Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13](=O)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>CO>[C:1]1([CH:11]=[CH:12][C:13](=[N:17][OH:18])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C=Cc1cccc2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1cccc2ccccc12)=NO
Yield: 60.9 %

Procedure:
In a 250 ml single neck flask was charged 5.88 g (30.3 mmoles, 1.0 eq.) of 4-(1-naphthyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.9 g of 4-(1-naphthyl)-3-buten-2-one 2-oxime (E/Z mixture of isomers) as an oil in 62% yield.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5].[CH3:16][Mg]Br>C1COCC1.C(OCC)C>[C:11]([N:9]1[CH:10]=[C:6]([C:4](=[O:5])[CH3:16])[CH:7]=[N:8]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)c1cnn(C(C)(C)C)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cnn(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under nitrogen, a solution of 5.87 g (27.7 mmol) 1-tert-butyl-1H-pyrazole-4-carboxylic acid methoxy-methyl-amide in 55 ml THF is cooled to 0° C. and 18.5 ml (55.5 mmol) of a 3 M solution of methylmagnesium bromide in diethyl ether is added dropwise at 0° C. The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between brine and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone as white solid; HPLC/MS 1.87 min (B), [M+H] 167;
Reaction SMILES: [N:1]1([C:6](=[O:24])[CH2:7][C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)[CH:5]=[CH:4]N=[CH:2]1.[CH2:25](NCCC)[CH2:26]C.[CH:32]1C=CC=CC=1>>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[C:8]([CH2:7][C:6]([N:1]([CH2:2][CH2:25][CH3:26])[CH2:5][CH2:4][CH3:32])=[O:24])=[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:22][CH:21]=1
Reactant: c1ccccc1
Reactant: CCCNCCC
Reactant: Cc1ccc(-c2nn3cccnc3c2CC(=O)n2ccnc2)cc1
Product: CCCN(CCC)C(=O)Cc1c(-c2ccc(C)cc2)nn2cccnc12
Yield: 39.6 %

Procedure:
A mixture of 3.25 g (0.010 mole) of 3-[2-(1H-imidazole-1-yl)-2-oxoethyl]-2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (prepared from 2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 1,1'-carbonyldiimidazole) and 1.1 g (0.011 mole) of dipropylamine in 25 ml of benzene was stirred at reflux for 5 hours. After cooling, the reaction mixture was washed with water, dried over magnesium sulfate, and concentrated in vacuo (2.6 g). The crude solid residue was purified by a liquid-solid extraction with isopropyl ether in a soxhlet. The purified product was collected by filtration from the isopropyl ether (extraction solvent) to yield 1.4 g (39.6%) of golden yellow crystals, mp 110°-111° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.[C:25]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1=CCCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCCC3)c2)CC1
Temperature: 85 °C
Yield: 45.1 %

Procedure:
A solution of 230 mg (0.647 mmol) 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 6 mL toluene and 3 mL EtOH was treated with 118 mg (0.842 mmol) cyclohept-1-enylboronic acid and 2.60 mL (5.18 mmol) 2.0 M Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 52.3 mg (0.0453 mmol) Pd(PPh3)4, and heated to 85° C. for 23 h. The mixture was diluted with EtOAc (15 mL) and washed with water (1×15 mL) and brine (1×15 mL). The combined aqueous layers were extracted with EtOAc (15 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gm column with 10-18% EtOAc-hexane afforded 108 mg (45%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C19H27N2O2, 315.2 (M−C4H9+2H), found 315.2.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1OC
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1OC
Yield: 351.9 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11-B(v), ethyl 2-chloro-3-(2-methoxyphenyl)-3-oxopropanoate (600 mg, 2.3 mmol) produced in the above and 2-propanol (40 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (1.8 g, 71%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1ccc(Cl)nc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 2-chloro-5-methylpyridine (10 mL) in 155 mL of glacial acetic acid was added 19 mL of 30% aqueous hydrogen peroxide. The mixture was stirred at 80° C. for 8 hours. The mixture was diluted with 100 mL of water and then concentrated in a vacuum. The residue was made strongly alkaline with anhydrous sodium carbonate and shaken with 200 mL of chloroform. The solids were removed via filtration, and the filtrate was dried over sodium sulfate, filtered and concentrated to give 10.8 g of the 2-chloro-5-methylpyridine-N-oxide (82%). Mass Spec. M+H=144.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][C:25]1[C:33]([NH2:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>CN(C=O)C.N1C=CC=CC=1>[NH2:24][C:25]1[C:26]([C:27](=[O:28])[NH2:29])=[CH:30][CH:31]=[CH:32][C:33]=1[NH:34][C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: NC(=O)c1cccc(N)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)c2cc(Cl)nnc2Cl)c1N
Temperature: 50 °C

Procedure:
3,6-Dichloropyridazine-4-carboxylic acid (1.15 g, 5.96 mmol) and 1,1′-carbonyldiimidazole (CDI (0.97 g) in DMF (25 ml) were stirred at room temperature for 2 h. A solution of 2,3-diaminobenzamide (1.30 g, 5.96 mmol) in pyridine (25 ml) was added and the solution heated at 50° C. for 4 h. The cooled solution was concentrated and partitioned between ethyl acetate (EtOAc) and water, the organic layer separated, dried, filtered and concentrated to give the product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19]/[C:20](/[CH3:24])=[CH:21]\[C:22]#[N:23].[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26][C:27]([CH3:29])=O.N#N>C(O)C>[C:22]([C:21]1[CH:17]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C:15]=2[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]3)[C:26]([C:25]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([CH3:29])[NH:19][C:20]=1[CH3:24])#[N:23]
Reactant: O=Cc1ccnc2ncc(-c3ccccc3)cc12
Reactant: C/C(N)=C/C#N
Reactant: CCOC(=O)CC(C)=O
Agent: N#N
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1ccnc2ncc(-c3ccccc3)cc12

Procedure:
2 g (8.54 mmol) of 3-phenyl-1,8-naphthyridine-5-carboxaldehyde, 0.7 g (8.54 mmol) of 3-aminocrotononitrile and 1.08 ml of ethyl acetoacetate (8.54 mmol) are boiled in 16 ml of ethanol in an N2 atmosphere for 16 hours. Chromatography over silica gel and elution with ethyl acetate gives 0.38 g (10.8% of theory) of the title compound of melting point 265° C.
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=[O:8].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=[O:8]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C=O)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 102.2 %

Procedure:
Methyl iodide (55.2 g, 389.2 mmol) was added dropwise to a stirred mixture of 3-hydroxy-4-nitrobenzaldehyde (50 g, 288.4 mmol) and potassium carbonate (53.8 g, 389.2 mmol) in DMF (250 ml). The reaction mixture was stirred overnight, poured into ice-cold water, and the precipitated solid was collected by filtration. The resulting solid was dried on a high vacuum overnight to obtain 53.4 g of 3-methoxy-4-nitrobenzaldehyde.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[NH2:21]/[C:22](/[C:33]([F:36])([F:35])[F:34])=[C:23](/[C:29](=[O:32])[CH2:30][CH3:31])\[C:24]([O:26][CH2:27][CH3:28])=[O:25].[F:37][C:38]([F:48])([F:47])[C:39]([F:46])([F:45])[C:40](OCC)=O>CCOCC.O>[OH:32][C:29]1[C:30]([CH3:31])=[C:40]([C:39]([F:45])([F:46])[C:38]([F:37])([F:47])[F:48])[N:21]=[C:22]([C:33]([F:34])([F:35])[F:36])[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)/C(C(=O)CC)=C(\N)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)C(F)(F)F)c(C)c1O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
To a -78° C. solution of LDA (0.10 mol), prepared from 0.10 mol of n-BuLi and 14 ml (0.10 mol) of diisopropylamine in 70 ml ether was added a solution of 10.0 g (0.042 mol) of product of Example 34 in 20 ml of ether slowly to maintain a temperature below -60° C. After stirring for 30 minutes, the reaction mixture was treated with 21 ml (0.042 mol) of ethyl pentafluoropropionate. After stirring at -78° C. for 15 minutes, the reaction mixture was warmed to 10° C. in 0.5 hour and poured into 100 ml of water, and extracted with ether. The ether extract was extracted with 10% K2CO3. The combined aqueous layer and K2CO3 extract was acidified with concentrated HCl to give 4.73 g (29.5%) of beige solid; mp 115°-117° C. (dec). A 2.73 g (0.00709 mol) of the solid was heated in a kugelrohr pot at 130° C. for 0.5 hour. The distillate and residue were combined and dissolved in ether. The ether solution was dried (CaSO4) and concentrated to give 2.0 g (76.9%) of product as a solid; mp 36°-38° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30](O)=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)=[O:10])[CH2:12][C@H:13]3[CH3:17])=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Reactant: COc1cccc(C(=O)N2CCN[C@H](C)C2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(Cl)c4)n3)[C@H](C)C2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 71 mg (0.30 mmol) (6-methoxy-pyridin-2-yl)-((R)-3-methyl-piperazin-1-yl)-methanone, 67 mg (0.30 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 77 μL (0.45 mmol) DIPEA in 1.5 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: [Li][CH2:2]CCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CI.[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][C:31]2=O>C1COCC1>[Br:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][C:31]2=[CH2:2]
Reactant: [Li]CCCC
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CI
Product: C=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of n-BuLi (2.5 M, 3.80 mL) was added to a mixture of PPh3.MeI. (4.092 g, 10.13 mmol) in THF at −10. The mixture was stirred for 1 h at the same temperature, and then 6-bromo-2-phenylchroman-4-one (2 g, 6.62 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was concentrated and purified by column chromatography to give 6-bromo-4-methylene-2-phenylchroman (400 mg, 20%). 1H-NMR (CDCl3): 2.76 (m, 2H), 4.90 (d, 1H), 5.01 (m, 1H), 5.48 (d, 1H), 6.76 (d, 1H), 7.31 (m, 6H), 7.62 (d, 1H).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH:10]=[CH:9][CH2:8][N:7]1[C:11](=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]1[CH2:22][CH:21]=[CH:20][C@@H:19]1[C:23]([O:25]CC)=[O:24])=[O:17])=[O:5])C.Cl>>[C:23]([C@H:19]1[CH:20]=[CH:21][CH2:22][N:18]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]([N:7]1[CH2:8][CH:9]=[CH:10][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:28])([OH:25])=[O:24]
Reactant: CCOC(=O)[C@H]1C=CCN1C(=O)CCCCC(=O)N1CC=C[C@@H]1C(=O)OCC
Agent: Cl
Product: O=C(O)[C@H]1C=CCN1C(=O)CCCCC(=O)N1CC=C[C@@H]1C(=O)O
Yield: 118.9 %

Procedure:
0.09 g (0.0002 mol) (R)-1-[6-[(R)-2-ethyloxycarbonyl-2,5-dihydropyrrole-1-yl]-6-oxo -hexanoyl]-2,5-dihydropyrrole-2-carboxylic acid ethyl ester were stirred with aqueous HCl at 50° C. for 3 hours. The solvent was evaporated and the residue dissolved in water and lyophilized to yield 0.08 g (97%) (R)-1-[6-[(R)-2-carboxy-2,5-dihydropyrrole-1-yl]-6-oxo-hexanoyl]-2,5-dihydropyrrole-2-carboxylic acid as light yellow foam. ISP-MS: 335 (M−H)−.
Reaction SMILES: [CH:1]([N:4]1[C:13](OS(C(F)(F)F)(=O)=O)=[C:12]2[C:6]([CH2:7][C:8]([CH3:25])([CH3:24])[NH:9][C:10]([CH3:23])([CH3:22])[CH2:11]2)=[N:5]1)([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:13]2[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]3[C:12]=2[CH2:11][C:10]([CH3:22])([CH3:23])[NH:9][C:8]([CH3:24])([CH3:25])[CH2:7]3)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CC(C)(C)NC(C)(C)C2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CC(C)(C)NC(C)(C)C2
Yield: 59.4 %

Procedure:
The title compound (100 mg) was prepared as in Example 296 using 196 mg of trifluoro-methanesulfonic acid 2-isopropyl-5,5,7,7-tetramethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl ester and 100 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C20H28FN3, 329.23; found, m/z 330.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.27 (m, 4H), 4.31 (m, 1H), 3.10 (s, 2H), 2.70 (s, 2H), 1.47-1.34 (m, 18H).
Reaction SMILES: FC(F)(F)S([C:6]1[CH:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=O)=O.[C-:25]#[N:26].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCC>C(#N)C.[Zn].C(OCC)(=O)C>[C:25]([C:6]1[CH:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)#[N:26]
Reactant: [C-]#N
Reactant: O=S(=O)(c1cccc(-c2cc(-c3ccccn3)no2)c1)C(F)(F)F
Agent: [K+]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: N#Cc1cccc(-c2cc(-c3ccccn3)no2)c1
Temperature: 60 °C
Yield: 23.3 %

Procedure:
A mixture of 5-[3-trifluoromethanesulfonylphenyl]-3-[pyridin-2-yl]-1,2-oxazole (98 mg, 0.26 mmol), KCN (230 mg, 4 mmol), NiBr2(PPh3)2 (52.4 mg, 0.07 mmol), and PPh3 (42 mg, 0.16 mmol) in acetonitrile (1 mL) was treated with zinc powder (20 mg, 0.3 mmol) and the mixture was heated overnight at 60° C. Silica gel chromatography of the resulting mixture using a gradient of hexane to ethyl acetate afforded 15 mg (23%) of 5-[3-cyanophenyl]-3-[pyridin-2-yl]-1,2-oxazole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][C:11]([NH:13][C:14]1[C:18]([CH3:19])=[CH:17][S:16][CH:15]=1)=S.CI>>[ClH:8].[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[N:1]=[C:11]([NH:13][C:14]3[C:18]([CH3:19])=[CH:17][S:16][CH:15]=3)[NH:10][C:3]=2[CH:4]=1
Reactant: Cc1cscc1NC(=S)Nc1cc(Cl)c(Cl)cc1N
Solvent: CI
Product: Cc1cscc1Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Product: Cl

Procedure:
is obtained analogously to the procedure described in example 1 c) from N-(2-amino-4,5-dichlorophenyl)-N′-(4-methyl-3-thienyl)thiourea and methyl iodide. Crystalline solid, m.p. 290-294° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([NH:40][CH3:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([N:40]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:41])=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Reactant: CNCc1ccccc1
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3OC)CCN2CC(=O)N(C)Cc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with N-benzyl-N-methylamine
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([C:11](=[O:15])[CH:12]([OH:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[F:10].[C:16](O)(=[O:18])C.[C:20](O)(=O)C.IC1C=CC=CC=1>CO>[CH3:20][O:15][C:11]([O:18][CH3:16])([C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:4]([F:3])[CH:5]=1)[CH:12]([OH:14])[CH3:13]
Reactant: CC(O)C(=O)c1ccc(F)c(F)c1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: Ic1ccccc1
Solvent: CO
Product: COC(OC)(c1ccc(F)c(F)c1)C(C)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a round bottom flask containing 200 mL of MeOH was added pellets of potassium hydroxide (23.0 g, 410.0 mmol). The solution was cooled to 0° C. and 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one (7.0 g, 41.2 mmol) in 10 mL MeOH was added dropwise. The solution was stirred for 10 min and then iodobenzene diacetate (22.5 g, 70 mmol) was added in two portions. The solution first became orange and then turned yellow. It was stirred overnight at room temperature and then solvent was removed in vacuo. The residue was dissolved in water and was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine and then dried over Na2SO4. After filteration, the solvent was removed in vacuo to get 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one dimethyl acetal as a yellow viscous oil (crude wt.=9.2 g). It was dissoled in 150 mL of acetone and 10 drops of concentrated sulfuric acid were added. After stirring for 3 h, TLC analysis indicated that the reaction was complete. Acetone was removed in vacuo and after basification with saturated NaHCO3, the residue was extracted in EtOAc and was washed with brine. The organic layer was separated, dried over Na2SO4 and then filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (Rf=0.4, 3:2 hexane/EtOAc) to obtain 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one as a pale yellow oil (3.3 g, 51% yield over two steps).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][N:12]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][N:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@@H:11]([CH3:10])[CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C[C@H]1CNCCN1C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc(Br)cc2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of 4-bromobenzaldehyde (1.19 g, 6.42 mmol), phenylmethyl (2S)-2-methyl-1-piperazinecarboxylate (1.505 g, 6.42 mmol) and sodium triacetoxyborohydride (2.04 g, 9.63 mmol) in 1,2-DCE (15 ml) was stirred at room temperature overnight. Saturated aq. NaHCO3 solution was added and the mixture stirred for 30 mins. Product was extracted and the extracts dried (Na2SO4). Chromatography (0-30% EtOAc in pentane) gave the title compound (2.18 g). MS (ES): MH+ 403/405.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:14][OH:15]>O>[NH2:8][C:6]1[N:7]=[CH:2][C:3]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH2:14][OH:15])=[CH:4][CH:5]=1
Reactant: OCC1CCCN1
Reactant: Nc1cccc(F)n1
Solvent: O
Product: Nc1ccc(N2CCCC2CO)cn1
Temperature: 205 °C
Yield: 91.1 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and pyrrolidin-2-ylmethanol (0.678 g, 6.7 mmol) in water (0.3 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:3) to afford (1-(6-aminopyridin-3-yl)pyrrolidin-2-yl)methanol (0.785 g, 91%) as a yellow oil. LC-MS: [M+1]+=194, tR=0.968 min.