Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]([CH2:15][CH3:16])=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=1.[Na+].[Cl-:18].OS(O)(=O)=O>O.[Cl-].[Na+].O.Cl[Cu]>[Cl:18][C:6]1[S:7][C:8]([CH2:15][CH3:16])=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=1
Reactant: [Cl-]
Reactant: CCc1sc(N)nc1C(=O)OC
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1sc(Cl)nc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The following diazotization step was adapted from Barton, A.; Breukelman, S. P.; Kaye, P. T.; Meakins, G. D.; Morgan, D. J. J. C. S. Perkin Trans 11982, 159-164: A solution of NaNO2 (166 mg, 2.4 mmol) in water (0.6 mL) was added slowly to a stirred, cold (0° C.) solution of methyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate (186 mg, 1.0 mmol), CuSO4.5H2O (330 mg, 1.32 mmol), NaCl (260 mg, 4.45 mmol) and H2SO4 (5.5 mL) in water (7.5 mL). The mixture was stirred at 0° C. for 45 min and allowed to warm up to room temperature where it stirred further for 1 h before CuCl (118 mg) was added. This mixture was stirred further at room temperature for 16 h before it was diluted with brine and extracted with ether twice. The organic layers were combined, dried over MgSO4 and concentrated to give methyl 2-chloro-5-ethylthiazole-4-carboxylate (i.e. Cap-172, step a) (175 mg, 85%) as an orange oil (80% pure) which was used directly in the next reaction. Rt=1.99 min (Cond. -MD1); LC/MS: Anal. Calcd. for [M+H]+ C7H9ClNO2S: 206.01; found: 206.05.
Reaction SMILES: FC(F)(F)C1C=CC(C=C)=CC=1.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.CS[C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[N:26]1[CH:21]=[CH:22][CH:23]=[C:24]([O:27][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:25]=1
Reactant: BrC1=NOCC1
Reactant: CSc1ccc(O)cn1
Agent: C=Cc1ccc(C(F)(F)F)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-238a and I-238b were prepared in 2 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition conditions from Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 6-(methylthio)pyridin-3-ol (prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5 to provide compound I-238. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=355.3 m/z. Activity: A
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.O.C(O)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1N1CCc2ccccc21
Temperature: 180 °C
Yield: 85.7 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (30 mg 76 μmol) and indoline (0.10 ml, 790 μmol) were mixed in xylene (mixture of isomers, 0.75 ml) and heated in a microwave oven at 180° C. for 20 min. When cool again, water (0.75 ml) and acetic acid (0.75 ml) were added to the mixture, causing separation of two phases. The aqueous phase was separated and subjected to semi-preparative HPLC-C18. The appropriate fractions were pooled and evaporated in vacuo. The yellow oily residue was dissolved in EtOAc (20 ml). This solution was washed with 1% aqueous NaHCO3 (20 ml) and brine (10 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to afford the pure product (31 mg, 85%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29].O>ClCCl>[CH3:31][O:30][C:28]([N:15]1[CH2:16][CH2:17][CH:12]([CH:3]([O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])[C:2]([F:18])([F:1])[F:19])[CH2:13][CH2:14]1)=[O:29]
Reactant: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C1CCN(C(=O)OC)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
4-[2,2,2-Trifluoro-1-(triethylsiloxy)ethyl]piperidine (303 mg, 1.02 mmol) was dissolved in dichloromethane (6 mL). To this, triethylamine (0.213 mL, 1.53 mmol) and methyl chloroformate (0.213 mL, 1.53 mmol) were added at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by addition of water to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=17/3) to give 1-methoxycarbonyl-4-[2,2,2-trifluoro-1-(triethylsiloxy)-ethyl]piperidine (287 mg, yield: 79%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[NH:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.C1(C)C=CC=CC=1>S(Cl)(Cl)=O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1[nH]c(OCCN2CCCC2)nc2ccccc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: c1ccc2nc(OCCN3CCCC3)ncc2c1
Yield: 83.5 %

Procedure:
A solution of 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy-3,4-dihydroquinazolin-4-one (909 mg, 3.14 mmol) in thionyl chloride (12 ml) containing DMF (0.5 ml) was refluxed for I hour. After cooling toluene was added and the volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH8 with sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography eluting with methylene chloride/methanol (95/5 followed by 85/15). The residue was triturated with ether, collected by filtration and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxyquinazoline (638 mg, 66%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:25]([C:32]([NH:34][NH:35][C:36](=O)[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=O)=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=1>N1C=CC=CC=1.O>[CH2:37]([C:36]1[S:10][C:32]([C:25]2[C:24]([Cl:23])=[CH:29][N:28]=[C:27]([S:30][CH3:31])[N:26]=2)=[N:34][N:35]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CSc1ncc(Cl)c(C(=O)NNC(=O)Cc2ccccc2)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CSc1ncc(Cl)c(-c2nnc(Cc3ccccc3)s2)n1
Temperature: 100 °C
Yield: 47 %

Procedure:
Lawesson's Reagent (0.487 g (1.2 mmol) and 5-chloro-2-(methylthio)-N′-(2-phenyl-acetyl)pyrimidine-4-carbohydrazide (0.442 g, 1.2 mmol) were dissolved in 8 mL pyridine. This solution was heated to 100° C. for 30 h, giving −50% conversion. Upon cooling, the reaction mixture was diluted with excess H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were dried with magnesium sulfate and concentrated under vacuum. Flash chromatography was used to obtain 0.190 g (47% yield) product as a brown solid. MS (M+H)+ 335.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][C@H:18]2[CH2:31]SC2C=CC=CC=2)[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.O.[Ni]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:19][C@H:18]2[CH3:31])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CSc2ccccc2)C1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Yield: 53 %

Procedure:
Tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(phenylthiomethyl)cyclohexylcarbamate (150 mg) was dissolved in EtOH (2 mL) prior to the addition of Raney 2800 nickel (100 mg) in water. The reaction was heated at reflux for 12 h. After cooling to rt, the reaction was concentrated. The resulting residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-methylcyclohexylcarbamate (64 mg). MS found: (M+H)+=446.4.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:17]([NH:18]2)[NH:16][C:15](=[O:21])[N:14]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:24][CH2:23]2)[CH:13]=3)=[CH:9][CH:8]=1)=[O:6]>C1COCC1>[C:35]([O:34][C:32]([NH:31][CH2:30][CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][CH:22]([N:14]2[CH:13]=[C:12]3[C:17]([NH:18][C:19]4[C:10]([O:11]3)=[CH:9][CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:20]=4)=[N:16][C:15]2=[O:21])[CH2:27][CH2:26]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1ccc2c(c1)NC1NC(=O)N(C3CCN(CCCNC(=O)OC(C)(C)C)CC3)C=C1O2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(C(=O)O)ccc2O3)CC1
Temperature: 50 °C
Yield: 55.8 %

Procedure:
1M of LiOH aqueous solution (4.5 mL, 3 equiv) and 3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,3,9,9a-tetrahydro-1H-10-oxa-1,3,9-triaza-anthracene-7-carboxylic acid methyl ester (5, 760 mg, 1.52 mmol, 1.0 equiv) was added to THF (5 mL), warmed up to 50° C. and stirred until LCMS showed no starting material left. The reaction solution was cooled to RT and extracted with EtOAc. The aqueous layer was acidified to pH 2 and the desired product was precipitated and filtered to yield 3-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-2-oxo-2,9-dihydro-3H-10-oxa-1,3,9-triaza-anthracene-7-carboxylic acid (412 mg, 738 mg theoretical, 56%) as a light brown solid. For 6: C24H31N5O6, LCMS (EI) m/e 486(M++H).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH:6]([CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(OC(=O)C)C>O=P(Cl)(Cl)Cl.CCCCCC>[CH3:18][CH:6]1[CH2:7][C:8]2[C:13](=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:4](=[O:3])[NH:5]1
Reactant: CCOC(=O)NC(C)Cc1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1
Yield: 11.4 %

Procedure:
[1-Methyl-2-(4-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester (I-43c: 420 mg, 1.525 mmol) in POCl3 (4.2 mL) was refluxed with P2O5 (433 mg, 3.05 mmol) at 110° C. for 2 hours to afford the crude product. The reaction was monitored by TLC (20% ethylacetate in hexane). Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 40 mg of the product (11.46% yield).
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[N:44]=[C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[O:46][CH:47]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[N:44]=[C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)[O:46][CH:47]=1
Reactant: COCc1coc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COCc1coc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (50 mg, 0.26 mmol) in CH2Cl2 (1.3 mL) was treated at rt with DMAP (8 mg, 0.07 mmol), HOBt (43 mg, 0.32 mmol), EDC (127 mg, 0.67 mmol) and DIPEA (0.18 mL, 1.06 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(methoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (55 mg, 0.26 mmol) in CH2Cl2 (1.3 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (5 mL), the layers were separated and the org. phase was washed with water (5 mL), dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a white solid: TLC: rf (4:6 hept-EA)=0.13. LC-MS-conditions 07: tR=0.81 min, [M+H]+=381.14.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].C(O)(C)(C)C.[OH:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[N:21][C:20]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:25][C:23]1[N:22]=[N:21][C:20]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:19]([OH:18])[CH:24]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1[O-]
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of t-butanol in an autoclave was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 80.0 g of pure water and 90.0 g of toluene were added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.74 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 90.1%) and 12.5 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.3%) were obtained.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([C:9]#[CH:10])[CH2:5][CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([C:6]3([C:9]#[CH:10])[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]3)[CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(OC)(OC)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one dimethyl ketal (0.13 g, 0.36 mmol) and p-toluenesulfonic acid (catalytic amount) in acetone (5 mL) was stirred under an argon atmosphere at room temperature for 1.5 h. The mixture was concentrated, diluted with ethyl acetate and washed with water. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo to provide an oil (0.11 g, 97%).
Reaction SMILES: [F:1][C:2]([F:20])([O:10][C:11]1[CH:19]=[CH:18][C:14]([CH:15](Br)[CH3:16])=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([SH:33])[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([S:33][CH:15]([CH3:16])[C:14]2[CH:18]=[CH:19][C:11]([O:10][C:2]([F:20])([F:1])[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6])=[CH:12][CH:13]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(Br)c1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(Sc1cnn(C(C)(C)C)c(=O)c1Cl)c1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
1.4 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-α-methyl-benzyl bromide (Example 2) and 1 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.8 g of potassium carbonate in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 0.58 g of pure product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[CH:7]=[CH:8]/[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[C:18]([CH:23]=O)=[N:19][CH:20]=[CH:21][N:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1>[CH3:15][O:16][C:17]1[C:18]([CH2:23][N:12]2[CH2:13][CH2:14][CH:9](/[CH:8]=[CH:7]/[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[N:19][CH:20]=[CH:21][N:22]=1
Reactant: COc1nccnc1C=O
Reactant: Cc1ccsc1/C=C/C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1nccnc1CN1CCC(/C=C/c2sccc2C)CC1
Reaction time: 8 h
Yield: 54.3 %

Procedure:
After dissolving 139 mg of (E)-4-[2-(3-methyl-2-thienyl)vinyl]piperidine in 7 ml of tetrahydrofuran, 111 mg of 3-methoxypyrazine-2-carboxaldehyde and 213 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture to render it alkaline, and then extraction was performed with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (120 mg, 54% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:21])=O.O>COCCOC>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([Cl:21])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2c[n+]([O-])c(N)c(C#N)n2)cn1
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2nc(C#N)c(N)nc2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile 4-oxide (6.65 g) was dissolved in DME (133 ml). To the solution was added phosphorus oxychloride (12.6 g) at 25° C. The mixture was stirred at ambient temperature for 2 hours. To the mixture was added water (520 ml). The solution was stirred at 20-25° C. for 15 hours. The precipitated crystals were collected by filtration and dried in vacuo, to give 3-amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile as powder (4.6 g). The filtrate was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4. Evaporation of solvent in vacuo gave oily residue. The residue was purified by chromatography on silica gel (EtOAc:n-Hexane=1:1, v/v) to give 3-amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile as powder (1.0 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl)[CH:2]=1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].[I-].[K+]>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:22]2[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]2=[O:23])[CH:2]=1
Reactant: ClCCCCCCc1cnc2ccccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCc1cnc2ccccc2c1
Temperature: 130 °C
Yield: 82.4 %

Procedure:
A solution of 7.8 g of 3-quinolinehexanol in 35 ml of dry dichloromethane was treated dropwise with a solution of 6.07 g of thionyl chloride in 15 ml of dichloromethane. The reaction mixture was heated to reflux for 1 hour and evaporated to dryness. The residue was dissolved in dichloromethane, washed successively with water, saturated sodium bicarbonate solution and brine, dried over potassium carbonate and evaporated to give 8.3 g of crude 6-(3-quinolinyl)hexylchloride. A suspension of 8.3 g of 6-(3-quinolinyl)hexylchloride, 12.6 g of potassium phthalimide, and 0.50 g of potassium iodide in 60 ml of dimethylformamide was heated to a bath temperature of 130° C. for one hour. The cooled mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with water, dried over potassium carbonate and evaporated. The crude solid was crystallized from ethyl acetate-hexane to give 9.9 g (82%) of 2-[6-(3-quinolinyl)hexyl]-1H-isoindole-1,3-(2H)-dione, mp 90°-91° C. An analytical sample was obtained from toluene, mp 95.5°-96.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](OCC)=[O:11])=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][OH:11])=[N:2]1
Reactant: CCOC(=O)c1noc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1noc2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
589 mg (3.0 mmol) of ethyl 1.2-benzoisoxazole-3-carboxylate in solution in 10 ml of tetrahydrofuran are added to a suspension of 129 mg (3.5 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction mixture is stirred for one hour at 60° C. and then treated by adding 2 ml of methanol dropwise, filtered through celite and rinsed with ethyl acetate. The organic phases are combined, dried over sodium sulfate and evaporated. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 180 mg (39%) of benzoisoxazol-3-ylmethanol are obtained in the form of a white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[N:12]=[CH:11][CH:10]=[CH:9]2.[OH-].[Na+].Cl>CCO>[N+:16]([C:15]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])([O-:18])=[O:17]
Reactant: COC(=O)/C=C/c1cc2cccnc2cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1cc2cccnc2cc1[N+](=O)[O-]
Yield: 96.7 %

Procedure:
(E)-3-(7-Nitroquinolin-6-yl)-acrylic acid methyl ester (470 mg, 1.82 mmol) in EtOH (9 ml) was treated with 2N NaOH (1.38 ml; 2.76 mmol) for 30 min. at 50° C. The reaction mixture was acidified with 2N HCl to pH 3.5 and extracted with EtOAc/EtOH (10/1) three times. The combined organic phases were washed with water, dried over Na2SO4 and evaporated to dryness to yield the title compound as colorless crystals (430 mg; 90%).