Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([NH:12][S:13]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])(=[O:15])=[O:14])[CH:5]=1.Br[CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[C:7]2[O:11][CH2:28][CH2:27][N:12]([S:13]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][CH3:24])(=[O:15])=[O:14])[C:6]=2[CH:5]=1)=[O:25]
Reactant: BrCCBr
Reactant: COC(=O)c1cc(F)c(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Product: COC(=O)c1cc(F)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=519.1 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-5-fluoro-4-hydroxy-benzoic acid methyl ester (example 44, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([NH:25][NH2:26])=[O:24])(=[O:19])=[O:18])[CH2:13][CH2:12]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([S:17]([N:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)(=[O:18])=[O:19])[CH:21]=2)/[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(Cl)c1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1ccnc(Cl)c1
Temperature: 120 °C
Yield: 60 %

Procedure:
1-(2-Chloropyridin-4-yl)ethanone (20 mg, 0.129 mmol) and 3-(morpholinosulfonyl)benzohydrazide (36.7 mg, 0.129 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography affording the title compound in a 60% yield. 1H NMR (400 MHz, CDCl3): δ 9.43 (m, 1H), 8.39 (m, 2H), 8.15 (d, 1H, J=8.0 Hz), 7.93 (d, 1H, J=7.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.52 (m, 1H), 3.73 (m, 4H), 3.02 (m, 4H), 2.35 (s, 3H). ESI-MS: 423.1 [M+H]+.
Reaction SMILES: O[CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH2:8][CH2:9][N:10]=2)[CH2:3]1.[C:11]([OH:14])(=[S:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:11]([S:13][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH2:8][CH2:9][N:10]=2)[CH2:3]1)(=[O:14])[CH3:12]
Reactant: OC1CN(C2=NCCS2)C1
Reactant: CC(O)=S
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CN(C2=NCCS2)C1
Reaction time: 1 h
Yield: 65 %

Procedure:
There were added 119 mg of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) and two molar equivalents of thioacetic acid, while cooled with ice, to 10 ml of tetrahydrofuran solution containing two molar equivalents of triphenylphosphine and two molar equivalents of diethylazodicarboxylate, and the resultant solution was stirred for one hour at the same temperature, and for further one hour at a room temperature. The solvent of the reaction liquid was evaporated in a vacuum, and the obtained residue was subjected to silica gel column chromatography (eluent: chloroform-ethanol), and, thus, there was obtained 107 mg (yield: 65%) of 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine (7).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8](O)=[O:9])[CH2:7][CH2:6]1)=[O:4].ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[OH:9][CH2:8][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(CO)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
1-Methoxycarbonylcyclopropane carboxylic acid (16.4 g, 113.89 mmol), TEA (17.6 mL, 127.55 mmol), and THF (325 mL) are charged in a round bottom flask. The mixture is cooled to −10° C. and isobutyl chloroformate (16.5 mL, 127.55 mmol) is added dropwise. The solution is stirred for 1 h. In a separate flask, sodium borohydride (13 g, 341.67 mmol) is dissolved in a mixture of THF (165 mL) and water (40 mL) and cooled in an ice bath. The insoluble material is removed by filtration from the first solution. To the borohydride solution is added the 1-methoxycarbonylcyclopropane carboxylic acid solution described above, dropwise over a period of 1.5 h. The resulting solution is stirred at the same temperature for 1 h. The reaction mixture is poured into a cooled 20% aqueous solution of citric acid and extracted with ethyl acetate (3×150 mL). The combined organic layers are washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (13.5 g, 91%). 1H NMR (400 MHz, CDCl3); δ 0.9-0.8 (m, 2H), 1.3-1.2 (m, 2H), 3.62 (s, 2H) 3.69 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][S:21][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: OCCCCS
Product: CC1(c2ccccc2)OC(CC(SCCCCO)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 4-mercapto-1-butanol to provide 5-[2-[(4-hydroxybutyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.52-1.70 (broad s with fine structure, ˜5H) and 1.65 and 1.67 (singlets, 3H), 2.41 (m, 2H), 3.08-3.24 (m, 2H), 3.60 (m, 2H), 4.40 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.16 (m, 2H), 7.25-7.40 (m, 6H); MS (HR-EI) m/z 388.1161 (M+ calcd. for C21H24O3S2 388.1167).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[C:9]([NH:16][C@H:17]([C:22]([OH:24])=O)[CH2:18][CH2:19][CH2:20][CH3:21])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN1CCOCC1.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>C1COCC1>[CH2:32]([NH:36][C:22](=[O:24])[C@H:17]([CH2:18][CH2:19][CH2:20][CH3:21])[NH:16][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCN
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCNC(=O)[C@H](CCCC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
One equivalent of isobutylchloroformate is added to a solution of N-Boc-L-norleucine and one equivalent of a base such as N-methylmorpholine in THF at 0□C. After two minutes, one equivalent of butylamine is added and the mixture allowed to warm to room temperature. After thirty minutes, the reaction mixture is passed through a bed of Celite and all volatiles are removed under reduced pressure to yield N-Boc-L-norleucine butylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.Cl[C:34]([C:36]1[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=1)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:35]>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:2]([NH:1][C:34]([C:36]2[CH:37]=[C:38]([CH:50]=[CH:51][CH:52]=2)[CH2:39][S:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])=[O:35])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)[CH:22]=1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (191 mg, 0.50 mmol, 1.00 equiv) in dichloromethane (5 mL), pyridine (120 mg, 1.50 mmol, 3.00 equiv), and tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (158 mg, 0.50 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with 2×50 mL of water. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (20:1) to give 100 mg (30%) of product as yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O.[OH-].[Na+]>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cccc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 33.4 %

Procedure:
Sodium hydroxide (4.24 g, 106 mmol) was dissolved in water (50 ml). 3-Trifluoromethyl-phenol (5.19 g, 32 mmol) was dissolved in 25 ml of the sodium hydroxide solution and heated to reflux. 3-Bromopropionic acid (9.79g, 64 mmol) in the other 25 ml of sodium hydroxide solution was added dropwise over 15 minutes. The reflux was continued for 45 minutes more, with portions of 10M sodium hydroxide solution added to maintain the pH of the solution at appoximately pH 10. The reaction mixture was then cooled, acidified with hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were extracted with saturated aqueous sodium bicarbonate, and the aqueous layers acidified with hydrochloric acid. The acidified aqueous layers were extracted with diethyl ether. The ether layers were dried with magnesium sulfate, and the solvent removed under vacuum to give 2.5 g of the crude product which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:14]1[O:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=1)([O-])=O>CS(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[O:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.7 %

Procedure:
To a solution of 4-fluorophenol (2.39 g, 21.3 mmol) in dimethylsulfoxide (20 mL) was added sodium hydride (785 mg, 19.6-23.6 mmol, 60-72% in oil), and the solution was stirred at room temperature for 20 minutes. Next, a solution of 5-nitro-furan-2-carbaldehyde (3 g, 21.3 mmol) in dimethylsulfoxide (10 mL) was added dropwise, the solution was then stirred for 2 hours at room temperature. The reaction mixture was poured into brine, and the mixture was extracted with ethyl acetate. The fractionated organic layer was dried over anhydrous magnesium sulfate, then concentrated, and the title compound (4.3 g, 20.8 mmol, 98%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[C:33]([OH:35])=[O:34])[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1.[C:37]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:36])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[C:33]([O:35][CH3:37])=[O:34])[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnccc1CC(=O)N1CCC([C@H]2c3ncc(Br)cc3CCc3cc(Cl)cc(Br)c32)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1CC(=O)N1CCC([C@H]2c3ncc(Br)cc3CCc3cc(Cl)cc(Br)c32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the product of Example 2 (1.0 mmol) dissolved in anhydrous DMF add solid K2CO3 (1.2 mmol, anhydrous) and CH3I (1.2 mmol). After stirring the reaction mixture at room temperature for 24 hours, concentrate the mixture in vacuo, dilute with CH2Cl2 and wash with water. Dry the organic phase over anhydrous MgSO4, filter and concentrate in vacuo to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1F

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 3-fluoro-4-methoxyphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3-fluoro-4-methoxy-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:22]1([N:28]=[C:29]=S)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:29]([NH:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C=Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(Nc4ccccc4)o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add phenyl isothiocyanate (97 uL, 0.512 mmol) and stir for 3.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling to room temp dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and suspend the resulting residue in 1 N NaOH (5 mL). Collect the solid and wash with water. Take the solid up in boiling toluene/EtOAc. Allow to cool. Collect the solid, wash with Et2O, and dry in a vac-oven to afford the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.03 (t, J=7.39 Hz, 1H) 7.39 (t, J=7.96 Hz, 2H) 7.63-7.69 (m, 3H) 7.71 (d, J=1.26 Hz, 1H) 7.73 (t, J=1.89 Hz, 1H) 7.77 (tautomer A, d, J=8.59 Hz, 1H) 7.83 (tautomer B. dd, J=8.46, 1.52 Hz, 1H) 7.91 (dd, J=8.46, 1.52 Hz, 1H) 8.05 (tautomer B. d, J=1.01 Hz, 1H) 8.17 (tautomer A, s, 1H) 10.68 (s, 1H) 13.30 (d, J=4.17 Hz, 1H); MS (m/z)=422.0 (M+1).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[N+:5]([C:8]1[CH:16]=[C:12]([C:13](O)=[O:14])[C:11](N)=[CH:10][CH:9]=1)([O-:7])=[O:6]>O>[N+:5]([C:8]1[CH:16]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:4][C:2](=[O:3])[NH:1][C:13]2=[O:14])([O-:7])=[O:6]
Reactant: NC(N)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 150 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
Urea (9.89 g, 0.165 mol) and 5-nitroanthranilic acid (6.00 g, 32.9 mmol) were heated to 200° C. with vigorous stirring for 1 h. The melt was allowed to cool to 150° C., and water (150 mL) was slowly added. The resulting slurry was sonicated for 1 h and stirred vigorously for an additional 2 h. It was then cooled to 0° C., and the precipitate was collected and rinsed with water to yield the titled compound (6.43 g, 94% yield). This material was dried in a vacuum oven and used without further purification. This compound did not yield MS data.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>CN(C)C=O>[CH:33]1([CH2:36][N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH2:35][CH2:34]1
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2CC2CC2)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (62%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:3]4[C@@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:17][CH:16]=3)=[O:15])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: C[C@H]1COC(=O)N1Cc1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4C(=O)OC[C@@H]4C)cc3)CC2)c(C)c1
Yield: 95.6 %

Procedure:
Using (S)-4-(4-methyl-2-oxooxazolidin-3-ylmethyl)benzoic acid (141 mg) described in Preparation Example 66 and 1-(3,5-dimethylpyridin-2-yl)piperazine (126 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (234 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16](OC)[CH3:17])[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]>CO.[Pd]>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH3:17])[CH:11]=2)=[CH:8][C:2]=1[F:1]
Reactant: CON(C)c1cc(Oc2ccc(N)c(F)c2)ccn1
Agent: [Pd]
Solvent: CO
Product: CNc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.7 %

Procedure:
A mixture of 2-fluoro-4-(2-(methoxy(methyl)amino)pyridine-4-yloxy)aniline (2.0 g, 7.6 mmol) and 10% Pd/C (200 mg, 0.18 mmol) in MeOH (15 mL) was stirred under a H2 atmosphere (50 psi) at RT for 48 h. The mixture was filtered through Celite® and the cake was washed with MeOH. The filtrate was concentrated to afford 4-(4-amino-3-fluorophenoxy)-N-methylpyridin-2-amine (1.2 g, 68% yield). 1H NMR (DMSO-d6) δ 7.86 (d, J=6.3 Hz, 1H), 6.82-6.69 (m, 3H), 6.18 (dd, J=6.0, 2.1 Hz, 1H), 5.84 (d, J=2.1 Hz, 1H), 5.41 (br s, 1H), 3.62 (s, 2H), 2.84 (d, J=3.0 Hz, 3H); MS (ESI) m/z: 234.2 (M+H+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[N:12][C:11]=1[CH3:18].[CH:19](=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[OH:28][CH:19]([CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][C:11]1[C:10]([CH3:9])=[N:15][C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1
Reactant: O=CC=Cc1ccccc1
Reactant: Cc1nc(C)c(C)nc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CC(O)C=Cc2ccccc2)nc1C
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of cinnamaldehyde (14.5 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:9](=[O:30])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:24][C:23]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:38].[ClH:40].[NH2:7][CH:8]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:9]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[C:17]3[S:24][C:23]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:14][CH2:15]1)=[O:30]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(-c4ccsc4)sc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(-c4ccsc4)sc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of product {1-(4-chlorobenzyl)-2-oxo-2-[4-(6-thiophen-3-yl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-thiophen-3-yl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 484.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]5[N:31]=[C:30]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[NH:29][N:28]=5)[CH2:24]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:38][C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:24][CH:25]([C:27]5[N:31]=[C:30]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=6)[NH:29][N:28]=5)[CH2:26]4)=[CH:18][CH:17]=3)=[N:9][C:10]2=[N:15][CH:14]=1
Reactant: c1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Brc1cnc2nc(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)c(-c3ccccc3)cn12
Yield: 11.3 %

Procedure:
143 mg (0.3 mmol) 6-Phenyl-7-{4-{3-[5-(pyridine-2-yl)-1H-[1,2,4]triazole-3-yl)azetidine-1-ylmethyl]-phenyl}-imidazo[1,2-a]pyrimidine are dissolved in 11.8 mL chloroform. 57.8 mg (0.3 mmol) N-bromosuccinimide are added and the reaction mixture is heated for one hour at reflux. The solvent is evaporated and the residue is purified by chromatography (silicagel, eluents: dichloromethane/methanol). 19.1 mg (10%) pure compound and 75.8 mg (41%) slightly contaminated product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21]Cl)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH2:39]([NH:41][CH3:42])[CH3:40]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][CH2:21][N:41]([CH2:39][CH3:40])[CH3:42])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCCl)Cc1cccc(CC(=O)OC)c1
Reactant: CCNC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN(C)CC)Cc1cccc(CC(=O)OC)c1

Procedure:
The title compound was prepared by the method of example 11 step (x) using the product of example 11 step (ix) (627 mg) and N-ethylmethylamine (1 ml) as a white solid 65 mg.