Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH2:17]([O:19][P:20]([CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:5]([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH:4]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccnc(Oc2cccc(CCl)c2)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(Oc2cc(C)ccn2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
2-(3-Chloromethyl-phenoxy)-4-methyl-pyridine (5.16 g, 22 mmol) from Step 2 was treated neat with triethylphosphite (4.68 mL, 27.3 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (30-60%, EtOAc:DCM) to afford the desired product (2.9 g, 40% yield) as a thick oil.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[O:5])[CH3:3].C(OC1C(OC)=CC(C(O)=O)=C([N+]([O-])=O)C=1)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46]CNC[CH2:42]1>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:42][CH2:3][N:2]([CH:4]=[O:5])[CH2:1][CH2:46]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CN(C)C=O
Agent: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccccc1N1CCN(C=O)CC1
Reaction time: 6 h
Yield: 93 %

Procedure:
DMF was added to a stirred suspension of 4-benzoyloxy-5-methoxy-2-nitro benzoic acid (6) (0.500 mg, 1.65 mmol) and thionyl chloride (3 ml) in dry benzene (30 ml) and the stirring was continued for 6 h. The benzene was evaporated in vacuum and the resultant oil dissolved in dry THF (50 ml) and added drop wise over a period of 1 h to a stirred suspension of 1-(2-methoxyphenyl)piperazine (316 mg 15.6 mmol) triethyl amine (5 ml). After the completion of addition, the reaction mixture was brought to ambient temperature and stirred for an additional hour. The THF was evaporated in vacuum and the aqueous layer was washed with ethyl acetate. The aqueous phase was then adjusted to pH 3 using 6 N HCl and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product of 2-amino-4-benzyloxy)-5-methoxyphenyl][4-(2-methoxyphenyl)piperazino]methanone (7a) in 93% yield (670 mg, 85% yield). 1H NMR (CDCl3) δ 3.20-3.30 (m, 4H), 3.40-3.55 (m, 4H), 3.85 (S, 3H), 3.95 (s, 3H), 5.20 (s, 2H), 6.80-7.00 (m, 5H), 7.30-7.50 (m, 5H), 7.70 (s, 1H); FABMS: 477 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH:20]([O:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][CH:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH:20]([CH3:22])[CH3:21])[CH:25]=3)[CH2:31]2)=[CH:4][CH:3]=1
Reactant: CC(C)Oc1cccc(C2CCNC2)c1
Reactant: Fc1ccc(C(OCCBr)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1cccc(C2CCN(CCOC(c3ccc(F)cc3)c3ccc(F)cc3)C2)c1
Yield: 72.6 %

Procedure:
Proceeding as in Example 9, using 16.4 g (50 mmole) of 1-[bis(4-fluorophenyl)methoxy]-2-bromoethane, 10.3 g (50 mmole) of 3-(3-1isopropoxyphenyl)pyrrolidine and 13.8 g (100 mmole) of potassium carbonate, there was obtained after silica gel column filtration, 16.4 g (yield: 73%) of 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-3-(3-isopropoxyphenyl)pyrrolidine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[CH3:19][O:20][CH2:21][CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13]
Reactant: COCCN
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCNc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F

Procedure:
4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.536 g, 5 mmol), 2-methoxyethanamine (0.376 g, 5 mmol), and triethylamine (1.939 g, 15 mmol) in anhydrous tetrahydrofuran (30 mL) solution was heated at 55° C. for 3 hours. The solution was diluted with ethyl acetate, washed with water and brine, and dried (Na2SO4), filtered and the filtrate was concentrated. The crude material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[CH2:21][C@@:14]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:22])[CH:12]=2)[O:7]1)=[O:5])[CH3:2].Br[CH2:24][CH2:25][CH2:26][Cl:27].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([NH:3][C:4]([C@@H:6]1[CH2:21][C@@:14]2([C:18](=[O:19])[N:17]([CH2:24][CH2:25][CH2:26][Cl:27])[C:16](=[O:20])[NH:15]2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:22])[CH:12]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)[C@@H]1C[C@]2(NC(=O)N(CCCCl)C2=O)c2cc(F)ccc2O1
Reaction time: 15 h
Yield: 73.5 %

Procedure:
To a solution of (2S,4S)-N-ethyl-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (21.0 g, 68.4 mmol) in N,N-dimethylformamide (100 ml, 1.29 mmol) was added 1-bromo-3-chloropropane (21.5 g, 137 mmol). After adding 60% NaH (2.75 g, 68.8 mmol) over 30 minutes at 15°-20° C., the mixture was stirred for 15 hours at 15°-25° C. The reaction mixture was poured into iced water (500 ml), extracted with AcOEt (1000 ml×3), dried over MgSO4. The solvent was distilled off, the residue was chromatographed on silica gel, eluted with CH2Cl2 -CH2Cl2 /MeOH (9/1), and recrystallized from AcOEt to give the desired compound (19.3 g, 73.8%) as colorless prism crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([CH2:12][C:13]2[C:14](=[O:18])[O:15][CH2:16][CH:17]=2)=[CH:10][CH:9]=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]=1[CH3:26])(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO>[C:1]([O:4][CH2:5][C:6]1[C:11]([CH2:12][C@H:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[CH:10][CH:9]=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]=1[CH3:26])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCc1c(CC2=CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OCc1c(C[C@H]2CCOC2=O)ccc(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-2,5-dihydrofuran-3-yl)methyl)benzyl acetate (280 mg, 0.75 mmol) was dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL). A catalytic amount of (−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 16 hours. A fresh portion of (−)-1,2-bis((2R,5-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate was added to the mixture. Reaction vessel was charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 24 hours. Reaction mixture was concentrated in vacuo. Residue was passed through a plug of silica gel eluting 80% ethyl acetate-hexanes. Filtrate was concentrated in vacuo. Title compound was obtained as clear colorless oil in 69% yield. MS m/e (M−H)−=376.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:15].CCCCCC.C1(S(N([F:41])S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1>C1COCC1>[F:41][C:10]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1ccc(C)c(OCOC)c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C)c(OCOC)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 2,4-bis(methoxymethoxy)-1-methyl-benzene (WO2012/076877 Intermediate 150, 2000 mg, 9.4233 mmol) in dry THF (20 mL) butyllithium 1.6M in hexane (6.77 ml, 10.84 mmol) was slowly added and the reaction mixture was stirred for 30 minutes at room temperature. The reaction was cooled to −15° C. and it was added (via cannulation) to a solution of N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (3565.8 mg, 11.308 mmol) in dry THF (10 mL) at −15° C. The reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with brine (5 ml) diluted with water (20 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 50 g as column and cyclohexane/ethyl acetate from 100:0 to 80:20 as eluent affording the title compound (1950 mg) as colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CS(O[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(=O)=O>>[C:17]([C:12]1[C:13](=[O:16])[N:14]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:15]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:11]=1)([OH:19])=[O:18]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CCCc3ccc(Cl)cc3)n2)cc1F
Yield: 56.1 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(4-chlorophenyl)-1-propanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1 (7) to yield the title compound as a pale yellow solid (yield: 56.1%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.Cl.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)[C:5]2=[N:4][CH:3]=1
Reactant: Clc1nccn2c(Br)cnc12
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)CO
Product: NS(=O)(=O)c1ccc(CNc2nccn3c(Br)cnc23)cc1
Temperature: 108 °C
Reaction time: 16 h
Yield: 37.7 %

Procedure:
To a solution of 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (2 g, 8.6 mmol) in iBuOH (5 ml) is added 4-aminomethyl-benzenesulfonamide hydrochloride (2.1 g, 9.5 mmol) and DIPEA (3.7 ml, 21.5 mmol). The reaction is heated to 108° C. and stirred for 16 h. After this time the solution is allowed to cool, resulting in a thick white precipitate. The precipitate is filtered and washed with diethyl ether to give 4-[(3-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide as a white solid (1.24 g, 38%)
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C#CC(=O)OC
Product: COC(=O)C=COc1ccc(Cl)cc1

Procedure:
Following the method of Example 14, methyl propiolate and 4-chlorophenol are reacted to yield methyl 3-(4-chlorophenoxy)-2-propenoate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([SH:9])=[N:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([S:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(S)nc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccc(C(F)(F)F)cn2)cc1
Temperature: 110 °C
Yield: 86.6 %

Procedure:
A mixture of 5-trifluoromethyl-pyridine-2-thiol (6.99 g, 39.0 mmol), 4-fluorobenzaldehyde (4.79 g, 38.6 mmol), anhydrous K2CO3 (8.16 g, 59.1 mmol) and DMF (70 mL) was heated at 110° C. for 18 h. The mixture was cooled to room temperature and partitioned between MTBE and water. The phases were separated. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to give a crude product which was purified by flash column chromatography (eluent: 5% MTBE in petroleum ether). Evaporation of the appropriate fractions gave the product (9.47 g, 87% yield). 1H NMR (CDCl3) δ 10.06 (s, 1H), 8.69-8.66 (m, 1H), 7.97-7.92 (m, 2H), 7.78-7.72 (m, 3H), 7.23-7.16 (m, 1H).
Reaction SMILES: F[C:2]([C:4]([O:10][C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([C:6]([F:9])([F:8])[F:7])[F:5])=[O:3].[F:21][S:22]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])(=[O:24])=[O:23]>>[F:21][S:22]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:2]([C:4]([O:10][C:11]([C:14]([C:17]([F:18])([F:19])[F:20])([F:15])[F:16])([F:12])[F:13])([C:6]([F:9])([F:8])[F:7])[F:5])=[O:3])(=[O:24])=[O:23]
Reactant: O=S(=O)(F)CCOCCO
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Product: O=C(OCCOCCS(=O)(=O)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F

Procedure:
FCOCF(CF3)OCF2CF2CF3 obtained in Example 4 was reacted with FSO2CH2CH2OCH2CH2OH under the same conditions as in the above esterification to obtain FSO2CH2CH2OCH2CH2OCOCF(CF3)OCF2CF2CF3. The obtained FSO2CH2CH2OCH2CH2OCOCF(CF3)OCF2CF2CF3 was fluorinated under the same conditions as in the above fluorination step to obtain FSO2CF2CF2OCF2CF2OCOCF(CF3)OCF2CF2CF3. The obtained FSO2CF2CF2OCF2CF2OCOCF(CF3)OCF2CF2CF3 was decomposed under the same conditions as in the above decomposition step to obtain FSO2CF2CF2OCF2COF and FCOCF(CF3)OCF2CF2CF3.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:19]=[C:18]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]=2[CH3:34])=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:19]=[C:18]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:17]=2[CH2:34][Br:1])=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Yield: 110.4 %

Procedure:
4.8 g of N-bromosuccinimide and 20 mg of benzoyl peroxide are added to a solution of 10.73 g of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate in 200 ml of CCl4 and the mixture is then refluxed for 16 hours. The insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is extracted with DCM, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 14.13 g of the expected product.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH:27]=[O:28])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 3 h

Procedure:
3,4,5-Triphenyl-1H-pyrazol-1-butanol (4 g, 10.9 mmol) in dry CH2Cl2 (10 mL) was added to a stirred suspension of pyridinium chlorochromate (7.03 g, 32.6 mmol) in dry CH2Cl2 (370 mL). After 3 hours, the CH2Cl2 was removed in vacuo and the residue diluted with diethyl ether (800 mL) and filtered through diatomateous earth. The organic phase was washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated to furnish 3,4,5-triphenyl-1H-pyrazol-1-butanal as a viscous oil. MS(CI): m/e=367 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](O)[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][O:17]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: OCC1CCCO1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(OCC2CCCO2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-5-nitrophenol (3.39 g, 19.52 mmol), tetrahydrofurfuryl alcohol (1.99 g, 19.52 mmol), and Ph3P (5.12 g, 19.52 mmol) in 34 ml THF, cooled to −15° C., was added dropwise, over 90 min, a solution of DIAD (4.15 g, 20.5 mmol). The reaction was warmed to RT and stirred for 18 h. The reaction was concentrated to dryness. The crude residue was treated with a small mix of Et2O and hexanes and sonicated so as to triturate out bulk of impurities, which were filtered off. The filtrate was concentrated to dryness. The resulting residue was purified by silica gel column chromatography using EtOAc in hexanes to elute the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]3[CH:19]=[N:20][C:21]([C:22](=[S:24])[NH2:23])=[C:11]3[CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[CH:25]1([C:28]([CH2:30]Br)=O)[CH2:27][CH2:26]1>C(O)C>[CH:25]1([C:28]2[N:23]=[C:22]([C:21]3[N:20]=[CH:19][N:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:9]([C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[O:8])[CH2:10][C:11]=34)[S:24][CH:30]=2)[CH2:27][CH2:26]1
Reactant: O=C(CBr)C1CC1
Reactant: NC(=S)c1ncn2c1CN(C(=O)N1CCOCC1)c1ccccc1-2
Solvent: CCO
Product: O=C(N1CCOCC1)N1Cc2c(-c3nc(C4CC4)cs3)ncn2-c2ccccc21
Reaction time: 24 h

Procedure:
A mixture of 4,5-dihydro-5-(morpholinocarbonyl)imidazo[1,5-a]quinoxaline-3-thiocarboxamide (0.29 g) and 1-bromomethyl cyclopropyl ketone (0.165 g) in ethanol (10 ml) is stirred at 20°-25° for 1 day and then at 80° for 5.5 hr, after which it stirred at 20°-25° for an additional 20 hr. The mixture is then concentrated under reduced pressure and chromatographed on silica gel eluting with methanol/dichloromethane (2/98). The product fractions are combined and rechromatographed using ethyl acetate/dichloromethane (25/75) to give a solid. Crystallization from dichloromethane/hexane gives the title compound; mp 193°-194°; MS (m/z) 407; IR (mineral oil) 1511, 1669, 1115, 1392, 1227 cm-1 ; NMR (CDCl3) 0.98, 2.09, 3.35, 3.66, 5.09, 6.79, 7.19, 7.28, 7.53, 8.01 δ.
Reaction SMILES: [CH3:1]I.[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH:7]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH:7]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1SC(c2cccnc2)N(CCO)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(C)SC1c1cccnc1
Reaction time: 1 h
Yield: 48.1 %

Procedure:
Methyl iodide (0.72 g, 5.0 mmol) was added to a solutoin of 3-(2-hydroxyethyl)-5-methyl-2-(3-pyridyl)- thiazolidin-4-one (1 g, 4.2 mmol) in dry dimethylformamide (5 ml), and 40% sodium hydride (176 mg, 4.4 mmol) was added in limited amounts to the mixture under cooling with ice. Then, cooling with ice was continued for 1 hour. The product mixture was poured into aqueous NaC1, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and subjected to medium-pressure chromatography (hexane-acetone), giving 3-(2-methoxyethyl)-5-methyl-2-(3-pyridyl)-thiazolidin-4-one (0.51 g, 48% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10]CC)=O.C[Al](C)C>O1CCCC1>[S:3]1[C:2]2[NH:1][C:8](=[O:10])[CH2:7][C:6]=2[CH:5]=[CH:4]1
Reactant: CCOC(=O)Cc1ccsc1N
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: O=C1Cc2ccsc2N1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
Ethyl 2-aminothiophene-3-acetate (100 mg, 0.54 mmol) was dissolved in dry tetrahydrofuran (5 ml) and treated at −78° C. with trimethylaluminium (2M in n-heptane, 0.59 mmol). The reaction mixture was allowed to warm slowly to room temperature over 4 hours, cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution. The solution was extracted with ethyl acetate and the organic phase dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate (2:1) as eluent to give 45 mg of 4,6-dihydrothieno[2,3-b]pyrrol-5-one as a brown solid. MS(ES): m/e 140 [M+H].
Reaction SMILES: [C:1]1([C:7]2[N:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:8]=2[C:9]([O:11]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>C(OCC)C>[CH3:18][C:14]1[CH:15]=[CH:16][N:17]=[C:7]2[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:9](=[O:11])[C:8]=12
Reactant: CCOC(=O)c1c(C)ccnc1-c1ccccc1
Agent: N
Solvent: CCOCC
Product: Cc1ccnc2c1C(=O)c1ccccc1-2
Temperature: 140 °C
Reaction time: 7 h

Procedure:
A mixture of 51 g (0.211 mol) of ethyl 2-phenyl-4-methylnicotinate and 500 g of polyphosphoric acid was stirred at 140° C. for 7 hours, cooled, stirred into 700 g of ice, rendered alkaline with conc. ammonia solution and extracted with ethyl acetate. The combined extracts were washed twice with water, dried over K2CO3 and concentrated. The product thus obtained was then digested with diethyl ether for 2 hours, filtered off with suction and dried. Yield 18.6 g (45% of theory), yellowish crystals of m.p. 137°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.O.Cl>[Fe].C1(C)C=CC=CC=1>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2ccsc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(Sc2ccsc2)cc1N
Reaction time: 3 h

Procedure:
1.6 G. of 2-amino-4-(3-thienylthio)-1-nitrobenzene is treated with 1.6 g. of iron powder in a refluxing mixture of 1.6 ml. of water, 0.16 ml. of conc. hydrochloric acid and 100 ml. of toluene. After 3 hours when the reaction is complete, the iron residue is filtered off and the filtrate stripped under vacuum to afford 1,2-diamino-4-(3-thienylthio)-benzene.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[O:16]([CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:24]([CH2:23][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(COc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(COc2ccccc2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 0.85 mL of methyl acetoacetate, 350 mg of NaH 60% dispersion in oil, 5 mL of 1.6M n-butyl lithium in hexane, 2.0 g of 2-phenoxy-1-phenyl ethanone and 60 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 1 hour. The crude product was triturated from diethyl ether to afford a solid (m.p. 133°-135° C.). 1 H NMR (DMSO-d6) δ 3.03 (d, 1 H), 3.35 (d, 1 H), 4.18 (dd, 2 H), 4.90 (s, 1 H), 6.92-6.95 (m, 3 H), 7.24-7.49 (m, 7 H), 11.56 (s, 1 H).