, and concentrated under reduced pressure. The crude material (191 g) was purified by flash chromatography (1.00 kg of silica gel, pentane/ether, 19:1, Rf=0.40) to afford 57.9 g (78%) of (5Z)-3-methylnon-5-enyl acetate as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.Cl.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:15].CCN(C(C)C)C(C)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:23]1[C:24]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])[CH2:13][NH:12][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1
Reactant: NCC(=O)Nc1ccc2cnccc2c1
Reactant: O=Cc1cccc(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: O=C(CNCc1cccc(Cl)c1)Nc1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To m-chlorobenzaldehyde in MeOH was added 2-amino-N-(isoquinolin-6-yl)acetamide dihydrochloride (from Example 40) and the pH was adjusted to 5 with DIPEA. The mixture was stirred at room temperature for 2 hours, then NaCNBH3 was added and the pH was adjusted to ˜5.0 with acetic acid. The mixture was stirred 12 hours, quenched with Na2CO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated to give N-(isoquinolin-6-yl)-2-(3-chlorobenzylamino)acetamide (E59).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.[CH:21]1([CH2:25]Br)[CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:25][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1
Reactant: BrCC1CCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](CC(C)C)N1CC1CCC1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclobutylmethyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[Br:32][C:33]1[CH:34]=[C:35]([C@@H:39](O)[CH3:40])[CH:36]=[CH:37][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[Br:32][C:33]1[CH:34]=[C:35]([C@H:39]([N:14]2[C:13]3[CH:18]=[C:19]([F:20])[C:10]([S:7]([N:6]([CH2:5][C:4]4[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:3]=4[O:2][CH3:1])[C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:8])=[O:9])=[CH:11][C:12]=3[O:16][C:15]2=[O:17])[CH3:40])[CH:36]=[CH:37][CH:38]=1
Reactant: C[C@H](O)c1cccc(Br)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4cccc(Br)c4)c3cc2F)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Accordingly, the compound of Formula 28-1 ((R)-3-(1-(3-bromophenyl)ethyl)-N-(2,4-dimethoxybenzyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide) was prepared from a solution provided by dissolving 2 g of the compound of Formula 11-3 (4.29 mmol, prepared as described above) and 0.862 g of (S)-1-(3-bromophenyl)ethanol (4.29 mmol) in 10 mL of THF. This solution was cooled to 0° C. and treated with triphenylphosphine (2.25 g, 8.58 mmol) followed by DEAD (1.36 mL, 8.58 mmol). After stirring at 0° C. for 120 min, the reaction mixture was diluted with EtOAc (50 mL) and sat'd sodium bicarbonate (10 mL), the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by normal phase chromatography (10-80% EtOAc in hexane) yielded the compound of Formula 28-1 as a solid which was used as isolated.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH:7]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:4]([O:28][CH2:27][CH2:26][N:23]1[CH2:22][CH2:21][N:20]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:25][CH2:24]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
Diketene (5.1 g) was added to 4-benzhydryl-1-piperazineethanol (18.1 g) and the mixture was heated at 70°-80° C. with stirring for 1.5 hours and purified by silica gel chromatography [eluent: hexane-ethyl acetate (3:2)] to give 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate as an oil. Yield 17.1 g (73.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]3[C:13]([NH2:16])=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([Cl:28])[N:22]=1.Cl>O>[NH2:16][C:13]1[C:12]2[C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:25]4[CH:24]=[C:23]([Cl:28])[N:22]=[C:21]([NH2:20])[N:26]=4)=[CH:3][C:4]=3[F:19])=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][N:14]=1
Reactant: Nc1ccc(Oc2cccc3onc(N)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3cccc4onc(N)c34)c(F)c2)n1

Procedure:
100 mg (0.39 mmol) of 4-(4-amino-2-fluorophenoxy)-1,2-benzisoxazole-3-amine (from example VII) and 63.3 mg (0.39 mmol) of 2-amino-4,6-dichloropyrimidine are suspended in 3 ml of water, and 0.04 ml of concentrated hydrochloric acid is added. The reaction mixture is heated at reflux overnight, resulting in the formation of a colorless precipitate. This is filtered off, washed repeatedly with water and dried under high vacuum.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]([C@@H:28]3[CH2:30][C@H:29]3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)C(=O)C(F)(F)F)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([NH:5][C:6](=[O:37])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C@@H:28]3[CH2:30][C@H:29]3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:19]2)=[CH:11][CH:12]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)NC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of N-(methylsulfonyl)-4-((4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzamide (80 mg, 0.149 mmol) in methanol (2 mL) was added sodium hydroxide (6M, 0.5 mL, 0.500 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was purified using reverse-phase HPLC under the acidic conditions and the fractions containing the product was treated with 1N HCl and concentrated. The residue was dried under vacuum to give 36 mg of product as pale yellow solid. MS: (M+H)+=442.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.36 (m, 1H), 1.48-1.72 (m, 3H), 1.91-2.09 (m, 2H), 1.93-2.10 (m, 3H), 2.85-3.26 (m, 5H), 4.30-4.53 (m, 2H), 7.12-7.39 (m, 5H), 7.76 (d, J=8.34 Hz, 2H), 7.71-7.82 (m, 2H), 7.98-8.09 (m, 2H).
Reaction SMILES: Cl[C:2]([CH:4]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3].[CH2:17]([NH2:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN1CCOCC1>C(OCC)(=O)C>[CH:11]1([CH2:10][CH:4]([C:2]([NH:25][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:3])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCCC1)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
A mixture of ethyl 2-chlorocarbonyl-3-cyclohexylpropionate (2.65 mmol), phenethylamine (0.376 mL, 3 mmol) and N-methylmorpholine (0.44 mL, 4 mmol) in ethyl acetate (6 mL) was cooled to between −20 and −10° C. and stirred for 15 minutes. The mixture was allowed to warm to room temperature, stirred for approximately 12 hours and then diluted with ethyl acetate (5 mL) and ice (5 mL). The organic layer was separated, washed with cold 0.05 N hydrochloric acid, sodium bicarbonate solution and brine, dried (MgSO4) and concentrated to provide ethyl 2-cyclohexylmethyl-N-phenethylmalonamate (366 mg, 1.106 mmol).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:25])[C:15]=2[N:14]=[CH:13]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([Cl:25])[C:15]=2[N:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)NCCCn1cnc2c(Cl)nc3ccccc3c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCn1cnc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
50 mg (0.139 mg) of 1-[3-(tert-butoxycarbonylamino)-propyl]-4-chloro-1H-imidazo[4,5-c]quinoline was dissolved in 3 ml of methylene chloride. 0.11 ml (1.39 mmol) of trifluoroacetic acid was added thereto and the mixture was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure and 1 ml of a 1N sodium hydroxide aqueous solution and brine were added to the residue. The resulting solution was extracted with chloroform five times, thereafter the extract was dried (Na2SO4), and concentrated under reduced pressure. The residue was triturated with diethyl ether (containing a small amount of methylene chloride) and the precipitate thus formed was collected by filtration to obtain 14 mg (0.0536 mmol) of 1-(3-aminopropyl)-4-chloro-1H-imidazo[4,5-c]quinoline shown below as white powder. ##STR37## Its spectroscopic data are as follows: IR (KBr) cm- 1 : 340, 1590, 1510. 1H-NMR (CDCl3 +CD3OD) 5 (ppm) : 2.06 (2H, m), 2.72 (2H, t, J=6.8 Hz), 2.98 (2H, b r), 4.64 (2H, t, J=7.0 Hz), 7.57 (1H, t, J=7.6 Hz), 7.61 (1H, t, J=7.6 Hz), 8.03 (1H, s), 8.05 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([OH:24])=O)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:51][C@H:50]([OH:52])[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([N:40]1[CH2:51][C@H:50]([OH:52])[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:24])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Example 1 was repeated, except that (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) and (4R)-1-t-butoxycarbonyl-N-t-butyl-4-hydroxy-L-prolinamide (prepared as described in Preparation 5) were used as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound as colorless powdery crystals, melting at 115°-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH:30]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)CC1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CC(=O)O)C2)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 38.7 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1.03 mmol) was reacted with 2-(morpholin-2-yl)acetic acid hydrochloride (0.19 g, 1.03 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.22 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.C([O:17][C:18]1[C:22]([CH:23]=O)=[C:21]([CH3:25])[N:20]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:19]=1)C1C=CC=CC=1.C(OC1C(C=O)=C(C)N(C2C=CC=CC=2)N=1)C1C=CC=CC=1>>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:23][C:22]2[C:18](=[O:17])[NH:19][N:20]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:21]=2[CH3:25])=[CH:3][CH:4]=1)[CH3:9]
Reactant: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccc(F)cc1
Reactant: CCc1ccc(Br)cc1
Agent: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccccc1
Product: CCc1ccc(Cc2c(C)n(-c3ccc(F)cc3)[nH]c2=O)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 1-bromo-4-ethylbenzene and 3-benzyloxy-1-(4-fluorophenyl)-4-formyl-5-methyl-1H-pyrazole instead of 4-bromoanisole and 3-benzyloxy-4-formyl-5-methyl-1-phenyl-1H-pyrazole, respectively.