Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:30]1[C:34](B(O)O)=[CH:33][C:32]2[CH:38]=[CH:39][CH:40]=[CH:41][C:31]1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[N:1]1([C:8]2[C:9]([C:34]3[S:30][C:31]4[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=4[CH:33]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (2 mL) was added benzo[b]thiophen-2-ylboronic acid (180 mg, 1.00 mmol), K3PO4 (210 mg, 1.00 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) under nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in water (25 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 3-(azepan-1-yl)-2-(benzo[b]thiophen-2-yl)quinoxaline-6-carboxylate as a light yellow solid (82 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH:8]([Cl:10])[Cl:9]>>[CH2:1]([Si:8]([CH3:7])([Cl:10])[Cl:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCC=C
Reactant: C[SiH](Cl)Cl
Product: C=CCCCC[Si](C)(Cl)Cl
Temperature: 40 °C
Yield: 87.6 %

Procedure:
5-Hexenylmethyldichlorosilane was prepared by combining 1,5-hexadiene (160 g, 1.95 m), 0.1 g of a platinum complex ##STR7## and methyldichlorosilane (5 g) in a flask equipped with a condenser and a thermometer. The mixture was heated to 40° C. to initiate the reaction. Additional methyldichlorosilane (120 g) was added dropwise to the mixture so that the temperature was kept below 55° C. The product was isolated in 87.6% yield by distillation under reduced pressure (bp 67°-9° C./2 mm Hg).
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(O)C>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1ccncc1
Agent: I
Solvent: O
Solvent: CCO
Product: N=C(NCc1ccncc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide and 3.24 g. of 4-(aminomethyl)pyridine in 25 ml. of absolute ethanol is heated under reflux for 24 hours and then diluted with 75 ml. of water, causing the separation of an oil. On standing, the oil crystallizes. Filtration and recrystallization from aqueous ethanol gives the desired product as colorless crystals, m.p. 159°-161° C.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][Si](C(C)C)(C(C)C)C(C)C)=[CH:20][N:19]=1)[OH:17].O>C1(C)C=CC=CC=1.[Cu]Cl>[CH:12]1([CH2:11][O:10][C:8]2[CH:7]=[CH:6][C:5]3[CH2:15][CH:16]([C:18]4[N:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=4)[O:17][C:4]=3[CH:9]=2)[CH2:14][CH2:13]1
Reactant: CC(C)[Si](Oc1ccc(C(O)Cc2ccc(OCC3CC3)cc2Br)nc1)(C(C)C)C(C)C
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(C2Cc3ccc(OCC4CC4)cc3O2)nc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 55.1 %

Procedure:
Sodium hydride (27.7 mg) was added to a suspension of 2-[2-bromo-4-(cyclopropylmethoxy)phenyl]-1-(5-{[tris(1-methylethyl)silyl]oxy}pyridin-2-yl)ethanol (600 mg) and copper(I) chloride (5.71 mg) in toluene (10 mL) at room temperature. The reaction mixture was stirred at 120° C. for 3 hr, and allowed to cool to room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (10 mL), and a THF solution (1.0 M, 5.76 mL) of tetrabutylammonium fluoride was added thereto. The reaction mixture was stirred at room temperature for 30 min, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (180 mg).
Reaction SMILES: [CH2:1]([N:3]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][N:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([N:3]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1Oc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1ccccc1Oc1ccccc1)c1ccc(C(=O)O)cn1
Reaction time: 60 h

Procedure:
A solution of methyl 2-(N-ethyl-N-(2-phenoxybenzyl)amino)pyridine-5-carboxylate (0.65 g, 1.74 mmol) in THF (3 ml) and methanol (3 ml) was treated with aqueous sodium hydroxide (1N, 4 ml). The reaction mixture was heated at reflux for 3 hours cooled to ambient and allowed to stand for 60 hours, then heated at reflux for 3 hours. The organic solvent was evaporated, the residue diluted with water and acidified (pH1) with HCl (conc.). The aqueous suspension was extracted with ethyl acetate, the organic phase was dried (MgSO4) and evaporated and the solid was recrystallized from ethyl acetate/water and dried under reduced pressure to give the title product.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(C#N)cc1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 4-ethynylbenzonitrile (Aldrich, 64 mg, 0.6 mmol). 1H NMR (300 MHz, DMSO-d6) δ7.69 (dd, J=8.0, 4.9 Hz, 2H), 7.96 (s, 1H), 8.03-8.20 (m, 3H), 8.39 (d, J=7.8 Hz, 1H), 8.78 (dd, J=4.7, 1.7 Hz, 1H), 9.16 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:21])[CH:10](C(OC)=O)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C@H:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][C:11](=[O:21])[CH2:10][C:9]1=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1C(=O)C[C@@H](Cc2ccccc2)N(Cc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1CC(=O)N(Cc2ccccc2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 106.1 g (0.301 mol) of methyl (6R)-1,6-dibenzyl-2,4-dioxo3-piperidine carboxylate in 298 ml of toluene and 445 ml of 10% strength (vol/vol) acetic acid is heated at 80° for 21/2 hours. The reaction mixture is cooled to room temperature, neutralised by adding 48 g of solid sodium carbonate while cooling in ice-water, the phases are separated, and the aqueous phase is extracted once more with 300 ml of ethyl acetate. The combined organic phases are washed with water, then with brine dried over sodium sulfate and evaporated to dryness. The resulting oil is crystallised from ether, resulting in the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24])[C:15]([NH:17]O)=[NH:16]>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]2[N:17]=[C:4]([C:3]3[CH:7]=[CH:8][N:9]=[CH:10][C:2]=3[Cl:1])[O:5][N:16]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: O=C(Cl)c1ccncc1Cl
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2noc(-c3ccncc3Cl)n2)cc1Cl
Temperature: 100 °C
Yield: 70.4 %

Procedure:
To a solution of 3-chloroisonicotinoyl chloride (about 2.6 mmol) (prepared by General procedure F) in pyridine (5 mL) was added 3-chloro-4-isopropoxy-N-hydroxy-benzamidine (300 mg, 1.31 mmol) (prepared by General procedure B). The mixture was heated at 100° C. overnight. The solvent was removed under reduced pressure and the crude product was purified via normal phase silica gel chromatography (0-50% ethyl acetate/heptane gradient over 30 min) to give 3-(3-chloro-4-isopropoxyphenyl)-5-(3-chloropyridin-4-yl)-[1,2,4]-oxadiazole (323 mg, 70.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:25]([C:24]1[CH:23]=[CH:22][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:28][CH:27]=1)=[N:1]2
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1
Temperature: 155 °C
Reaction time: 14 h
Yield: 38.8 %

Procedure:
A mixture of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.765 mmol), 4-morpholin-4-yl-benzaldehyde (0.15 g, 0.765 mmol), sodium hydrogensulfite (0.136 g, 0.765 mmol) and p-toluenesulfonic acid (10 mg) in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The solid was collected by filtration, washed with water and MeOH to yield 5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one (0.109 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[Si:11]1([CH2:16][Cl:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:17][CH2:16][Si:11]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: ClC[Si]1(Cl)CCCC1
Product: ClC[Si]1(c2ccc(Cl)cc2)CCCC1

Procedure:
In the same apparatus and procedures as Example 1 was reacted 83 ml of 4-chlorophenylmagnesiumbromide solution (1.0 M in diethylether) with 1-chloro-1-chloromethyl-1-silacyclopentane prepared from the above procedure i) for 5 hrs. In the same method as Example 1 was treated the reaction product to give 5.20 g of 1-chloromethyl-1-(4-chlorophenyl)-1-silacyclopentane (b.p. 108°-110° C./0.5 mmHg).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C@@H:11]([OH:18])[C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1)([CH3:4])[CH3:3].[H-].[Na+].[Cl:22][C:23]1[C:30]([F:31])=[CH:29][C:26]([C:27]#[N:28])=[C:25](F)[CH:24]=1.O>CN(C)C=O>[Cl:22][C:23]1[C:30]([F:31])=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH:24]=1)[O:18][C@@H:11]([C:12]1[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=1)[CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:19])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: Cn1ccnc1[C@H](O)CCCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1[C@@H](CCCNC(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
The product of step (b) (0.24 g, 0.9 mmol) was dissolved in dry dimethylformamide (20 ml), sodium hydride (60% dispersion in oil, 0.04 g, 0.95 mmol) was added in one portion and the mixture stirred at room temperature for 0.5 h. 4-Chloro-2,5-difluorobenzonitrile (0.16 g, 0.9 mmol), as a solution in dry dimethylformamide (5 ml), was added dropwise and the reaction stirred for 18hat room temperature. Water (25 ml) was added and the reaction mixture extracted with ethyl acetate (3×60 ml). The combined organic extracts were washed with water (2×20 ml), dried (magnesium sulphate) and evaporated. The residue was eluted down a flash chromatography column using hexane:ethyl acetate (1:3) as eluent to give the sub-title compound as a white crystalline solid (0.34 g, 88%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:4]=1.[C:24](#[N:26])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[F:10][C:9]([F:12])([F:11])[CH2:8][N:7]1[C:3]([CH2:2][C:24]#[N:26])=[CH:4][C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[N:6]1
Reactant: CC#N
Reactant: FC(F)(F)Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: N#CCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described for example 9 b], 5-chloromethyl-1-(2,2,2-trifluoro-ethyl)-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole was reacted with tetrabutylammonium cyanide in acetonitrile to give [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetonitrile as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:33][C@@H:14]2[O:15][Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)[O:19][CH2:20][C@H:13]2[CH2:12]1.F.N1C=CC=CC=1>C1COCC1.N1C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:33][C@H:14]([OH:15])[C@@H:13]([CH2:20][OH:19])[CH2:12]1
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)C[C@@H]2O[Si](C(C)C)(C(C)C)O1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Reaction time: 14 h
Yield: 63.6 %

Procedure:
To a solution of 6-chloro-9-[(6aR,8R,9aS)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purine (0.518 g, 1.0 mmol) in THF/pyridine (5.2 mL, 1:1) was added hydrofluoric acid in pyridine (0.381 mL, 15.2 mmol). The reaction was stirred for 14 h then quenched with saturated aq NaHCO3 and concentrated under reduced pressure. The residue was dissolved in 10% solution of MeOH/DCM, filtered, the organic layer was concentrated and the residue purified by flash chromatography (0 to 10% MeOH/DCM to afford the title compound (0.171 g, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:28][CH:29](Br)[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH2:30][CH2:29][Br:28])[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(CCBr)c(C(=O)OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (1.0 g, 3.45 mmol) in anhydrous DMF (20 mL) were added Cs2CO3 (1.35 g, 4.13 mmol) and dibromoethane (2.27 g, 12.1 mmol). The reaction mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using a 0-25% EtOAc/hexanes gradient elution. Collection and concentration of the appropriate fractions provided the title compound as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 7.45-7.34 (m, 5H), 5.06 (s, 2H), 4.88 (t, J=6.4 Hz, 2H), 3.86-3.79 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:10][C:3]=12.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]3[CH:36]=[CH:35][C:20]4/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=5[O:24][CH2:25][C:19]=4[CH:18]=3)[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:10][C:3]=12
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: Clc1ccnc2[nH]c(C3CCC3)nc12
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CCC4)nc4c(Cl)ccnc43)cc2COc2cc(F)ccc21
Yield: 62.8 %

Procedure:
Using 7-chloro-2-cyclobutyl-3H-imidazo[4,5-b]pyridine (WO2009/29592, 69 mg, 0.335 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (102 mg, 62%) was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([OH:51])=O)[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[C:53]1([CH:59]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C=O)C>[CH:59]([N:66]1[CH2:71][CH2:70][N:69]([C:49]([C:47]2[N:48]=[C:43]3[CH2:42][CH2:41][CH:40]([C:36]4[CH:37]=[C:38]([CH3:39])[C:33]([O:32][CH3:31])=[C:34]([CH3:52])[CH:35]=4)[CH2:45][N:44]3[CH:46]=2)=[O:51])[CH2:68][CH2:67]1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCN(C(c5ccccc5)c5ccccc5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then diphenylmethylpiperazine (166 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and poured onto water. The precipitated solid was filtered. Yield: 232 mg (88%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]Cl)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:9]([C:10]#[N:11])([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: ClCC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(CC1CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Sodium hydride (1.69 g, 42.1 mmol; 80% dispersion in oil) was added portionwise over 10 minutes to a solution of diphenylacetonitrile (7.4 g, 38.3 mmol) in toluene (40 ml) and the mixture was heated under reflux for 45 minutes, treated with 1-benzyl-4-chloromethylpiperidine (4.3 g, 1.92 mmol; prepared by partitioning the hydrochloride salt, which was obtained by the method described in J. Het. Chem., 1978, 15, 675, between 10% aqueous sodium carbonate solution and dichloromethane, drying the organic layer over magnesium sulphate and evaporating), heated under reflux for one hour, allowed to cool to room temperature and partitioned between toluene and water. The organic layer was dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (7.57 g, 52%) as a colourless foam which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C(O)C.[H][H]>[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C(=O)c2cccc(N)c2)CC1
Yield: 80.9 %

Procedure:
(4-Methyl-piperazin-1-yl)-(3-nitro-phenyl)-methanone (2.46 g, 9.87 mmol) was dissolved in Ethanol (30.0 mL, 514 mmol) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (0.750 g, 56.2 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 1.75 g of (3-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone without further purification. (M+H)=220.6.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C)C=O>[C:12]1([NH:11][C:5]2([CH2:4][NH:3][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCC1(Nc2ccccc2)CCCCC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
110 mg (2.69 mmol) of sodium hydride are added to a solution of 500 mg (2.45 mmol) of (1-aminomethylcyclohexyl)phenylamine in 20 ml of dimethyl formamide. The solution is stirred for 1 h at room temperature and 270 μl (2.45 mmol) of ethyl bromoacetate are added. The reaction medium is stirred at room temperature for 2 h. It is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane then heptane/ethyl acetate 90/10, v/v). 530 mg of ethyl [(1-phenylamino-cyclohexylmethyl)amino]acetate are obtained in the form of a colorless oil. Yield=75%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=[N:25][OH:26])[CH3:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)C(Cc1ccc(Cl)cc1)N1CCCC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-3-pyrrolidin-N-yl-butan-2-one (200 mg, 0.79 mmol, from Step B) dissolved in ethanol (2 mL), was added pyridine (63 mg, 0.79 mmol), and hydroxylamine hydrochloride (78 mg, 1.12 mmol). The mixture was refluxed for 24 h when LC/MS indicated disappearance of all starting material. The mixture was cooled to room temperature, concentrated under reduced pressure, treated with 33% aqueous potassium carbonated, and extracted with chloroform 5 times. The organic layers were combined and filtered over glass wool and dried over potassium carbonate. The filtrated obtained after passing through sintered glass was concentrated to give the oxime, homogeneous by TLC, Rf=0.3 in 95:5 CH2Cl2:MeOH. LC/MS m/e=267 (M+1). 500 MHz 1H NMR (CDCl3) δ 1.73(m, 4H), 1.76 (s, 3H), 2.40 (m, 2H), 2.60 (m, 2H), 2.72 (dd, J=2.7, 10.8 Hz, 1H), 2.94 (dd, J=4.3, 8.8 Hz, 1H), 3.03 (dd, J=4.4, 13.3 Hz, 1H), 3.8 (s, 1H), 6.96 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H)