Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].ClC1C=CC(C2N(CCN(C)C)N=C3C=2CCNCC3)=CC=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CN(C)CCCl
Agent: CN(C)CCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Agent: Cl
Product: CN(C)CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.33 mmol) using (2-chloro-ethyl)-dimethyl-amine hydrogen chloride (0.66 mmol) in place of chloro-cyclobutane. The title compound was obtained as a 2:1 mixture (10 mg) with {2-[3-(4-chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-ethyl}-dimethyl-amine. Data for the mixture: MS (ESI): exact mass calculated for C17H23ClN4, 318.16; found, m/z 319.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.45 (m, 2H), 7.37-7.33 (m, 2H), 4.51-4.49 (m, 1.3H), 4.27-4.26 (m, 0.7H), 3.63-3.61 (m, 1.3H), 3.48-3.42 (m, 2H), 3.33-3.29 (m, 2H), 3.24-3.23 (m, 2H), 3.14-3.12 (m, 0.7H), 3.00-2.98 (m, 1.3H), 2.91 (s, 4H), 2.84 (s, 2H), 2.75-2.73 (m, 0.7H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][N:23](C)[CH2:22]4)=[O:17])[C:7]=2[CH:29]=1)#[N:2]>C(O)(=O)C.C(Cl)(Cl)Cl.[Zn]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][NH:23][CH2:22]4)=[O:17])[C:7]=2[CH:29]=1)#[N:2]
Reactant: CN1Cc2ccc(NC(=O)N[C@@H]3c4cc(C#N)ccc4OC(C)(C)[C@H]3O)cc2C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2ccc3c(c2)CNC3)[C@@H]1O
Temperature: 80 °C
Yield: 29.4 %

Procedure:
A solution of (3S-trans)-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(2,3-dihydro-2-methyl-1H-isoindol-5-yl)urea (1.0 g, 1.8 mmol, compound of example 19) in acetic acid (4 mL) was treated with zinc dust (0.35 g, 5.4 mmol) under argon and heated at 80° C. for 16 hours. Additional amount (0.4 g) of zinc dust was added and the reaction mixture was heated for eight hours. It was cooled to room temperature, diluted with chloroform (100 mL) and filtered. The solvent was evaporated in vacuo and the residue was acidified with 10% hydrochloric acid (10 mL). It was then extracted with ethyl acetate and the organic extract was discarded. The acid layer was made basic (pH~11) with 10% sodium hydroxide solution, saturated with salt and extracted with chloroform (3×100 mL). The aqueous layer was filtered and the filtrate was concentrated in vacuo. The residue was diluted with 40% aqueous isopropanol. The precipitate was faltered and dried to yield the title compound (0.2 g) as a colorless solid, m.p. 215°-217° C. [αD ]25 =-13.9° (c=0.42, DMF).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]([OH:7])=[O:6].Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl>CS(C)=O>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:10][CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: O=C(O)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc2c(OCC(=O)O)ccnc2c1
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
A 250-mL, 3-neck, rb flask equipped with a magnetic stirbar, a reflux condenser and a powder funnel was charged with potassium hydroxide (6.0 g, 90 mmol) then 2-hydroxyacetic acid (5.0 g, 65 mmol) with stirring. The solid reactants gradually reacted and liquified as significant heat was generated. Upon dissolution of all the reagents, flask containing the hot syrupy liquid was immersed in a 170° C. oil bath, then a solution of 4-chloro-7-methoxyquinoline (5.0 g, 26 mmol) in anhydrous DMSO (20 mL, 4 vol wrt quinoline) was added dropwise over 20-30 min via addition funnel. The resulting brown solution was maintained in the oil bath with stirring. After 2.5 h, the flask was removed from the oil bath, then quenched by the addition of water (100 mL, 5 vol wrt DMSO). The resulting brown solution was immersed in an ice bath, and the mixture was neutralized by the dropwise addition of 6 N HCl (15 mL, 1 equiv to KOH), which resulted in the formation of a thick yellow ppt and brought the mixture to pH 3. The mixture was filtered and washed with water and ACN. The solid products were dried under vacuum to yield 2-(7-methoxyquinolin-4-yloxy)acetic acid (2.16 g, 36% yield) as a yellow solid. (ESI, pos. ion) m/z: 234.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](OC)=[O:14].[BH4-].[Li+]>C1COCC1.CCOCC>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14]
Reactant: COC(=O)Cc1ccc(C#N)c(OC)c1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(C#N)ccc(CCO)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl (2-chloro-4-cyano-3-methoxyphenyl)acetate (700 mg, 2.92 mmol) in THF (30 mL) was added 2M lithium borohydride (1.46 mL, 2.92 mmol) and the reaction was stirred at RT for 16 hours. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product mixture was separated by flash chromatography (10-40% ethyl acetate/hexanes) to afford the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 3.10 (t, J=6.4 Hz, 2H), 3.94 (t, J=6.4 Hz, 2H), 4.08 (s, 3H), 7.175 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(C)(C)C.[Br:29]Br.S([O-])([O-])=O.[Na+].[Na+]>CCOCC.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:13][C:14]=1[Br:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1cccc(OCc2ccccc2)c1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(C)(C)N
Product: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a -78° C. solution of 42.6 g. (0.134 mole) of 1-benzyloxy-3-(1,1-dimethylheptyl)benzene and 12.2 g. (0.200 mole) of t-butylamine in 300 ml. of dichloromethane is added a solution of 27.2 g. (0.151 mole), bromine in 100 ml. of dichloromethane. The reaction mixture is then allowed to warm to 25° C. and added to 500 ml. saturated sodium sulfite and 500 ml. ether. The organic extract is washed with two 500 ml. portions of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to an oil. The crude product is purified via column chromatography on 500 g. of silica gel eluted with 10% ether-hexane to give 41.9 g. (80%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[F:24][C@@H:25]([CH3:28])[CH2:26]O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:24][C@@H:25]([CH3:28])[CH2:26][O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: C[C@H](F)CO
Reactant: Oc1ccncc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](F)COc1ccncc1
Yield: 89.9 %

Procedure:
A solution of 1.5 g of 4-hydroxypyridine, 7.6 g of cyanomethylenetributylphosphorane, and 1.4 g of (2S)-2-fluoro-1-propanol in 20 mL of toluene was stirred at 105° C. overnight. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate, and the organic layer was separated. The aqueous layer was adjusted to pH 11 by the addition of a 1 M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 2.2 g of 4-{[(2S)-2-fluoropropyl]oxy}pyridine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([CH2:17][CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[CH2:11][C:12]#[C:13][C:14](=[O:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOCC.CCCCCC>ClC1C=CC=CC=1Cl>[Si:1]([O:8][CH2:9][C:10]1([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:17][C:18]2=[CH:19][C:20]3[C:25]([C:13]([C:14](=[O:16])[CH3:15])=[C:12]2[CH2:11]1)=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(=O)C#CCC(CC=Cc1ccccc1Cl)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Clc1ccccc1Cl
Product: CC(=O)c1c2c(cc3c(Cl)cccc13)CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)C2
Yield: 92 %

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added compound 4c (0.09 g, 0.17 mmol) in 1,2-dichlorobenzene (3 mL). The reaction was irradiated with stirring at 180° C. for 45 min until complete by TLC (Et2O/n-hexane 1:9). The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then Et2O/n-hexane 2:8 to collect the pure product. The title compound was isolated as a light yellow oil in a 92% yield (0.083 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:15])[N:10]=[N:11][C:12]=1[CH2:13][OH:14].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[N:10][NH:11][C:12]=1[CH2:13][OH:14]
Reactant: O=C1N=NC(CO)=C1c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2n[nH]c(CO)c2-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
To a suspension of 4-(2-fluorophenyl)-5-(hydroxymethyl)pyrazol-3-one (28.7 g, 0.138 mol) in dry dichloromethane (300 ml) was added p-toluenesulfonyl chloride (28.9 g, 0.152 mol) followed by triethylamine (21.2 ml, 0.152 mol) dropwise. The solution was stirred at room temperature for 2 days. Dichloromethane (300 ml) was then added to dilute and the solution was washed with brine (300 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with 0%→40% ethyl acetate/dichloromethane as eluent to give the title compound (23.7 g). Data for the title compound: 1H NMR (360 MHz, DMSO) δ 2.34 (3H, s), 4.66 (2H, s), 6.94 (1H, t), 7.06 (3H, m), 7.17-7.25 (2H, m), 7.51 (2H, d); MS (ES+) m/e 362 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([N:56]=[C:57]=[O:58])=[CH:52][CH:51]=1)([O-:49])=[O:48].N1C=CC=CC=1.CCCCCC>C1(C)C=CC=CC=1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([O:16][C:57]([NH:56][C:53]2[CH:52]=[CH:51][C:50]([N+:47]([O-:49])=[O:48])=[CH:55][CH:54]=2)=[O:58])=[C:12]([NH:17][C:18](=[O:46])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:45])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH:20]=2)[NH:11]1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3O)c2)c(C(C)(C)CC)c1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3OC(=O)Nc3ccc([N+](=O)[O-])cc3)c2)c(C(C)(C)CC)c1

Procedure:
0.01 moles of 1-(2,4,6-trichlorophenyl)-3-[3-{α-(2,4-di-t-amylphenoxy)acetamido}benzamido]-hydroxy-5-pyrazolone and 0.01 moles of p-nitrophenyl isocyanate are dissolved in 100 ml of dehydrated toluene, then added with 0.02 moles of pyridine and heated for 1 to 1.5 hours under reflux. After the reaction the solvent is eliminated under reduced pressure and n-hexane is added. The obtained solid is collected by filtration, then washed with n-hexane and dried to obtain the coupler (3) in a state of colorless powder with a melting point of 96°-100° C.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:30])[N:24]([CH2:26][CH2:27][O:28][NH2:29])[CH3:25])([CH3:21])([CH3:20])[CH3:19].Cl>CCO.C(OCC)C>[CH3:25][N:24]([CH2:26][CH2:27][O:28][N:29]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)[C:23](=[O:30])[O:22][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: CN(CCON)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN(CCON=C(c1ccccc1)c1cc2ccncc2[nH]1)C(=O)OC(C)(C)C
Reaction time: 15.5 h

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (200 mg, 90 mmol) and tert-butyl[2-(aminooxy)ethyl]methylcarbamate (Reference Example 14) (180 mg, 94 mmol) in EtOH (20 mL) was adjusted to pH 4-5 with HCl (1.2 mL of a 1 N HCl solution in diethyl ether, 1.2 mmol). The reaction mixture was heated to reflux. After 15.5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (25 mL) and washed with saturated NaHCO3 (2×10 mL). The combined organic layers were washed with saturated NaCl (10 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 99:1 CH2Cl2/MeOH to 95:5 CH2Cl2/MeOH) gave tert-butyl methyl[2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethyl]carbamate (geometry of the oxime double bond undefined).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([N:12]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:3]=1.C([O-])=O.[NH4+]>CC(O)C.O.[Pd]>[CH:17]1([N:12]([CH2:13][CH:14]2[CH2:15][CH2:16]2)[C:4]2[N:3]=[CH:2][N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)nc(Cl)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-chloro-6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylate (Intermediate 11, 4.77 g; 14.7 mmol) in 150 ml of iPrOH was treated with 780 mg of palladium (10% on C). The suspension was degassed and a solution of ammonium formate (6.96 g; 110 mmol) in 20 ml of water was added. After stirring at RT for 45 minutes, the suspension was filtered on a pad of Celite, the remaining residue was twice rinsed with 50 ml of iPrOH and the combined filtrates were evaporated under reduced pressure. The remaining colorless residue was partitioned between 150 ml of MTBE and 150 ml of water. Both layers were separated. The organic phase was once washed with 100 ml of brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as colorless oil (4.14 g, 97%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1cccc(-c2ccccn2)c1F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccccn4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2-fluoro-3-(pyridin-2-yl)benzeneboronic acid as described in Example 1 to give 2-[3-(2-fluoro-3-(pyridin-2-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 1.57 (6H, s), 7.62 (1H, dd, J 7 and 5), 7.64 (1H, s), 7.80-7.85 (1H, m), 7.89 (1H, d, J 7), 8.03 (1H, s), 8.10-8.19 (2H, m), 8.62 (1H, s), 8.83 (1H, d, J 5), 9.35 (1H, dd, J 7 and 3); m/z (ES+) 349 (M++H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.[CH3:17][N:18]([CH:20]=O)[CH3:19]>O>[F:1][C:2]([F:11])([F:12])[C:3]([C:4](=[CH:17][N:18]([CH3:20])[CH3:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:10]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of ethyl trifluoroacetoacetate (4.6 g, 0.025 mol) and acetic acid (3.0 g, 0.05 mol) at room temperature, DMF diusopropyl acetal (8.75 g, 0.05 mol) was added dropwise at a rate which maintained the reaction temperature below 35° C. After stirring the mixture at ambient temperature for 2 hours to complete the reaction (TLC), it was poured into water and extracted with ether. The ether extract was washed with water, brine solution, then dried (MgSO4), and concentrated. The residual yellow oil was column-chromatographed on silica gel (Hexanes:Ethyl acetate/7:3) to give ethyl 2-trifluoroacetyl-3-(N,N-dimethylamino)-2-propenoate (Compound 2; Rf=0.3) as the main product; 4.5 g (75%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][N:16]=3)[CH:10]=2)[N:6]=[C:5]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])[CH:4]=[CH:3]1.B1([O-])O[O:39]1.O.O.O.O.[Na+].[Cl-].[NH4+]>C1COCC1.O.ClCCl>[OH:39][C:18]1[CH:17]=[N:16][C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:30]3[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=3)[C:33]#[N:34])=[N:6]2)=[N:20][CH:19]=1
Reactant: CC1(C)OB(c2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)OC1(C)C
Reactant: [O-]B1OO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50.46 g of 3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile (102.7 mmol) and 33.81 g of sodium perborate tetrahydrate (339 mmol) are mixed in a mixture of 220 ml of THF and 220 ml of water in a 1000 ml one-necked flask and stirred at room temperature for 2 h, during which a pale precipitate deposits. The reaction mixture is diluted with 800 ml of dichloromethane, shaken with 500 ml of saturated aqueous ammonium chloride solution, dried over sodium sulfate and evaporated to dryness in a rotary evaporator. The residue is slurried in methanol, filtered off with suction and washed with diethyl ether, m.p. 245-8° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26])[CH:20]=[CH:21][CH:22]=1.C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23](=[O:28])[C:24](=[CH:13][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:25](=[O:27])[CH3:26])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(C(=O)CC(C)=O)c1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)c1

Procedure:
250 mg (1.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 280.9 mg (1.46 mmol) of 1-(3-methoxyphenyl)butane-1,3-dione, 99.7 mg (1.66 mmol) of acetic acid and 11.3 mg (0.13 mmol) of piperidine in 5 ml of dichloromethane and, after addition of molecular sieves, heated under reflux under argon for 4 h. The solvent is removed after filtration in vacuo. 479 mg (98% of theory) of the title compound are obtained and are employed without further purification in the next stage.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:19]=[CH:18][N:17]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccnc(Cl)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
A mixture of 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol), 2-chloro-4-iodopyridine (172 mg, 0.72 mmol), triethylamine (209 μl, 1.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.02 mmol) in N,N-dimethylformamide (1.2 mL) was evaporated and flushed with argon. Cuprous iodide (2 mg, 0.01 mmol) was added and the reaction mixture was stirred for 1.5 h at 90° C. before it was cooled to ambient temperature and separated between aqueous sodium hydroxide (1 M, 20 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were washed with aqueous sodium hydroxide (1 M, 20 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (160 mg, 91%) as a colorless oil. MS: m/e=295.0/297.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].[C:33]([N:40]1[CH:44]=[CH:43]N=[CH:41]1)(N1C=CN=C1)=[O:34].Cl[CH2:46]Cl>>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:33](=[O:34])[N:40]([CH3:41])[CH2:44][CH2:43][CH3:46])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: ClCCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Product: CCCN(C)C(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 8 h

Procedure:
To a stirred solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (400 mg) in dichloromethane (5 ml) was added 1,1'-carbonyldiimidazole (140 mg) at room temperature. The resulting mixture was stirred overnight. Additional 1,1'-carbonyldiimidazole (70 mg) was added to the mixture and then stirred for 1 hour. After the dichloromethane was removed under reduced pressure, N-methylpropylamine (1 g) was added. The mixture was stirred at room temperature for 2 hours and then at reflux temperature for 12 hours. After cooling, dichloromethane and water were added to the reaction mixture. The organic layer was separated, washed with aqueous 0.5N hydrochloric acid and brine. After evaporation of the solvent, the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (99:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(N-methyl-N-propylcarbamoyl)piperazine (0.18 g).