Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[CH3:20][O:21][C:22]([C:24]1([CH2:30][CH:31]=O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH3:20][O:21][C:22]([C:24]1([CH2:30][CH2:31][NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: COC(=O)C1(CC=O)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
2-Methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (58 mg, 0.22 mmol) was dissolved in DCE (1 mL). To this solution was transferred a solution of 4-(2-oxo-ethyl)tetrahydro-pyran-4-carboxylic acid methyl ester (40 mg, 0.22 mmol) in DCE (1 mL). To this clear solution was then added acetic acid (38 μL, 0.66 mmol), followed by addition of powdered NaBH(OAc)3 (140 mg, 0.66 mmol) in one portion under N2 at rt. The yellowish milky solution was stirred at rt. overnight. The reaction was diluted with DCM (40 mL) and quenched with 30 mL of concentrated NH4OH in 70 mL of water. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (15 mL), dried (anhydrous potassium carbonate), filtered, and concentrated obtain 92 mg of a crude solid, which was used in the next step of the reaction without purification.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10](N)=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].Cl>O>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:1])=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14]
Reactant: NC(=O)c1ccc(C(F)(F)F)c(N)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(C(=O)O)ccc1C(F)(F)F

Procedure:
Into 160 ml. of water containing 9.6 g. of sodium hydroxide is suspended 16 g. of 2-amino-α,α,α-trifluoro-p-toluamide. The solution is refluxed 5 hours, then cooled, poured onto ice and acidified to a pH of 6 with concentrated hydrochloric acid. The resultant precipitate is filtered, washed with water and dried in vacuo to yield 2-amino-α,α,α-trifluoro-p-toluic acid (4-trifluoromethylanthranilic acid), m.p. 175°-177° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:20])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:21]([C@@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C@@H:25]1[CH2:26][CH2:27][C@H:28]([C:31]([NH:1][CH:2]([C:5]2[C:6](=[O:20])[NH:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:32])[CH2:29][CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(=O)Cl)CC1
Reactant: CCC(N)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Product: CCC(NC(=O)[C@H]1CC[C@@H](C(C)(C)C)CC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 16A, 3.2 g (11.6 mmol) 6-(1-aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one (Example 15A), 2.4 g (11.6 mmol) cis-4-tert.-butylcyclohexanecarbonyl chloride (Example 42A) and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: C([O:5]O)(C)(C)C.[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=1.[Na+].[Cl-].[OH-].[Na+]>C(Cl)Cl.O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(C(C(C(OC(C)C)=O)O)O)(OC(C)C)=O.CCOCC>[F:7][C:8]([F:19])([F:20])[C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[O:5][C@H:16]2[CH2:17][OH:18])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OO
Reactant: OC/C=C/c1ccc(C(F)(F)F)cc1
Agent: [Ti+4]
Agent: CC(C)OC(=O)C(O)C(O)C(=O)OC(C)C
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: OC[C@@H]1O[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: -20 °C
Yield: 89.4 %

Procedure:
Into a 2000 mL flame-dried flask were introduced dry powdered 4A molecular sieves (9.0 g) and anhydrous DCM (1000 mL) under nitrogen. After cooling to −20° C., the following reagents were introduced sequentially via cannula under stirring: (diisopropyl 1-tartrate (5 g, 21 mmol), titanium tetraisopropoxide (4 mL, 14 mmol) and 5.5 M solution of t-butylhydroperoxide (101 mL, 554 mmol). The mixture was stirred 1 hour at −20° C. and a solution of (E)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-ol (56.0 g, 277 mmol) in 150 mL DCM was added over a 30 minute period. After 8 hours of stirring at the same temperature, the reaction was quenched by addition of 24 mL of a 10% aqueous solution of NaOH saturated with NaCl (100 mL of a 10% solution were prepared by adding 10 g of NaCl to a solution of 10 g of NaOH in 95 mL water). 300 mL ether was added dropwise while the cold bath was maintained at −20° C. After the ether addition, the cold bath was removed, and the mixture was allowed to warm to 10° C. Stirring was maintained for an additional 15 minutes at 10° C., and anhydrous MgSO4 (24 g) and Celite (3 g) were added. After a final 30 minutes of stirring, the mixture was allowed to settle, and the upper portion was filtered through a pad of Celite. The Celite was washed with 20 mL ether. The solvents were evaporated, and tert-butyl hydroperoxide was removed by azeotropic evaporation with toluene (3×100 mL) under high vacuum. The crude product was then chromatographed eluting with 30% EtOAc in hexane. After removing the solvent, a colorless oil was obtained as the desired product (54 g, yield=90%). 1H NMR (400 MHz, CD3OD) δ ppm 3.17 (ddd, J=4.74, 2.89, 2.15 Hz, 1H) 3.72 (dd, J=12.72, 4.70 Hz, 1H) 3.90 (dd, J=12.72, 2.93 Hz, 1H) 3.96 (d, J=1.96 Hz, 1H) 7.50 (d, J=8.02 Hz, 2H) 7.66 (d, J=8.22 Hz, 2H).
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl.[CH3:8][NH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Cl>C(O)C>[CH3:8][NH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1
Reactant: Sc1ncc[nH]1
Reactant: CNc1ccccc1CCl
Agent: Cl
Solvent: CCO
Product: CNc1ccccc1CSc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a solution of 693 mg (6.9 mmol) of 2-mercapto-imidazole in 26 ml of ethanol was added 1.33 g (6.9 mmol) of 2-methylaminobenzyl chloride hydrochloride, and the mixture was stirred for 15 min. at room temperature. Ethanol was distilled off under reduced pressure. The residue was made alkaline by addition of saturated aqueous sodium hydrogencarbonate and then to the alkaline solution was added 20 ml of water to precipitate a crystalline product. The product was collected by filtration and washed successively with two portions of water and each one portion of chilled ethanol and ether to give 990 mg of the desired compound as a white crystalline powder, yield 65.5%.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:26][S:27]([O:1][C@H:2]1[C@@H:3]([CH3:25])[CH2:4][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][C@H:7]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])(=[O:29])=[O:28]
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 46 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,5S,6S)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate (1.0 equiv.) in pyridine (0.20 M) was added MsCl (5.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with 10% CuSO4, H2O, Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-(1S,2R,6S)-2-((tert-butoxycarbonyl)amino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-en-1-yl methanesulfonate in 46% yield. LC/MS (m/z)=428.2 (MH+), Rt=0.89 min.
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.[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[N:17]1.[I-].[K+].C(=O)([O-])O.[Na+]>O.CC(=O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:13][CH2:14][N:27]([C:24]3[CH:23]=[CH:22][C:21]([N:16]4[CH:20]=[CH:19][CH:18]=[N:17]4)=[CH:26][CH:25]=3)[CH2:2][CH2:3]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-n2cccn2)cc1
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(N2CCN(c3ccc(-n4cccn4)cc3)CC2)cc1

Procedure:
A mixture of 12.5 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 8 parts of 4-(1H-pyrazol-1-yl)benzenamine, 2 parts of potassium iodide, 80 parts of 2-propanone and 100 parts of water is stirred and refluxed for 24 hours. The reaction mixture is cooled. The precipitated product is filtered off (the filtrate is set aside), washed with water and with 2-propanone, yielding a first crude fraction of 6 parts. The filtrate (see above) is neutralized with a sodium hydrogen carbonate solution and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is triturated in 2-propanol. The product is filtered off and washed with methanol, yielding a second crude fraction of 2 parts. The combined crude crops (resp. 6 and 2 parts) are crystallized from 1-butanol, yielding 7.1 parts of 1-(4-methoxyphenyl)-4-[4-(1H-pyrazol-1-yl)phenyl]piperazine; mp. 207.7° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1CCN2C(=NCCC2)CC1.[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>C(OCC)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@@H:13]([O:15][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
A solution of 25.82 g (100 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in 200 mL dry diethyl ether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3 mL (20 mmol, 0.2 equiv.) DBU was added to the reaction flask then the mixture was stirred at 0° C. for ten min. Slowly 15 mL (150 mmol, 1.5 equiv.) trichloroacetonitrile was added dropwise over 15 min. The reaction was stirred at 0° C. for 2 hr. during which time it became deep yellow in color. The volatiles were removed under vacuum using a cool bath (<35° C.) to give a pale brown mobile liquid which was purified by column chromatography on silica gel (3″×10″ pad) in two batches eluting with hexanes/EtOAc (9/1) then hexanes/EtOAc (4/1). The product fractions were combined and the solvent removed under vacuum to give 37.5 g of the title compound as a pale yellow oil. 1H-NMR (CDCl3): δ: 1.74 (3H, d,.J=6.5 Hz), 6.07 (1H, q, J=6.5 Hz), 7.82 (1H, s), 7.86 (2H, s), 8.40 (1H, br. s) ppm.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[I:10]Cl>CN(C)C=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[I:10]
Reactant: Nc1cc(Br)c(Cl)cn1
Reactant: ClI
Solvent: CN(C)C=O
Product: Nc1ncc(Cl)c(Br)c1I
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of Example 52A (3 g, 14.46 mmol) in N,N-dimethylformamide (60 mL) was heated to 40° C. and iodine chloride (2.82 g, 17.35 mmol) was added. After stirring at 40° C. for 3 hours, a second lot of iodine chloride (2.82 g, 17.35 mmol) was added and the mixture was stirred overnight at 40° C. The mixture was cooled to room temperature and quenched with ice cold water. The mixture was extracted with ethyl acetate (100 mL×2) and the organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 20% ethyl acetate in hexane) afforded the title compound. LCMS: 334.6 (M+H)+.
Reaction SMILES: [N+](C(CC)CC)([O-])=O.[CH2:9]([C:11]([N+:24]([O-])=O)([CH2:22][CH3:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:10].C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:9]([C:11]([NH2:24])([CH2:22][CH3:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:10]
Reactant: CCC(CC)(Cc1c[nH]c2ccccc12)[N+](=O)[O-]
Agent: CCC(CC)[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(N)(CC)Cc1c[nH]c2ccccc12

Procedure:
If the procedure of Example 3 is applied to the corresponding quantity of 3-nitropentane instead of 2-nitrobutane, 3-(2'-ethyl-2'-nitrobutyl)-indole is initially obtained with a melting point of 92°-94°C. (from benzine). Reduction yields 3-(2'-ethyl-2'-aminobutyl)-indole with a melting point of 130.5°-131.5°C. (from CCl4).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:4])=[O:3]>ClCCl.CO.[Pd]>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:12])(=[O:3])=[O:4]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(N)cc1S(N)(=O)=O
Reaction time: 0.25 h

Procedure:
To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10% Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87%; MS (m/e): 187 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[OH:8].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:9][C:4]1([OH:8])[CH2:5][CH2:6][CH2:7][CH:3]1[CH2:2][O:1][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(O)CCCC1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 7a (1.78 g, crude), pyridine (5.5 mL, 68.0 mmol) and 4-dimethylaminopyridine (0.17 g, 1.37 mmol) in CH2Cl2 (40 mL) was added p-toluenesulfonyl chloride (3.13 g, 16.4 mmol) in one portion, and the mixture was left to stand at 4° C. overnight. The mixture was stirred at ambient temperature for 100 min. To the mixture was added ice and the mixture was stirred at ambient temperature and the organic layer was separated. The aqueous layer was extracted with EtOAc and ,he combined organic layers were washed with water, CuSO4 solution, water, NaHCO3 solution and NaCl solution, and dried over Na2SO4. Filtration and concentration gave 3.86 g of 8a, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].ClS([N:14]=[C:15]=O)(=O)=O.CN(C)C=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:15]#[N:14])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1cc(C#N)c[nH]1
Temperature: -20 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
4-Cyano-1H-pyrrole-2-carboxylic acid methyl ester was prepared as described in Can. J. Chem., 59, 2673-76 (1981). 1H-Pyrrole-2-carboxylic acid methyl ester (2.00 g, 16.00 mmol) was dissolved in acetonitrile (5 mL) and the solution was cooled to −20° C. Chlorosulfonylisocyanate (3.40 g, 24.00 mmol) was dissolved in acetonitrile (5 mL) and added dropwise via syringe over a period of 5 min to the above solution. The solution was allowed to warm to 25° C. and was stirred for 20 h. The solution was cooled back to 0° C., N,N-dimethylformamide (2 mL) was added and the solution was heated to 50° C. for 15 min. The reaction mixture was poured into ice and was extracted with chloroform, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 40% ethyl acetate in hexanes) afforded the desired product, 4-cyano-1H-pyrrole-2-carboxylic acid methyl ester (1.09 g, 7.265 mmol, 45.4% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 3.91 (3H, s), 7.12 (1H, t, J=2.0 Hz), 7.40-7.41 (1H, m), 9.60 (1H, bs). FT-IR (ATR) νmax (neat): 2228, 1691 cm−1.
Reaction SMILES: COC[O:4][CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[NH:14]2)=[CH:9][C:8]=1[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].Cl.[OH-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C1COCC1>[OH:4][CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[NH:14]2)=[CH:9][C:8]=1[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27]
Reactant: COCOCCc1c(CCNC(=O)OC(C)(C)C)cc2c(c1C)NC(=O)CC2
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CCO)c(CCNC(=O)OC(C)(C)C)cc2c1NC(=O)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 123.2 %

Procedure:
To a suspension of 1.01 g of t-butyl (2-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}ethyl)carbamate in 10 ml of THF was added 10 ml of 6 M hydrochloric acid, followed by stirring at 50° C. for 1 hour. The reaction mixture was alkalified by the addition of sodium hydroxide and then 675 mg of di-t-butyl dicarbonate was added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 1.105 g of t-butyl {2-[7-(2-hydroxyethyl)-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]ethyl}carbamate as a white foamed substance.
Reaction SMILES: [I:1][C:2]1[C:7]([NH2:8])=[C:6](I)[N:5]=[CH:4][N:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[I:1][C:2]1[C:7]([NH2:8])=[C:6]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1ccccc1
Reactant: Nc1c(I)ncnc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1c(I)ncnc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
4,6-Diiodopyrimidin-5-amine (2.2 g) was dissolved in 1-methyl-2-pyrrolidone (11.5 mL), phenol (656 mg) and potassium carbonate (964 mg) were added, and the mixture was stirred at 100° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and saturated brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound (2.0 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: Cc1cc(CC(=O)O)c(C)s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(C)sc1C
Yield: 90 %

Procedure:
A solution of 2,5-dimethyl-3-thiophene acetic acid (34 g, 0.200 mol) and concentrated sulfuric acid (1.0 ml) in MeOH (500 ml) was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, diluted to 500 ml with H2O, and neutralized with solid NaHCO3. The product was extracted with Et2O (2×200 ml), the organic layer was washed with H2O (1×100 ml), dried over MgSO4, and treated with activated charcoal. The solvent was removed in vacuo to give the product (33.2 g, 90% yield) as an oil; IR (neat) 1750 cm-1 ; mass spectrum m/z 184 (M+); 1H NMR (CDCl3) δ 2.32 (s, 3H, thiophene-CH3), 2.38 (s, 3H, thiophene-CH3), 3.45 (s, 2H, CH2CO2), 3.67 (s, 3H, CO2CH3), 6.53 (s, 1H, thiophene-H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([NH2:12])[CH:10]=2)[NH:5][C:4](=[O:14])[CH2:3]1.[N:16]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>O.C(O)C>[CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]3[NH:12][C:25]([C:24]4[CH:23]=[CH:22][C:21]([N:16]5[CH:20]=[CH:19][N:18]=[CH:17]5)=[CH:28][CH:27]=4)=[N:13][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(-n5ccnc5)cc4)[nH]c3cc21

Procedure:
2 g. (9.7 mmole) 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one (see Example 13 a)), 1.67 g. (9.7 mmole) 4-(1H-imidazol-1-yl)-benzaldehyde, 0.17 g. p-toluenesulphonic acid and 120 ml. ethanol were mixed together and heated under reflux for 3 hours while passing through air. The evaporation residue was suspended in water, neutralized with 2N aqueous ammonia and recrystallized from methanol to give 1.7 g. (49% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C(O)=O>[ClH:14].[Cl:15][C:10]1[CH:9]=[C:8]([C:4]2([CH:1]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH3:2])[CH2:7][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: C1CCNC1
Agent: Cl
Solvent: O=CO
Product: CC(N1CCCC1)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (7.0 g) prepared as described in Example 1 was slowly added to a mixture of pyrrolidine (25 ml) and 98% formic acid (15 ml) heated to 130°-135° C. for five hours. The mixture was stirred and heated at 160°-165° C. for sixteen hours. After cooling the mixture was poured into 5N hydrochloric acid (200 ml). The solution was washed with ether, basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract was washed with water, dried and hydrogen chloride gas was passed into the extract which was then evaporated to dryness. The residue was triturated with dry ether to give a solid which was recrystallised from propan-2-ol to give N-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethyl pyrrolidine hydrochloride (m.p. 233°-235° C.) (Formula I R1 =Me; R2 =H; R3 and R4 together with the nitrogen to which they are attached form a pyrrolidine ring; R5 =4-Cl and R6 =3-Cl).