Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=2[Cl:23])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].ClCCl>O>[C:31]([O:22][C:20]1[CH:19]=[CH:18][C:17]([Cl:23])=[C:16]([N:3]2[C:2]([NH2:1])=[C:6]3[C:7](=[O:15])[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]3=[N:4]2)[CH:21]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1cc(O)ccc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Cl)c(-n2nc3c(c2N)c(=O)[nH]c2ccccc23)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-amino-2-(2-chloro-5-hydroxyphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (65 mg), triethylamine (31 μl), acetyl chloride (15 μl) and dichloromethane (1.7 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and chloroform-hexane was added to the residue. The precipitated solid was collected by filtration to obtain the target compound (52 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1cccc(NN2C(=O)c3[nH]c4cc(Cl)ccc4c(=O)c3C2=O)c1
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1cccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.8 %

Procedure:
A stirred suspension of 6-chloro-2-(3-methoxyanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.85 g, 5.00 mM) in a solution of methanol (0.93 L) and methanesulfonic acid (93 mL) was refluxed for 16 hours to give a tan suspension. This suspension was cooled to room temperature and stirred for 24 hours. The suspension was filtered (the filtrate saved for use in Example 33) and the collected solids were washed with methanol and then ether to give the title compound (0.385 g, 21%) as a tan powder, mp 393-395° C.; MS(CI): 370 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:30]=1)[C:22]1[CH:21]=[C:20]([OH:23])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C.CCOC(C)=O>[C:1]([NH:5][C:6]1[S:7][CH2:8][C:9]2([N:30]=1)[C:22]1[CH:21]=[C:20]([O:23][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH:19]=[CH:18][C:17]=1[O:16][C:15]1[C:10]2=[CH:11][C:12]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CI
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)COc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 100 °C

Procedure:
To a solution of 2-(tert-butylamino)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (0.075 g, 0.179 mmol) in DMF (2 mL) was added cesium carbonate (0.175 g, 0.538 mmol) followed by 1-iodo-2,2-dimethylpropane (0.048 mL, 0.358 mmol). The mixture was heated to 100° C. After 6 hrs the mixture was cooled to RT, diluted with EtOAc, and washed with water and brine. The organic fraction was concentrated in vacuo and purified by silica gel chromatography using 40-60% Hexanes:EtOAc to afford N-tert-butyl-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine as an off-white foam. MS: MH+=489.2.
Reaction SMILES: [OH-].[K+].O.C([O:6][C:7](=[O:22])[CH:8](Br)[CH:9](Br)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)C>C(O)C>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:7]([OH:22])=[O:6])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(OC)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C#CC(=O)O)cc1OC
Temperature: 10 °C

Procedure:
To a solution of 52.7 g (0.80 mol) of potassium hydroxide (85%) in 300 ml of ethanol and 30 ml of water 59.4 g (0.15 mol) of 2,3-dibromo-3-(3,4-dimethoxyphenyl)propionic acid ethyl ester are added at 25° C. over 10 minutes. The mixture is stirred under reflux for 2.5 hours. The solvent is evaporated, the residue dissolved in 200 ml of water and, with cooling to 10° C., the solution acidified with 2N hydrochloric acid. The resulting crystals are filtered off, washed with water and recrystallized from methanol/water.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:3])=[O:2].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(Cl)Cl>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([CH:5]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:4][N+:1]([O-:3])=[O:2])[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])C=CC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(C[N+](=O)[O-])C2CCCCC2)CC1
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of (2-nitrovinyl)-cyclohexane (2.63 g, 16.94 mmol), prepared as in J. Org. Chem. 1993, 58, 3850, in dry CH2Cl2 (22 mL), N-Boc piperazine (2.63 g, 14.12 mmol) was added at room temperature and reaction stirred overnight. Solvent was removed under reduced pressure to afford the adduct product (99%) as an oil. MS m/z 342.4 (M++1) .
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.CN1CCOCC1.[NH2:42][OH:43].Cl.[OH-].[K+]>C1COCC1.CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:17]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6](=[O:5])[NH:42][OH:43])(=[O:19])=[O:18])=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
{Carboxymethyl-[4-(4-bromo-phenoxy)-benzenesulphonyl]-amino}-acetic acid (4b) (500 mg, 1.30 mmol) was dissolved in dry THF (10 mL). ECF (100 μL, 1.12 mmol), and NMM (120 μL, 1.12 mmol) were added and stirred for 40 min at 0° C. NH2OH×HCl (90 mg, 1.30 mmol) and KOH (73 mg, 1.30 mmol) were dissolved in dry MeOH (10 mL) and stirred at 0° C. for 30 min. The solids were filtered off, and the THF solution was added dropwise to the methanol filtrate and stirred for 2 h at 0° C. The reaction mixture was filtered, the solvent evaporated, and the residue dissolved in H2O (25 mL). After adjusting the pH to 1-2, the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4, evaporated in vacuo, and co-evaporated with EtOAc (3×3 mL) to yield the pure product as light-pink solid. Yield: 267 mg, 0.67 mmol, 52%. 1H-NMR (DMSO-d6): δ 7.91 (dd, 2H, 3JHH=9.0 Hz, 4JHF=5.1 Hz, ArH), 7.42 (t, 2H, 3JHH=9.0 Hz, 3JHF=9.0 Hz, ArH), 4.07 (s, 4H, 2×CH2CO2H). ESI-MS calcd for C16H15FN2O7S 398.06 [M-H]−, obsd 399.10
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1)[CH3:8].[C:21](O)(=[O:24])[CH:22]=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)CCl>[CH:16]([C:11]1[C:12]2[O:15][C:22](=[O:23])[CH:21]([OH:24])[C:13]=2[CH:14]=[C:9]([C:7]([CH3:19])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:20])[CH:10]=1)([CH3:17])[CH3:18]
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)c(C(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCCC(C)(C)c1cc(C(C)C)c2c(c1)C(O)C(=O)O2
Temperature: 25 °C

Procedure:
5-Methyl-5-(4-hydroxy-3-isopropyl phenyl)-hexanoic acid methyl ester (10.0 g), glyoxylic acid (6.4 g of the 50% solution in water) and p-toluene sulphonic acid (40 mg) are heated in 40 ml of ethylene chloride under nitrogen at reflux in an apparatus designed for the removal of water. After 5 hours the reaction mixture is cooled to room temperature, washed two times with 25 ml water, dried over magnesium sulphate and evaporated under reduced pressure to give 13 g of 7-isopropyl-5-(4-methoxycarbonyl-1,1-dimethylbutyl)-3-hydroxy-3H-benzofuran-2-one as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[NH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[NH2:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Product: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-aminobenzene boronic acid, gave 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)[CH:12]=[O:13]
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of [3-bromo-5-(trifluoromethyl)phenyl]methanol (409 mg, 1.61 mmol) in CH2Cl2 (25 mL) was cooled to 0° C. and then Dess-Martin periodinane (1.02 g, 2.41 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and then warmed to room temperature. After stirring at room temperature for thirty minutes, the reaction was poured into 1N NaOH (25 mL). The mixture was extracted with EtOAc (100 mL), and the organic extracts were washed with 1N NaOH (25 mL), then brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 25% EtOAc/hexanes afforded 3-bromo-5-(trifluoromethyl)benzaldehyde. Rf=0.60 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 10.02 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23](OC(F)(F)F)=[CH:22][CH:21]=3)[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1.[F:31][C:32](OB(C1C=CC=CC=1)O)([F:34])[F:33]>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:32]([F:34])([F:33])[F:31])=[CH:24][CH:25]=3)[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: O=C1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2OCCN1Cc1ncccn1
Reactant: OB(OC(F)(F)F)c1ccccc1
Product: O=C1c2cc(-c3ccc(C(F)(F)F)cc3)ccc2OCCN1Cc1ncccn1

Procedure:
Compound 2 is prepared in a manner similar to that of Compound 1 except that 4 trifluoromethyl phenyl boronic acid is used in place of 4-trifluoromethoxy phenyl boronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Sc2ncc(Br)cn2)cc1
Yield: 74 %

Procedure:
A solution of 5-bromo-2-chloropyrimidine (5 g, 0.026 mol), 4-aminothiophenol (3.24 g, 0.026 mol), and K2CO3 (7.14 g, 0.052 mol) in dry DMSO (50 mL) was stirred at 120 ° C. for 2.5 hours under N2. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried. The solvent was evaporated to give a residue that was purified by silica gel flash column chromatography (ethyl acetate-hexane 1:3) to give 4-(5-bromopyrimidin-2-ylsulfanyl)phenylamine (4n), yield 74%. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 7.37 (d, J) 8.0 Hz, 2H), 6.72 (d, J) 8.0 Hz, 2H), 2.63 (s, 2H); EI-MS m/z 281 [M]+, 283 [M+2]+.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Cl:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].Cl>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:19][CH:20]([C:22]([F:25])([F:24])[F:23])[CH2:21][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C=C(Cl)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#CC(C#N)(CC(Cl)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile was dissolved in 10 ml of a solution (1 mol/L) of tetrabutylammonium fluoride in tetrahydrofuran and thereto 5 ml of 2-chloro-3,3,3-trifluoropropene was added at 0° C. The mixture was then stirred at room temperature for 3 days. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.03 g of 2-(2-chloro-3,3,3-trifluoropropyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (69)).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl[C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=2)[C:16]#[N:17])[CH:9]=[C:8]([C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:7]=1>>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=3)[C:16]#[N:17])[CH:9]=[C:8]([C:21]3([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccnc(Nc2cc(C3(C#N)CCOCC3)cc(Cl)n2)c1
Reactant: C1CNC1
Product: N#Cc1ccnc(Nc2cc(C3(C#N)CCOCC3)cc(N3CCC3)n2)c1
Yield: 17 %

Procedure:
Reaction of azetidine with 2-((6-chloro-4-(4-cyanotetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrile (50.0 mg, 0.147 mmol) following procedure of Method A afforded the target compound as a colorless solid (8.9 mg, 17%); 1H NMR (400 MHz, DMSO) δ 9.95 (br s, 1H), 8.48 (s, 1H), 8.42 (d, J=5.0 Hz, 1H), 7.23 (dd, J=5.0, 1.4 Hz, 1H), 6.89 (d, J=1.2 Hz, 1H), 5.99 (d, J=1.2 Hz, 1H), 4.06-3.98 (m, 6H), 3.70-3.59 (m, 2H), 2.41-2.28 (m, 2H), 2.08-1.96 (m, 4H); ESI-LRMS m/z [M+1]+=361.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:22]3[CH:23]=[CH:24][S:20][CH:21]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1ccsc1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1ccsc1
Yield: 90 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 90% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][OH:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][CH2:29][CH2:30][OH:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Reactant: NCCO
Product: CCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 58 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.081 mmol) and 2-aminoethanol (0.05 mL) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (18 mg, 58% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.47 (br s, 1 H), 8.53 (s, 1 H), 7.35 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.20-4.13 (m, 4 H), 3.85 (m, 2 H), 3.63 (m, 2 H), 1.22 (m, 3 H); HRMS m/z calcd for C20H21FN3O4: 386.1510. Found: 386.1517.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:22][N:21]=2)[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2cccs2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2.0 g 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester in 5 ml DMF, 360 mg NaH (60% in mineral oil) and subsequently 2.8 g 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] were added and the mixture was stirred at 80° C. for 1 h. After the addition of 5 ml water the mixture was filtered through a Chem Elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 4 g.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[CH:22]=1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Reactant: Nc1cccnc1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2cccnc2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 3-Aminopyridine instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=309.3 (M+H)+.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:14][CH2:15][CH3:16])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:15]([O:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:11])([F:12])[F:13])[C:4]#[N:5])[CH3:16]
Reactant: CCOc1cc(C#N)c(N)cc1C(F)(F)F
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C#N)ccc1C(F)(F)F
Yield: 84.8 %

Procedure:
To a solution of 2-amino-5-ethoxy-4-trifluoromethyl-benzonitrile from step 4 (31.62 g, 137.4 mmol) in dry THF (410 mL) was added isoamyl nitrite (40.4 mL, 302 mmol) and the mixture was refluxed for 16 h. The solvent was removed in vacuum to give an orange oil, which was dissolved in sat. NaHCO3-sol., extracted three times with diethyl ether. The combined organic layers were washed with 1 N HCl and brine, dried over Na2SO4. Removal of the solvent in vacuum left an orange oil, which was purified by double Kugelrohr distillation (up to 160° C. bath temperature at 1.5 mbar) to give the title compound as a light yellow solid (25.06 g, 85%). MS (EI) 185.1 [M].
Reaction SMILES: [CH3:1][C:2](=[C:4]([CH3:6])[CH3:5])[CH3:3].[Cl:7][SiH:8]([Cl:10])[Cl:9].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH3:1][C:2]([Si:8]([Cl:10])([Cl:9])[Cl:7])([CH3:3])[CH:4]([CH3:6])[CH3:5]
Reactant: Cl[SiH](Cl)Cl
Reactant: CC(C)=C(C)C
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CC(C)C(C)(C)[Si](Cl)(Cl)Cl
Temperature: 130 °C
Yield: 88 %

Procedure:
A two-liter autoclave (Husteroy) equipped with a stirrer was charged in a nitrogen atmosphere with 177 grams (2.10 mols) of 2,3-dimethyl-2-butene, 562 grams (4.16 mols) of trichlorosilane and 100 grams (0.41 mol) of 1,1'-azobiscyclohexanecarbonitrile. The mixture was stirred and heated at a temperature of 130° C. for 3 hours. The resulting reaction liquid was purified by distillation thereby obtaining 406 grams of 1,1,2-trimethylpropyltrichlorosilane (yield: 88%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[CH:14]=[C:15]([F:16])[C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 31.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.12 g, 0.21 mmol) prepared in Example 46a, triethylsilane (0.10 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (2.0 mL), to yield the title compound (0.030 g, 30%) as a colorless solid.
Reaction SMILES: O.[OH-].[Ba+2:3].[OH-].[P:5](=[O:9])([OH:8])([OH:7])[OH:6].[OH-].[Ba+2].[OH-]>O>[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Ba+2:3].[P:5]([O-:9])([O-:8])([O-:7])=[O:6].[Ba+2:3].[Ba+2:3]
Reactant: O=P(O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
Barium phosphate was prepared by the following procedure. Barium hydroxide monohydrate (20.0 g, 105.6 mmoles) was dissolved in 3000 ml of distilled water with stirring for a few minutes. Phosphoric acid (8.1 g of 85%w phosphoric acid, containing 70.4 mmoles of the acid) was diluted with 100 ml of distilled water and the dilute acid was added dropwise to the barium hydroxide solution over a ten minute period. A milky white suspension formed and remained as the mixture was stirred for four hours. A solid was recovered upon filtration through a Buchner funnel, washed with 1200 ml of distilled water, and filtered to dryness. The solid was placed in a vacuum oven at 120° C. and 20mm of mercury for several hours to effect more complete dryness. The white solid was analyzed by X-ray powder diffraction and found to contain Ba3 (PO4)2 as the only crystalline product.