Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
To a mixture of 2-aminoindan hydrochloride (10.40 g), potassium carbonate (34.2 g), water (100 ml) and ethyl acetate (150 ml) is added dropwise acetyl chloride (9.68 g) under ice cooling. The mixture is stirred at 0° C. for 1.5 hour, and the ethyl acetate layer is separated, washed with aqueous saline solution, dried, and then the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate - n-hexane to give 2-acetylaminoindan (9.5 g) as colorless crystals. m.p. 126.5°-127.5° C.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4].O>CCOCC>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:3][CH3:4])=[CH:7][C:8]=1[C:12]([F:13])([F:14])[F:15]
Reactant: BrBr
Reactant: CCOc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: O
Product: CCOc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Bromine (18.2 g) was slowly added dropwise to Compound (b) (19.3 g) at room temperature, and then the mixture was stirred at room temperature for 1 hour. Water and ether were added for liquid separation, and the aqueous layer was extracted three times with ether. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 21.0 g of Compound (c).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccc(F)cc1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-fluorobenzyl chloroformate.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:31][O:32][C:33](=[O:49])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][C:35]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]>CN(C=O)C.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:49])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:13][CH2:12][C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[CH:36][C:35]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Reactant: OCc1ccc(-c2ccccc2)o1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCc2ccc(-c3ccccc3)o2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
The 5-phenyl-2-hydroxymethylfuran prepared in Example 327B (345 mg, 1.98 mmol) was dissolved in 5 mL of dry DMF and NaH (50 mg, 1.98 mmol) was added followed by 15-crown-5 (436 mg, 1.98 mmol) and the reaction stirred for 5 minutes at ambient temperature. To the reaction was then added 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (659 mg, 2.40 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3×) and brine (3×), dried over Na2SO4, filtered, evaporated and purified by flash chromatography (15% ethyl acetate-hexanes) to give the desired compound (670 mg, 82%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:3]=1[C:29](=[O:31])[CH3:30].Br[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.CCN(C(C)C)C(C)C>C1COCC1>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH2:27][CH2:28]2)[C:3]=1[C:29](=[O:31])[CH3:30]
Reactant: BrCc1cccnc1
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)c1c(C2CCN(Cc3cccnc3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (0.049 mmol, 20 mg), 3-(bromomethyl)pyridine (0.049 mmol, 12 mg) and DIEA (0.29 mmol, 37 mg) in THF (2 mL) was stirred at room temperature overnight. Concentration and purification by prep-LC afforded 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(1-(pyridin-3-ylmethyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone: LCMS tR=2.71 Min (10 min run, UV254nm). Mass calculated for, M+ 503.24, observed LC/MS m/z 503.99 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1>ClCCl>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCCC2
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCCC2
Yield: 31.3 %

Procedure:
Synthesized as described for 52 except using a solution of 77 (1.30 g; 5.64 mmol) in anhydrous dichloromethane (11 mL), methyl 3-aminothiophene-2-carboxylate (892 mg; 5.67 mmol), pyridine (1.14 mL; 14.10 mmol) and anhydrous dichloromethane (11 mL). This afforded the desired product as yellow solid (0.62 g).
Reaction SMILES: [CH2:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH:4][CH3:5])[CH3:2].[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[CH2:4]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH:7]=1)[CH:21]=[O:22])=[CH:1][CH3:2])[CH3:5]
Reactant: CN(C)C=O
Reactant: CC=C(CC)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC=C(CC)c1ccc(F)c(C=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
A solution of 1-(1-ethyl-propenyl)-4-fluoro-benzene (15.3 g, 93.2 mmol) in THF (150 mL) at −78° C. is treated with n-BuLi (70 mL, 1.6 M). The reaction mixture is allowed to warm to 0° C. over 60 min, cooled to −78° C., and treated with DMF (10.2 g, 140 mmol). The mixture is stirred for 10 min and quenched with HOAc (10 mL) and water (200 mL). The mixture is allowed to warm to RT, and the THF is removed under vacuum. The residue is extracted with EtOAc (2×100 mL, and the organic layer is dried over Na2SO4 andconcentrated. The crude product is purified using silica gel column chromatography (7% EtOAc/Hex) to afford the title compound (8.70 g, 49%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][OH:12].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]=[O:12]
Reactant: Cc1cccc(CCCO)c1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cccc(CCC=O)c1F
Yield: 60.2 %

Procedure:
According to procedures described above, 3-(2-fluoro-3-methyl-phenyl)-propan-1-ol (300 mg, 1.78 mmol) was oxidized by PCC in DCM to give 178 mg (60%) of 3-(2-fluoro-3-methyl-phenyl)-propionaldehyde. LC-MS: tR=0.86 min; [M+H]+=no ionization.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Product: COc1ccc(-c2cc(F)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, white solid (33 mg, 43%), MS (ISP) m/z=311.3 [(M+H)+], mp 274.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:23]([NH:25][C:26](=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:40]=1)OC1C=CC=CC=1)#[N:24]>>[C:23]([NH:25][C:26]([NH:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:20])=[N:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]2[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]2)[CH:40]=1)#[N:24]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.30 g (1.0 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=601 ([M+H]+, 7), 76 (100); IR (KBr): 2169 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from ethanol/petroleum ether; m.p.: 106° C. (ethanol/petroleum ether).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[N:11]O)[CH3:10].CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([CH3:10])=[N:11]1
Reactant: CC(Cc1ccccc1Br)=NO
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC1=NC1c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-bromophenyl)propan-2-one oxime (1.36 g, 5.96 mmol) and TEA (722 mg, 7.15 mmol) in anhydrous THF (50 mL) at RT was added dropwise a solution of methanesulfonyl chloride (819 mg, 7.15 mmol) in anhydrous THF (5 mL). After stirring at RT for 1 h, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.26 g, 14.9 mmol) was added and stirring continued at RT for 1 h. The reaction mixture was passed through a pad of SiO2, concentrated in vacuo, and purified by SiO2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 2-(2-bromophenyl)-3-methyl-2H-azirine as yellow oil (758 mg, yield, 60.5%). MS (ESI): m/z=242.1 [M+33]+.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([N:2]3[CH2:3][CH2:4][CH2:5][S:1]3(=[O:7])=[O:6])=[CH:14][N:13]=2)=[O:16])[CH2:22][CH2:21]1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 37.8 %

Procedure:
Using isothiazolidine 1,1-dioxide (52 mg) and (5-bromopyridin-2-yl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (160 mg) described in Preparation Example 137 and by the reaction and treatment in the same manner as in Example 1, the title compound (67 mg) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[O:16]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C1C=CC=CC=1>C(O)(C)C>[ClH:2].[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[CH:5][N:4]=[C:3]2[NH:27][C:26]1[CH:25]=[CH:24][C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(C)O
Product: Nc1ccc2ncnc(Nc3ccc(Oc4ccccc4)cc3)c2c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A suspension of crude 4-chloro-6-nitroquinazoline hydrochloride (5 mmol) (Morley J. S. and Simpson J. C. E., J. Chem. Soc., 1948:360) was refluxed under nitrogen with stirring in isopropanol (10 mL) containing 4-phenoxyaniline (926 mg, 5 mmol) and N,N-dimethylaniline (1.215 g, 10 mmol) for 3 hours. The mixture was allowed to cool to 25° C., and the precipitate was collected by Buchner filtration, rinsed with isopropanol (2×10 mL) and dried at 60° C. in a vacuum oven to give 6-amino-4-(4-phenoxyanilino)quinazoline hydrochloride (1.702 g, 86%) as an orange solid; mp 293-294° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:20]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CC1CCNCC1
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1CCN(Cc2ccccc2)CC1

Procedure:
Ethyl 4-piperidylacetate was dissolved in 50 ml CH2Cl2 while chilling the mixture on an ice bath, 3.1 ml (22 mmol) triethylamine then benzyl chloride was added; the mixture was refluxed for 2 hours. After cooling the organic layer was extracted with water, brine and then dried over magnesium sulfate. After crystallization, 2.05 g of ethyl N-benzyl-4-piperidylacetate was obtained (Formula XI: Y'=CH2, alkyl=C2H5).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:20])([CH3:19])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:21](O)[CH2:22][OH:23].COC(OC)OC>C([O-])(O)=O.[Na+]>[C:3]([SiH2:7][O:8][C:9]([CH3:20])([CH3:19])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2([CH3:17])[O:23][CH2:22][CH2:21][O:18]2)[CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)ccn1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(C2(C)OCCO2)c1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-ethanone (1.78 g, 6.71 mmol) in ethylene glycol (7.14 mL, 127.95 mmol) was treated with trimethylorthoformate (1.50 mL, 13.67 mmol) followed by LiBF4 (128 mg, 1.34 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 1:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.50. LC-MS-conditions 02: tR=0.91 min, [M+H]+=310.40.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][S:11][C:12](S(C)=O)=[CH:13][N+:14]([O-:16])=[O:15].C[O-].[Na+]>CO>[CH3:10][S:11][C:12]1[NH:2][CH:3]=[C:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CCCCC(=O)CN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1c[nH]c(SC)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 48.5 %

Procedure:
1-Amino-2-hexanone hydrochloride (5.8 g) was dissolved in methanol (100 ml) and mixed with a solution of 1-methylthio-1-methylsulphinyl-2-nitroethylene (6.8 g) in warm methanol (100 ml). A solution of sodium methoxide in methanol (from 1.7 g sodium) was added dropwise, with stirring, over 2 hours at 60°, and the mixture was evaporated to dryness. The residue was triturated with water, and the solid was filtered off and dried, to give 2-methylthio-3-nitro-4-n-butylpyrrole (3.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][CH2:20][OH:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1.C[OH:23].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([OH:23])=[O:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1
Reactant: CO
Reactant: OCCCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reaction time: 0.75 h
Yield: 72.6 %

Procedure:
10.3 ml (41 mmol of O) of Kiliani solution was added at −10° to −5° C. within 20 minutes to a solution of 6.44 g (20 mmol) of 5-chloro-2-(2-chlorophenyl)-7-(3-hydroxy-propyl)-benzoxazole in 130 mg of acetone. After 45 minutes, 5 ml of methanol and 130 ml of water were added. The acetone was removed in vacuo, the solid suspended, collected, and washed with 1 N sulfuric acid and water. The residue was taken up in 35 ml of 1 N NaOH and 50 ml of water, and extracted with ether. The water phase was acidified with 5 N HCl to pH 3. Filtration and washing gave the title compound (4.88 g, 72.6%), mp 152-4° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:23]2[S:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])[CH:19]=[CH:20][C:21]=1[CH3:22]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:29]([C:24]3[N:25]=[C:26]([CH3:28])[S:27][C:23]=3[C:18]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([CH3:15])[CH:17]=3)=[O:30])[CH2:10]2)=[N:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C)c(C)c2)s1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Product: Cc1nc(C(=O)N2CCC[C@@H](Nc3ncc(Br)cn3)C2)c(-c2ccc(C)c(C)c2)s1

Procedure:
prepared by reaction of (R)-(5-bromo-pyrimidin-2-yl)-piperidin-3-yl-amine with 5-(3,4-dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:20]1([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:13]=3)[CH:19]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1cc(-c2ccccc2)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cc(-c3ccccc3)ccn2)sc2ccccc12
Yield: 53 %

Procedure:
A mixture of methyl thiosalicylate (1.00 g, 5.9 mmol), 2-cyano-4-phenylpyridine (1.10 g, 5.9 mmol), triethylamine (1.30 ml, 9.0 mmol) and toluene (2.5 ml) was refluxed for 20 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.99 g, 53%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:21](=[O:25])[NH:20][C:19]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[N:18][C:17]1=2)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:21](=[O:25])[NH:20][C:19]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])=[N:18][C:17]1=2
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a solution of compound 15 (5.8 g, 12.7 mmol) in methanol (50 mL) was added 10% Pd/C (2 g) and formic acid (3 mL). The mixture was refluxed for 5 h, cooled to ambient temperature and filtrated through silica gel column. The column was washed with methanol (50 mL), all the filtrate was concentrated under reduced pressure to yield 4.55 g (98%) of compound 16 as a glass-like solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[NH:18]([CH3:20])[CH3:19]>C1COCC1>[CH3:19][N:18]([CH3:20])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.673 mmol) and aqueous Me2NH (4 mL) in THF (10 mL) was stirred at room temperature overnight. It was then concentrated under reduced pressure to give the title compound. MS (m/z): 262 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5](F)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[OH:21][CH:22]([CH2:32][OH:33])[CH2:23][NH:24][C:25]([CH3:31])=[CH:26][C:27]([O:29][CH3:30])=[O:28]>C(O)(C)C>[OH:21][CH:22]([CH2:32][OH:33])[CH2:23][NH:24][C:25]([CH3:31])=[C:26]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][N:6]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=[N+]([O-])c1cnc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)C=C(C)NCC(O)CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)NCC(O)CO)c1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.5 g (0.0026 m) 3,5-dinitro-2-fluoropyridine (1) and 0.3 g (0.0026 m) triethylamine in 10 ml isopropanol is added 0.48 g (0.0025 m) methyl 3-(2,3-dihydroxypropyl)amino-2-butenoate (2). This solution is stirred at room temperature for two days, concentrated to an oil in vacuo and the residue is chromatographed on silica gel with 8% methanol/chloroform. The material with Rf =0.5 is collected. This reddish brown material is recrystallized from acetonitrile/n-butylchloride, m.p. 128°-9°.
Reaction SMILES: [CH2:1]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[C:2](=[CH2:4])[CH3:3].[H-].[Na+].[CH2:16](Cl)[C:17](=[CH2:19])[CH3:18].O>CN(C=O)C>[CH2:1]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[N:8]([CH2:18][C:17](=[CH2:16])[CH3:19])[C:6]1=[O:7])[C:2](=[CH2:3])[CH3:4]
Reactant: C=C(C)CN1C(=O)NC(=O)C1(C)C
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CN1C(=O)N(CC(=C)C)C(C)(C)C1=O
Temperature: 15 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
In a 100 ml three necked flask is placed 10 g (0.055 mol) of N-methallyl-5,5-dimethylhydantoin in 100 ml DMF under nitrogen. The solution is cooled to 15° C. and 2.7 g of sodium hydride/mineral oil is added. The reaction is stirred for 2 hours at 15° C. and then warmed to 25°C. Methallyl chloride (5.1 g, 0.056 mol) is added dropwise over 10 minutes, keeping the temperature at 30° C. The reaction is stirred overnight, then poured into 200 ml water, extracted with 2 X 100 ml ether and dried over magnesium sulfate. After removing the ether in vacuo, the residue is distilled under vacuum (BP 100°-105°0 C. 0.3 mm Hg) to give 11.9 g N,N'-bismethallyl-5,5-dimethylhydantoin.