Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([F:41])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>ClCCl>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([F:41])[C:38]=1[O:39][CH3:40])[C:33]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:34]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(F)cc(C(=O)Cl)cc1F
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(F)cc(C(=O)N2CSc3ccccc32)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (316 mg) and 37% formalin (0.21 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and diisopropylethylamine (0.56 mL) and 3,5-difluoro-4-methoxybenzoyl chloride (347 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (c).
Reaction SMILES: [Na+].[I-:2].CNCCNC.Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([N:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)[CH:14]=[C:13]2[CH3:27].CCOC(C)=O>O1CCOCC1.[Cu]I>[I:2][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([N:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)[CH:14]=[C:13]2[CH3:27]
Reactant: Cc1cc(N2CCC(C)CC2)nc2ccc(Br)cc12
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCC(C)CC2)nc2ccc(I)cc12
Temperature: 110 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 39 mg (0.2 mmol) of CuI, 0.6 g (4.0 mmol) of NaI, and 43 μL N,N′-dimethylethylenediamine are added to a solution of 0.69 g (2.0 mmol) of 6-bromo-4-methyl-2-(4-methylpiperidin-1-yl)quinoline in 2 mL of 1,4-dioxane and the reaction mixture is shaken for 14 hours at 110° C. After cooling, it is combined with 60 mL of EtOAc, and the organic phase is washed twice with 20 mL of 5% NH3 solution and dried over magnesium sulfate. After the desiccant and solvent have been eliminated, the residue is reacted further without purification. Yield: 0.65 g (88% of theoretical); C16H19IN2 (M=366.240); calc.: molpeak (M+H)+: 367; found: molpeak (M+H)+: 367; HPLC-MS: 7.0 min (method A).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH2:25]([O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:26].CC(C)=O>CS(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:36])=[CH:34][CH:33]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)CCn2cnc3c(=O)[nH]cnc32)cc1
Yield: 30 %

Procedure:
165 mg (0.50 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 84 mg (0.50 mmol) of 4-aminobenzoic acid ethyl ester were heated together in 1.5 ml of dimethylsulfoxide at 35°-40° C. for 72 hours. A white precipitate was observed at the bottom of the flask. 10 ml acetone was added and the solid was collected by Buchner vacuum filtration. The solid was washed twice with acetone and was allowed to dry. This yielded 53 mg of 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid, ethyl ester (AIT-0079) as a white solid. m.p. 265°-269° C. Yield: 30%.
Reaction SMILES: [N+:1]([C:4]1[CH:44]=[CH:43][CH:42]=[CH:41][C:5]=1[CH2:6][O:7][C:8](=[O:40])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([C:33]([O:35]C(C)(C)C)=[O:34])[CH:23]=[C:24]([CH:32]=1)[C:25]([O:27]C(C)(C)C)=[O:26])([O-:3])=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:44]=[CH:43][CH:42]=[CH:41][C:5]=1[CH2:6][O:7][C:8](=[O:40])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:32]=[C:24]([C:25]([OH:27])=[O:26])[CH:23]=[C:22]([CH:21]=1)[C:33]([OH:35])=[O:34])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCCC(=O)OCc2ccccc2[N+](=O)[O-])cc(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCCCCCCCCOc1cc(C(=O)O)cc(C(=O)O)c1)OCc1ccccc1[N+](=O)[O-]

Procedure:
The previously prepared compound, di-tert-butyl 5-(11-(2-nitrobenzyloxy)-11-oxoundecyloxy)isophthalate, was dissolved in CH2Cl2 (10 mL) producing a yellow solution. Trifluoroacetic acid (TFA) (10 mL) was slowly added while stirring. The solution was stirred at room temperature for 1 hour. The solvent was removed by rotovap producing a white solid, which was washed four times with CH2Cl2 and dried under vacuum. A white power was produced. Yield: 0.127 g (100%). 1H-NMR (DMSO-d6) δ (ppm): 13.3 (s, 2H, OH), 8.1 (d, 1H, Ar), 8.0 (s, 1H, Ar), 7.8 (t, 1H, Ar), 7.7 (d, 1H, Ar), 7.6 (t, 11H, Ar), 7.6 (s, 2H, Ar), 5.4 (s, 2H, O—CH2), 4.0 (t, 2H, CH2—O), 2.4 (t, 2H, CH2—C═O), 1.7 (m, 2H, CH2), 1.5 (m, 2H, CH2), 1.4 (m, 2H, CH2), 1.2 (m, 10H, CH2). 13C-NMR (DMSO-d6) δ (ppm): 172.8, 166.7, 159.1, 147.8, 134.4, 132.9, 131.8, 129.9, 129.7, 125.2, 122.4, 119.3, 68.4, 62.6, 33.6, 29.2, 29.1, 29.0, 28.9, 28.8, 28.7, 25.7, 24.7. MS (ESI): (M)=500.4 (calc. 501.53).
Reaction SMILES: C(O)(=O)C.[C:5]1([CH3:20])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[C:14]([CH3:19])=[N:15][NH:16][C:17]=1[NH2:18].[C:21]([CH:24]([C:30](OCC)=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=O)[CH3:22]>C1(C)C(C)=CC=CC=1>[C:5]1([CH3:20])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[C:14]([CH3:19])=[N:15][N:16]2[C:30](=[O:31])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH3:22])[NH:18][C:17]=12
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Yield: 36.6 %

Procedure:
Acetic acid (5 mL) was added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (5 g, 23.22 mmol) and diethyl 2-acetylmalonate (4.7 g, 23.22 mmol) in xylene (40 mL), followed by heating under reflux for seven hours. The reaction mixture was evaporated as it was, and water was added thereto. After extracting with ethyl acetate, the organic layer was washed with an aqueous saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give the title compound (3 g).
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Br[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:17]([N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccnc1Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ncccc1Cl)C2
Temperature: 120 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (435 mg, 2.26 mmol), 2-bromo-3-chloropyridine (400 mg, 1.88 mmol), and potassium carbonate (390 mg, 2.83 mmol) were combined in dry dimethylformamide (10 mL) and stirred at 120° C. for 48 hours. The mixture was allowed to cool room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (85:15 hexanes:ethyl acetate) to provide the title compound.
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43]>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]3)[OH:14])[N:10]=[C:5]([NH:4][CH2:3][CH:2]([CH:26]3[CH2:27][C:28]([CH3:35])([CH3:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH2:31]3)[OH:1])[N:6]=2)[N:6]=1
Reactant: NCCCCCCN
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Solvent: Cc1ccccc1C
Product: CC1(C)CC(C(O)CNc2nc(NCCCCCCNc3nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)n3)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
2,4-Bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (20.5 g) and hexamethylenediamine (2.0 g) were dissolved in xylene (700 ml), and the mixture was refluxed for 12 hours. The xylene was distilled off from the reaction mixture, and the residue was put into aqueous ammonia, extracted with chloroform and dried over anhydrous magnesium sulfate. The residue obtained by removing the chloroform was chromatographed through silica gel (eluent=ethyl acetate:triethylamine:ethanol=5:1:5), giving the desired product as white crystals with a melting point of 165°-168° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[C@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]I.O>CN(C=O)C>[CH3:16][O:14][C:13](=[O:15])[C@H:9]([C@H:10]([CH3:12])[OH:11])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CI
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To a solution of N-Boc-L-allo-threonine (500 mg, 2.28 mmol) in DMF (5 mL), KHCO3 (637 mg, 4.56 mmol) and MeI (227 μl, 3.65 mmol) were added and the reaction was stirred 5 h at rt. Water (20 mL) was added and the mixture was extracted with ether (3×20 mL), dried (Na2SO4) and evaporated to afford the methyl ester 106 (494 mg, 93%) that was used without purification in the next step. 1H-NMR (500 MHz, CDCl3): 1.19-1.25 (m, 3H), 1.48 (s, 9H), 3.78 (s, 3H), 4.05-4.10 (m, 1H), 4.32-4.40 (m, 1H), 4.45-4.54 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[CH3:38][C:39]1([O:42][CH2:41]1)[CH3:40].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:42][C:39]([CH3:41])([CH3:40])[CH2:38][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: CC1(C)CO1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OCC(C)(C)O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (4.93 g, 9.93 mmol) and isobutylene oxide (8.8 mL, 100 mmol) in DMF/H2O (21 mL/4 mL) was added K2CO3 (2.74 g, 2 mmol). The reaction mixture was stirred at 60° C. for 12 hours, then cooled to room temperature and treated with aqueous NaH2PO4 (saturated solution, 10 mL) to adjust the pH of the mixture to 7˜8. The solid was collected by filtration and washed with EtOAc/EtOH (80 mL/15 mL). The title compound was obtained as a pale yellow solid (1.93 g, 34.3%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[S:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:33]2[S:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(OCCN(Cc2ccccc2)c2nc3ccccc3s2)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1

Procedure:
4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy)benzaldehyde (3 g) and 2,4-thiazolidinedione (1 g) were dissolved in toluene (200 ml) containing piperidine (0.2 ml) and benzoic acid (0.2 g) and heated to reflux for 4 h. in a Dean and Stark apparatus. On cooling, the solution was concentrated under vacuum to 50% of its volume and the title compound, which crystallised, was collected by filtration and dried in vacuo (m.p. 185°-188° C.). It was used in Example 27 without further purification.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 50 %

Procedure:
As described for example 125, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (120 mg, 50%) which was obtained as a white solid. MS: m/e=430.3 [M+H]+.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=2)=[O:39])=[CH:36][N:35]=[C:34]1[CH3:47].C(=O)=O.CC(C)=O>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:37]3[N:33]([CH3:32])[C:34]([CH3:47])=[N:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[C:43]([CH3:46])=[N:42][CH:41]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1ncc(C(=O)c2cnc(C)n2C)n1C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-BuLi (1.63 M in hexane, 0.124 mL, 0.203 mmol) was added dropwise under argon at ˜−70° C. to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (81.6 mg, 0.19 mmol, Intermediate 10) in THF (1.9 mL). After 2 additional minutes, an opaque milky suspension of bis(1,2-dimethyl-1H-imidazol-5-yl)methanone (42.4 mg, 0.194 mmol, Intermediate 11) in LaCl3-2LiCl (0.5 M in THF, 0.381 mL, 0.19 mmol) and THF (2.5 mL) was added rapidly dropwise over 1.5 minutes. The resulting yellow slurry was stirred in the dry ice/acetone bath for 10 minutes, and was then transferred to an ice bath and stirred overnight as the bath warmed to room temperature. The reaction was then quenched with 5 M aqueous NH4Cl (0.06 mL) and diluted with DCM (˜5 mL) and MeOH (˜2 mL), and the suspension was partitioned with 0.75 M aqueous tetrasodium EDTA (4 mL) and 9:1 DCM/MeOH (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by C18 HPLC (20% to 100% CH3CN gradient with 0.1% TFA throughout) and the lyophilisate neutralized with 9:1 DCM/MeOH) and 2 M aqueous K2CO3. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.86 (d, J=2.53 Hz, 1H), 7.63-7.70 (m, 2H), 7.58 (d, J=8.59 Hz, 2H), 7.38 (d, J=8.59 Hz, 2H), 7.37 (m, 1H), 6.42 (t, J=1.99 Hz, 1H), 6.14 (s, 2H), 5.82 (br. s., 1H), 4.29 (s, 2H), 4.08 (s, 3H), 3.38 (s, 6H), 2.26 (s, 6H); MS m/e 568.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([Br:17])=[C:15]([Br:18])[S:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=[O:23].OO.S(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([Br:17])=[C:15]([Br:18])[S:14](=[O:23])[C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Br
Reactant: O=C(O)C(F)(F)F
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S1C(Br)=C(Br)c2ccc(OCc3ccccc3)cc21
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Dissolve 6-benzyloxy-2,3-dibromo-benzo[b]thiophene (20 g, 50 mmol) in dichloromethane (88 mL) and add trifluoroacetic acid (88 mL). Stir for 10 minutes, then add 30% aqueous solution of hydrogen peroxide (5.1 mL, 50 mmol) and stir for 4 hours. Add solid sodium bisulfite (2.2 g, 21 mmol), dilute with water (30 mL), stir for 15 minutes, and then concentrate in vacuo. Partition residue between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (150 mL), separate layers, wash organic layer with additional saturated aqueous sodium bicarbonate (150 mlT) and brine (100 mL). Dry with sodium sulfate, filter, and concentrate in vacuo; Chromatograph on a SiO2 column eluting with 100% dichloromethane to give 12.8 g of 6-benzyloxy-2,3-dibromo-benzo[b]thiophene 1-oxide (62%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[OH2:20].[OH2:21].O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+3].C(Cl)Cl.Cl(O)(=O)(=O)=O>CO>[O:1]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:21])=[O:20])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+3]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)Cc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 3 h
Yield: 17.1 %

Procedure:
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-ethanone (2.61 g, 10 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) was added to a solution of thallium trinitrate trihydrate (4.44 g, 10 mmol) (McKillop, A., Swann, B. P., Taylor, E. C. J. Am. Chem. Soc., 1971, 93, 4919) in methanol (40 mL) and methylene chloride (20 mL) containing perchloric acid (70%, 10 mL). After 5 hours at room temperature the precipitated thallium (I) nitrate was removed by filtration, and the filtrate was diluted with water (100 mL). The organic phase was separated, the aqueous layer was extracted with methylene chloride, and the combined organic phases were washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in concentrated hydrochloric acid (250 mL) at room temperature. After 3 hours the solution pH was adjusted to 5 by ˜28% ammonium hydroxide. The aqueous layer was extracted with methylene chloride, and the combined organic phases were washed with water, dried over sodium sulfate and concentrated. The product was purified by chromatography on silica gel with ethyl acetate/hexanes eluant to give the title compound as a pale yellowish solid (0.4 g, 17%); 1H NMR (300 MHz, DMSO-d6) δ 2.42 (t, J=6.0 Hz, 4H), 3.41 (s, 2H), 3.56 (t, J=6.0 Hz, 4H), 6.98 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H), 12.20 (s, 1H); MS (ES) m/z: 234.3 (MH+); HRMS Calcd. for C13H15NO3 (M+): 233.1052. Found: 233.1045.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[CH2:15](B(CC)CC)[CH3:16].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([CH2:15][CH3:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CN1C(=O)COc2cc(Br)c(N)cc21
Reactant: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc2c(cc1N)N(C)C(=O)CO2
Yield: 56.2 %

Procedure:
A mixture of 6-amino-7-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one (0.21 g, 0.82 mmol), triethylborane (2.47 ml of 1.0 M solution in hexane, 5.56 mmol), PdCl2dppf.CH2Cl2 (0.067 g, 0.082 mmol) and Cs2CO3 0.81 g, 2.46 mmol) in DMF (6 ml) was heated at 50° C. under argon for 18 hours. The mixture was partitioned between EtOAc and water. The EtOAc layed was dried (MgSO4), filtered, concentrated under reduced pressure and purified with prep-plate TLC (hexanes:EtOAc 1:1) to give 0.095 g of 6-amino-7-ethyl-4-methyl-4H-benzo[1,4]oxazin-3-one as a tan solid, 63%.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)(C)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CC(C)O
Product: CN1CCN(c2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)CC1
Yield: 78.4 %

Procedure:
A mixed solution of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.43 g), 1-methylpiperazine (2.5 g) and isopropyl alcohol (20 mL) was heated under reflux for 10 hrs. The reaction mixture was concentrated, diluted with water, and acidified with 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 3-[4-(4-chlorophenyl)-2-(4-methyl-1-piperazinyl)-5-oxazolyl]propionic acid (1.37 g, yield 70%) as colorless prism crystals. melting point: 157–160° C.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][CH2:14][N:15]([CH2:21][CH2:22]Br)[C:16](=[O:20])[O:17][CH2:18][CH3:19].[H-].[Na+]>CN(C)C=O>[CH2:18]([O:17][C:16]([N:15]1[CH2:21][CH2:22][C:2]2([CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]2=[O:11])[CH2:13][CH2:14]1)=[O:20])[CH3:19]
Reactant: CCOC(=O)N(CCBr)CCBr
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CCc3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 25.6 %

Procedure:
To a solution of 2.92 g (20.0 mmoles) 1-tetralone and 9.0 g (30.0 mmoles) ethyl bis(2-bromoethyl)carbamate (S. Huybuchts and G. J. Hoornaert, Synth. Commum., 11, 17 (1981) in 20 ml dry dimethylformamide heated to 50° C. under argon was added in portions 2.00 g (50.0 mmol) of 60% sodium hydride dispersion is mineral oil. The mixture was stirred 14 hours at 50° C. and the solvent was removed in vacuo. The residue was taken up in 50 ml ether, quenched with 5 ml saturated ammonium chloride solution, diluted with 10 ml water, and the layers were separated. The aqueous layer was extracted with 2×50 ml ether. The combined extracts were washed with 2×15 ml water and brine, dried, and the solvent was removed in vacuo to give 7.77 g crude product as an oil. This was purified by flash chromatography on silica gel eluting with ethyl acetate:hexane (30:70) to give 1.47 g (26%) product as an oil; 1H NMR (deuteriochloroform): δ1.26 (t, 3H), 1.52 (m, 2H), 1.97 (m, 2H), 2.06 (t, 2H), 3.01 (t, 3H), 3.59 (m, 4H), 4.14 (q, 2H), 7.24 (t, 1H), 7.31 (t, 1H), 7.97 (m, 1H), 8.01 (d, 1H).