Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:36])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:37][C:38]1[S:42][CH:41]=[N:40][CH:39]=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH2:2][N+:40]3[CH:39]=[C:38]([CH3:37])[S:42][CH:41]=3)[CH:8]=[CH:7][CH:6]=2)=[O:36])=[CH:14][CH:15]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: Cc1cncs1
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2cccc(CBr)c2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]
Yield: 76 %

Procedure:
A mixture of 1.9 g of N-[3-(bromomethyl)phenyl]-2-[4-(hexadecyloxy)phenoxy]acetamide and 1.68 g of 5-methyl thiazole in 25 ml of toluene is refluxed under argon for 5.5 hours then concentrated to a residue which is mixed with ether and the solid collected by centrifugation then washed several times with ether. The solid is vacuum dried to give 1.7 g of the desired product as a white solid, m.p. 121°-124° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.CO.Br[CH2:30][CH2:31][CH2:32][Cl:33]>CN(C)C=O>[Cl:33][CH2:32][CH2:31][CH2:30][O:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc2cc(O)c(C(=O)OC)cc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCCCCl)c(C(=O)OC)cc2c1

Procedure:
3.1 g of 2-hydroxy-3,6-dimethoxycarbonyl naphthalene was suspended in 30 g of N,N-dimethylformamide and 1.6 g of 1-bromo-3-chloropropane, 1.5 g of sodium carbonate and 0.1 g of polyethyleneglycol (average molecular weight 3000) were added thereto and reacted for 15 hours at 50° C. Then, the reaction mixture was poured into a mixed solution of 400 g of water and 100 g of methanol, about 1 hour after, the precipitates were collected by filtration. The filtrate was washed well with methanol and water and dried to give 2-(3′-chloropropyloxy)-3,6-dimethoxy carbonyl naphthalene as 2.6 g of pale yellow powder(melting point: 115° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][NH2:13])=[CH:4][CH:3]=1.[C:14]([C:19]1[C:20](=[O:32])[CH2:21][CH:22]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][C:24]=1[OH:25])(=O)[CH2:15][CH2:16][CH3:17]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:19]2[C:20](=[O:32])[CH2:21][CH:22]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23][C:24]=2[OH:25])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:7]=1
Reactant: CCCC(=O)C1=C(O)CC(C2CCOCC2)CC1=O
Reactant: NOCCC#Cc1ccc(F)cc1
Product: CCCC(=NOCCC#Cc1ccc(F)cc1)C1=C(O)CC(C2CCOCC2)CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
2.7 g (15 mmol) of 4-(4-fluorophenyl)-but-3-ynoxyamine were added to a solution of 4 g (15 mmol) of 2-butyryl-3-hydroxy-5-tetrahydropyran-4-ylcyclohex-2-enone in 60 ml of drymethanol. The mixture was stirred for 16 hours at room temperature, after which the methanol was removed under reduced pressure from a water pump. The crude product was purified by chromatography over silica gel (mobile phase: methylene chloride). Yield: 81.2%.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([CH2:26][N+:27]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C.CC(C)([O-])C.[K+]>COCCOC>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:26]#[N:27])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzoyl-4-piperidone (2.0 g, 9.8 mmol), tosylmethyl isocyanide (2.5 g, 12.8 mmol) and ethanol (1.0 mL, 17.1 mmol) in 30 mL DME was cooled in an ethanol/ice bath, and potassium tert-butoxide was added at such a rate to maintain the reaction temperature at <10° C. The cold bath was removed, and the reaction was allowed to stir overnight at room temperature. The solids were removed by filtration, rinsed with DME, and the filtrate was evaporated. The residue was dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered through silica gel, and concentrated to give 2.14 g (66%) of a slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O=[As](O[As](=O)=O)=O.OS(O)(=O)=O.[C:24]([O-])(O)=O.[Na+].C(O[CH2:33][CH3:34])(=O)C>OCC(CO)O>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[C:5]2[C:3]=1[N:4]=[CH:34][CH:33]=[CH:24]2
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Agent: [Na+]
Solvent: OCC(O)CO
Product: CC(C)c1cc(Br)c2ncccc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-4-isopropylaniline (3.0 gm) [obtained from Aldrich Chemical Co.], glycerol (2.8 mL) and arsenic pentoxide (3.22 g) were combined and heated to 100° C. H2SO4 (concentrated, 1.9 mL) was added to the reaction mixture in a dropwise manner. The mixture was then heated to 150° C. for 2.5 hours. The resulting black oil was added in a dropwise manner to a stirring mixture of saturated NaHCO3 (300 mL) and ethyl acetate (100 mL). After completion of the addition, the reaction mixture was stirred for 30 minutes. The reaction mixture was then extracted with ethyl acetate (2×200 mL). The organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The resulting material was further purified and isolated by chromatography on silica gel (30:70 ethyl acetate/hexanes) which yielded 2.5 g of 8-bromo-6-isopropylquinoline as a brown oil.
Reaction SMILES: CN(C)C=[O:4].O=[C:7]([Cl:13])OC(Cl)(Cl)Cl.[CH2:14]([N:21](C=CC)C(=O)C)[C:15]1[CH:20]=C[CH:18]=[CH:17][CH:16]=1>>[Cl:13][C:7]1[C:17]([CH:18]=[O:4])=[CH:16][C:15]([CH3:20])=[CH:14][N:21]=1
Reactant: CN(C)C=O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC=CN(Cc1ccccc1)C(C)=O
Product: Cc1cnc(Cl)c(C=O)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
Dimethylformamide (13.54 g, 0.185 moles) was added to a well stirred and cooled material of diphosgene (36.64 g, 0.185 moles) at 10° C. in 30 minutes in an ice bath followed by N-benzyl-N-(1-Propenyl)acetamide (5 g, 0.026 moles) at the same temperature. The reaction mixture was further continued for 2 hours at 25° C. The ice cold bath was removed and heated to 75° C. for 5 hours. The orange-yellow coloured organic mass was poured in ice cold water (200 g) with stirring. The mass was extracted with methylenechloride (2×200 ml) and the layer separated. The organic layer was dried over sodium sulfate, and solvent removed under reduced pressure. Residue obtained was subjected to chromatographic purification on silica gel to give 2-chloro-5-methylpyridine-3-carbaldehyde (3.78 g) in 92% yield.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH:22]=O)[CH3:17].[CH3:31][NH:32][C:33]([NH:35][CH3:36])=[O:34].C[Si](Cl)(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:35]([CH3:36])[C:33](=[O:34])[N:32]2[CH3:31])[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[C:26]=1[OH:27])[CH3:17]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CNC(=O)NC
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCOc1cc(C2C(c3ccccc3)=C(c3ccccc3)N(C)C(=O)N2C)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
A mixture of 1,2-diphenylethanone (300 mg, 1.53 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (324 mg, 1.53 mmol), and 1,3-dimethylurea (174 mg, 1.98 mmol) in DMF (5 mL) was added TMSCl (1.0 g, 9.12 mmol), and the reaction mixture was stirred at room temperature overnight under nitrogen. LCMS showed that about 30% of starting materials were consumed. H2O (10 mL) was added to quench the reaction, and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (PE:EtOAc=1:2) and preparative HPLC to afford Compound 41 as a yellow solid (82 mg, yield: 11.6%). 1H NMR (DMSO-d6 400 MHz): 610.40 (s, 1H), 7.50 (s, 1H), 7.30 (d, J=6.0 Hz, 3H), 7.25 (d, J=8.0 Hz, 3H), 7.00 (d, J=6.8 Hz, 3H), 6.75 (d, J=6.4 Hz, 2H), 5.11 (s, 1H), 4.00-4.17 (m, 2H), 2.82 (s, 3H), 2.75 (s, 3H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 460.1 [M+1]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25]3=[C:26]([NH:28][C:29](=[S:30])[N:24]3[CH2:23][CH2:22][CH2:21]2)[CH:27]=1.[OH-].[Na+]>C(O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25]3=[C:26]([N:28]=[C:29]([S:30][CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:5]=4)[N:24]3[CH2:23][CH2:22][CH2:21]2)[CH:27]=1
Reactant: ClCc1cccc(-c2ccccc2)n1
Reactant: COc1cc2c3c(c1)[nH]c(=S)n3CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c3c(c1)nc(SCc1cccc(-c4ccccc4)n1)n3CCC2
Temperature: 25 °C

Procedure:
2-Chloromethyl-6-phenylpyridine hydrochloride 1.942 g, 8.1 mmol) was added to a solution of 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-ij]quinoline-2[1H]-thione (1.78 g, 8.1 mmol) in ethanol (16 ml) and 1N-sodium hydroxide (16.2 ml). The mixture was heated under reflux for 15 seconds and cooled to room temperature. The ethanol was removed by evaporation in vacuo and the aqueous mixture extracted with dichloromethane (2×150 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give a brown solid which was recrystallised from MeOH to give the title compound as the quarter hydrate (2.77 g, 88%), mp 134°-135° C. (Found: C, 70.5; H, 5.8; N, 10.4; C23H21N3OS1/4H2O requires C, 70.5; H, 5.5; N, 10.7%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([CH:10]=O)[CH2:9][CH2:8]1.[S].C(O)(=O)C.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:32])[CH2:26]2)=[N:22][C:23]=1[NH2:24]>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1([C:10]2[NH:24][C:23]3=[N:22][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:26]4)=[CH:20][CH:19]=[C:18]3[N:17]=2)[CH2:8][CH2:9]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=CC1(c2ncccn2)CC1
Agent: [S]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5ncccn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 80 °C

Procedure:
1-(Pyrimidin-2-yl)cyclopropanecarbaldehyde (0.11 g, 0.747 mmol), sulfur (40 mg, 1.24 mmol), and acetic acid (0.6 mL) were added to a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared during the previous step, in ethanol. The reaction mixture was heated to 80° C. for 18 h. The solvent was removed under reduced pressure and the crude material was purified via preparative HPLC to afford the title compound (8 mg). MS (ES+APCI) (M+H) 418.2; LCMS retention time 3.273 min (Method S1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14]O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
Combine (3-nitrophenyl)acetic acid (20.0 g, 110 mmol) and anhydrous methanol (125 mL). Add 7 drops of concentrated sulfuric acid. Heat to 50° C. After 14 hours, cool to ambient temperature. Evaporate in vacuo to give a residue. Partition the residue between water and diethyl ether. Separate the organic layer and extract with aqueous saturated sodium bicarbonate solution and brine. Dry the organic layer over MgSO4 and filter. Slowly evaporate to give methyl (3-nitrophenyl)acetate. 1H NMR (CDCl3) δ 8.17 (d, 1 H, J=1.1 Hz), 8.14 (dd, 1 H, J=1.0, 7.7 Hz), 7.63 (dd, 1 H, J=1.1, 7.7 Hz), 7.52 (t, 1 H, J=7.7 Hz), 3.75 (s, 2 H), 3.73 (s, 3 H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][NH:32][C:28]=2[CH:27]=1)([O-:25])=[O:24]>>[N+:23]([C:26]1[CH:34]=[CH:33][C:29]2[N:30]([CH2:2]/[CH:3]=[C:4]3/[C:5]4[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=4[O:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/3=4)[CH:31]=[N:32][C:28]=2[CH:27]=1)([O-:25])=[O:24].[N+:23]([C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][N:32]([CH2:2]/[CH:3]=[C:4]3/[C:5]4[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=4[O:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/3=4)[C:28]=2[CH:27]=1)([O-:25])=[O:24]
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1cnc3cc([N+](=O)[O-])ccc31)c1ccccc1CO2
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1cnc3ccc([N+](=O)[O-])cc31)c1ccccc1CO2

Procedure:
Compound h, 2.0 g, and 5.2 g of 5-nitrobenzimidazole were treated in a manner similar to Example 23 to give a 1:1 mixture of Compounds E-55a and E-56a. The mixture was separated and purified by silica gel column chromatography (eluting solvent, hexane:ethyl acetate:triethylamine=10:10:1) to give 1.1 g of methyl (E)-11-[2-(5-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound E-55a) and 0.7 g of methyl (E)-11-[2-(6-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound E-56a).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]([F:28])([F:27])[CH2:23][CH2:24][CH2:25]I.O>CN(C)C=O>[Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:24][CH2:23][C:22]([F:28])([F:27])[F:21])[C:6](=[O:11])[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cccc3c(Br)ccc(c23)N1CCCC(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a solutiion of 6-bromo-benzo[cd]indol-2(1H)-one (1 g, 4 mmol) in N,N-dimethyl formamide was added K2CO3 (5.53 g, 40 mmol) and the resulting mixture was stirred for 0.5 hour under nitrogen. 4,4,4-trifluorobutyl iodide (915 mg, 4 mmol ) was next injected to the solution and the mixture was heated at 60° C. for 18 hours. The reaction media was next poured into 200 ml water and extracted with trichloromethane (3×100 ml). Column chromatography using gradient ethyl acetate in hexane (10˜20%) gave the desired product (1.225 g, 85%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4](C(=O)C2C=C(C)C=CC=2C2C=NN(C)C=2)[C@@H:3]1[CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].[Br:35][C:36]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=1[C:38]([OH:40])=O>>[Br:35][C:36]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=1[C:38]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34])=[O:40]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Reactant: O=C(O)c1cc(F)ccc1Br
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2Br)[C@@H]1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for 2-(((2S,3R)-3-methyl-1-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione in Example A1, using 2-bromo-5-fluorobenzoic acid. ESI-MS (m/z): 459, 461 [M]+[M+2]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[C:3]1[C:20]([O:22]C)=[O:21].[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[C:3]1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1cc(COc2cccc(C)c2)c(C(=O)OC)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc(OCc2cc(C(=O)O)n(C)c2C(=O)O)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a stirred suspension of dimethyl 1-methyl-3-[(m-methylphenoxy)methyl]pyrrole-2,5-dicarboxylate (0.32 g, 0.001 m) in a mixture of methanol (10 ml) and water (6 ml), ice cooling, was added under a nitrogen atmosphere 2.5 N sodium hydroxide solution (1.2 ml). The mixture was allowed to come to room temperature, and then set in an oil-bath at 50° C., the temperature of the bath raised to 75° C., and kept at this temperature for ca. one hour. After stirring overnight at ambient temperature, water (55 ml) was added over 5 minutes, the mixture filtered, the volume of the filtrate adjusted to 100 ml with water, and the stirred filtrate acidified dropwise with 2 ml of 2 N hydrochloride acid. After aging for 20 minutes, the mixture was filtered, the precipitate washed with water and dried to give 0.27 g (90%) of 1-methyl-3-[(m-methylphenoxy)methyl]-pyrrole-2,5-dicarboxylic acid.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[NH:17])OC.[OH2:18].[NH2:19][NH2:20].C(OCC)C>CO>[OH:18][C:2]1[C:7]([CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]([NH:19][NH2:20])=[NH:17]
Reactant: NN
Reactant: O
Reactant: COC(=N)c1cccc(Cc2c[nH]cn2)c1O
Solvent: CO
Solvent: CCOCC
Product: N=C(NN)c1cccc(Cc2c[nH]cn2)c1O
Reaction time: 0.25 h
Yield: 157.2 %

Procedure:
A solution of 2 g (0.0066 mole) of methyl 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzenecarboximidate prepared in 6.a) above in 20 ml of methanol is added in one go to a solution of 1.52 ml (0.0033 mole) of hydrazine hydrate in 20 ml of methanol. The reaction is allowed to proceed for 15 minutes, then 40 ml of diethyl ether are added. The precipitate which has formed is filtered off and the filtrate is concentrated under reduced pressure. The evaporation residue is purified by preparative liquid chromatography (silica: 400 g; eluent: 89:10:1 (v/v/v) mixture of dichloromethane-methanol-ammonia). The pale yellow solid product obtained after evaporation of the solvents is recrystallized from methanol. 1.2 g of 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzenecarboximidic acid hydrazide are obtained. Yield: 80%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[S:12]1(=[O:20])(=[O:19])[CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]1.[NH2:21][C:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=1>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[C:23]3[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:22]=3[NH:21][C:14]3[CH2:15][CH2:16][CH2:17][S:12](=[O:20])(=[O:19])[C:13]2=3)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NC1=CC(=O)CCC1
Reactant: O=C1CCCS(=O)(=O)C1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C1=C(CCCS1(=O)=O)N2

Procedure:
A solution of 3-nitrobenzaldehyde (151 mg, 1.00 mmol), tetrahydrothiopyran-3-one-1,1-dioxide (148 mg, 1.00 mmol), prepared according to the method described in J. Heterocycl. Chem. (1990), 27, 1453, and 3-amino-2-cyclohexen-1-one (111 mg, 1.00 mmol) in ethanol (7 mL) was heated at reflux for 24 hours and cooled. The solid that precipitated was washed with ethanol, dried, and triturated with hot methanol to provide the title compound. MS (APCI) m/e 375 (M+H)+; 1H NMR (DMSO-d6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 4H), 2.55 (m, 4H), 3.22 (m, 2H), 5.15 (s, 1H), 7.55 (t, 1H), 765 (d, 1H), 8.00 (m, 1H), 9.48 (br s, 1H); Anal. Calcd for C, 57.74; H, 4.85; N, 7.48. Found: C, 57.41; H, 4.75; N, 7.39.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:3]=1[CH2:20][CH2:21][N:22]([OH:26])C(N)=O.ClC1C=C(C=CC=1)C(OO)=[O:32]>ClCCl>[NH:22]([CH2:21][CH2:20][C:3]1/[C:4](=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:32])=[CH:16][CH:17]=2)/[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(/C=C2/C(CCN(O)C(N)=O)=C(C)c3ccccc32)cc1
Solvent: ClCCl
Product: CC1=C(CCNO)/C(=C/c2ccc(S(C)=O)cc2)c2ccccc21

Procedure:
To a solution of the hydroxylamine from Example 16, Step 6 (130 mg, 0.40 mmol) in dichloromethane (5 mL) at 0° C. was added in one portion 85% m-chloroperoxy benzoic acid (90 mg, 0.44 mmol, 1.1 eq.). After 45 minutes the reaction mixture was diluted with dichloromethane and washed successively with 1N aqueous sodium hydroxide, water, brine, dried over MgSO4 and evaporated to dryness. The residue was chromatographed on silica gel eluting with a 30:1 mixture of dichloromethane:methanol to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]1([C:7]([S:10][CH2:11][CH2:12][OH:13])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:29])[CH:27]=[CH2:28]>CO>[C:26]([O:13][CH2:12][CH2:11][S:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])(=[O:29])[CH:27]=[CH2:28]
Reactant: CC(C)(SCCO)c1ccccc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C=CC(=O)OCCSC(C)(C)c1ccccc1
Temperature: -77 °C
Reaction time: 8 h

Procedure:
2-(2-Phenylpropan-2-ylthio)ethanol (45.0 g, 229 mmol) was weighed into a 1 L 3-neck round-bottomed flask which was then attached to a 125 mL pressure-equalising funnel (centre-socket), a Suba-seal (side-arm) and a double layer coil condenser (side-arm) which was connected in turn to a nitrogen-vacuum manifold. The apparatus was then purge-filled with nitrogen three times. Dichloromethane (anhydrous, 300 mL) was then cannula transferred into the reaction flask. DIPEA (anhydrous, 60 mL) was then added to the reaction solution using a 20 mL gastight syringe (3×20 mL transfers). Freshly distilled acryloyl chloride (22.35 mL) was then placed in the pressure-equalising addition funnel. The reaction flask was then surrounded with a dry-ice/acetone cooling bath and the reaction mixture cooled to a temperature of −77° C. The acryloyl chloride was then added slowly dropwise to the chilled reaction mixture under nitrogen over a period of 90 minutes (ca. 1 drop every 2 seconds). The reaction mixture was then stirred in the cooling bath under nitrogen overnight and allowed to warm slowly to room temperature. Next day the reaction flask was surrounded with a water/ice cooling bath and methanol (50 mL) was added to the pressure-equalising addition funnel. The reaction mixture was cooled to <5° C. and the methanol then added dropwise over a period of 30 minutes in order to quench the excess acryloyl chloride. The reaction mixture was then allowed to warm to room temperature before being extracted with 1×300 mL portion of 1M HCl (aq) and 2×300 mL portions of brine. The organic layer was then partitioned and separated and then dried over anhydrous magnesium sulfate for a period of 1 hour. The drying mixture was then filtered and the collected solid washed with 3×40 mL portions of dichloromethane. The filtrate and washings were combined and then CAREFULLY stripped to dryness in vacuo (rotary evaporator) at a bath temperature of 25° C. The resultant orange liquid (with a small quantity of white “gel-like” material on the walls of the evaporation flask, presumably polymer) was distilled in vacuo through a Claisen head with a spatula measure of 5,5′,6,6′-tetrahydroxy-3,3,3′,3′-tetramethyl-1,1′-spirobisindane inhibitor added to the distillation mixture.