Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[N:5]=[C:6]([CH2:12][C:13]#[N:14])[NH:7]2.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[CH:10]1[CH:11]=[C:2]([Cl:1])[C:3]2[C:4]([NH:5]/[C:6](/[NH:7][C:8]=2[CH:9]=1)=[C:12](\[C:26]([C:25]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=1[Cl:23])=[O:27])/[C:13]#[N:14])=[O:15]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: N#CCc1nc(=O)c2c(Cl)cccc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1/NC(=O)c2c(Cl)cccc2N1
Yield: 27.2 %

Procedure:
To solution of 2-(5-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (26.4 mg, 120 μmol) and triethylamine (18.4 μL, 132 μmol) in dioxane (4 mL) was added 2,4-dichlorobenzoyl chloride (18.5 μL, 132 μmol), and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin B (3) (12.8 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 (dd, J1=7.5 Hz, J2=1.4 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.55 (dd. J1=8.2 Hz, J2=1.9 Hz, 1H), 7.68-7.79 (m, 3H). 13C NMR (500 MHz, DMSO-d6) δ ppm 71.69, 114.6, 117.63, 118.45, 127.65, 128.1, 129.2, 129.65, 130.49, 133.35, 134.8, 135.47, 138.2, 154.81, 156.48, 188.71. HRMS (m/z): [M+Na]+ calc. for C17H8N3O2Cl3Na, 413.9580; observed, 413.9582.
Reaction SMILES: [PH2:1](=[O:3])[O-:2].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[CH2:14]=[C:15]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>ClCCl>[OH:3][PH:1]([CH2:14][CH:15]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:2]
Reactant: C=C(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[PH2][O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Temperature: 105 °C
Yield: 99.8 %

Procedure:
A mixture of ammonium phosphinate (162.6 g, 1.96 mol) and 1,1,1,3,3,3-hexamethyldisilazane (316 g, 1.96 mol) was heated to 105° C. for 2 hours. The reaction mixture was cooled in an ice bath and di-tert-butyl 2-methylenepentane-1,5-dioate (251 g, 0.979 mol) dissolved in dichloromethane (1000 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then quenched with distilled water (500 ml) and the organic layer was retained. The aqueous layer was washed a second time with dichloromethane and the combined organic layers were dried over magnesium sulfate. Then the solvent was removed under reduced pressure leaving a slightly yellow oil (315 g, 100%) This product was found to be of sufficient purity for use in the next reaction. 1H NMR (CDCl3): δ1.4 (m, 18H), 1.9 (m, 3H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7 (m, 1H), 6.5 & 7.9 (d, 1H, the P—H), 11.0 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:25])=[CH:27][CH:28]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc2ncccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2ncccc2c1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 6-aminoquinoline (500 mg, 3.47 mmol) and 4-benzyloxybenzoic acid (792 mg, 3.47 mmol) in dichloromethane (25 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.84 g, 4.16 mmol) and triethylamine (0.58 mL, 4.16 mmol), and the solution was stirred overnight at room temperature. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (218 mg, 18%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])NC2C=CSC=2C=1Cl)=[O:5])[CH3:2].[CH3:17][O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH2:26])=[O:20].C(C(C(Cl)=O)C(Cl)=O)C>>[CH3:17][O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH:26][C:11](=[O:12])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:20]
Reactant: COC(=O)c1sccc1N
Reactant: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O
Agent: CCC(C(=O)Cl)C(=O)Cl
Product: CCOC(=O)CC(=O)Nc1ccsc1C(=O)OC

Procedure:
A preferred intermediate in the preparation of compound of structure (I) is 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (4) below. To prepare this intermediate, methyl-3-amino-thiophene-2-carboxylate was reacted with ethylmalonyl chloride to yield intermediate 3-(2-ethoxycarbonyl-acetylamino)-thiophene-2-carboxylic acid methyl ester, depicted by formula (1). This intermediate was converted to 7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (2), by reacting with sodium ethoxide, and was then converted into 5,7-dihloro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (3). Hydrolysis of 5,7-dihloro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (3), yielded 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyrdine-6-carboxylic acid ethyl ester, depicted by formula (4) as shown in Scheme 1.
Reaction SMILES: I[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I-].[Na+].C(O)(C)C.O.O.[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH3:26][NH2:27]>O1CCCC1>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH3:26][NH:27][CH2:2][CH2:3][C@@H:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:26][NH:27][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CN
Reactant: O[C@H](CCI)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CNCC[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-3-iodo-1-phenylpropanol (5.0 g, 19 mmol) and catalytic amount of sodium iodide in tetrahydrofuran (20 mL) and 40% aqueous methylamine (40 mL) was stirred at room temperature for 5 hours. The reaction mixture was evaporated to 15 mL and the pH of the solution was adjusted to pH>12 via the addition of aqueous NaOH solution. The mixture was then twice extracted with toluene and the combined extracts were washed with brine. The toluene layer was evaporated to dryness and the residue dissolved in toluene (25 mL) and isopropanol (25 mL) and oxalic acid dihydrate (1.2 g, 9.5 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered and rinsed with toluene/isopropanol to give 3.0 g of (R)—N-methyl-3-hydroxy-3-phenylpropylamine hemioxalate salt as an off-white solid. The solid (2.9 g) was free based with sodium hydroxide solution and extracted with toluene. The extracts were washed with brine and then evaporated to dryness to give 2.2 g of (R)—N-methyl-3-hydroxy-3-phenylpropylamine as an off-white solid [α]D23=36° (c 1, CHCl3).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([Mg:16][Cl:17])C=CC=CC=1.C1OC1>ClC1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][O:9][Mg:16][Cl:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: Cl[Mg]c1ccccc1
Solvent: Clc1ccccc1
Solvent: C1CO1
Product: Cl[Mg]OCCc1ccccc1

Procedure:
2-phenylethanol is also prepared by the Grignard synthesis, starting from chlorobenzene, which is converted to phenyl-magnesium chloride, which then reacts with ethylene oxide to give phenylethoxy magnesium chloride. Phenylethoxy magnesium chloride thus obtained is decomposed with sulphuric acid to give 2-PEA. The main drawbacks of this process are (i) generation of potentially dangerous and air and moister sensitive phenyl-magnesium chloride (ii) requirement of sulphuric acid for the decomposition of Grignard complex and subsequent extraction of the desired product, (iii) produces large amounts of hazardous effluent and poor quality of the 2-phenylethanol which has low acceptability in perfumery industry [E. T. Theimer in Fragrance Chemistry, Academic Press, New York, (1982) p. 271].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]([S:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][Cl:23])=[CH:33][CH:32]=1)(=[O:35])=[O:36])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(OCCCCl)cc1
Reactant: COC(=O)CNCc1ccc(OC)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 30.97 g (0.148 mol) of (4-methoxy-benzylamino)-acetic acid methyl ester in 200 ml of dioxane and 200 ml of H2O, 25 ml (0.178 mol) of triethylamine a solution of 43.9 g (0.163 mol) of 4-(3-chloro-propoxy)-benzenesulfonyl chloride in 100 ml of dioxane is added at 0-5° C. The mixture is allowed to warm to r.t. and stirred for 3 h. The reaction mixture is neutralized with 1N HCl and extracted with AcOEt. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give {[4-(3-chloro-propoxy)benzenesulfonyl]-(4-methoxy-benzyl)-amino}-acetic acid methyl ester; NMR (CDCl3): 2.25-2.35 (m, 2H), 3.56 (s, 3H), 3.75 (t, 2H, J=6.04 Hz), 3.79 (s, 3H), 3.9 (s, 2H), 4.2 (t, 2H, J=6.04 Hz), 4.39 (s, 2H), 6.84 (d, 2H, J=8.56 Hz), 6.99 (d, 2H, J=9.08 Hz), 7.16 (d, 2H, J=9.08 Hz), 7.83 (d, 2H, J=8.56 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:7]([O-:9])=[O:8])=[CH:4][S:5][CH:6]=1.[Li+].[Cl:11]N1C(=O)CCC1=O>O.CC(O)C>[CH3:1][C:2]1[C:3]([S:7]([Cl:11])(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cscc1S(=O)[O-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cscc1S(=O)(=O)Cl
Temperature: 20 °C
Reaction time: 1.17 h

Procedure:
To 34 g of lithium 4-methyl-3-thiophenesulfinate in 220 ml of water cooled to 10° C. was added a suspension of 26.7 g of N-chlorosuccinimide in 80 ml of 2-propanol portionwise during 5 minutes. An additional 75 ml of 2-propanol was added to dissolve the reagents and the mixture was stirred for 70 minutes at 20° C. A large excess (1 liter) of water was then added and the mixture was extracted with methylene chloride 3 times. The methylene chloride portions were combined, dried over sodium sulfate and the solvent removed in vacuo to yield 4-methyl-3-thiophenesulfonyl chloride. This product was dissolved in 100 ml of tetrahydrofuran and 70 ml of concentrated aqueous ammonia was then added, and the mixture stirred overnight. Concentration of the resultant solution in vacuo and dilution of the residue with water yielded a solid which was filtered, washed with water and stirred with hot 1-chlorobutane, cooled and filtered to yield 14 g of the desired solid compound, m.p. 73°-85°.
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1CO.[CH:35]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:35][C:31]4[CH:32]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][N:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(O)cn2)o1)C1CCCCC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ccccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(OCc3cccnc3)cn2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 34.2 %

Procedure:
To a solution of 5-(5-hydroxy-pyridin-2-yl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (170 mg, 0.47 mmol.), 2-pyridine methanol (103 mg, 0.95 mmol) and PPh3 (supported on polystyrene resin, 320 mg 0.95 mmol) in THF (2 mL) is added DIAD (0.18 mL, 0.95 mmol) dropwise at 0° C. under argon. The mixture is allowed to warm to room temperature, stirred for 19 hours, diluted with THF, and filtered through celite. The filtrate is evaporated in vacuo, and the crude material is purified on reverse phase HPLC to yield a white solid 72 mg, 34%, LC/MS ESI m/z (M+H)+=449.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=O)=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.Cl.[NH2:36][OH:37].O>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](/[CH:12]=[N:36]\[OH:37])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2
Reactant: NO
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C=O)n4)ncnc32)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(/C=N\O)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde 5 (270 mg, 0.57 mmol, 1.0 eq) and hydroxylamine hydrochloride (495 mg, 7.1 mmol, 13 eq) in pyridine (4 mL) and MeOH (20 mL) was stirred at RT overnight. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product, (S,Z)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde oxime (240).
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:10]([NH:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH3:1])=[CH:18][CH:19]=1
Reactant: [Li]C
Reactant: Fc1ccc(C(=Nn2cncn2)c2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: CC(Nn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 10 mL (1.5M, 150 mmol) of methyllithium in 30 mL of tetrahydrofuran was cooled to -78° C. A solution of 2.0 g (7.0 mmol) of N-[bis(4-fluorophenyl)methylene]-1H-1,2,4-triazol-1-amine in 10 mL tetrahydrofuran was added dropwise. The solution was stirred 10 min. quenched with saturated ammonium chloride and warmed to room temperature. Dilution with ethyl acetate, washing with water and brine, drying (MgSO4) and removal of solvent gave product as a viscous oil. Chromatography on silica gel (10:1 methylene chloride-acetate) gave of desired product as a white solid; yield 1.1 g, mp 114°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][CH:20](N)[CH2:19][CH2:18]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:26]([N:28](CC)CC)[CH3:27].C(Cl)(=[O:35])C.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C@H:17]4[CH2:18][CH2:19][C@H:20]([CH2:27][C:26]([NH2:28])=[O:35])[CH2:21][CH2:22]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: NC1CCC(CCN2CCC(c3noc4cc(F)ccc34)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)C[C@H]1CC[C@H](CCN2CCC(c3noc4cc(F)ccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine (0.03 g, 0.087 mmol) is suspended in dichloromethane (0.600 mL) and triethylamine is added (0.013 mL, 0.096 mmol) followed by acetylchloride (0.008 mL, 0.104 mmol) and the mixture was stirred for 30 minutes at room temperature until TLC indicated the end of the reaction. Sodium bicarbonate solution was added until pH 9 and the reaction extracted 3 times with dichloromethane. The organic phase was dried and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 0.022 g (0.056 mmol, 65% yield) of a white solid. MS (m/e): 388.5 (M+H+).
Reaction SMILES: CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH2:31][CH2:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[CH2:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][C:46]1=[O:51])[CH3:44]>CN(C=O)C.C(Cl)Cl>[CH2:43]([N:45]1[CH2:50][CH2:49][N:48]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH2:31][CH2:32][C:33]5[N:34]([C:36]([C:39]([F:41])([F:40])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:47][C:46]1=[O:51])[CH3:44]
Reactant: CS(=O)(=O)OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CCN1CCNCC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
DIPEA (0.219 mL, 1.23 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (200 mg, 0.41 mmol) and 1-ethylpiperazin-2-one (52.6 mg, 0.41 mmol) in DMF (5 mL) at 20° C. under nitrogen. The resulting solution was stirred at 110° C. for 3 hours and the solvent was removed in vacuo to give an orange gum, which was dissolved in DCM (100 mL) and the solution washed with water (100 mL). The organic layer was passed through a phase separating cartridge and then evaporated to dryness to give an orange gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane then 10% methanolic ammonia in EtOAc. Pure fractions were evaporated to dryness to afford a yellow gum, which was triturated with ether to give 1-ethyl-4-[2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one (77 mg, 36.1%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[C:5]([O:9][C:10]([NH:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[C:15]([OH:17])=[O:16])=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl>C(OCC)(=O)C.O.O1CCCC1>[C:5]([O:9][C:10]([N:12]([CH3:3])[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[C:15]([OH:17])=[O:16])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CI
Reactant: COc1ccc(Cl)cc1C[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1C[C@@H](CN(C)C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 60% mineral oil dispersion of sodium hydride (1.9 g) in a tetrahydrofuran (50 ml) solution, methyl iodide (2.7 ml) was added under ice cooling, then the (2S)-3-[(tert-butoxycarbonyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoic acid (5 g), described in WO 06-059801A, in a tetrahydrofuran (20 ml) solution was slowly added, then the mixture was stirred at room temperature for 72 hours. To the reaction solution, water (50 ml) and ethyl acetate (20 ml) were added and the layers were separated. The organic layer was extracted with water (20 ml) and was combined with the aqueous layer previously obtained, and acidified (pH2) with 6M hydrochloric acid. This aqueous mixture was extracted with ethyl acetate, then the combined extract was washed with water, saturated aqueous sodium thiosulfate solution, and brine. The organic layer was dried over sodium sulfate, then concentrated to obtain (2S)-3-[tert-butoxycarbonyl(methyl)amino]-2-(5-chloro-2-methoxybenzyl)propanoic acid (5.28 g) (compound S17a).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[OH-:13].[Na+].[NH2:15]O.Cl>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N:15][OH:13]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccccc1C(F)(F)F
Reaction time: 3 h
Yield: 85.5 %

Procedure:
2-(trifluoromethyl)benzaldehyde (34.82 g, 200.0 mmol) was dissolved in ethanol (200 mL), and added with sodium hydroxide (12.00 g, 300.0 mmol) dissolved in purified water (50 mL). Hydrochloric acid hydroxylamine (16.68 g, 240 mmol) dissolved in purified water (50 mL) was added thereto, followed by stirring for 3 hours. After the reaction was completed, the resultant product was added with ice. The produced solid was filtered, washed with purified water (600 mL), and dried so as to provide a white solid required compound (32.15 g, 171 mmol, 85%).
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:4](=[NH:8])[O:5]CC.[O:16]1CCC[CH2:17]1>C1(C)C=CC=CC=1>[CH3:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:3]1[O:2][C:17](=[O:16])[NH:5][C:4]1=[O:8]
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1ccccc1C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccccc1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 3, ethyl 1-hydroxy-1-(2-methylphenyl)methanecarboximidate hydrochloride (14.4 g.) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-methylphenyl) oxazolidine-2,4-dione (9.1 g., 77%, m.p. 111°-113° C., m/e 191).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: OCCCCCCN1CCCc2ccccc21
Temperature: 25 °C

Procedure:
A stirred solution of 133.2 g (1 mole) of 1,2,3,4-tetrahydroquinoline, 181.1 g (1 mole) of 6-bromohexanol, and 138.2 g (1 mole) of potassium carbonate in toluene is heated at 80° C. for 3 hours. The solution is cooled to room temperature, and the solids are removed by filtration. The solvent is removed in vacuo, and the N-hydroxyhexyltetrahydroquinoline is purified by chromatography (silica gel, hexane:ethyl acetate).