Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:6][C:7]=1[CH:8]([OH:10])[CH3:9])[CH3:2].[CH3:21][O:22][C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][C:27]=1[CH3:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:21][O:22][C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:10][CH:8]([C:7]2[O:6][C:5]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:4][C:3]=2[CH2:1][CH3:2])[CH3:9])=[CH:28][C:27]=1[CH3:33]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)Oc1ccc(CCC(=O)OC)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 1-[4-ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.114 g, 0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.0789, 0.400 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine (0.200 mL, 0.800 mmole) followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.800 mmole) in toluene (2 mL). The reaction is stirred overnight, then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0–15%) and concentrated to provide the titled compound as a white solid. Mass [EI+] 462 (M+H)+.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:30][C:31]1[CH:42]=[CH:41][C:34]([CH2:35][O:36][CH2:37][CH:38]([NH2:40])[CH3:39])=[CH:33][CH:32]=1>C(Cl)Cl.O>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][O:36][CH2:37][CH:38]([NH:40][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:39])=[CH:41][CH:42]=1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(N)COCc1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Solvent: O
Product: CC(COCc1ccc(Cl)cc1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
0.5 g of N-methylpiperidine was added to a solution containing 1 g of N-isopropoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 15 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40° C., and stirred for 1 hour at -20° C. 1 g of 2-(4-chlorobenzyloxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained oily residue was purified by column chromatography on silica gel, thus obtaining 0.9 g of the desired product in the form of a colorless plated crystal (yield: 48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[BH3-]C#N.[Na+]>CO.CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)C=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)CCc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of [2-(3-fluoro-4-nitro-phenyl)-vinyl]-dimethyl-amine (1.7 g, 8 mmol) in MeOH, was added NaBH3CN (770 g, 12 mmol) and one drop of AcOH. The reaction mixture was stirred at room temperature for 2 hours and quenched with water. After removal of all volatiles in vacuo, the residue was extracted with 10% methanol in DCM twice. The combined extracts were washed with brine, dried over anhydrous sodium sulfate. Concentration under vacuum gave a crude product, which was purified by reverse phase column to afford the title compound (1.08 g, yield: 63%). MS (ESI): 213 [M+H]+
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([F:23])([F:34])[F:35])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 95 %

Procedure:
To a stirred solution of 1-Boc-piperazine (1.960 g, 10.50 mmol) and diisopropylethylamine (2.714 g, 21 mmol, 3.63 mL) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.086 g, 10.00 mmol) dropwise. The resulting mixture was stirred at ambient temperature for 1 minute and then quenched with water (25 mL). The organic phase was separated and washed with H2O, brine, dried over MgSO4 and then concentrated in vacuo to afford product 4-(2-trifluoromethylbenzoyl)-piperazine-1-carboxylic acid tert-butyl ester as pale yellow solid. Yield 95%, 3.575 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35](=[O:43])([O:39][CH:40]([CH3:42])[CH3:41])[O:36][CH2:37]I>CC(C)=O>[C:35](=[O:43])([O:39][CH:40]([CH3:42])[CH3:41])[O:36][CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: CC(C)OC(=O)OCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)OC(=O)OCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To (+)-3-hydroxy-N-(benzyloxycarbonyl)morphinan (33.0 g, 87.4 mmol) and cesium carbonate (28.5 g, 87.4 mmol) in acetone (450 mL) was added iodomethyl isopropyl carbonate (21.3 g, 87.4 mmol) (see Rigel Pharmaceuticals, Inc. US2006/247287 A1, Appl.; US2006-381215 (2006 May 2)) at room temperature. The reaction mixture was stirred vigorously at room temperature overnight. The acetone was then removed by rotary evaporation under vacuum. To the residue was added saturated NaHCO3 solution. The mixture was extracted with EtOAc (300 mL×2). The combined organics were washed with 1N HCl solution (300 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide the title compound (42.0 g, 97%) as a yellow gum.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.O1CCCNCC1.[C:16]([OH:23])(=[O:22])/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20]>CO>[C:16]([OH:23])(=[O:22])/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20].[OH:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: OCC1CNCCO1
Agent: C1CNCCOC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: OC[C@H]1CNCCO1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-hydroxymethylmorpholine and 1,4-oxazepane compound (20.0 g, 2-hydroxymethylmorpholine:1,4-oxazepane compound=75.8:24.2) synthesized in Example 5 were added methanol (100 ml) and maleic acid (17.5 g, 0.151 mol) and the mixture was stirred for 30 min. Methanol was evaporated under reduced pressure. To the residue was added 2-propanol (50 ml) and the mixture was subjected twice to azeotropic distillation with dehydrating. To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C., and the mixture was cooled to 10° C. After crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (25 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine maleate (13.8 g) (2-hydroxymethylmorpholine:maleic acid=1:1, yield from (S)-epichlorohydrin: 39.2%). The obtained (R)-2-hydroxymethylmorpholine maleate was analyzed by HPLC to find an optical purity of 99% ee.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:5][CH:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+].C(OC(=O)C)C>O1CCOCC1.O.CCCCCC>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([N:16]=[N+:17]=[N-:18])=[O:12])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 120 %

Procedure:
3-(4-Trifluoromethyl-phenyl)-acryloyl chloride (I-29b: 4.5 g, 0.019 mol) in 1,4-dioxane (20 mL) was added to a stirred mixture of sodium azide (2.7 g, 0.042 mol) in water (10 mL) at 0° C. under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for 20 minutes under nitrogen atmosphere. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was partitioned between water and diethyl ether. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 5.5 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]#[N:18])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)[CH:7]=1.Br[CH:20]([CH3:24])[C:21]([OH:23])=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]#[N:18])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][N:11]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])[C:12](=[O:14])[CH:13]=2)[CH:7]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C#N
Reactant: CC(Br)C(=O)O
Product: CC(C(=O)O)n1cc(C#N)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
312 mg (purity 91%, 1.11 mmol) of 4-(5-chloro-2-cyanophenyl)-6-oxo-1,6-dihydropyridin-3-carbonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 45° C. Yield: 240 mg (purity 85%, 56% of theory)
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].BrBr.N(CCO)(CCO)CCO.[NH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:27]([OH:29])=[O:28])=[N:23][C:24]=1[O:25][CH3:26].[Na]>CO.C(O)C.O.C(OCC)C>[C:1]([CH:2]1[CH2:3][N:17]1[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:27]([OH:29])=[O:28])=[N:23][C:24]=1[O:25][CH3:26])#[N:4]
Reactant: COc1nc(C(=O)O)ccc1CN
Reactant: C=CC#N
Agent: BrBr
Agent: [Na]
Solvent: CO
Solvent: OCCN(CCO)CCO
Solvent: CCOCC
Product: COc1nc(C(=O)O)ccc1CN1CC1C#N
Reaction time: 0.08 h

Procedure:
2.33 g. (44 mmol) acrylonitrile are diluted with 1 ml. diethyl ether and, while stirring and illuminating, 7.05 g. (44 mmol) bromine are added dropwise thereto. The mixture is occasionally cooled in order to ensure that the internal temperature does not exceed 40° C. Stirring is continued for a further 5 minutes, the reaction mixture is diluted with 60 ml. methanol and a solution of 6.55 g. (44 mmol) triethanolamine in 60 ml. methanol is added dropwise thereto. After a further hour, there are simultaneously added dropwise thereto a solution of 6.55 g. (44 mmol) triethanolamine in 60 ml. methanol and a solution of 8 g. (44 mmol) 5-aminomethyl-6-methoxypyridine-2-carboxylic acid (m.p. 269°-270° C. (decomp.)) in 1 liter methanol/200 ml. water. The solution is left to stand for 24 hours, then evaporated substantially on a rotary evaporator and the aqueous solution adjusted with 2N hydrochloric acid to a pH of 4.5, followed by extracting continuously for 2 days with methylene chloride. The methylene chloride phase is then dried and evaporated to give 4.8 g. of an oil which is dissolved in 50 ml. ethanol. While cooling, the solution is mixed with a solution of 440 mg. sodium in 15 ml. ethanol. The sodium salt of 5-[(2-cyano-1-aziridinyl)-methyl]-6-methoxypyridine-2-carboxylic acid precipitates out and, after the addition of 100 ml. isopropanol, it is filtered off with suction, dried and washed with diethyl ether to give 3.7 g. (33% of theory) of the desired compound; m.p. 230°-232° C.
Reaction SMILES: O.CO.CN([C:7]1[CH:12]=[CH:11][C:10]2[C:13]3CCC[C:14]=3[C:18]([O:20][C:9]=2[CH:8]=1)=[O:19])C.CCOC(C1C(=O)OC2C(=CC3CCCN4C=3C=2CCC4)C=1)=O.C1C(CN)CCC(C(O)=O)C1>ClCCl.C(O)C>[O:20]1[C:9]2[C:10](=[CH:11][CH:12]=[CH:7][CH:8]=2)[CH:13]=[CH:14][C:18]1=[O:19]
Reactant: CN(C)c1ccc2c3c(c(=O)oc2c1)CCC3
Agent: CCOC(=O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Agent: NCC1CCC(C(=O)O)CC1
Solvent: CCO
Solvent: O
Solvent: CO
Product: O=c1ccc2ccccc2o1

Procedure:
To a vigorously stirred 200 mL suspension 0.282 micrometer carboxylate-modified latex (Interfacial Dynamics Corp., Portland, Oreg.; 2.75% solids in 50% v/v distilled water/methanol) is added a solution of 30 mg of Coumarin 138 (Eastman Kodak, Rochester, N.Y.) and 30 mg of Coumarin 314 (Eastman Kodak) dissolved in a homogeneous mixture of 7.5 mL of dichloromethane and 17.5 mL of absolute ethanol. The addition of the dye and purification of the product is carried out as described in EXAMPLE 3. Visual analysis of a dilute aqueous suspension of the product by fluorescence microscopy using standard AMCA excitation and emission filters shows uniformly dyed particles that are highly monodisperse. Spectral analysis of the product, exciting at 360 nm shows an emission peak centered at 410 nm and an emission peak centered at 460 nm. The integrated ratio of the 460 nm peak (from coumarin 314) to the 410 peak (from coumarin 138) is 92:8, indicating efficient transfer of emission energy from coumarin 138 to coumarin 314.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([NH:18][C:19](=O)[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1>[Fe].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:19]([CH3:20])[NH:18][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])c(NC(C)=O)c2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc3nc(C)[nH]c3c2)cc1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 76.9 %

Procedure:
A mixture of N-(4′-methoxy-4-nitrobiphenyl-3-yl)acetamide (500 mg), acetic acid (6 ml) and iron powder (308 mg) was stirred at 100° C. for 50 minutes, and then cooled to room temperature, and insoluble matter was removed by filtration using celite. A saturated sodium carbonate aqueous solution was added to the filtrate to render the liquid about pH 7, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 5-(4′-methoxyphenyl)-2-methylbenzimidazole (320 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.[NH3:25]>CO>[CH3:24][N:6]1[C:5]([C:3]([NH2:25])=[O:2])=[CH:9][C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)nn1C
Reactant: N
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(N)=O)n(C)n1
Yield: 20 %

Procedure:
As described for example 42e, 2-methyl-5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (170 mg, 0.52 mmol) was converted, using ammonia in methanol instead of ethanolamine, to the title compound (32 mg, 20%) which was obtained as a white solid. MS: m/e=313.1 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH:20]([CH:26]([CH3:31])[C:27](=O)[CH2:28][CH3:29])[C:21]([O:23]CC)=[O:22]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:28]([CH3:29])=[C:27]2[CH:26]([CH3:31])[CH:20]([CH3:19])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)C(C)C(C)C(=O)CC
Agent: Cl
Product: Cc1c(C(C)C(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[4-chlorobenzyl]-1-(4-fluorophenyl) hydrazine hydrochloride and ethyl 2,3-dimethyl-4-oxohexanoate as starting materials, the title compound was prepared.
Reaction SMILES: [NH2:1]C1C=CC=CC=1.[C:8]12[C:17](=[O:18])O[C:14](=[O:15])[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13]2.O>C(O)(=O)C>[C:17]1(=[O:18])[NH:1][C:14](=[O:15])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]1=2
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C2=C1CCCC2

Procedure:
4.5 g (0.017 mole) of the above aniline and 2.7 g (0.018 mole) of cyclohexene-1,2-dicarboxylic anhydride in 70 ml of glacial acetic acid are stirred for 3 hours at 70° C. After the mixture has been cooled, 100 ml of water are added and the precipitate is filtered off, washed with water and dried. 3.5 g (52%) of N-[4-tetrahydropyran-4-ylmethyl)-3,3-dihydro-2H-1,4-benzoxazin -3-on-6-yl]-3,4,5,6-tetrahydrophthalimide (mp. 187-189° C.) are obtained.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([CH3:16])=[N:14][NH:15][C:7]=12>C1(C)C(C)=CC=CC=1>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([CH3:16])=[N:14][NH:15][C:7]=12
Reactant: Cc1cc(Cl)c2[nH]nc(C)c2n1
Reactant: NCCO
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCO)c2[nH]nc(C)c2n1
Yield: 66 %

Procedure:
A mixture of ethanolamine (1.0 g, 0.016 mole) and 7-chloro-3,5-dimethyl-1H-pyrazolo[4,3-b]pyridine (1.0 g) in dry xylene (20 ml) was heated under reflux for 48 h. After cooling, the brown oil in the reaction vessel solidified. The solvent was then decanted off and the solid washed several times with xylene. The brown solid was dissolved in aqueous methanol and the pH adjusted to pH 8-9 with 10% sodium carbonate solution. The resulting solid was filtered off, dried and recrystallised from chloroform/methanol to give the title compound as a white solid (0.750 g, 71%), m.p. 225°-230° C. (Found: C, 58.29; H, 6.89; N, 27.06. C10H14N4O requires C, 58.18; H, 6.84; N, 27.17%).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)C.[OH-].[Na+]>C(O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:21])=[O:3])=[C:6]([NH:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:7]=1)([O-:13])=[O:12]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1NC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc([N+](=O)[O-])cc1NC1CCOCC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
4-Nitro-2-(tetrahydro-pyran-4-ylamino)-benzoic acid ethyl ester (11.2 g, 38 mmol) was dissolved in 200 mL of ethanol at 60° C. then 2N NaOH was added (40 mL, 80 mmol). The mixture was stirred at 60° C. for 4 hours, then the solvent removed under reduced pressure. The residue was taken-up with 200 mL of water and the mixture brought to acidic pH with 2N HCl (35 mL). The precipitated yellow solid was filtered, washed with plenty of water and dried in oven at 40° C. affording the title compound (9.3 g).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][NH2:9])=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](O)=[O:24].CCN=C=NCCCN(C)C>C1COCC1>[Br:1][C:2]1[O:6][C:5]([CH:7]([S:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][NH:9][C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccn1
Reactant: NCC(Sc1ccccc1)c1ccc(Br)o1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: O=C(NCC(Sc1ccccc1)c1ccc(Br)o1)c1ccccn1

Procedure:
2-(5-Bromofuran-2-yl)-2-phenylsulfanylethylamine (0.28 g, 0.0009389 mol), 2-pyridinecarboxylic acid (0.12 g, 0.001005 mol) and EDCI were stirred in dry THF (10 ml). After disappearing of the starting material the solvent was evaporated. Then chloroform was added and the solution was washed with 1 M Na2CO3 and water, dried with Na2SO4 and evaporated. The crude product was purified by flash chromatography using heptane-EtOAc as a gradient eluent (85:15-70:30). 1H NMR (400 MHz, DMSO-d6): 3.75-3.80 (2H, m), 4.78-4.84 (1H, m), 6.33-6.37 (2H, m), 6.44 (1H, d), 7.26-7.40 (4H, m), 7.59-7.62 (1H, m), 7.97-8.04 (2H, m), 8.62-8.64 (1H, m), 9.08 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.CCCCCCC>C1COCC1>[OH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:10])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87.8 %

Procedure:
To a cooled (0° C.) solution of (S)-methyl 4-(1-(tert-butoxycarbonylamino)ethyl)benzoate (6.35 g, 22.7 mmol) in THF (114 mL) was added a solution of LAH in THF (2.0 M, 13.64 mL, 27.3 mmol) and the resulting mixture was stirred at room temperature for 40 min. The reaction mixture was quenched by addition of a 1N NaOH solution until gas evolution ceased. The reaction mixture was filtered, washed with EtOAc. After separation, the aqueous phase was washed with EtOAc (2×150 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 0 to 100%) provided (S)-tert-butyl 1-(4-(hydroxymethyl)phenyl)ethylcarbamate as a white solid (5.01 g, 84% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:23][CH:22]2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=3[CH:53]=2)=[CH:17][CH:16]=1)=O.B#B.O1CCCC1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:23][CH:22]2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]3[O:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:43]=3[CH:53]=2)=[CH:19][CH:20]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)Cc4ccccc4F)cc3)cc21
Agent: B#B
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNCCc4ccccc4F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.455 g of benzyl 4-(4-{2-[2-(2-fluorophenyl)acetylamino]ethoxy}phenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benz[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 5 ml of tetrahydrofuran is admixed at 0° C. with 1.84 ml of diborane-tetrahydrofuran complex (1M solution in tetrahydrofuran). The reaction solution is subsequently heated to reflux over 3 hours. The reaction solution is cooled to room temperature, quenched with 2 ml of methanol and finally admixed with 2 ml of 2M HCl. The mixture is stirred at room temperature over 30 minutes, neutralized with 20 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with 3×20 ml of ethyl acetate. The combined organic phases are washed with 20 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F). Rf=0.52 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.83.