Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C)c1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (ABCR AV19078; 15 g; 65.48 mmol; 1 eq.), o-tolylboronic acid (Aldrich 393606; 10.68 g; 78.5 mmol; 1.2 eq.), potassium carbonate (45.25 g, 327.4 mmol, 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (3.78 g; 3.27 mmol; 0.05 eq.) in toluene (200 mL) and water (200 mL) was stirred at 120° C. for 6 hours. The resulting mixture was allowed to return to room temperature and the two phases were separated. The organic layer was concentrated in vacuo and purified by column chromatography (c-hexane) to afford the title compound (15 g, 95%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>CCOC(C)=O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:25][CH2:21][CH:22]([CH3:24])[CH3:23])[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=1
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Reactant: CC(C)CN
Solvent: CCOC(C)=O
Product: CC(C)CNc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Temperature: 150 °C
Yield: 85.5 %

Procedure:
In a sealed tube, a mixture of 8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (20 mg, 0.062 mmol) and isobutylamine (0.037 mL, 0.37 mmol) was heated at 150° C. for 14 h. The reaction mixture was cooled to RT, poured into AcOEt (5 mL) and washed with a 2.0 M Na2CO3 solution in water (2×2 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→8:2) to yield the title compound (19.1 mg, 0.053 mmol, 85%) as a reddish solid. MS: 359 [M+1]+; HPLC: AtRet=2.61; TLC: RF 0.64 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[F:57][C:58]([F:64])([F:63])[CH2:59][C:60](O)=[O:61]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:60](=[O:61])[CH2:59][C:58]([F:64])([F:63])[F:57])[CH2:25][CH2:26]3)=[CH:17][CH:16]=1)=[N:8]2
Reactant: O=C(O)CC(F)(F)F
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)CC(F)(F)F)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g, 0.54 mmol) in THF (10 mL) was added EDCl (0.105 g, 0.54 mmol), HOBt (0.074 g, 0.54 mmol), Et3N (0.08 mL, 0.54 mmol) and trifluoropropionic acid (0.070 g, 0.54 mmol). The reaction was stirred at room temperature for 4 hours and concentrated in vacuo. Purification by flash chromatography, eluting with 20% to 100% of 92:7:1 CHCl3/MeOH/concentrate NH4OH in CH2Cl2, afforded the title compound (0.135 g, 52%). 1H NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.03 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.70-3.78 (m, 2H), 3.60-3.67 (m, 4H), 3.34-3.38 (m, 4H). APCI MS m/z 477 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:33][CH3:34])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Cl:42])C(=O)C1>CN(C=O)C>[Cl:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH2:33][CH3:34])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Solvent: CN(C)C=O
Product: CCC(CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 60.3 %

Procedure:
Following General Procedure H, tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)butylcarbamate (100 mg, 0.21 mmol) in (DMF) was reacted with NCS (34 mg, 0.25 mmol) to afford the desired product (65 mg, 61%) as a yellow solid: ESI MS m/z 513 [C27H29ClN2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]#[N:11].S(=O)(=O)(O)[OH:21].O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[C:10]([NH2:11])=[O:21]
Reactant: O=S(=O)(O)O
Reactant: N#CC(Nc1ccc(Cl)cc1)c1c(Cl)cccc1Cl
Solvent: O
Product: NC(=O)C(Nc1ccc(Cl)cc1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 Parts of 2,6-dichloro-α-[(4-chlorophenyl)amino]benzeneacetonitrile are added portionwise to 270 parts of sulfuric acid/water (10:1 by volume) and the whole is stirred overnight at room temperature. The reaction mixture is poured onto 2000 parts of ice-water. The precipitated product is filtered off, washed on the filter successively with water and 2-propanol and recrystallized from 560 parts of 2-propanol at -20° C., yielding 43.1 parts of 2,6-dichloro-α-[(4-chlorophenyl)amino]benzeneacetamide; mp. 178° C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8].Cl>O>[N:1]([N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]([O:6][CH3:5])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:3]
Reactant: COC(=O)CCCCCNc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)CCCCCN(N=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.4 g of sodium nitrite in 5 ml of water is added dropwise at 0°-10° to a mixture of 4.42 g of N-(5-methoxycarbonylpentyl)-aniline, 2.9 ml of concentrated hydrochloric acid, and ice as needed to maintain the desired temperature. The mixture is then allowed to stir at ambient temperature for 1 hour and is then extracted with ether. The extract is washed with water, dried over magnesium sulfate, and evaporated in vacuo to give N-nitroso-N-(5-methoxycarbonylpentyl)-aniline as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].Cl[C:15]1[N:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=1>>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)[N:20]=2)[CH2:23][CH2:24]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(-n3ccc4cc(S(C)(=O)=O)ccc43)n2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate 21) and tert-butyl 4-((6-chloropyridin-2-yl)oxy)piperidine-1-carboxylate (intermediate 42) (0.19 g, 63%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C:24]2=[O:29])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].C(O)CCC>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:13][CH2:14][N:16]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][N:25]([CH3:28])[C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:2][CH2:3]2)=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc(N)cc2)C1=O
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4CCN(C)C4=O)cc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 16.5 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 12.5 parts of 1-(4-aminophenyl)-3-methyl-2-imidazolidinone, 11 parts of sodium hydrogen carbonate and 240 parts of 1-butanol was stirred and refluxed for 24 hours. After cooling, 100 parts of water were added and the whole was stirred. The precipitated product was filtered off, washed with water and with 1-butanol and dried, yielding 17.5 parts (73%) of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2-imidazolidinone; mp. 240.9°-241.0° C. (28).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.ICS[C:20]1[NH:21][CH2:22][CH2:23][N:24]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:20]3[NH:24][CH2:23][CH2:22][N:21]=3)=[N:10][C:9]=2[CH3:16])=[CH:6][CH:7]=1
Reactant: Cc1nc(NN)nnc1-c1ccc(Cl)cc1
Reactant: ICSC1=NCCN1
Solvent: CCCCO
Product: Cc1nc(NNC2=NCCN2)nnc1-c1ccc(Cl)cc1
Yield: 17 %

Procedure:
A mixture of 6-(4-chlorophenyl)-3-hydrazino-5-methyl-1,2,4-triazine (7 g), 2-iodomethylthio-2-imidazoline (8.11 g) and n-butanol (50 ml) was refluxed for 3 hours with stirring. After cooling, the mixture was evaporated under reduced pressure and the residue was dissolved in 1N hydrochloric acid. The solution was washed with ethyl acetate and made alkaline with an aqueous solution of potassium carbonate. The resultant precipitates were collected by filtration, washed with water, dried and recrystallized from methanol and then from ethanol to give dark red crystals of 6-(4-chlorophenyl)-3-[2-(2-imidazolin-2-yl)hydrazino]-5-methyl-1,2,4-triazine (1.53 g), m.p. 230°~231° C. (decomp.).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@H:6]1[O:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[O:21][CH3:22])[C:10]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:9]=2[N:8]([CH2:28][C:29]([CH2:33][OH:34])([CH3:32])[CH2:30][OH:31])[C:7]1=[O:35])C.[OH-].[Na+].O.Cl>C(O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:9]2[N:8]([CH2:28][C:29]([CH2:33][OH:34])([CH3:32])[CH2:30][OH:31])[C:7](=[O:35])[C@@H:6]([CH2:5][C:4]([OH:36])=[O:3])[O:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][CH3:22])[C:10]=2[CH:23]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc(OC)c2OC)c2cc(Cl)ccc2N(CC(C)(CO)CO)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc([C@H]2O[C@H](CC(=O)O)C(=O)N(CC(C)(CO)CO)c3ccc(Cl)cc32)c1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a solution of (3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (1.0 g) in ethanol (10 ml) was added a 1N aqueous solution of sodium hydroxide. The mixture was stirred at 60° C. for one hour. To the reaction mixture was added water, which was neutralized with 1N HCl, followed by subjecting to extraction with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixture of ethyl acetate and hexane to afford 0.38 g of (3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid, m.p. 208-210° C.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:18][CH:19]=2)=[O:13])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OC1CN(C(=O)c2ccc(O)cc2)C1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)N2CC(Oc3ccccc3C(C)(C)C)C2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of 4-{[3-(2-tert-butylphenoxy)azetidin-1-yl]carbonyl}phenol (552 mg, 1.7 mmol) obtained in Example 139 in DMF (20 mL) were added potassium carbonate (1.04 g, 7.5 mmol) and methyl bromoacetate (352 mg, 2.3 mmol), and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 85:15-40:60) to give the title compound (578 mg, 69%) as a colorless solid.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[OH:28][C@H:29]1[CH2:33][CH2:32][NH:31][C@@H:30]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:31]1[CH2:32][CH2:33][C@H:29]([OH:28])[C@H:30]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@H]1NCC[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N2CC[C@H](O)[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 4.23 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 17-2 (crude form 15.1 mmol) as starting materials, respectively 2.75 g (Isomer A) and 2.28 g (Isomer B) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.[C:9]1(S(C2C=CC=CC=2)=C(C)C)[CH:14]=CC=C[CH:10]=1>CO>[CH3:10][C:9]1([CH3:14])[CH:5]2[CH:4]1[CH:3]([O:2][CH3:1])[O:7][C:6]2=[O:8]
Reactant: COC1C=CC(=O)O1
Reactant: CC(C)=S(c1ccccc1)c1ccccc1
Solvent: CO
Product: COC1OC(=O)C2C1C2(C)C

Procedure:
In a preferred embodiment of the invention, the alcohol ZOH is methanol and the 5(RS)-methoxy-2,5-dihydrofuran-2-one is reacted with diphenyl isopropylidene sulfurane to obtain (1RS, 5SR) 6,6-dimethyl-4(RS)-methoxy-3-oxabicyclo (3,1,0) hexan-2-one which is then subjected to acid hydrolysis to obtain (1RS, 5SR) 6,6-dimethyl-4(RS)-hydroxy-3-oxabicyclo (3,1,0) hexan-2-one.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](C(OCC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O=C1CCCC([C:23]([O:25][CH2:26][CH3:27])=[O:24])C1.O=C1CCC(C(OCC)=O)CC1>>[O:4]1[C:5]2([CH2:6][CH2:7][CH2:8][CH:9]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CCOC(=O)C1CCC(=O)CC1
Product: CCOC(=O)C1CCCC2(C1)OCCO2

Procedure:
Ethyl 1,4-dioxaspiro[4.5]decane-7-carboxylate was synthesized in a manner similar to the synthesis of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate, but with ethyl 3-oxocyclohexanecarboxylate substituted for ethyl 4-oxocyclohexanecarboxylate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C1COCC1.C([Li])CCC.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>[Cl-].[Cl-].[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1ccsc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cccs2)cc1
Temperature: -20 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
23.30 g of thiophene (0.277 mole) and 140 ml of dry THF were introduced into a 500 ml three-necked round bottom flask placed under nitrogen; after cooling to -20° C., 160 ml of butyllithium (46 M/1 in hexane) were run in slowly; the temperature was allowed to return to 0° C.; time 2 hours 30 min. 34.6 g (0.254 M) of ZnCl2 and 275 ml of dry THF were charged under nitrogen into a one-liter three-necked vessel with mechanical stirring. After allowing to dissolve, the above solution was run in over 30 min; the reaction was slightly exothermic. 20 ml of THF were added again for rinsing. 0.3907 g (6.80 ×10-4 mole) of Pd(DBA)2, 0.714 g (2.72 ×103 mole) of TPP and 220 ml of dry THF were charged into a 2 liter three-necked vessel placed under nitrogen; after allowing to react (10 min), 45.9 g (0.245 mole) of para-bromoanisole were added and the above solution was run in at normal temperature; heating under reflux was carried out for 16 hours. After allowing to cool, water was added and the mixture was extracted with ethyl acetate; the material was washed with water, dried over MgSO4 and was evaporated down; a solid was recovered. 27.3 g of a solid were obtained by recrystallization (melting point: 111° C.) (2-paramethoxyphenylthiophene).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.[NH2:26][CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Br:37])[CH:33]=2)[C:28]1=[O:38].C(N(C(C)C)CC)(C)C>ClCCl.N1C(F)=NC(F)=NC=1F>[Br:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:38])[CH:27]([NH:26][C:16]([C:10]1[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=1[C:12]([F:13])([F:14])[F:15])=[O:18])[CH2:36][CH2:35]2
Reactant: NC1CCc2cc(Br)ccc2C1=O
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: Cl
Agent: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCc2cc(Br)ccc2C1=O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.8 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 0.465 g, 1.808 mmol) in dichloromethane (5 mL) was added pyridine (0.175 ml, 2.170 mmol) followed by cyanuric fluoride (0.188 ml, 2.172 μmol) at room temperature. The reaction mixture was stirred at room temperature for 20 h., and partitioned between dichloromethane (30 mL) and cold 0.5N HCl (15 mL). The dichloromethane layer was separated, dried over sodium sulfate, and concentrated to afford an orange-red solid. The solid was dissolved in dichloromethane (5 mL) and added dropwise over a period of 2 min. to 2-amino-6-bromo-3,4-dihydronaphthalen-1(2H)-one hydrochloride (Preparation 82B, 0.5 g, 1.808 mmol) in dichloromethane (5.00 mL) and diisopropylethylamine (0.789 ml, 4.52 mmol) at 0° C. The reaction mixture was allowed to come to room temperature over a period of 20 min., stirred at room temperature for 2 h., and partitioned between dichloromethane (30 mL) and cold 0.5N HCl (10 mL). The dichloromethane layer was separated, dried over sodium sulfate, and concentrated. The resulting solid was triturated with ether (15 mL), sonicated for 5 min. and filtered to yield N-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide (0.640 g, 1.335 mmol, 73.9% yield) as a light tan solid. LC/MS M+1=480.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Br:17]P(Br)Br>C(Cl)(Cl)Cl>[Br:17][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[N:14][CH:13]=1
Reactant: BrP(Br)Br
Reactant: CCN1CCN(c2ccc(CO)cn2)CC1
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(CBr)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of [6-(4-ethylpiperazin-1-yl)pyridin-3-yl]methanol (3.0 g, 13.55 mmol) in anhydrous chloroform was added at 0° C. tribromophosphane (4.03 g, 14.91 mmol). The reaction mixture was allowed to stir at room temperature for 3 hours. The solvent was evaporated to provide 1-[5-(bromomethyl)pyridin-2-yl]-4-ethylpiperazine (3.85 g), which was used in the next step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.[OH-].[K+]>CCO>[C:1]([O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:32]/[C:31]([C:28]2[CH:27]=[CH:26][C:25]([N:22]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)=[CH:30][CH:29]=2)=[O:33])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Reactant: CC(=O)c1ccc(N2CCN(C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)OC(C)(C)C)nc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (261 mg, 1.12 mmol), 1-[4-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (246 mg, 1.2 mmol) and KOH (125 mg, 2.24 mmol) in 10 ml of EtOH was stirred at room temperature for 24 hours, observing the formation of a precipitate. The solid was then filtered off through a Buchner funnel to obtain 222 mg of (E)-3-(5-{(E)-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid tert-butyl ester.
Reaction SMILES: O[C:2]1([CH3:10])CS[C:5]([OH:9])([CH3:8])[CH2:4][S:3]1.O1CCCC1.N1CCCCC1.[C:22]([O:26][CH3:27])(=[O:25])C=C>O>[CH2:4]([S:3][CH2:2][CH2:10][C:22]([O:26][CH3:27])=[O:25])[C:5]([CH3:8])=[O:9]
Reactant: C=CC(=O)OC
Reactant: CC1(O)CSC(C)(O)CS1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)CCSCC(C)=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
90.1 g (0.5 mol) of 2,5-dihydroxy-2,5-dimethyl-1,4-dithiane are initially introduced into 100 ml of absolute tetrahydrofuran. 1.0 g of piperidine is then added, and 94.7 g (0.945 mol) of methyl acrylate are added dropwise at 10°-15° C, during which process another two portions of 0.5 g of piperidine are added at the same time. The mixture is subsequently stirred for 60 minutes at 60° C. It is allowed to cool and introduced into 500 ml of water.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH2:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](C(=O)CC#N)=[CH:10]1)[CH3:8]>>[CH2:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:5]2[CH:6]=[C:2]([NH2:1])[NH:3][N:4]=2)=[CH:10]1)[CH3:8]
Reactant: Nc1cc[nH]n1
Reactant: CCn1cc(C(=O)CC#N)c2ccccc21
Product: CCn1cc(-c2cc(N)[nH]n2)c2ccccc21
Yield: 70 %

Procedure:
The product was prepared according to general procedure for aminopyrazole synthesis (route A2) starting from 3-(1-ethyl-1H-indol-3-yl)-3-oxo-propionitrile (820 mg, 3.87 mmol, 1.0 eq). The solvent was removed under reduced pressure; the solid residue was washed with EtOH to obtain the title product (612 mg, 70% yield).