Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:19]=[C:18]([C:28]([OH:30])=O)[CH2:17]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].S(Cl)([Cl:33])=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:19]=[C:18]([C:28]([Cl:33])=[O:30])[CH2:17]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cccc(-c2ccc(C3CC(C(=O)O)=NN3c3ccccc3F)cc2)c1
Product: CCOc1cccc(-c2ccc(C3CC(C(=O)Cl)=NN3c3ccccc3F)cc2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(3′-Ethoxy-biphenyl-4-yl)-1-(2-fluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (200.0 mg, 0.49 mmol) prepared in Step 2 was added to thionyl chloride (2.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(3′-ethoxy-biphenyl-4-yl)-1-(2-fluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:13]1[CH:18]=[C:17](C=O)[C:16]([CH:21]=O)=[CH:15][CH:14]=1>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:21][C:16]3[C:15](=[CH:14][CH:13]=[CH:18][CH:17]=3)[C:11]2=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: O=Cc1ccccc1C=O
Solvent: ClCCl
Product: CC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 42.6 %

Procedure:
A mixture of 4-acetylphenylisocyanate (27.5 g, 0.17 mol) and o-phthalicdicarboxaldehyde (25.0 g, 0.186 mol) is heated in an oil bath at 170°-175° C. for 4.0 hours under nitrogen atmosphere. On cooling the melt solidified which is pulverized and refluxed with CH2Cl2 and CH30H and filtered to give 18.2 g (41.4%) of the desired 2-(4-acetylphenyl)-2,3-dihydro-lH-isoindole-1-one, mp 235°-237° C. The residue is recrystallized from DMF (1800 ml). Yield 13.0 g (29.6%), mp 236°-239° C. (Jap. patent J5 7050-960; mp 243°-244° C. for the nonsolvated compound, prepared by a different route).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCCC1=O>CO>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CO
Product: Clc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3-chloroaniline (365 mg) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 80° C. for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the 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 obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→15:75) and recrystallized from ethanol-ethyl acetate to give the title compound (226 mg) as a pale-brown powder.
Reaction SMILES: C([S:8][CH2:9][CH:10]([N:20]([CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:21](=[O:41])[NH:22][C@@H:23]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:24]([O:26]CC1C=CC=CC=1)=[O:25])[CH2:11][S:12]CC1C=CC=CC=1)C1C=CC=CC=1.N.C(=O)=O.CO.[Na].[Cl-].[NH4+]>O1CCCC1>[SH:8][CH2:9][CH:10]([N:20]([CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:21](=[O:41])[NH:22][C@@H:23]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:24]([OH:26])=[O:25])[CH2:11][SH:12]
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)N(CCc1ccccc1)C(CSCc1ccccc1)CSCc1ccccc1
Agent: N
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(CCc1ccccc1)C(CS)CS
Reaction time: 1 h

Procedure:
A solution of benzyl (2S)-2-[3-[2-(benzylthio)-1[(benzylthio)methyl]ethyl]-3-phenethylureido]-3-phenylpropionate (Compound No. 1-72, 996 mg) in anhydrous tetrahydrofuran (20 ml) is added dropwise to liquid ammonia (80 ml) under a nitrogen atmosphere and dry ice-methanol cooling. Then, metallic sodium (300 mg) by portions is added thereto until coloration does not disappear, and the mixture is stirred as it is for one hour. Ammonium chloride by portions is added to the reaction mixture to decolorize it, and then a nitrogen gas is bubbled through the mixture at room temperature to evaporate ammonia. To the resulting residue is added 1 N hydrochloric acid to acidify it, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (Compound No. 9-1).
Reaction SMILES: Cl.[O:2]([C:9]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:12]([NH2:13])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S-:22][C:23]#[N:24].[Na+].O.Cl>CC1C=CC=CC=1C>[O:2]([C:9]1[CH:10]=[C:11]([CH:19]([CH3:21])[CH3:20])[C:12]([NH:13][C:23]([NH2:24])=[S:22])=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N
Reactant: N#C[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1NC(N)=S
Temperature: 25 °C
Yield: 95.9 %

Procedure:
305 g (1 mol) of 4-phenoxy-2,6-diisopropylaniline hydrochloride, 97 g (1.2 mol) of sodium thiocyanate, 10 ml of water and 10 ml of concentrated hydrochloric acid are suspended in 800 ml of o-xylene. The mixture is heated to 90° C. over 6 hours, during which time 2 ml of concentrated hydrochloric acid are added after 3 hours and then after each further hour. Thereafter the reaction mixture is cooled to room temperature and the product is isolated by filtration, washed with water and dried, giving 315 g (96% of theory) of N-(4-phenoxy-2,6-diisopropylphenyl)thiourea in the form of pale grey crystals which melt at 219°-221° C.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:12](=[O:13])[CH:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:9]=2[CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:7]1)C.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:10]2[CH:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:12](=[O:13])[N:6]([CH2:5][C:4]([OH:31])=[O:3])[CH2:7][CH:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:9]=2[CH:21]=1
Reactant: CCOC(=O)CN1CC(c2ccccc2OC)c2cc(Cl)ccc2C(CC(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1C1CN(CC(=O)O)C(=O)C(CC(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
85 mg of the compound from Example 23A (0.19 mol) are dissolved in 3.5 ml of dioxane/water (1:1) and mixed with 0.29 ml of 1 N sodium hydroxide solution (0.29 mol). The reaction mixture is stirred at room temperature for 3 h. It is acidified with 5 ml of 1 N hydrochloric acid, and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator. 80 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+].CCOC(C)=O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1[nH]c2ncc(Br)cc2c1C
Yield: 71.1 %

Procedure:
To a suspension of 5-bromo-2,3-dimethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-6-3) (0.9 g, 2.5 mmol) in THF (30 mL) and MeOH (30 mL) was added aq. NaOH (20%, 19 mL) at room temperature. The mixture was heated to reflux overnight. TLC (Petroleum ether: EtOAc=5:1) showed the reaction was complete. After the solvent was removed under reduced pressure, water (20 mL) and CH2Cl2 (20 mL) were added into the mixture. The organic layer was separated, dried over anhydrous Na2SO4. The mixture was concentrated to give crude mixture which was purified via prep. HPLC to afford 5-bromo-2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (B-6-4) (0.4 g, 72.4%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+]>CN(C)C=O>[O:12]=[C:10]([CH3:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCBr
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(CCC(C)=O)cc1

Procedure:
The hapten [10-O-(carboxypropyl)]ractopamine ether(Hapten A—derivatised at position 10) was prepared in three steps according to FIG. 3 of the accompanying drawings, from 4-(4-hydroxyphenyl)-2-butanone, 2. The reaction of 4-(4-hydroxyphenyl)-2-butanone, 2 with ethyl 4-bromobutyrate in dimethylformamide (DMF) in the presence of sodium hydride (NaH), gives ethyl 4-[4-(3-oxobutyl)phenoxy]butanoate 3. The ketoester, 3, obtained was reacted with octopamine hydrochloride, 4, in methanol in the presence of triethylamine (TEA) and sodium cyanoborohydride (Na BH3CN) to give 10-O-[3-(ethoxycarbonyl)propyl]ractopamine ether 5, in moderate yields. The hapten A was obtained after saponification of the ester, 5, with sodium hydroxide (NaOH) (2N) in methanol.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.S[C:12]1[N:17]([CH3:18])[C:16](=[O:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:13]=1>C(OCC)(=O)C>[Cl:3][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(S)nc(-c2ccncc2)cc1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
Phosphorous oxychloride (26.11 g, 170 mmol) was added to dimethylformamide (180 ml) and stirred 20 min. 2-mercapto-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (24.15 g, 110 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 2 hours. Ethyl acetate (630 ml) was added to the ice-cooled solution and precipitate was collected by filtration after 20 minutes stirring. After drying, the precipitate was dissolved in water (400 ml) and pH was adjusted to 10 by aqueous sodium hydroxide. The precipitate was washed with water, filtered and dried to give the title compound (18.82 g, 77%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]([NH2:18])[CH:10]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]([NH2:18])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cn1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2cc(N)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 64.9 %

Procedure:
1-methylpiperazine (265.5 mg, 294.0 mL, 2.651 mmol) in THF (5 mL) was added to a stirred suspension of 4-chloro-5-nitro-pyridin-2-amine (400 mg, 2.305 mmol) and DIPEA (357.5 mg, 481.8 mL, 2.766 mmol) in THF (10 mL) at 0° C. under an atmosphere of nitrogen. The reaction was allowed to stir at ambient temperature for 90 hours before the solvent removed in vacuo. The residue was tritruated from DCM/MeOH and the resultant precipitate was washed with DCM/MeOH solutions. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% 2M NH3 in MeOH/DCM) to give 4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine as a yellow solid (355 mg, 65% Yield). MS (ES+) 238.1.
Reaction SMILES: NC1C=CC(C)=C(N[C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=1.ClC1C=C(C2(N)C=C(Cl)N=CN2)C=CC=1F.[CH3:41][C:42]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:43]=1[NH2:44].Cl>C(O)CCC.CCOC(C)=O>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[CH:14]=[C:9]([NH:44][C:43]3[CH:45]=[C:46]([N+:49]([O-:51])=[O:50])[CH:47]=[CH:48][C:42]=3[CH3:41])[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: NC1(c2ccc(F)c(Cl)c2)C=C(Cl)N=CN1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Temperature: 120 °C

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stirring, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: C12(CO)CC3CC(CC(C3)C1)C2.[CH3:13][C:14]1([CH3:23])[C@H:19]2[CH2:20][C@@H:15]1[CH2:16][CH2:17][C@@H:18]2[CH2:21][OH:22].ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:40][C:41]1[C:42](F)=[CH:43][C:44]([F:56])=[C:45]([CH:55]=1)[C:46]([NH:48][S:49](=[O:54])(=[O:53])[N:50]([CH3:52])[CH3:51])=[O:47]>>[Cl:40][C:41]1[C:42]([O:22][CH2:21][C@H:18]2[CH2:17][CH2:16][C@H:15]3[CH2:20][C@@H:19]2[C:14]3([CH3:23])[CH3:13])=[CH:43][C:44]([F:56])=[C:45]([CH:55]=1)[C:46]([NH:48][S:49](=[O:53])(=[O:54])[N:50]([CH3:52])[CH3:51])=[O:47]
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC[C@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace adamantan-1-ylmethanol with ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol and 5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide (as prepared in Example 31), the title compound was obtained as a colorless solid (0.25 g, 45%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.24 (d, J=12.3 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 2.87 (s, 6H), 2.50-2.40 (m, 1H), 2.10-1.65 (m, 6H), 1.48-1.37 (m, 2H), 1.21 (s, 3H), 0.85 (s, 3H); MS (ES−) m/z 431.2, 433.2 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH2:13][C:14]([O:16]CC)=O)[C:10]([NH2:12])=[O:11])=[N:6][CH:7]=1.C[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:13][C:14](=[O:16])[NH:12][C:10]2=[O:11])=[N:6][CH:7]=1
Reactant: CCOC(=O)CN(Cc1ccc(Br)cn1)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CN(Cc2ccc(Br)cn2)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(1-((5-Bromopyridin-2-yl)methyl)ureido)acetate (9J2) (35.0 mmol, 11.08 g) was dissolved in dry methanol (150 ml), and sodium methoxide (70.1 mmol, 3.79 g) added and the solution stirred at room temperature for 3 hours. The reaction was quenched with water and acidified with saturated ammonium chloride solution to ˜pH 7. The mixture was extracted with DCM (3×) and the combined organics washed with brine and dried over sodium sulphate, filtered and concentrated to afford a crude product which was purified on silica eluting with Heptane/EtOAc/EtOH 5/4/1 to give 1-((5-bromopyridin-2-yl)methyl)imidazolidine-2,4-dione. (9J3) 6.12 g (64%); 1H NMR (400 MHz, CDCl3) 8.68 (bs, 1H) 8.63 (d, 1H) 7.86 (dd, 1H) 7.22 (d, 1H) 4.61 (s, 2H) 4.04 (s, 2H).
Reaction SMILES: Cl[O-].[Na+].C1COCC1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19](/[CH:24]=[N:25]/[OH:26])[CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:27]=[C:28]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(OCC)(=O)C.O>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:24]2[CH2:27][C:28]([CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[O:26][N:25]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(/C=N/O)cc(OCc2ccccc2)c1
Reactant: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.4 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 2715 mg) was added dropwise to a THF (4 mL) solution of (E)-1-(3-(benzyloxy)-5-methylphenyl)-N-hydroxymethanimine (400 mg) and di-tert-butyl 2-methylenesuccinate (402 mg) at 0 C, and the obtained mixture was stirred at 0 C for 2 hours and subsequently at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and water was added thereto. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (674 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 89 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 89%). H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 3.01 (s, 4H), 3.76 (s, 4H), 4.14 (s, 3H), 7.03-7.52 (m, 6H), 7.68-7.77 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:39])=[C:34](B(O)O)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:39])=[C:32]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:31]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br
Reactant: Cc1ccc(Cl)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C
Reaction time: 8 h

Procedure:
Under argon (in a flask dried by heating), 92 mg (0.20 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 41 mg (0.24 mmol, 1.2 eq.) of 5-chloro-2-methylphenylboronic acid, 84 mg (0.61 mmol, 3.0 eq.) of potassium carbonate and 16 mg (0.02 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. The reaction mixture was filtered through Celite and the residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, washed with water and dried under reduced pressure. Yield: 105 mg (purity 91%, 95% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.[BH4-].[Na+].O>CO>[N:15]1[CH:16]=[C:12]([CH2:10][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[NH:13][CH:14]=1
Reactant: COc1ccccc1N
Reactant: O=Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1NCc1cnc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 2-methoxyaniline (0.62 g, 5 mmol) in methanol (5 ml) was added 4-formylimidazole (0.48 g, 5 mmol). After stirring the mixture overnight at 60° C. the solution was cooled and sodium borohydride (0.28 g, 7.5 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by recrystallisation from heptane/ethyl acetate to yield off-white crystals (0.85 mg, 84%); MS (ISP): 204.3 ((M+H)+.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[NH:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[O:18].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:21])[CH2:22][NH:16][C:17]3=[O:18])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: O=C1CNC(=O)N1
Reactant: ClCCCCSc1cccc2nccn12
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CNC(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2.41 g (10.0 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 1.00 g (10.0 mmol) of hydantoin in 30 ml of N,N-dimethylformamide, 1.50 ml (10.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 16 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=20/1→10/1) to yield 1.27 g (41.7%, yellow solid) of the desired product.