Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:3])C.Cl.CO[C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][C:30]=1[C:31]([N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[O:32])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:27])OCC)=[CH:19][CH:18]=1.[NH3:40].Cl>O.C(Cl)Cl.CO>[NH2:40][N:27]=[CH:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:30]([C:31]([N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:35])[CH3:36])=[O:32])=[CH:29][C:28]=2[O:3][CH3:1])=[CH:22][CH:21]=1
Reactant: N
Reactant: CCOC(=N)c1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(OC)c2)cc1
Reactant: CCO
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C=NN)cc1
Temperature: 5 °C
Reaction time: 7.5 h

Procedure:
Ethanol 2 B (42 L) is added to the reactor and the ethyl 4-[5-[3-methoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-pentoxy]benzenecarboximidoate monohydrochloride is dissolved. The solution is cooled to 5° C. and anhydrous ammonia is bubbled into the solution for 7.5 hours until saturation is obtained. After stirring overnight in the ice bath, and ammonia addition is continued another 7.5 hours at 5° C. The reaction mixture is followed by TLC (CH2Cl2 /MeOH, 9:1) using silica plates. A total of four days is required for completion of reaction with periodic resaturation with ammonia gas. The reaction mixture is filtered and the filtrate divided into two equal portions. Concentration in vacuo (55° C., 3 mm Hg) gives an oily viscous suspension which is charged into a 20 gallon reactor. This is admixed with hydrochloric acid (12 N, 560 ml), diluted with water (44 L). At this point, the compound dissolves (pH is 1.62). The solution is washed with diethyl ether (3×18 L), and the pH adjusted to 12.6 with a 6 N sodium hydroxide solution (3.0 L). The oily suspension crystallizes after stirring overnight at 20° C. The product is filtered, washed with water (5×4 L) and dried in vacuo (60° C. 3 mm Hg) to give the product. The second half of the reaction mixture is worked up in a similar manner to give 4-[5-[4-(aminoiminomethyl)phenoxy]pentoxy]-3-methoxy-N,N-bis(1-methylethyl)-benzamide is obtained, mp 112°-114° C. HPLC indicates a purity of 98.5%.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([NH2:11])=[O:10].Cl[C:13]1[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-:23])=[O:22].CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:15]1[C:14]([N+:21]([O-:23])=[O:22])=[C:13]([NH:1][C@@H:2]2[C@@H:7]3[O:8][C@@H:4]([CH2:5][CH2:6]3)[C@@H:3]2[C:9]([NH2:11])=[O:10])[C:18]([Cl:19])=[CH:17][N:16]=1
Reactant: NC(=O)[C@@H]1[C@H](N)[C@H]2CC[C@@H]1O2
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])[C@H]2CC[C@@H]1O2
Temperature: 60 °C
Yield: 100.7 %

Procedure:
(1S,2R,3S,4R)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxamide (15) (170 mg, 0.67 mmol), 4,5-dichloro-3-nitropyridin-2-amine (127 mg, 0.6 mmol), DIPEA (5.5 eq) were taken in IPA and heated at 60° C. for 15 h when a yellow precipitate appeared. The precipitate was filtered, washed well with IPA and dried to afford the desired product, (198 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:4]=1[C:5]1[N:6]=[C:7]3[C:12](=[CH:13][C:14]=1[N:15]2[C:20](=[O:22])[CH3:21])[CH:11]=[CH:10][CH:9]=[CH:8]3.[CH3:23][I:24]>>[I-:24].[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:4]=1[C:5]1[N+:6]([CH3:23])=[C:7]3[C:12](=[CH:13][C:14]=1[N:15]2[C:20](=[O:22])[CH3:21])[CH:11]=[CH:10][CH:9]=[CH:8]3
Reactant: COc1cccc2c1c1nc3ccccc3cc1n2C(C)=O
Reactant: CI
Product: COc1cccc2c1c1c(cc3ccccc3[n+]1C)n2C(C)=O
Product: [I-]
Temperature: 150 °C
Reaction time: 24 h
Yield: 26.7 %

Procedure:
6-Methoxy-10-acetylquindoline from Example 36 (194 mg, 0.668 mmol) was suspended in CH3I (1.25 mL, 200 mmol) and heated in a pressure vessel at 150° C. with stirring for 24 h. After cooling, the resulting precipitate was filtered and dried to obtain 77 mg (27%) of the title compound as brown crystals, mp >250° C. (sublimes); 1H NMR (DMSO-d6) 9.84 (s, 1H), 8.83 (d, J=8.0, 1H), 8.56 (d, J=8.8, 1H), 8.22 (m, 1H), 8.09 (m, 1H), 7.94 (t, J=8.0, 1H), 7.79 (m, 2H), 5.07 (s, 3H), 4.17 (s, 3H), 3.06 (s, 3H); 13C NMR (DMSO-d6) δ 170.5, 150.8, 143.7, 143.1, 135.5, 132.5, 130.1, 129.3, 129.12, 129.09, 127.5, 125.1, 122.3, 117.5, 116.8, 115.2, 57.3, 47.7, 27.7; MS (LSIMS, m/z) 305 (M+).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-])=O.[CH2:11]([O-:13])[CH3:12].[Na+]>C1COCC1>[CH2:11]([O:13][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)[CH3:12]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a mixture of 4-nitropyridine 1-oxide (28 g, 200 mmol) in THF (50 mL) was added sodium ethanolate (40.8 g, 600 mmol). The mixture was stirred at 25° C. for 16 h. The reaction residue was then concentrated and the crude material was purified by silica column chromatography (DCM/MeOH=25:1). All fractions found to contain product by TLC (DCM/MeOH=25:1, Rf=0.6) were combined and concentrated to yield a dark red solid of 4-ethoxypyridine 1-oxide (20 g, 101 mmol, 50% yield). 1H NMR (400 MHz, MeOH-d4) δ 8.20 (d, J=7.6 Hz, 2H), 7.12 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.42 (t, J=6.8 Hz, 3H); ES-LCMS m/z: 140.0 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-phenoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (86%, white crystals). HPLC-MS m/z=320.1 (M+1), Rt: 5.13 min.
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2].[Br:10][C:11]1[CH:12]=[CH:13][C:14](O)=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1.N1CCCC1>CO>[Br:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[O:9][C:6]1([CH2:7][CH2:8][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]1)[CH2:18][C:17]2=[O:19]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)C1CCC(=O)C1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)C1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Yield: 78.1 %

Procedure:
A mixture of 3-isopropylcyclopentanone (0.5 g, 3.962 mmol), 1-(5-bromo-2-hydroxyphenyl)ethanone (0.424 g, 1.98 mmol) and pyrrolidine (0.143 g, 1.98 mmol) in MeOH (25 mL) was refluxed overnight. The solvent was removed in vacuo to give crude 6-bromo-3′-isopropylspiro[chroman-2,1′-cyclopentan]-4-one (500 mg, 79%). 1H-NMR (CDCl3): 0.78 (m, 3H), 0.82 (m, 3H), 1.34 (m, 1H), 1.58 (m, 3H), 1.75 (m, 1H), 1.91 (m, 2H), 2.08 (m, 1H0, 2.73 (s, 2H), 6.74 (m, 1H), 7.44 (m, 1H), 7.89 (d, 1H).
Reaction SMILES: C([Mg]Br)C.O1CCCCC1[O:11][CH2:12][C:13]#[C:14][CH2:15][C:16]#[CH:17].I[CH2:19][C:20]#[C:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[O:23]([CH2:22][C:21]#[C:20][CH2:19][C:17]#[C:16][CH2:15][C:14]#[C:13][CH2:12][OH:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ICC#CCOc1ccccc1
Reactant: C#CCC#CCOC1CCCCO1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC#CCC#CCC#CCOc1ccccc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
3.99 ml (2.15 g, 0.016 mol) of a 4.05N solution of ethylmagnesium bromide in ether was added dropwise under argon to a solution of 2.879 (0.0161 mol) of hexa-2,5-diyn-1-ol tetrahydropyranyl ether [D. Van der Steen et al, Recueil 82, 1015 (1963)] in 30 ml of tetrahydrofuran maintained at -20° C. After the addition was finished, the reactionmixture was stirred for 2 hours further at -20° C. Then, 52.8 mg (0.53 mmol) of cuprous chloride was added. The mixture was stirred for 20 additional minutes, warmed to room temperature and 2.2 g (0.008 mol) of 1-iodo-4-phenoxybut-2-yne was added. The reaction mixture was then stirredat room temperature for 3 hours, poured into 50 ml of saturated ammonium chloride solution and extracted with ether (3×50 ml). The combined extracts were dried over sodium sulfate and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography on80 g of silica gel, using hexane:ether (90:10) as eluant thus obtaining thetetrahydropyranyl ether of 10-phenoxydeca-2,5,8-triyn-1-ol, as an oil. Thisproduct was stored in dry ice.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:13]=1[C:14]([NH:16][CH2:17][CH3:18])=[O:15].[C:27](Cl)(=O)[CH3:28].C1C[O:34]CC1>>[C:17]([N:16]([CH2:27][CH3:28])[C:14](=[O:15])[C:13]1[C:19]([Si:23]([CH3:25])([CH3:24])[CH3:26])=[CH:20][CH:21]=[CH:22][C:12]=1[Cl:11])(=[O:34])[CH3:18]
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCN(C(C)=O)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: -25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
1M sodium bis(trimethylsilyl)amide in THF (5.5 mL, 5.5 mmol) was added dropwise over several min to a solution of the compound of Example 45 (1.28 g, 5 mmol) in THF (30 mL). The resulting mixture was cooled with a water bath while a solution of acetyl chloride (0.432 g, 5.5 mmol) in THF (10 mL) was added, maintaining the internal reaction temperature −25° C. After 1 h, the resulting reaction mixture was partitioned between sat aq NaHCO3 and ether. The ether phase was dried (MgSO4), concentrated, and purified by RC with 1:4 ethyl acetate/hexanes to afford 0.25 g of the title compound as a pale yellow oil, a 17% yield.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)[CH3:3].O.[OH-].[Li+]>CO>[OH:1][CH:2]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)[CH3:3]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)O)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(C)O)c([N+](=O)[O-])cc1OCCCC(=O)O

Procedure:
Methyl 4-[4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy]butyrate (5.04 g) from above was stirred with lithium hydroxide monohydrate in methanol using conventional protocols. 4-[4-(1-Hydroxyethyl)-2-methoxy-5-nitrophenoxy]butyric acid was obtained as an amorphous yellow solid (4.0 g, 83%). 1H NMR (CDCl3) δ1.34 (3 H, d, J=11 Hz, MeCOH), 2.03 (2 H, m, CCH2C), 2.38 (2 H, t, J=7.3 Hz, CH2CO), 3.81 (3 H, s, OMe), 3.96 (2 H, t, J=7.4 Hz, CH2O), 4.13 (2 H, brs, OH), 5.38 (1 H, q, J=10.8 Hz, CHOH), 7.19 (1 H, s, aromatic, and 7.43 (1 H, s, aromatic).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C[O-].[Na+].Cl.[C:18](=O)([O:21]C)[O:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]([C:18]([O:19][CH3:20])=[O:21])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: COC(=O)OC
Reactant: O=C1CCCSc2ccc(Br)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCSc2ccc(Br)cc2C1=O

Procedure:
To a solution of 7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-one (13.5 g) in dimethyl carbonate (200 ml) was added at room temperature sodium methoxide (14.2 g), and the mixture was refluxed for 8 hours under nitrogen atmosphere. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give brown prism of methyl 7-bromo-5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-4-carboxylate (11.5 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[C:13]([C:18]2([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:20][CH2:19]2)[N:12]=3)=[C:5]([N+:27]([O-:29])=[O:28])[CH:4]=1.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CC(=O)OCC>[N+:27]([C:5]1[CH:4]=[C:3]([CH2:2][N:31]2[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]2)[CH:8]=[CH:7][C:6]=1[C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:20][CH2:19]1)[N:12]=2)([O-:29])=[O:28]
Reactant: COC(=O)C1CNC1
Reactant: O=[N+]([O-])c1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c([N+](=O)[O-])c2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(bromomethyl)-2-nitrophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (0.363 g, 0.778 mmol), methyl azetidine-3-carboxylate hydrochloride (0.354 g, 2.34 mmol), N,N-diisopropylethylamine (0.812 mL, 4.67 mmol) in 3 mL DMF was heated in a sealed vial to 80° C. for 1 h. The reaction mixture was cooled and allowed to stand overnight. In the morning the reaction mixture was treated with ice, sat'd aq. NaHCO3, and EA. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography, 40 g, 0-10% MeOH/DCM gave methyl 1-((3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as a yellow oil. MS (ESI) m/z: Calculated: 500.2; Observed: 500.7 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:33]([O:32][C:30](=[O:31])[NH:21][C:17]1[CH:16]=[C:15]([C:13]2[O:14][C:10]([CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:11][N:12]=2)[CH:20]=[CH:19][N:18]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(-c2nnc(CCc3cccc(F)c3)o2)ccn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(-c2nnc(CCc3cccc(F)c3)o2)ccn1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
To a solution of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]pyridin-2-amine (280 mg, 0.985 mmol), triethylamine (0.82 mL, 5.92 mmol) and 4-dimethylaminopyridine (12 mg, 0.0985 mmol) in tetrahydrofuran (10 mL) was added benzyl chloroformate (0.70 mL, 4.92 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (30 mg, yield 7%) as colorless crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3cccs3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3cccs3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.95 g of 4,5-bis(4-methoxyphenyl)-2-(2-thienylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.47 g of 4,5-bis(4-methoxyphenyl)-2-(2-thienylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [N+:1]([C:4]1C=C(N)C=[CH:8][C:9]=1NCC=C)([O-])=O.F[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[CH:18][C:17]=1[N+:29]([O-:31])=[O:30]>>[N+:29]([C:17]1[CH:18]=[C:19]([N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])[CH:20]=[CH:21][C:16]=1[NH:1][CH2:4][CH:9]=[CH2:8])([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1cc(N(CCO)CCO)ccc1F
Reactant: C=CCNc1ccc(N)cc1[N+](=O)[O-]
Product: C=CCNc1ccc(N(CCO)CCO)cc1[N+](=O)[O-]

Procedure:
Synthesis and working up same as for compound 1, but with 4-fluoro-3-nitro-N,N-bis-(2-hydroxyethyl)-aminobenzene instead of 4-fluoro-3-nitroaminobenzene. Black crystals, melting point 73°-75° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+]=[N-])[CH3:11].[O-]CC.[NH4+].[Cl-]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[NH:15][C:4]2[C:3]([CH3:9])=[C:2]([Cl:1])[S:6][C:5]=2[CH:7]=1)=[O:18])[CH3:11]
Reactant: Cc1cc(C=O)sc1Cl
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2sc(Cl)c(C)c2[nH]1
Temperature: 10 °C

Procedure:
5-Chloro-4-methyl-thiophene-2-carbaldehyde was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester was added as ethanol solution (1 M of ester) to −20° C. ethoxide solution; allow to warm to 10° C. over 2 h, 10° C. 2 h; reaction poured into cold saturated aqueous NH4Cl; after ether extraction, acrylate organic phase washed with water until aqueous phase was neutral; solution of crude acrylate added to refluxing xylenes over 5 min and then heated at reflux).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([S:12]([O-:15])(=[O:14])=[O:13])=[N:3][CH:4]=[CH:5][CH:6]=1.[Na+:16]
Reactant: O=S([O-])O
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1ncccc1C(F)(F)F
Yield: 67.9 %

Procedure:
In a flask, 2-chloro-3-(trifluoromethyl)pyridine (20.0 g, 110 mmol) , sodium hydrogen sulfite (46 g, 442 mmol), ethanol (200 ml) and water (200 ml) were charged and heated under reflux for 138 hours. After evaporating off the solvent from the reaction mixture, conc. hydrochloric acid was added to the residue and then evaporated to dryness. This residue was extracted with methanol, and the methanol phase was filtered and evaporated to dryness to obtain sodium 3-(trifluoromethyl)pyridine-2-sulfonate (18.6 g). Yield, 68%.
Reaction SMILES: Cl.[C:2]([CH2:4][NH2:5])#[N:3].[C:6](Cl)(=[O:10])[C:7]([Cl:9])=[O:8].Cl>O1CCOCC1>[C:2]([CH2:4][NH:5][C:6](=[O:10])[C:7]([Cl:9])=[O:8])#[N:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CCN
Agent: Cl
Solvent: C1COCCO1
Product: N#CCNC(=O)C(=O)Cl

Procedure:
20 mM of cyanomethylamine hydrochloride and 25 mM of oxalyl chloride in 100 mM of absolute dioxane are heated at 60-70° while passing through a stream of nitrogen. After one hour a clear solution results and there is no evidence of hydrogen chloride in the nitrogen stream. The solvent is evaporated under vacuum and the residual, light brown oil is taken up in methylene chloride, filtered over charcoal and stored at -30° until it is to be used.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[CH:13]2[CH2:21]C=O>C(O)C.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[CH:13]2[CH:21]=[N:2][OH:3]
Reactant: COc1c(C)cc(C)c2c1C(CC=O)C1=C2CCCC1
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1c(C)cc(C)c2c1C(C=NO)C1=C2CCCC1

Procedure:
500 Milligrams of hydroxylamine hydrochloride was added to an ethanol-chloroform (5:1) solution containing 910 mg of 5,7-dimethyl-8-methoxy-9-formylmethyl-1,2,3,4-tetrahydro-9H-fluorene in 18 ml of ethanol-chloroform and the mixture was refluxed with heating for 2 hours. The reaction mixture was diluted with chloroform and then washed with saturated aqueous sodium chloride solution and subsequently the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) to obtain 670 mg of 5,7-dimethyl-8-methoxy-9-hydroxyiminomethyl-1,2,3,4-tetrahydro-9H-fluorene
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].Cl.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([S:12]([CH2:11][C:5]3([C:3]([OH:2])=[O:4])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)(=[O:14])=[O:13])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: COC(=O)C1(CS(=O)(=O)Cl)CCOCC1
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
4-Chlorosulfonylmethyltetrahydropyran-4-carboxylic acid methyl ester (5.10 g) was added to a stirred suspension of 4-bromophenylpiperazine hydrochloride (5.51 g) and triethylamine (6.09 ml) in dichloromethane (120 ml), and the mixture was stirred at room temperature for 18 h. The dichloromethane was then removed under reduced pressure, and the residue redissolved in tetrahydrofuran (60 ml), methanol (30 ml) and water (15 ml), treated with lithium hydroxide monohydrate (4.15 g) and heated to reflux for 2 h. The organic solvents were removed in vacuo and the residue was diluted with 1 M sodium hydroxide (30 ml) and washed with diethyl ether (3×40 ml). The aqueous phase was then acidified to pH 4-5 with citric acid, forming a white precipitate, which was filtered, washed with water and dried to constant weight under vacuum at 40° C. to provide the title compound as a white solid (4.55 g, 51%).