Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]1[O:20][C:19]2[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][C:11]=2[O:10]1>ClCCl.C(N(CC)CC)C>[CH2:9]1[O:20][C:19]2[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH:16][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[CH:12][C:11]=2[O:10]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccc2c(c1)OCO2)c1ccco1

Procedure:
N-[2-(3,4-methylenedioxyphenyl)ethyl]furan-2-carboxamide was prepared by condensation of 2-furoyl chloride and 3,4-methylenedioxyphenethylamine in dichloromethane with triethylamine as catalyst.
Reaction SMILES: CN([CH:4]([CH3:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O)C.[NH2:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:4]=[CH:14][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[N:15]=2)=[CH:12][CH:11]=1
Reactant: CC(C(=O)c1ccc(F)cc1)N(C)C
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)nc1C

Procedure:
The title compound was prepared from dimethylamino-(4-fluorophenyl)propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. MS (ES): MH+ 260.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25]I>CN(C)C=O.O>[C:1]([NH:9][C:10]([S:11][CH3:25])=[N:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1N=C(NC(=O)c1ccccc1)SC
Reaction time: 0.5 h

Procedure:
To 0.10 g of 2-[[(benzoylamino)thioxomethyl]amino]-N-methylbenzamide in 2.0 ml of N,N-dimethylformamide was added 0.35 ml of 1N sodium hydroxide at 0° C., followed by 0.04 ml of methyl iodide. The solution was stirred and allowed to reach room temperature over 30 minutes. This was diluted with water to give 0.074 g of N-benzoyl-N'-(2-methylaminocarbonylphenyl)carbamimidothioic acid, methyl ester as colorless crystals, mp 193°-195° C. This compound was reacted with sodium hydride in tetrahydrofuran by refluxing for 21/2 hours to give N-(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl)benzamide, mp 185°-187° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.[Br:14]Br.Cl.Cl[Sn]Cl>O.C(O)(=O)C>[Br:14][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=2
Reactant: BrBr
Reactant: N#Cc1cccc2ccc(O)cc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(Br)cc2ccc(O)cc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 38.4 %

Procedure:
To a mixture of 7-hydroxy-1-naphthonitrile (26.03 g, 154.0 mmol) and glacial acetic acid (400 mL) was added bromine (51.8 g, 323 mmol). The mixture was stirred at 100° C. for 6 hr. HCl (400 mL of 12 N solution) and SnCl2 (69 g, 308 mmol) were added and the mixture was stirred at 100° C. for 1 hour. The resulting solution was cooled to room temperature and poured into water (1 I). The resulting yellow precipitate was collected by filtration, dried under vacuum, and triturated with ethyl acetate to yield 14.68 g (38%) of the title compound as an off-white solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 222–224° C.;1H NMR (DMSO-d6): δ 7.28–7.35 (2H, m), 7.97 (1H, d, J=8.73 Hz), 8.26 (1H, s), 8.47 (1H, s), 10.65 (1H, s); MS (ESI) m/z 246/247 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([O-:18])(=O)=[O:16].[Na+].CC(C)=O.P(Cl)(Cl)([Cl:26])=O>CN(C)C(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([Cl:26])(=[O:18])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 40 °C

Procedure:
59 g of sodium 2-(2-methoxyethoxy)-5-nitrobenzenesulfonate prepared as described in Synthesis Example 1 was added to a mixture of 200 ml of acetone and 75 ml of phosphorous oxychloride. 75 ml of N,N-dimethylacetamide was added dropwise to the mixture with stirring while the reaction mixture was maintained at 30°to 40° C. After completion of the addition, the mixture was allowed to stand with stirring until it cooled to room temperature. The reaction mixture was then poured into 600 ml of ice water, stirred for 30 minutes and the crystals thus precipitated were collected by filtration. The crystals were washed with 100 ml of water and air-dried. Yield:56 g; Melting Point: 74°-74.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:13]=2[C:14]#[N:15])(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH3:21].CCOC(C)=O>CO>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([S:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)(=[O:11])=[O:10])[C:13]=1[C:14]#[N:15]
Reactant: Cc1cc(C)cc(S(=O)(=O)c2cccc(F)c2C#N)c1
Reactant: N
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C)cc(S(=O)(=O)c2cccc(N)c2C#N)c1
Temperature: -78 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
2-[(3,5-Dimethylphenyl)sulfonyl]-6-fluorobenzonitrile (Example 20) (0.5 g 1.7 mmol) was dissolved in 80 ml of methanol and chilled to -78° C. Condensed ammonia (20 ml, 15.4 g, 905 mmol) was added and the mixture was heated to150° C. in a sealed Parr bomb for 24 h. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 0.28 g (56%) of 2-amino-6-[(3,5-dimethylphenyl)sulfonyl]benzonitrile: mp 208°-209° C.;; NMR (Me2SO-d6, 200 MHz) δ 2.36 (s, 6H), 6.59 (br s, 2H), 7.10 (apparent d, 1H), 7.3-7.4 (m, 2H) 7.54 (apparent d, 1H), 7.58 (m, 2H); mass spec (CI) M+ +1=287. Anal. Calc. for C15H14N2O2S: C, 62.92; H, 4.93; N: 9.78; S, 11.20. Found: C, 63.02; H, 4.98; N, 9.72; S, 11.12.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([NH:44][S:25]([C:2]([F:1])([F:29])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:19])([F:20])[C:6]([F:18])([F:17])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:12])[F:11])(=[O:26])=[O:27])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccccc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.72 g (100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted 3 times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[C:21]([O:22][CH3:23])=[C:20]2[C:15]([CH:16]=[C:17]([C:25]([OH:27])=O)[C:18](=[O:24])[O:19]2)=[CH:14][CH:13]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:52]1[C:53]([C:61]2[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=2)=[CH:54][N:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=12>CN(C=O)C>[N:52]1[C:53]([C:61]2[CH:62]=[C:63]([NH:67][C:25]([C:17]3[C:18](=[O:24])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[C:21]=4[O:22][CH3:23])=[O:27])[CH:64]=[CH:65][CH:66]=2)=[CH:54][N:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: COc1ccc2cc(C(=O)O)c(=O)oc2c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc2c1OC
Temperature: 25 °C
Yield: 77.8 %

Procedure:
DIEA (38.3 μL, 0.22 mmol) was added to 7,8-dimethoxy-3-carboxy-coumarin (500 mg, 0.20 mmol) and HATU (83.6 mg, 0.22 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (41.8 mg, 0.20 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 68.7 mg of product in 78% yield: LCMS (ESI) m/z 442 (MH+).
Reaction SMILES: [NH2:1][N+:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[CH3:9].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:37][CH3:38])(=[O:36])[C:30]#[C:31][C:32]([O:34][CH3:35])=[O:33].O>CN(C)C=O>[CH3:8][C:6]1[C:7]2[N:2]([N:1]=[C:30]([C:29]([O:37][CH3:38])=[O:36])[C:31]=2[C:32]([O:34][CH3:35])=[O:33])[C:3]([CH3:9])=[CH:4][N:5]=1
Reactant: Cc1c[n+](N)c(C)cn1
Reactant: COC(=O)C#CC(=O)OC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(C)cnc(C)c2c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of 1-amino-2,5-dimethylpyrazin-1-ium-2,4,6-trimethylbenzenesulfonate (4.72 g, 14.6 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added potassium carbonate (4.44 g, 32.1 mmol). The mixture was stirred at room temperature for 10 min. Then a solution of dimethyl but-2-ynedioate (1.87 g, 13.2 mmol) in DMF (30 mL) was added. The resulting mixture was stirred at room temperature for 1 h. Then the mixture was poured into water (400 mL), extracted with EtOAc (3×200 mL). The combined organic layer was dried over sodium sulfate, filtered, evaporated, and chromatographed on silica gel using 20% ethyl acetate (EtOAc) in petroleum ether (PE) as eluent to give 1.04 g (27% yield) of the title compound as a yellow solid. ESI MS: m/z 124.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=0.8 Hz, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 2.81 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [C:1]([CH:4]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2].[N+:23](/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-:25])=[O:24]>C(OCC)C>[CH2:11]([O:10][C:8]([CH2:7][C@@H:6]1[CH2:5][C@@:4]([C:1](=[O:3])[CH3:2])([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:26]1[N+:23]([O-:25])=[O:24])=[O:9])[CH3:12]
Reactant: CCOC(=O)C=CCC(C(C)=O)C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1C[C@@](C(C)=O)(C(=O)OCc2ccccc2)[C@@H](c2ccccc2)[C@@H]1[N+](=O)[O-]
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of 6-benzyl 1-ethyl 5-acetylhex-2-enedioate 4b (0.3 mmol, 1.0 eq) and 1-((E)-2-nitrovinyl)benzene (0.45 mmol, 1.5 eq) in diethylether (0.4 mL) was added catalyst VI (Q-NH2) (0.045 mmol, 0.15 eq) at room temperature (22° C.). The resulting mixture was stirred vigorously for 16 hours, then the reaction was continued for about 6 hours after removal of the solvent. After the reaction was completed (monitored by TLC and crude NMR), the title product was afforded by flash chromatography over silica gel (Ethyl acetate:Hexane=1:10 to 1:4) in 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][O:8][CH2:9][CH:10]=O)=[CH:5][CH:4]=1.C(OCC1[N:20](C)[C:21]([CH:31]([CH3:33])[CH3:32])=[C:22](SC2C=CC=CC=2)[N:23]=1)(=O)N.N.C(O)(=O)C(O)=O>C(#N)C.C(OCC)(=O)C>[CH:31]([C:21]1[N:20]=[C:10]([CH2:9][O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=2)[NH:23][CH:22]=1)([CH3:33])[CH3:32]
Reactant: COc1ccc(COCC=O)cc1
Reactant: CC(C)c1c(Sc2ccccc2)nc(COC(N)=O)n1C
Agent: N
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(COCc2nc(C(C)C)c[nH]2)cc1
Reaction time: 96 h
Yield: 65.5 %

Procedure:
In 970 ml of acetonitrile was dissolved 175 g (0.968 mol) of p-methoxybenzyloxyacetaldehyde (2d), followed by addition of 150 g (0.968 mol) of 2,2-dichloro-3-methylbutyraldehyde (1). Then, 1300 ml of 28% aqueous ammonia was further added dropwise under ice-cooling. After completion of dropwise addition, the mixture was allowed to stand at room temperature for 4 days. This reaction mixture was concentrated under reduced pressure and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over MgSO4 and the solvent was distilled off under reduced pressure. The crude product was dissolved in ethyl acetate. To this solution was added a solution of oxalic acid (89.8 g, 0.968 mol) in ethyl acetate (70 ml) and the resulting oxalate was collected by filtration and rinsed with ethyl acetate. This oxalate was neutralized with 2N-sodiums hydroxide arid extracted with ethyl acetate. The organic layer was washed with water and dried over magnisium sulfate. The solvent was then distilled off under reduced pressure to provide 165 g (yield 69%) of 4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (3d) as oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH:14]([CH3:21])[CH2:15][C:16]([O:18]CC)=[O:17])[CH:3]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH:14]([CH3:21])[CH2:15][C:16]([OH:18])=[O:17])[CH:3]=1
Reactant: CCOC(=O)CC(C)c1cc(F)c2cc(OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(C)CC(=O)O)cc(F)c2c1

Procedure:
The ester (9 g) was dissolved in methanol (180 ml) and 10% aqueous sodium hydroxide solution (90 ml) was added. The solution was heated under reflux for 2 hours. It was then poured into water (270 ml) and the suspension was acidified with dilute hydrochloric acid. The precipitate produced was extracted into ethyl acetate. The organic solution was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to give 3-(4-fluoro-6-methoxy-2-naphthyl)butanoic acid as an oil which crystallised on standing (12.4 g., >100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20](O)=[O:21])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](N1C=CN=C1)([N:25]1C=CN=[CH:26]1)=O.CN(C)C=O.CNC>O1CCCC1>[CH3:23][N:25]([CH3:26])[C:20](=[O:21])[CH2:19][N:18]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A suspension of 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.6 g, 0.0101 mole), and dry dimethylformamide (10 ml) in tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (26.4 ml of a 2.29M solution, 0.0606 mole) was added. The resulting solution was heated at 45° C. overnight under nitrogen. The solvents were evaporated under reduced pressure. The residue was triturated in water (300 ml), and the resulting solid was collected by filtration, rinsed with water, 5% potassium hydroxide solution and again with water. The solid was dissolved in hot isopropyl alcohol, filtered, and allowed to cool to room temperature. A solid precipitated which was collected by filtration and dried under high vacuum to give 1.26 g (38%) of title compound, mp 204°-207° C.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][SH:9].Cl[C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[C:12]=1[CH3:19]>O1CCOCC1.O>[CH3:18][C:13]1[C:12]([CH3:19])=[C:11]([S:9][CH2:8][C:4]2[O:3][CH:7]=[CH:6][CH:5]=2)[CH:16]=[CH:15][N+:14]=1[O-:17]
Reactant: SCc1ccco1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(SCc2ccco2)cc[n+]([O-])c1C
Reaction time: 0.25 h

Procedure:
6 g of (60%) NaOH are added in portions to 50 ml of dry dioxane, the mixture is stirred for 15 minutes, 11.7 g (0.11 mol) of 2-furylmethylmercaptan are metered in, in the course of 20 minutes, and the mixture is again stirred for 30 minutes until the evolution of gas has ceased. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide in 100 ml of dioxane is subsequently added dropwise in the course of 20 minutes, the reaction mixture is stirred at RT for 1 h, subsequently at 70° C. for 1 h and thereupon at 100° C. for a further 1 h. After the reaction has ended, the mixture is allowed to cool, diluted with 500 ml of water and extracted 4 times using in each case 300 ml of ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate, concentrated and crystallized by adding diisopropyl ether. This gives 18.8 g (80% of theory) of 2,3-dimethyl-4-(2-furylmethylthio)pyridine N-oxide of m.p. 111°-112° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[N:12][C:11]([CH2:14]Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][S-:18].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[N:12][C:11]([CH2:14][S:18][CH3:17])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Agent: [Na+]
Solvent: CC(C)=O
Product: CSCc1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (5-bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (prepared according to WO 02/070494, 1.03 g, 3.575 mmol) in acetone (11.6 mL) was treated with sodium thiomethoxide (0.33 g, 4.473 mmol). The reaction mixture was stirred at 25° C. for 5 h 15 min. The reaction was then concentrated in vacuo, and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 5% ethyl acetate/methylene chloride) afforded (5-methylsulfanylmethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester as a crude white solid (0.45 g, 49%) which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]2N=N[N:11]=[C:7]2[C:6]([CH2:12][CH:13]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:15])=[C:5]([CH3:24])[N:4]=1.O>C(O)(=O)C.[Zn]>[NH2:2][C:3]1[N:8]=[C:7]([NH2:11])[C:6]([CH2:12][CH:13]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:15])=[C:5]([CH3:24])[N:4]=1
Reactant: CC(=CCc1c(C)nc(N)n2nnnc12)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(=CCc1c(C)nc(N)nc1N)c1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
Zinc is activated by treating 2.5 grams (excess) of it with aqueous 10% hydrochloric acid for two minutes. The activated zinc is collected by filtration, washed with water then acetone, and dried in a vacuum oven for one hour. A solution of 1.5 grams (0.004 mole) of 5-amino-7-methyl-8-[3-(2,5-dichlorophenyl)-2-butenyl]tetrazolo[1,5-c]pyrimidine in 35 mL of acetic acid is stirred, and the activated zinc is added portionwise during a 20 minute period. Upon completion of addition, the reaction mixture is warmed to about 80° C. where it is stirred for about 18 hours. After this time, the reaction mixture is stirred with 50 mL of water. The mixture is then extracted with three 30 mL portions of methylene chloride. The combined extracts are washed with two 10 mL portions of an aqueous solution saturated with sodium bicarbonate. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel; using 15% methanol in methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 0.4 gram of 2,4-diamino-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine; mp 172°-174° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:25]=1[C:26](=O)[CH2:27]Br>>[F:23][C:24]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:25]=1[C:26]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:27]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)CBr)c(F)c1
Product: COc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)c(F)c1
Yield: 89 %

Procedure:
4-[4-(2-Fluoro-4-methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (253 mg, 89%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-fluoro-4-methoxyphenacyl bromide (available from ASDI Incorporated) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=1.8 Hz, 1H), 8.10-8.21 (m, 3H), 7.94 (d, J=2.4 Hz, 1H), 7.59-7.78 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 6.93-7.02 (m, 2H), 3.83 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([C:13]([O:15][CH3:16])=[O:14])=[N:5]1.C(N(C(C)C)CC)(C)C.[C:26]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH2:41])[CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[I-].[K+]>CC#N>[CH3:16][O:15][C:13]([C:6]1[CH:7]=[C:8]2[C:9](=[O:11])[N:41]([CH2:40][CH2:39][CH:36]3[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]3)[CH2:2][CH2:3][N:4]2[N:5]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: COC(=O)c1cc(C(=O)OC)n(CCBr)n1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc2n(n1)CCN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C2=O

Procedure:
A solution of 3-2 (14.0 g, 48.0 mmol), diisopropylethyl amine (25 ml, 144 mmol), Boc-4-aminoethylpiperidine (12.0 g, 52.6 mmol), and potassium iodide (2.39 g, 0.3 mmol) in 250 ml CH3CN was refluxed under N2 for 4.5 h then cooled, filtered and evaporated at reduced pressure. The resulting yellow residue was chromatographed on silica gel using EtOAc as eluent to give 3-3 as an off-white crystalline solid.