Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[F:15].[NH4+:17].[OH-]>>[NH2:13][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]([C:3]([NH2:17])=[O:2])=[C:5]([F:15])[C:6]=1[F:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Temperature: 25 °C
Reaction time: 192 h
Yield: 84.6 %

Procedure:
A mixture of 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (150 g, 0.646 mol) in 14 M NH4OH (1 L, 14 mol, ˜7 vol) was stirred at room temperature. After 8 days HPLC analysis showed the reaction was almost complete. The solid product was filtered off, washed with water (2×200 mL), and then dried at 50° C. in a vacuum oven to provide 4-amino-2,3-difluoro-5-nitrobenzamide (118.7 g, 85% yield) as a yellow powder. HPLC 93.3a %. 1H NMR (400 MHz, DMSO-d6) δ7.65 (2H, br s, NH2), 7.83 (2H, br s, NH2), 8.30 (1H, apparent dd, J 1.5, 7.2, Ar—H). 19F NMR (376 MHz, DMSO-d6) δ −130, −154. 13C (100 MHz, DMSO-d6) δ 110.7 (C, d, J 12), 123.8 (CH, s), 128.1 (C, s), 139.5 (C, dd, J 14, 4), 139.6 (CF, dd, J 243, 17), 151.7 (CF, dd, J 257, 11), 163.4 (C, s). IR νmax/cm−1 3496, 3419, 3385, 3179, 1653, 1279, 1240. MS APCI (−) 216 (M−1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[CH3:22][P:23]([O:26]C)[O:24][CH3:25]>>[CH3:22][P:23]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])(=[O:26])[O:24][CH3:25]
Reactant: COP(C)OC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1[N+](=O)[O-]
Product: COP(C)(=O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 11, 4-(2,4-dichlorophenoxy)-1,2-dinitrobenzene is reacted with dimethyl methylphosphonite to give methyl P-methyl-2-nitro-5-(2,4-dichloro-phenoxy)phenylphosphinate, m/s 376 (M+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=2[C:7]([OH:9])=O)[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18].C(N=C=NCCCN(C)C)C>ClCCl>[C:21]([O:20][C:16]([NH:17][NH:18][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:5]=1[NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1cc(F)c(F)cc1NC1CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1cc(F)c(F)cc1NC1CC1
Reaction time: 16 h
Yield: 81.4 %

Procedure:
To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid (Example 5) (1.32 g, 6.19 mmol) and tert-butyl carbazate (1.30 g, 9.75 mmol) in dichloromethane (30 mL) is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.87 g, 9.75 mmol). After 16 hours, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under vacuum and purified via flash column chromatography (1:2 ethyl acetate/hexanes) to afford N2-(2-cyclopropylamino-4,5-difluorobenzoyl)hydrazinecarboxylic acid tert-butyl ester as a solid (1.65 g). MS EI: m/z 328 (M+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH:22]([O:25][CH2:26][CH2:27][CH2:28][NH2:29])([CH3:24])[CH3:23]>ClCCl>[CH:22]([O:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CC(C)OCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 84.5 %

Procedure:
4-Chloro-3-nitro[1,5]naphthyridine (4.1 g), dichloromethane (150 mL), triethylamine (4.1 mL, 29.5 mmol), and 3-isopropoxypropylamine (3.3 mL, 23.8 mmol) were combined. The reaction mixture was maintained at ambient temperature overnight and then quenched with water (100 mL). The phases were separated. The aqueous phase was extracted with dichloromethane (100 mL). The organic phases were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. The oil was purified by flash chromatography (silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 4.8 g of N4-(3-isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow powder, m.p. 62.5-63.5° C. Analysis: Calculated for C14H18N4O3: %C, 57.92; %H, 6.25; %N, 19.30; Found: %C, 57.96; %H, 6.19; %N, 19.51. 1H NMR (300 MHz, CDCl3): δ10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78 (m, 1H), 8.21 (dd, J=8.4,1.6 Hz, 1H), 7.64 (dd, J=8.4,4.1 Hz, 1H), 4.57 (broad s, 2H), 3.65-3.57 (m, 3H), 2.05 (t, J=5.6 Hz, 2H), 1.19 (d, J=6.0 Hz, 6H); MS (EI): m/e 290.1366 (290.1378 calc'd for C14H18N4O3).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][N:23]=1)CCC>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2nccs2)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 4-bromo-2-(trifluoromethyl)benzonitrile (0.5 g, 2 mmol) in DMF (5 mL) was purged with argon and 2-(tributylstannyl)thiazole (1.12 g/0.9 mL, 3 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.14 g, 0.2 mmol) added. The reaction mixture was purged with argon for 5 min and retained in microwave for 30 min at 100° C. The reaction mixture was diluted with ice cold water (10 mL) and extracted with ethyl acetate (200 mL). The organic solvent was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel chromatography (100-200 mesh; 8% ethyl acetate in hexane) to give 4-(thiazol-2-yl)-2-(trifluoromethyl)benzonitrile (0.42 g, 84% yield) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.42-8.39 (m, 2H), 8.27 (d, 1H), 8.08 (d, 1H), 8.03 (d, 1H). LC-MS m/z calculated for [M+H]+ 255.01, found 255.0.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([Cl:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccccc2)c2ccccc21
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5.6 g (20 mmol) of 1-acetyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone are suspended in 45 ml of toluene and while cooling with ice combined with 4.2 g (20 mmol) of phosphorus pentachloride and then stirred for 18 hours at ambient temperature. The precipitate formed after cooling with ice is suction filtered and dried.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH:26]=O)[CH:22]=[CH:21]2.[NH2:28][CH2:29][CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1>ClC(Cl)C>[NH:33]1[CH:32]=[C:31]([CH2:30][CH2:29][NH:28][CH2:26][C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[C:16]([OH:15])[CH:17]=[CH:18][CH:19]=3)[N:24]=2)[N:35]=[CH:34]1
Reactant: NCCc1c[nH]cn1
Reactant: O=Cc1ccc2cccc(O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Oc1cccc2ccc(CNCCc3c[nH]cn3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
Sodium triacetoxyborohydride (225 mg, 1.061 mmol) was added to a stirred solution of 8-hydroxy-quinoline-2-carboxaldehyde 4 (200 mg, 1.156 mmol) and histamine (128 mg, 1.152 mmol) in dichloroethane (10 mL). The mixture was left to stir at RT for 16 h, neutralized (aqueous NaHCO3), and concentrated. The resulting residue, after column chromatography on silica (ethyl acetate/i-PrOH/2 N NH4OH, 6:2:1), afforded 2-{[2-(1H-imidazol-4-yl)-ethylamino]-methyl}-quinolin-8-ol F1 as a straw-colored solid (190 mg, 61%). The above method was repeated using other amines: 2-(aminomethyl)pyridine gave F2 and 2-(2-methylaminoethyl)pyridine gave F3, data given in Table 2.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH2:24][CH3:25])[C:18](=[O:26])[CH2:17]3)[CH2:9]1
Reactant: COC(=O)Cl
Reactant: CCN1C(=O)Cc2cc(N3C[C@@H](CN)OC3=O)cc(F)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC)OC3=O)cc(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.117 ml, 1.53 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-1-ethyl-7-fluoro-1,3-dihydro-indol-2-one (0.414 g, 1.02 mmol) and diisopropylethylamine (0.709 ml, 4.06 mmol) in dichloromethane (5 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as a yellow solid. HPLC r.t. 4.04 min; 1H NMR (300 MHz, CDCl3) 7.30 (s, 1H), 7.23 (dd, J=2, 13.2 Hz, 1H), 5.13 (t, 1H), 4.74-4.81 (m, 1H), 4.03 (t, J=9.2 Hz, 1H), 3.90 (q, J=6.8 Hz, 2H), 3.80 (dd, J=6.8, 9.2 Hz, 1H), 3.69 (s, 3H), 3.53-3.67 (m, 2H), 1.28 (t, J=6.8 Hz, 3H); MS for C16H18FN3O5 m/z 352.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=O)=[C:4]2[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:35][O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39].C(N(CC)CC)C>CN(C)C=O>[OH:41][CH2:40][C@H:38]([NH:39][C:16]([C:15]1[N:14]=[CH:13][N:5]2[C:6]3[CH:12]=[CH:11][S:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12)=[O:18])[C:37]([O:36][CH3:35])=[O:42]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccsc2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
A suspension of 15.5 g (0.0493 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid in 200 ml of dimethylformamide was treated portionwise with 8.07 g (0.0498 mol) of carbonyidiimidazole while gassing with argon. After completion of the CO2 evolution the mixture was stirred at 65° for 1 hr. After cooling to 0-5° the clear solution obtained was treated with 8.62 g (0.0554 mol) of L-serine methyl ester hydrochloride and with 12.3 ml (0.0554 mol) of triethylamine and stirred at room temperature for 16 hrs. The suspension was completely freed from the solvents. The residue was partitioned between water and ethyl acetate and extracted. The yellow oily residue was chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 17.09 g (95%) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-ylcarbonylamino)-propionate as a yellowish oil. An analytical sample was recrystallized from ethyl acetate and gave white crystals; m.p. 158-160°. [α]D20 =+3.9° (CHCl3, c=1%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[C:4]([F:10])[CH:3]=1
Reactant: C1=COCCC1
Reactant: OCc1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1cc(Br)ccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
Mix under nitrogen atmosphere 4-bromo-2-fluorobenzyl alcohol, (4.1 g, 20 mmol), dihydropyran (2 g, 24 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and anhydrous DCM (70 mL). Stir for 16 h at ambient temperature. Dilute with DCM, wash sequentially with saturated aqueous NaHCO3 then brine. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a clear oil (4.36 g, 75%). MS (ES+) m/z: 312 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCC2CCNCC2)cc1
Reaction time: 0.5 h
Yield: 108.3 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-[2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethoxycarbonyl]-1,2-benzenediamine (312 mg, 0.627 mmol) in methylene chloride (3 mL) was treated with trifluoroacetic acid (0.48 mL). After 0.5 h, the mixture was concentrated in vacuo. The residue was treated with 1 N aqueous sodium hydroxide followed by ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were dried and concentrated in vacuo. The residue was taken up in methanol and treated with hydrochloric acid (gas, 1-2 eq) and concentrated in vacuo to yield the hydrochloride salt of the title compound (270 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:21])[N:13]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:14]=2)=[CH:5][CH:4]=1.[OH-].[Li+].Cl>O.CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:21])[N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc(OC)cc2)ccc1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(=O)n(CC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
According to Scheme 9 Step 2: To a solution of ethyl 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetate (1 eq, 3.38 mmol, 0.97 g) in water/EtOH (1:1, 20 mL) at 0° C. was added lithium hydroxide (10 eq, 33.8 mmol, 1.44 g). The reaction was then allowed to warm to room temperature and stirred for 2 hours. The reaction was then cooled to 0° C. and acidified with HCl 1M solution till pH=2. The resulting precipitate was filtered under reduced pressure to yield 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetic acid (2.56 mmol, 0.66 g, 76%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11].O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(F)cc1O
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a 0° C. mixture of 4-bromo-3-fluorophenol (70.0 g, 366 mmol) in DCM (500 mL) was added HNO3 (23.0 g, 366 mmol) carefully and the reaction mixture was stirred 30 min. The reaction mixture was poured into water (1 L) and extracted with DCM (3×500 mL). The combined organic portion was washed with brine (300 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from EtOH to give 4-bromo-5-fluoro-2-nitrophenol (42.0 g, 49%). 1H NMR (DMSO-d6, 400 MHz): δ 11.72 (brs, 1H), δ 8.30 (d, J=7.2 Hz, 1H), 7.09 (d, J=10.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([O:23][CH3:24])[O:21][CH3:22])=[CH:16][CH:15]=3)[N:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]([S:31]([N:33]=[C:34]1[CH2:37][O:36][CH2:35]1)=[O:32])([CH3:30])[CH3:29]>C1COCC1>[CH3:22][O:21][CH:20]([O:23][CH3:24])[C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[N:10]([CH2:25][CH3:26])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:34]4([NH:33][S:31]([C:28]([CH3:30])([CH3:29])[CH3:27])=[O:32])[CH2:37][O:36][CH2:35]4)[CH:7]=[CH:6][CH:5]=3)[CH:12]=2)=[CH:15][CH:16]=1
Reactant: CCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(OC)OC)cc1
Reactant: CC(C)(C)S(=O)N=C1COC1
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(OC)OC)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
A solution of n-Butylllithium in hexanes (2.5M, 3.83 mL, 9.59 mmol, 2.0 equiv) was added dropwise to a solution of 3-(3-bromophenyl)-5-[4-(dimethoxymethyl)phenoxy]-1-ethyl-1H pyrazole (2.0 g, 4.79 mmol, 1.0 equiv) in THF (32 mL) at −78° C. To this mixture was added dropwise a solution of 2-methyl-N-oxetane-3-ylidenepropane-2-sulfinamide (0.840 g, 4.79 mmol, 1.0 equiv, Example 95, Step 4) in 5 mL THF. The reaction mixture was stirred at −78° C. for 10 minutes and the cooling bath was removed. Saturated aqueous ammonium chloride solution was added, and the crude product was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate:hexanes then flushing with 10% methanol/dichloromethane) to afford N-[3-{3-{5-[4-(dimethoxymethyl)phenoxy]-1-ethyl-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (2.17 g, 4.22 mmol, 88% yield). Calc'd (M+1)+501.23. Found: 468.1. Found mass is aldehyde formed from deprotection of acetal on LCMS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]2=[O:20])=[CH:5][CH:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH:31]1[O:33][CH2:32]1.[ClH:34]>C(O)(C)C>[ClH:34].[OH:33][CH:31]([CH2:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH3:21])[CH2:32][N:17]1[CH2:18][CH2:19][CH:14]([N:11]2[CH2:12][CH2:13][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]2=[O:20])[CH2:15][CH2:16]1
Reactant: COc1ccccc1OCC1CO1
Reactant: COc1ccc(N2CCN(C3CCNCC3)C2=O)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N2CCN(C3CCN(CC(O)COc4ccccc4OC)CC3)C2=O)cc1

Procedure:
A mixture of 17.9 g of 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone and 11.7 g of 1-(2-methoxyphenyloxy)-2,3-epoxypropane in 200 ml of isopropyl alcohol is refluxed for 6 hours. The mixture is thereafter acidified with 5 N methanolic hydrochloric acid and concentrated under reduced pressure. The residue is freed from moisture still adhering to it by treatment with toluene. Recrystallisation of the residue from methanol with the addition of activated charcoal yields the 1-{1-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-4-piperidyl}-3-(4-methoxy-phenyl)-imidazolidin-2-one-hydrochloride as a white crystalline substance with a melting point of 214°-215° C. The 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone used as starting material can be prepared as follows: A mixture of 61.5 g of 4-methoxy-aniline and 51.3 g of 2-bromoethylamine-hydrobromide in 125 ml of methyl ethyl ketone is refluxed for 5 hours with stirring. The viscous suspension is thereafter evaporated to dryness under reduced pressure. The residue is suspended in 150 ml of isopropanol and then collected by filtration. The filter cake is washed with three 50 ml portions of isopropanol and with two 50 ml portions of diethyl ether. The crystalline product is made alkaline with a concentrated aqueous ammonia solution and extracted with five 50 ml portions of chloroform. The extracts are dried over sodium sulphate and concentrated under reduced pressure. The oily residue crystallises after trituration to give the 1-(4-methoxyphenyl)-ethylenediamine with a melting point of 64° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[C:12]([S:16][CH2:17][C:18](=O)[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:15])([CH3:14])[CH3:13]>CC(O)(C)C>[C:12]([S:16][C:17]1[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:9]=2)[NH:10][C:18]=1[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Agent: Cl
Solvent: CC(C)(C)O
Product: COC(=O)C(C)(C)Cc1[nH]c2ccc(OC)cc2c1SC(C)(C)C
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A mixture containing 4-methoxyphenyl hydrazine HCl (70.66 g, 0.405 mol) and methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate (99.54 g, 0.405 mol) in tBuOH (400 ml) was heated at a gentle reflux for 48 hours. The mixture was allowed to cool to RT and the precipitated NH4Cl was removed by filtration. The residue was concentrated and fractionated on a plug of silica using EtOAc/hexane (1:3) as eluent. Evaporation of the appropriate fraction gave an orange-brown solid which was crystallized from EtOH (100 ml). Yield from two crops afforded 55.6g of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:10][C:3]1[C:2]([C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COc1ccc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(OC)nc2Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Under an argon atmosphere, to a solution of 3-bromo-2-chloro-6-methoxypyridine (4.61 g) in toluene (60 mL) were added (2-fluoro-5-methoxyphenyl)boronic acid (3.52 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichlorome thane adduct (1.69 g) and 2.0 M aqueous sodium carbonate solution (31.1 mL), and the mixture was stirred at 80° C. for 1 hr. Water was added at room temperature, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.06 g) as a white amorphous solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([O:13][CH2:14]Cl)[CH3:12]>O1CCCC1.CCCCCC>[CH2:11]([O:13][CH2:14][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:12]
Reactant: c1c[nH]cn1
Reactant: CCOCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCn1ccnc1
Temperature: -70 °C
Yield: 56.1 %

Procedure:
Imidazole (20 g) was dissolved in tetrahydrofuran (700 ml) under a nitrogen atmosphere, cooled to −70° C. and n-butyllithium (117.5 ml of a 2.5M solution in hexane) added dropwise, over 15 minutes. The mixture was allowed to warm to −20° C. and stirred at −20° C. for 30 minutes before the dropwise addition of chloromethyl ethyl ether (30.5 g). The mixture was allowed to warm to room temperature and stirred for a further hour. The solvent was removed under reduced pressure to give a residue which was triturated with dichloromethane and filtered through a short pad of Arbacel (trade mark) filter aid. The solvent was removed from the filtrate under reduced pressure to give a mobile oil which was distilled under reduced pressure (0.7 millibars, 0.53 mmHg) to give 1-ethoxymethylimidazole (20.8 g) as an oil.