Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16](C)=O)[C:13]([CH3:19])=[CH:12][C:11]=2[F:20])[N:8]=[C:7]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:6]=1)(=[O:3])[CH3:2]>C(OC(=O)C)(=O)C>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([SH:16])[C:13]([CH3:19])=[CH:12][C:11]=2[F:20])[N:8]=[C:7]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(S(C)=O)c(C)cc1F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(S)c(C)cc1F
Temperature: 120 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
Then, 4.5 g of 5-acetylamino-1-(2-fluoro-4-methyl-5-methylsulfinylphenyl)-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 200 mL of acetic anhydride, followed by stirring at 120° C. for 6 hours. Acetic anhydride was distilled off under reduced pressure, the obtained residue was dissolved in 150 mL of ethanol, and 4.0 g of potassium carbonate was added, followed by stirring at room temperature for 12hours. Neutralization with a 6N hydrochloric acid aqueous solution was carried out, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 3.8 g of 5-acetylamino-1-(2-fluoro-4-methyl-5-mercaptophenyl)-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole (1H-NMR (CDCL3/TMS δ (ppm) value) δ: 2.09 (3H, s), 2.38 (3H, s), 3.39 (1H, s), 4.66 (2H, t), 6.20 (1H, s), 7.09 (1H, d), 7.14 (1H, brs), 7.39 (1H, d)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[N:4][CH:3]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:8][C:6]1[C:5]([O:9][CH3:10])=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1ncc(Cl)nc1N
Product: COc1ncc(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.24 g) and 2,3-dichlorobenzenesulphonyl chloride (0.32 g). Yield 0.24 g.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[CH:8]=[C:7]1[CH2:15][O:16][CH3:17])[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.CCOC(C)=O>[CH2:1]([O:4][N:5]1[C:28](=[O:30])[N:10]2[CH2:11][C@H:6]1[C:7]([CH2:15][O:16][CH3:17])=[CH:8][C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON[C@H]1CN[C@H](C(N)=O)C=C1COC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(COC)=C[C@H]2C(N)=O
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a stirred solution of (2S,5R)-5-(allyloxyamino)-4-(methoxymethyl)-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 74, 1.12 g, 4.64 mmol) in acetonitrile (100 mL), N-ethyl-N-isopropylpropan-2-amine (4.04 mL, 3.00 g, 23.21 mmol) was added, then triphosgene (551 mg, 1.86 mmol) in 20 mL acetonitrile was added slowly via syringe pump over 4 h at 0° C. It was stirred from 0° C. to rt overnight. The solution was concentrated to give a residue, which was then taken up in 50 mL EtOAc and washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 0-100% ethyl acetate/hexanes gave a yellow oil (420 mg, 34%).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(N(CC)CC)C>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1csc(C2CCNC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)C1
Reaction time: 0.33 h

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-pyrrolidin-3-yl-thiophen-3-yl)-methanone (CC-177) (0.065 g, 0.19 mmol) was dissolved in triethylamine (2 mL) and acetic anhydride was added and the resulting mixture stirred for 20 minutes. The solvent was evaporated and the resulting gum was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.029 g). LCMS m/z 361.20[M+H]+ RT=9.24 min (Analytical Method 2).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1>[Ni]>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [Ni]
Product: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
In the middle of the column at a height of 331 cm, 900 g/h of liquid L-menthol of synthetic origin were fed to the dividing wall column in the feed section of the dividing wall, which had been obtained by catalytic hydrogenation of L-isopulegol over a nickel catalyst, and comprised 99.39 GC area % L-menthol, 0.29 GC area % isopulegol, 0.25 GC area % neomenthol and 0.011 GC area % isomenthol, and also 0.044 GC area % neoisomenthol. The column was operated at top pressure 50 mbar and a return rate of 3.0 kg/h. A pressure drop of about 35 mbar (±1 mbar) was established. At the top of the column, a temperature of 120° C. was measured, and in the bottom a temperature of 135° C. (±0.5 K). The column was operated without a bottom draw and the distillate withdrawal was adjusted by means of a balance control system to 15 g/h (±1 g/h). The reflux ratio was thus about 200:1. The condenser of the column was at a temperature of 40° C. in order to prevent solids formation.
Reaction SMILES: S(=O)(=O)(O)O.C(=O)=O.[N+:9]([O-:12])(O)=[O:10].[Cl:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:22]>C(Cl)Cl>[Cl:13][CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([N+:9]([O-:12])=[O:10])[CH:18]=[CH:17][N+:16]=1[O-:22]
Reactant: Cc1ccc[n+]([O-])c1CCl
Reactant: O=[N+]([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])cc[n+]([O-])c1CCl
Reaction time: 2 h

Procedure:
300 ml of concentrated sulfuric acid was added slowly while cooling with dry ice to 230 ml of concentrated nitric acid (68%:d=1.41), while the temperature of the mixture was not allowed to exceed 5°. A solution of 38.7 g of 2-chloromethyl-3-methylpyridine 1-oxide was added thereto and the mixture was stirred at 80° for 2 hours. The reaction mixture was poured into a mixture of ice and methylene chloride, the aqueous phase was washed several times with methylene chloride and the methylene chloride solution was extracted with 10% sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The residue is recrystallized from ethyl acetate, there being obtained 2-chloromethyl-3-methyl-4-nitropyridine 1-oxide. The product has a melting point of 126°-129°.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].I[CH2:12][CH2:13][O:14][CH:15]([O:17][CH2:18][CH2:19]I)[CH3:16]>O1CCCC1>[C:3]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH2:13][O:14][CH:15]([O:17][CH2:18][CH2:19][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:3]#[N:4])[CH3:16])#[N:4]
Reactant: CCOC(=O)CC#N
Reactant: CC(OCCI)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CCOC(C)OCCC(C#N)C(=O)OCC
Yield: 55.9 %

Procedure:
5.28 g (0.11 mol) of sodium hydride was added to 50 ml of dry tetrahydrofuran, and to this solution was added dropwise a mixed solution of 12.2 g (0.11 mol) of ethyl cyanoacetate and 10.0 g (0.027 mol) of bis(2-iodoethoxy)ethane, followed by 2-hours reflux under heating. After the reaction, the most portion of tetrahydrofuran was distilled off and the residue was added with 10 ml of water, neutralized with 1N hydrochloric acid and extracted three times with 50 ml of ether. After drying the extract over anhydrous sodium sulfate, ether was distilled off and the resultant oily product was passed through a basic alumina (activity II)-packed column and eluted with petroleum ether-ether (1:4) to obtain 5.14 g of bis(3-cyano-3-carboethoxypropoxy)ethane, ##STR32## (yield: 56%). The property analyses of this compound gave the following results.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][O-:16].[Na+].O>CN(C)C=O>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: C[O-]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 4′-fluoro-3′-trifluoromethylacetophenone (25.0 g) in N,N-dimethylformamide (70 ml) was added under ice-cooling sodium methoxide (7.21 g), and the mixture was stirred under ice-cooling for 2 hr and further at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (24.3 g) as a brown solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.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>[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
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: COCCOC
Solvent: O
Product: CCCCOc1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A mixture of sodium carbonate (0.978 g), tetrakis(triphenylphosphine)palladium(0) (0.267 g), 4-butoxyphenylboronic acid (1.16 g) and 3-bromopyridin-2-amine (0.799 g,) in DME (23 mL) and water (4.6 ml) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (0.690 g) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:26][CH2:27][CH3:28])[C:5]2[S:25][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[CH2:27]([O:26][C:4]1[C:5]2[S:25][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=[C:2]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:3]=1)[CH3:28]
Reactant: C1CNCCN1
Reactant: CCOc1nc(Cl)nc2c1sc1nc(-c3ccc(OC(C)C)cc3)nc(C)c12
Solvent: C1COCCO1
Product: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(OC(C)C)cc3)nc(C)c12

Procedure:
0.1 g (0.24 mmol) 2-chloro-4-ethoxy-9-methyl-7-(4-iso-propoxy-phenyl)-thieno[2,3-d:4,5-d′]dipyrimidine and 83 mg (0.96 mmol) piperazine are refluxed in 40 ml dioxane for 4 h. Thereafter, the solvent is removed and the residue is suspended in water and sucked off. Following flash chromatography (chloroform/ethanol 10:2) 20 mg (18%) of the title substance is obtained.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[C:19](Br)[C:12]2=[N:11][C:10]=1[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:30][N:31]=1)C1C=CC=CC=1.[Si]([I:44])(C)(C)C.CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C:29]2[O:28][C:27]([C:10]3[N:11]=[C:12]4[C:19]([I:44])=[CH:18][C:17]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])=[N:31][CH:30]=2)=[CH:34][CH:35]=1
Reactant: O=c1c(OCc2ccccc2)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(Br)cc(N3CCOCC3)cn12
Reactant: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=c1c(O)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(I)cc(N3CCOCC3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of the product of example 3 (25 mg, 0.042 mmol) in acetonitrile (1 ml) was added idodotrimethylsilane (TMSI) (0.05 ml, 0.338 mmol) at room temperature. The mixture was stirred at room temperature for 8 hours, after which methanol (0.1 ml) was added to quench the reaction. Then saturated solution of Na2S2O3 was added drop-wise till a yellow solid was precipitated. The resulting solids were collected by filtration, washed with ethyl acetate to give the titled compound (13 mg, 60% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[NH:8][C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([C:7]3[NH:8][C:9]4[CH:14]=[CH:13][N:12]=[CH:11][C:10]=4[N:15]=3)[CH2:2]2)[N:20]=[C:19]([NH2:24])[N:18]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: c1cc2[nH]c(C3CNCCO3)nc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4cnccc4[nH]3)C2)n1
Yield: 55.6 %

Procedure:
a solution of 2-(2-morpholinyl)-1H-imidazo[4,5-c]pyridine (0.996 g, 4.88 mmol), 4,6-dichloro-2-pyrimidinamine (0.8 g, 4.88 mmol) and Hunig's base (2.12 mL, 12.2 mmol) in ethanol (24.39 mL) was heated at 85° C. overnight. The mixture was concentrated and chromatographed (PE-EtOAc, 1:5) to afford the title compound (0.9 g). LC-MS (ES) m/z=332 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([C@:41]5([CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH2:45][CH2:44][CH2:43][N:42]5[CH3:46])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].N>C1COCC1.CO.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([C@:41]5([CH2:47][OH:48])[CH2:45][CH2:44][CH2:43][N:42]5[CH3:46])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@]5(CO[Si](C(C)C)(C(C)C)C(C)C)CCCN5C)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [F-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@]5(CO)CCCN5C)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a solution of Intermediate 85k (250 mg, 0.310 mmol) in THF (10 mL) at −30° C. was added TBAF (1M in THF, 620 μL, 0.620 mmol) and the mixture was allowed to warm to RT over 2 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave a crude product. Recrystallisation from hot diethyl ether (50 mL), EtOAc (10 mL) and cyclohexane (20 mL) gave the title compound as a white powder (113 mg, 56%). LCMS (Method 5): Rt 3.68 min, m/z 649.1 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.29 (9H, s), 1.86-2.34 (11H, m), 2.38 (3H, s), 3.02 (1H, m), 3.09 (1H, dt, J 8.8, 3.5), 4.07 (1H, d, J 11.0), 4.25 (1H, d, J 4.3), 4.52 (1H, br s), 4.90 (1H, m), 5.25 (1H, t, J 4.3), 6.33 (1H, s), 7.18-7.36 (9H, m), 7.62 (1H, d J 7.6), 8.44 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][NH:7][CH2:6]2)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:19]1[N:28]=[C:27]2[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]2[CH:29]2[CH2:31][CH2:30]2)=[CH:21][C:20]=1[F:36]>C(#N)C>[C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:19]1[N:28]=[C:27]3[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]3[CH:29]3[CH2:31][CH2:30]3)=[CH:21][C:20]=1[F:36])[CH2:6]2)(=[O:3])[CH3:2]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC12CNCC1C2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)NC12CC1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 51 %

Procedure:
A mixture of 1-acetylamino-3-azabicyclo[3.1.0]hexane (150 mg, 0.70 mmol) and triethylamine (0.48 ml, 3.5 mmol) in acetonitrile (7 ml) was treated with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (192.1 mg, 0.68 mmol) and heated to 80° for 18 hours. Filtration of the reaction mixture provided the title product as a white solid, mp 275° with decomposition (135.8 mg, 0.35 mmol, 51% yield). 1H NMR, (CDCl3): 8.55 (s, 1H), 8.49 (s, 1H), 7.96 (d, J=13 Hz, 1H), 4.22 (m, 1H), 3.98 (bs, 2H), 3.81 (m, 1H), 3.68 (m, 1H), 1.82 (bs, 4H), 1.12 (m, 5H), 0.78 (m, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]2[CH:17]=[C:18]([CH2:20]Cl)[N:19]=[C:11]2[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]2[CH:17]=[C:18]([CH2:20][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:19]=[C:11]2[CH:10]=1
Reactant: CSc1nc(Cl)cc2nc(CCl)cn12
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1nc(Cl)cc2nc(COc3ccccc3)cn12
Temperature: 50 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
Phenol (0.050 g, 0.53 mmol) was added to a suspension of 7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine (0.15 g, 0.53 mmol) and K2CO3 (0.21 g, 1.58 mmol) in ACN (2 mL). The mixture was stirred at 50° C. for 18 hours and then the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with diethyl ether and the solid thus obtained, filtered and dried in vacuo to yield 7-chloro-5-methylsulfanyl-2-phenoxymethyl-imidazo[1,2-c]pyrimidine (0.085 g, 53% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]1([Si:16]2(CCCCC)[CH2:21][CH2:20][CH:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)C=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:10]([Si@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=3)=[O:27])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(Cl)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 4-chloro-3-fluorophenol and 4-(4-phenyl-4-n-pentyl-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: S([O-])(=O)(=O)C.CS(O[CH2:11][C:12]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:13])(=O)=O.[Na].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>CO.CS(C)=O.O>[N:27]1([CH2:11][C:12]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CCCCOC(C)(COS(C)(=O)=O)c1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: CCCCOC(C)(Cn1cncn1)c1ccc(F)cc1
Temperature: 130 °C

Procedure:
The mesylate prepared in accordance with (a) is reacted with the sodium salt of 1,2,4-triazole. This is effected by dissolving 0.52 g (23 mmoles) of sodium in 20 ml of absolute methanol, and adding 1.55 g (23 mmoles) of 1,2,4-triazole to this solution. The methanol is then removed in vacuo, and the mesylate prepared in (a) is added, dissolved in 20 ml of dimethyl sulfoxide, to the crystalline residue. The mixture is heated for 6.5 hours at a bath temperature of 130° C. and is allowed to cool to room temperature, water is added and the mixture is extracted with chloroform. The combined extracts are washed with half-saturated sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is concentrated in vacuo. The 3.74 g of crude product obtained are purified by column chromatography (silica gel; 1:1 ethyl acetate/petroleum ether) and afford 1.57 g of the pure end product in the form of an oil. 60 MHz-1H-NMR (CDCl3): δ=8.10 and 7.85 ppm (2s, 2H of triazole); 6.9-7.4 ppm (m, 4H, aromatic); 4.3 ppm (s, 2H, --CH2N); 2.9-3.4 ppm (m, 2H, OCH2); 1.2-1.7 ppm ##STR47## and OCH2CH2CH2CH3); 0.7-1.1 ppm (m, 3H, OCH2CH2CH2CH3).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1.C(N(CC)CC)C>CC(O)C>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([N:22]5[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]5)=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: OC1CCNC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 70 °C
Yield: 99.5 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (5.00 g, 14.7 mmol), pyrrolidin-3-ol (2.55 g, 29.3 mmol), and triethylamine (4.09 mL, 29.3 mmol) in 2-propanol (32 mL) was heated in the microwave for 30 minutes at 70° C. in two vials. The reaction mixtures were combined and concentrated. The crude product was purified by flash chromatography using a Horizon purification system in three batches (2×40M and 1×40S columns) eluting with chloroform/methanol (0.1-8%). The resulting solid was dissolved in chloroform containing 0.1% methanol (810 mL) and washed with water and 1:1 water:brine, dried (MgSO4), filtered and concentrated to afford 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-ol (5.08 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:32])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([N:20]([CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:38](=[O:39])[O:40][CH3:41])=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCOCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(COCC(F)(F)F)C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 12.6 %

Procedure:
In a solution of 0.50 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl-N-(2,2,2-trifluoroethoxymethyl)benzoic acid amide in 10 mL of N,N-dimethylformamide, 0.0825 g of 60% oily sodium hydride was added under cooling with ice and with stirring, and stirred at room temperature for 10 minutes. Then, 0.268 g of methyl chloroformate was added, and continued to stir at the same temperature for 30 minutes. After the completion of the reaction, the reaction was poured in 50 mL of water, extracted with ethyl acetate (50 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.07 g of the aimed product as colorless resinous substance.