Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:18]#[C:19]Br>C1COCC1>[CH3:5][C:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][O:4][C:19]([NH2:18])=[N:1]1
Reactant: N#CBr
Reactant: CC(N)(CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)COC(N)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a stirred, cooled (0° C.) mixture of 2-amino-2-phenyl-propan-1-ol (266 mg) and K2CO3 (292 mg) in THF (5 ml) under an argon atmosphere was added a solution of cyanogen bromide (292 mg) in THF (5 ml). The ice bath was removed and stirring at r.t. was continued for 18 h. The mixture (white suspension) was taken up in EtOAc/H2O 1:1. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 4-methyl-4-phenyl-4,5-dihydro-oxazol-2-ylamine (204 mg) as white solid. MS (ISP): 177.1 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH:23]([CH2:27]Br)[C:24]([NH2:26])=[O:25]>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][CH2:13][N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]([C:24]([NH2:26])=[O:25])[CH2:27]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: NC(=O)C(Br)CBr
Reactant: COc1cc(NCCNCc2ccccc2)cc(OC)c1
Product: COc1cc(OC)cc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-(3,5-dimethoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine with 2,3-dibromopropanamide to obtain the title compound.
Reaction SMILES: [I-].[CH3:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[CH2:5][CH2:6][N+](C)(C)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[S:24])[S-:23])=[N:19][CH:20]=1.C([NH+](CC)CC)C.O>C(#N)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[S:23])[S:24][CH2:6][CH2:5][C:4](=[O:11])[C:3]([CH3:2])([CH3:12])[CH3:13])=[N:19][CH:20]=1
Reactant: CC(C)(C)C(=O)CC[N+](C)(C)C
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Agent: CC[NH+](CC)CC
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 6 h
Yield: 60.1 %

Procedure:
4,4-Dimethyl-3-oxopentyltrimethylammonium iodide (6.0 g) is added, at 20° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (6.1 g) in anhydrous acetonitrile (25 cc). The reaction is allowed to proceed for 6 hours at 20° C. Distilled water (25 cc) is added. The crystals which appear are filtered off, washed three times with distilled water (total 30 cc) and dried in air at 20° C. The product obtained (5.1 g; m.p.=110° C.) is recrystallised from acetonitrile (15 cc). 4,4-Dimethyl-3-oxopentyl 5-chloropyrid-2-yldithiocarbamate (3.8 g), which melts at 111° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Br:17])[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:19].[Li+]>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH2:16][C:15]1[C:14]([Br:17])=[CH:13][CH:12]=[CH:11][C:10]=1[C:9]([OH:18])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C1=O
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1c(Br)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a stirred solution of 4-bromo-1-oxo-1,3-dihydro-isoindole-2-carboxylic acid tert butyl ester (0.206 g, 0.66 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of aq. lithium hydroxide (1M, 2 ml, 1.98 mmol) and the mixture stirred at room temperature under nitrogen for 18 hours. The mixture was diluted with diethyl ether (30 ml) and washed with 1M HCl (10 ml). The aqueous layer was extracted with diethyl ether (2×20 ml) and the combined organics dried over magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure to give the title compound (0.188 g, 86%) as a white waxy solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(C#N)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C#N)ccc1-c1ccc(C(F)(F)F)cc1
Yield: 94.8 %

Procedure:
A mixture of 4-bromo-3-methoxybenzonitrile (500 mg, 2.36 mmol), 4-(trifluoromethyl)phenyl boronic acid (671.9 mg, 3.54 mmol) and potassium fluoride (411 mg, 7.08 mmol) in toluene (11 mL) and water (3 mL) was purged with nitrogen. Pd(PPh3)4 (272.7 mg, 0.236 mmol) was added. The resulting mixture was heated at reflux overnight. The reaction mixture was washed with water (200 ml) and extracted with ethyl acetate (150 mL*4). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-methoxy-4′-(trifluoromethyl)biphenyl-4-carbonitrile (620 mg) as a colorless solid. 1HNMR (400 MHz, CDCl3) δ 7.68 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.36-7.40 (m, 2H), 7.22 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I[CH3:21].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([C:17](=[O:19])[CH3:18])[CH3:21])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(NC(C)=O)c2c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(N(C)C(C)=O)c2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
To 4-acetylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (300 mg, 1.15 mmol, 1 eq, prepared according to Example 48, Step 1) under nitrogen was added 5 mL of DMF, iodomethane (79 uL, 1.26 mmol, 1.1 eq), and sodium hydride (60%, 51 mg, 1.26 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 4 h. After work up and flash column chromatography (5-40% ethyl acetate/hexanes), 4-(acetyl-methyl-amino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 35% yield (112 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.2 Hz, 3 H) 1.7 (s, 3 H) 2.5 (s, 3 H) 3.2 (s, 3 H) 4.4 (m, 2 H) 7.3 (dd, J=7.6, 0.8 Hz, 1 H) 7.6 (dd, J=8.5, 7.7 Hz, 1 H) 7.8 (dd, J=8.5, 0.9 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[CH2:13][C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[N:22]=2)[CH:17]=[N:16][CH:15]=1)=[O:5].O.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[CH2:13][C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[CH:24][NH:23][N:22]=2)[CH:17]=[N:16][CH:15]=1)=[O:5]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CN3C[C@@H]4C[C@H]3CN4C(=O)c3cccc(Cl)c3Cl)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(c1cccc(Cl)c1Cl)N1C[C@@H]2C[C@H]1CN2Cc1cncc(Nc2cc[nH]n2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
19 mg of 6-(((1S,4S)-5-(2,3-dichlorobenzoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazine-2-amine was dissolved in 1 ml of trifluoroacetic acid and 0.1 ml of water followed by stirring at room temperature for 15 hours. The reaction solution was concentrated in vacuo, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate, water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=5/1) to give the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9](C)C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[Br:12]CC(OC(C)(C)C)=O.C(OCC)C>C(#N)C>[Br:12][C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH2:7][CH2:8][NH2:9])=[O:5]
Reactant: C=C(C)C(=O)OCCN(C)C
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(Br)C(=O)OCCN

Procedure:
5 g 2-(Dimethylamino)ethyl methacrylate and 8.68 g tert-butyl bromoacetate were reacted in 20 ml acetonitrile for 24 h at 50° C. under N2 protection. Upon addition of 250 ml ethyl ether to the reaction mixture, the formed white crystals were isolated and dried. The resulting CB-tBu monomers were immediately stored in a desiccator at −20° C. (yield 96%). 1H NMR (D2O) δ (ppm): 1.44 (s, 9H, —OC(CH3)3), 1.87 (s, 3H, CH2═C(CH3)COO—), 3.31 (s, 6H, —CH2N(CH3)2CH2COO—), 3.98 (t, J=3 Hz, 2H, CH2═C(CH3)COOCH2CH2N(CH3)2CH2—), 4.28 (s, 2H, —CH2N(CH3)2CH2COO—), 4.60 (t, J=3 Hz, 2H, CH2═C(CH3)COOCH2CH2N(CH3)2CH2—), 5.73 and 6.10 (s, 2H, CH2═C(CH3)COO—).
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([CH3:24])[C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one [starting material (SM) prepared according to WO09/049,851] (500 mg, 1.58 mmol) in tetrahydrofuran (20 ml) at 0° C. was added a 1.0 M lithium bis(trimethylsilyl)amide solution in hexanes (3.32 ml, 3.32 mmol) dropwise over 15 minutes. The mixture was stirred one hour at 0° C., treated with methyl iodide (0.099 ml, 225 mg, 1.59 mmol) dropwise over 10 minutes, and further stirred at 0° C. for 30 minutes and at room temperature for one hour. The reaction mixture was quenched over cold saturated aqueous ammonium chloride and extracted with tert-butyl methyl ether (3×), the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue (210 mg) was suspended in hexane, stirred at room temperature for 10 minutes, filtered and dried. Yield: 171 mg of a clean mixture of starting material (SM) and 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a beige solid. 1H-NMR and LC-MS analysis of the crude material indicated a ˜1:2.5 ratio of this mixture SM/compound P2.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH2:20][CH2:21][S:22][CH2:23][CH2:24][OH:25])[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[CH3:26][Si](C=[N+]=[N-])(C)C>CCOCC.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH2:20][CH2:21][S:22][CH2:23][CH2:24][OH:25])[C:17]([O:19][CH3:26])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(CCSCCO)C(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)NC(CCSCCO)C(=O)OC)cc1

Procedure:
To a solution of 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(2-hydroxyethyl)sulfanyl]butanoic acid (20.8 g) in ether and methanol was dropwise added trimethylsilyidiazomethane (25 mL. 2.0 M in hexanes). The reaction mixture was concentrated in vacuo and the resulting oil was chromatographed on silica gel eluting with hexane/ethyl acetate to give methyl 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(2-hydroxyethyl)sulfanyl]butanoate as a light yellow oil (6.68 g). Electrospray Mass Spec 401.9 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:22](OCC)(=[O:25])[CH:23]=[CH2:24]>CCO.C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:24][CH2:23][C:22](=[O:25])[NH:17]2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CCN(c2ccc(OCc3ccccc3)cc2)N1
Temperature: 85 °C

Procedure:
To a mixture of 2.5 g of 4-benzyloxyphenylhydrazine HCl and sodium ethoxide (1.6 g) in 10 ml of EtOH and 10 ml of toluene are added 1.08 of ethyl acrylate at room temperature. The reaction mixture is then heated at 85° C. overnight. The reaction mixture is evaporated to dryness under vacuum and water added to the residue and the pH adjusted to pH 6 by 1N-HCl solution. Extraction with ethyl acetate and drying the organic solution and evaporating to dryness yields 2.8 g of crude product. Purification by dry column chromatography gives 0.3 g of product; mp. 130°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[F:27])[NH:16][S:17]([CH2:20][C:21](O)=[O:22])(=[O:19])=[O:18]>C(O)(=O)C>[NH2:12][C:13]1[CH:14]=[C:15]([NH:16][S:17]([C:20]2[C:21](=[O:22])[O:11][C:6]3[C:7]([CH:8]=2)=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:19])=[O:18])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: Nc1cc(NS(=O)(=O)CC(=O)O)ccc1F
Solvent: CC(=O)O
Product: COc1ccc2oc(=O)c(S(=O)(=O)Nc3ccc(F)c(N)c3)cc2c1

Procedure:
A solution of 5-methoxysalicylaldehyde (1 mmol) and 3-amino-4-fluoroanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 255-260° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[C:20]=3[CH3:28])[C@H:15]2[O:17][CH3:18])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:27][C:21]1[C:20]([CH3:28])=[C:19]([C:14]2[C@@H:15]([O:17][CH3:18])[C@@H:16]3[C@@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[N:13]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-((3S,3aR,4S)-4-(tert-butyldimethylsilyloxy)-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (400 mg, 0.954 mmol) in THF (10 mL) at 0° C. was added tetra butyl ammonium fluoride (1.9 mL, 1.909 mmol, 1M solution in THF) and the reaction mixture was stirred at room temperature for 3 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over Na2SO4 and concentrated to get the crude product. The product was purified by column chromatography over silica gel using 2% MeOH in DCM as solvent to provide the title compound. The absolute stereochemistry was confirmed by X-ray crystallography.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH3:27])[NH:19][C:18]([CH3:28])=[C:17]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[C:34]1([O:40][CH2:41][CH:42]2[O:44][CH2:43]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO>[OH:44][CH:42]([CH2:41][O:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:43][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH3:27])[NH:19][C:18]([CH3:28])=[C:17]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCC(O)COc1ccccc1
Yield: 31.9 %

Procedure:
In 500 ml of methanol were dissolved 5.2 g of diethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 1.7 g of glycidyl phenyl ether, and the solution thus formed was refluxed under heating for 16 hours. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chlroform-methanol (95:5 v/v). Crude crystals were recrystallized from ethanol to give 2.2 g of diethyl 4-[2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: BrC1C=CC(O[CH2:7][C:8]2([CH3:19])[O:12][C:11]3=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]3[CH2:9]2)=CC=1.[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:34][C@H:33]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:32][C:31]2=[O:40])[CH:26]=[CH:27][C:28]=1[OH:29]>>[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:34][CH:33]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:32][C:31]2=[O:40])[CH:26]=[CH:27][C:28]=1[O:29][CH2:7][C:8]1([CH3:19])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9]1
Reactant: CC1(COc2ccc(Br)cc2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(O)c(F)c2)C(=O)O1
Product: CC(=O)NCC1CN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by following the same procedure as described in the preparation of Example 36, 2-(4-Bromo-phenoxymethyl)-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole (prepared similarly as described by Sasaki, H. et al: Journal of Medicinal Chemistry (2006), 49(26), 7854-7860), except N-[3-(3-fluoro-4-hydroxy-phenyl)-2-oxo-oxazolidin-5(S)-ylmethyl]-acetamide was used in the place of 4-bromophenol. The product isolated as a solid. ESI MS m/z 450 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12](Cl)=[CH:11][C:10]=2[CH3:16])=[CH:5][CH:4]=1)#[N:2].[C:17]([O:21][CH3:22])(=[O:20])[NH:18][NH2:19]>C(O)CCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:19][NH:18][C:17]([O:21][CH3:22])=[O:20])=[CH:11][C:10]=2[CH3:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1
Reactant: COC(=O)NN
Solvent: CCCCO
Product: COC(=O)NNc1cc(C)c(-c2ccc(C#N)cc2)nn1

Procedure:
A mixture of 18.0 g. of 6-(p-cyanophenyl)-5-methyl-3-chloropyridazine, 13.3 g. of methyl carbazate and 200 ml. of n-butanol is refluxed for 3 hours. The solvent is removed to give an oil which crystallizes on addition of water to give 11.9 g. of product. Recrystallization from methanol-ether gives white crystals, m.p. 191°-192° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][CH2:15][CH3:16])[CH:7](C#N)[C:6](=[O:10])N[C:4](=[O:11])[CH:3]1C#N.[OH2:17]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH2:14][CH2:15][CH3:16])[CH2:3][C:4](=[O:11])[O:17][C:6](=[O:10])[CH2:7]1
Reactant: CCCC1(C)C(C#N)C(=O)NC(=O)C1C#N
Reactant: O
Agent: O=S(=O)(O)O
Product: CCCC1(C)CC(=O)OC(=O)C1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
Following the procedure of Vogel, A. I.; J. Chem. Soc., 1934; 1758–1765: 4-Methyl-2,6-dioxo-4-propyl-piperidine-3,5-dicarbonitrile was dissolved in 50 mL of sulfuric acid and stirred for 16 hrs. Water (50 mL) was added and the solution was refluxed for 18 hrs. Upon cooling, the crystals were collected. The crystals were suspended in 10 mL of acetic anhydride. The suspension was heated to 130° C. and stirred for 16 hrs. The solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The ether fraction was treated with anhydrous magnesium sulfate and concentrated under reduced pressure to give the productMS (ESI+) for C9H14O3 m/z 171.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[C:13]([O:22][CH3:23])(=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O-])=[O:19]>>[CH3:23][O:22][C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: COc1cccc(OC)c1OC
Reactant: COC(=O)CCCCC(=O)[O-]
Product: COC(=O)CCCCC(=O)c1ccc(OC)c(OC)c1OC
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
150 g of polyphosphoric acid (Acros) was added to a mixture of 1,2,3-trimethoxybenzene (10.0 g, 59.47 mmol), and mono-methyl adipate (13.04 mL g, 89.20 mmol) in a 250 mL round bottom flask equipped with a mechanical stirrer. The reaction mixture was stirred for 2.5 h at 45° C. The reaction mixture was then poured into a 1000 mL beaker containing around 500 mL of ice, and stirred well. Tan colored product precipitated out which was then filtered and washed with water and dried under vacuum. 17.18 g (93%) of 65 was obtained, which was pure by NMR. Rf: 0.42 (40:60 EtOAc:Hexanes)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[NH:11])=[CH:5][CH:4]=1)#[N:2].C([O-])(=O)C.[Na+].C([O:20][C:21](=O)[C:22](=COCC)[C:23](OCC)=O)C.O>CN1CCCC1=O>[O:20]=[C:21]1[CH:22]=[CH:23][NH:12][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[N:11]1
Reactant: N#Cc1ccc(NC(=N)N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Nc2nc(=O)cc[nH]2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of 64 g (0.4 mol) of (4-cyanophenyl)guanidine, 98.4 g (1.2 mol) sodium acetate and 76.6 g (0.44 mol) diethyl(ethoxymethylene)malonate in 600 ml N-methyl-pyrrolidinone (NMP) was heated to 100° C. and stirred for 1 hour at that temperature. 81 ml of demineralized water was added and the reaction mixture was further heated to reflux temperature. About 120 ml of the solvent was evaporated until the temperature of the reaction mixture reached the range of 155° C. to 160° C. Subsequently the reaction mixture was refluxed during 72 hours. The whole is allowed to cool to 20-25° C. and 25 g filtration aid was added. After stirring the mixture for 1 hour at 20-25° C., the precipitate was filtered off and washed with 50 ml of NMP. The solvent was distilled off under vacuum and the residue was heated to 130° C. 375 ml acetic acid was added dropwise (during 15 minutes) to the heated residue while keeping the temperature at 130° C. After addition of the acetic acid, the mixture was heated to 150° C. and stirred at that temperature for 15 minutes. Subsequently, the mixture was allowed to cool to 20-25° C. The formed precipitate was filtered off and washed with ethanol (1×250 ml and 1×100 ml). 500 ml ethanol was added to the washed precipitate and this mixture was heated and refluxed for 1 hour. After cooling to 20-25° C., the precipitate was filtered off, washed with 100 ml ethanol and dried at 50° C. under vacuum during 16 hours. Yield: 80.5 g of 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile (75.9% yield).