Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[C:9][Si](C)(C)C)=[C:6]([NH2:14])[N:5]2[N:15]=[CH:16][N:17]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O1CCCC1.O>[C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:15]=[CH:16][N:17]=2)[C:6]=1[NH2:14])#[CH:9]
Reactant: Cc1nc2ncnn2c(N)c1C#C[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1c(C)nc2ncnn2c1N
Yield: 40.4 %

Procedure:
A mixture of Example 72A (122 mg, 0.5 mmol), potassium carbonate (138 mg, 1.0 mmol) in a mixed solvent of methanol/tetrahydrofuran/H2O(3 mL/3 mL/0.5 mL) was stirred at room temperature for 1.5 h. The reaction mixture was acidified with 1N HCl. The solid was filtered, washed with water and ethyl acetate to provide the title compound as an off-white solid (35 mg, 40% yield).
Reaction SMILES: [CH:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH2:6][CH2:5]1)=O.[Cl-].[CH3:21][O:22]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH:21]([CH2:1][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH2:6][CH2:5]1)=[O:22]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reaction time: 0.5 h

Procedure:
8.2 g of 1-((trans-4-(formylmethyl)cyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 50 mL of THF, and 12.6 g of methoxymethyl triphenylphosphonium chloride was added thereto. To this solution, the THF (20 mL) solution containing 4.1 g of potassium-t-butoxide was added dropwise at an internal temperature of 5 to 20° C., and the solution was stirred for 30 min. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and dried over silicagel. After evaporating the solvent under reduced pressure, the residue was dissolved in 50 mL of THF, and 50 mL of 10% hydrochloric acid was added thereto, followed by reflux with heating for 2 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline 3 times, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 7.0 g of 1-((trans-4-(2-formylethyl)cyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:22]([OH:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]([CH:26]=[O:27])[C:18]=2[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[C:22]([OH:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]([CH2:26][OH:27])[C:18]=2[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(C=O)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c(CO)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a solution of 7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoic acid (1.8 g) in tetrahydrofuran (30 ml) was added sodium borohydride (176 mg) at 0° C. and the mixture was stirred at room temperature for 2 hours. Acetone was added and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added and the organic layer was separated. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crystals. They were recrystallized from acetonitrile to obtain 7-(4-fluorophenyl)-7-(6-hydroxy-3-hydroxymethyl-2,4,5-trimethylphenyl)heptanoic acid (740 mg) (Compound 32). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [CH2:1]([NH2:5])[C:2](=[CH2:4])[CH3:3].Cl[CH2:7][CH2:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]1([S:9]([CH2:8][CH2:7][NH:5][CH2:1][C:2](=[CH2:3])[CH3:4])(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: C=C(C)CN
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)CNCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of methallylamine (8.0 g; 1.12 mol), in toluene (20 ml) was added dropwise to a solution of 1-chloro-2-phenylsulphonylethane (11.54 g; 56.4 mmol) in toluene (100 ml) at 0° C. When the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 1 hr. Thin layer chromatography indicated that all of the starting material had been consumed. Ether (150 ml) was added and the precipitate filtered off. Removal of the solvent from the filtrate produced a colourless oil which was subjected to silica gel column chromatography using ethyl acetate as eluent. Fractions containing the component Rf=0.37 (ethyl acetate) were combined and evaporated to give the title amine as a colourless oil, in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[CH:12][C:3]=12.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=[CH:12][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: CSc1nc(Cl)c2cn[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2cnn(COCC[Si](C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
4-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (497 mg, 2.477 mmol) was dissolved in 5 mL dry DMF, and the reaction mixture was cooled to 0° C. Sodium hydride (109 mg of 60% suspension in mineral oil) was added, and the reaction mixture was stirred for five minutes. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.52 mL, 2.922 mmol) was then aded, and the reaction mixture was stirred for 10 minutes. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography using 5% EtOAc in hexanes to give 391 mg of 4-Chloro-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12]>FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH2:9]([O:13][C:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]([I:1])=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOc1ncccc1C(=O)O
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCOc1ncc(I)cc1C(=O)O
Yield: 67.9 %

Procedure:
N-Iodosuccinimide (6.0 g, 26.7 mmol) was added to a solution of 2-n-butoxypyridine-3-carboxylic acid (Preparation 4; 3.46 g, 17.7 mmol) in trifluoroacetic acid (28 mL) and trifluoroacetic anhydride (7 mL) and the reaction heated under reflux in the absence of light, for 3 hours. The cooled reaction mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate. This solution was washed sequentially with water (2×), aqueous sodium thiosulfate solution, aqueous sodium citrate solution, 2 N hydrochloric acid, and brine, then dried (MgSO4) and evaporated under reduced pressure. The solid was triturated with pentane, filtered, washed with additional pentane and dried, to give the title compound as a white solid (3.86 g, 68%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH3:32])[CH2:34][CH2:35]3)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCN2C
Yield: 61.6 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (0.130 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.064 g (58%) of the title compound.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:33]=1)[C:27](OC)=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C(OCC)C>[CH2:35]([O:34][C:32]1[CH:31]=[C:26]([CH:25]=[C:24]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:33]=1)[CH2:27][OH:28])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCCCCCCCCCC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Under an argon atmosphere, methyl [3,5-bis(docosyloxy)]benzoate (2.03 g, 2.59 mmol) was dissolved in dehydrating tetrahydrofuran (50 mL) and, under ice-cooling, lithium aluminum hydride (148 mg, 3.93 mmol) was added, and the mixture was stirred at 40° C. for 1 hr. Ethyl acetate was added dropwise to decompose unreacted lithium aluminum hydride. Diethyl ether was added, and the mixture was washed with aqueous hydrochloric acid. The organic layer was concentrated under reduced pressure, methanol was added to the concentrated solution, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (1.73 g, 88.0%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2F)=S)=[CH:4][CH:3]=1.[NH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(C(=S)c2ccccc2F)c2cc(Br)ccc2N1
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1CN(c2noc3ccccc23)c2cc(Br)ccc2N1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A screw-cap vial equipped with a magnetic stir bar was charged with a solution of (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanethione (0.021 g, 0.057 mmol) in dimethylsulfoxide (0.5 mL) and hydroxylamine (50% in water, 0.035 mL, 0.575 mmol). The vial was capped, and the solution heated to 100° C. for 90 min. Heating was increased to 150° C. for 3 h, and then the solution was stirred at rt overnight. Additional hydroxylamine (50% in water, 0.035 mL, 0.575 mmol) was added and heating resumed at 150° C. for 5 h. Potassium carbonate (ca. 10-15 mg) was added and heating resumed at 100° C. for 5 h. The mixture was diluted with water (1 mL) and extracted with dichloromethane. The dichloromethane extract was washed with 5% aqueous sodium chloride solution (1 mL) and concentrated. The crude product was purified by preparative thin layer chromatography (1×1000 micron plate, eluting with 4:1 hexanes-ethyl acetate). The major band was isolated to afford (S)-3-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)benzo[d]isoxazole (0.010 g, 51%). MS (ESI, pos. ion) m/z 344, 346 [M+1].
Reaction SMILES: C[O-].[Na+].CO.Cl.[NH2:7][C:8]([NH2:10])=[NH:9].Cl[C:12]([C:14]1[C:18]([CH3:19])=[CH:17][N:16]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:13]>COCCOC.C(Cl)(Cl)Cl>[NH:9]([C:12]([C:14]1[C:18]([CH3:19])=[CH:17][N:16]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:15]=1)=[O:13])[C:8]([NH2:10])=[NH:7]
Reactant: N=C(N)N
Reactant: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: Cc1cn(-c2ccnc3ccccc23)cc1C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
1.4 g (25.5 mmol) of sodium methoxide is added at a temperature in the region of 20° C. under an argon atmosphere to 25 mL of methanol. After complete dissolution, 2.5 g (26.2 mmol) of guanidine hydrochloride are added. After stirring at a temperature in the region of 20° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is suspended in 25 mL of 1,2-dimethoxyethane and then again concentrated to dryness. The residue is suspended in a mixture of 75 mL of tetrahydrofuran and 50 mL of dichloromethane at a temperature in the region of 20° C. under an argon atmosphere, and then 1.07 g (3.97 mmol) of 3-chlorocarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole, dissolved in 25 mL of chloroform, are added thereto. After stirring at a temperature in the region of 20° C. for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 100 mL of water. After filtering, a gum is obtained, which gum is triturated in 50 mL of methanol and filtered. The filtrate is partially concentrated to a volume of 5 to 10 mL and is then purified by silica gel chromatography [eluent: chloroform/methanol (75/25 by volume)]. After concentrating the fractions under reduced pressure and triturating in ethyl ether, 0.64 g of 3-guanidinocarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole is obtained in the form of an off-white solid melting at 215° C. Mass spectrum (EI): m/e 293 (M+.), m/e 234.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:29])=[C:20]([CH:28]=1)[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:29][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:28][C:20]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22]
Reactant: CCCCOC(=O)c1cc(N)ccc1Cl
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)c1cc(NC(=O)C2=C(C)OCCS2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Thionyl chloride (4.4 g, 0.037 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (5.0 g, 0.031 mole) and methylene chloride (50 ml). The mixture was warmed to 35°-40° C. for about 3 hours, left stirring overnight at room temperature, and evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the solution treated dropwise at 5°-10° C. over 2 hours with a solution of butyl 5-amino-2-chlorobenzoate (6.1 g, 0.031 mole) and triethylamine (3.6 g, 0.036 mole) in methylene chloride (50 ml). The reaction mixture was stirred at room temperature for a further 3 hours and then worked up by washing in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50ml). Evaporation of the solvent left an oil, which slowly solidified. Recrystallization from methanol (50 ml) gave beige crystals, m.p. 71°-73° C. (4.7 g, 41% yield).
Reaction SMILES: [OH-:1].[Li+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([O:14][CH:15]1[CH2:19][CH:18]([C:20]([O:22]C)=[O:21])[NH:17][C:16]1=[O:24])[CH:8]=[CH:7]2.Cl>O.O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([O:14][CH:15]([C:16]([OH:24])=[O:1])[CH2:19][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:17])[CH:8]=[CH:7]2
Reactant: COC(=O)C1CC(Oc2ccc3cc(Br)ccc3c2)C(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CC(Oc1ccc2cc(Br)ccc2c1)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of lithium hydroxide (0.156 g) in water (2.0 ml) and tetrahydrofuran (6.6 ml) was treated with methyl 3-(6-bromo-2-naphthyloxy)-2-pyrrolidone-5-carboxylate (0.615 g), and heated to 60° C. After about 3.0 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (1.30 ml). The insolubles were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (5 ml). The insolubles were dried overnight in at vacuum oven at 60° C. to afford the title compound.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:21])=[C:16]([CH2:18][CH2:19]O)[N:17]=2)=[CH:9][CH:8]=1.C([N:24]([CH2:27][CH3:28])[CH2:25]C)C.BrC1C=CC(C2OC(C)=C(CCOS(C)(=O)=O)N=2)=CC=1.N1CCC1>ClCCl.O1CCCC1>[N:24]1([CH2:19][CH2:18][C:16]2[N:17]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=3)[O:14][C:15]=2[CH3:21])[CH2:25][CH2:28][CH2:27]1
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Agent: C1CNC1
Agent: CS(=O)(=O)Cl
Agent: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Add methanesulfonyl chloride (0.745 g, 6.50 mmol) to a cool (0° C.) solution of 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (1.4 g, 5.0 mmol) and triethylamine (1.26 g, 12.5 mmol) in dichloromethane (20 mL). Warm to room temperature and stir for 1 hour. Remove solvents, transfer crude of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester residue to a sealed tube, add tetrahydrofuran (30 mL), azetidine (2.0 g, 35.5 mmol), and heat at 60° C. overnight. Wash the crude organic material with 1N HCl. Separate layers and add 5N NaOH to the aqueous layer until it is basic. Extract the aqueous layer with diethyl ether (2×50 mL), dry the organic extracts over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give 4-(2-azetidin-1-yl-ethyl)-2-(4-bromo-phenyl)-5-methyl-oxazole (1.22 g, 72%): mass spectrum (m/e): 323 (M+1).
Reaction SMILES: OC[C:3]([CH3:7])([CH2:5]O)C.[CH3:8][C:9]([CH3:11])=O.[CH3:12][CH:13](O)[CH3:14]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:8][CH2:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:5][CH2:3][CH3:7]
Reactant: CC(C)(CO)CO
Reactant: CC(C)=O
Reactant: CC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCCCCCCCC
Yield: 65 %

Procedure:
A solution of (0 mmol) of 0, (0.12 mmol) of 12, 14 mg (0.13 mmol) of neopentyl glycol, 95 mg (0.3 mmol) of Ba(OH)2.8H2O, 80 μl (6.08 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 2 ml of 95% i-PrOH is stirred at 80° C. for 12 hours. The solvent is subsequently removed under reduced pressure, 2 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×2 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is purified by recrystallisation ice from nonane (yield: 65%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][NH:28][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCN
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CC(C)O
Product: CC(C)CCNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 61 %

Procedure:
Part C. A solution of N-benzyloxycarbonyl 3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (30.1 g, 0.10 mol) and 165 mL of isoamylamine in 150 mL of isopropyl alcohol was heated to reflux for 2.5 hours. The solution was cooled to room temperature, concentrated in vacuo and then recrystallized. The product was isolated by filtration and from ethylacetate/hexane to afford 31.7 g (61%) of N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12]C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][NH:50][CH:51]1[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]1>CN(C)C=O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:38]([C:35]2([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][C:23]4[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:50]([CH3:49])[CH:51]5[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]5)=[O:12])[CH:24]=4)=[CH:27][CH:28]=3)=[O:34])[CH2:36][CH2:37]2)=[O:47])=[CH:45][CH:44]=1
Reactant: CNC1CCN(C)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccn2)CC1
Reaction time: 62 h
Yield: 86.8 %

Procedure:
[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and methyl(1-methylpiperidin-4-yl)amine (0.045 ml) was added thereto, followed by stirring for 62 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (37.6 mg, 86.8%).