Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:11][CH2:10]2)=[O:14])=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(O)cc1
Reactant: C=CCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCCC[C@H]1CC[C@H](C(=O)Oc2ccc(OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 520 mg of trans-4-(4-pentenyl)cyclohexanecarboxylic acid, 439.4 mg of p-ethoxyphenol, 765.5 mg of dicyclohexylcarbodiimide and 45 mg of 4-(dimethylamino)pyridine were dissolved in 80 ml of methylene chloride and the solution was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was diluted with diethyl ether, the precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in hexane and the solution was washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The aqueous phases were back-extracted twice with hexane. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave an 0.7 g (83%) of trans-4-(4-pentenyl)cyclohexanecarboxylic acid p-ethoxyphenyl ester. After recrystallization from 3 ml of methanol there were finally obtained 455 mg of product in the form of colourless crystals; m.p. (C-N) 32.7° C., cl.p. (N-I) 57.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14](F)[CH:13]=1.O>CN(C)C=O>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 34.5 %

Procedure:
Dissolve 1-methyl-piperidin-4-ol (3.62 g, 31.43 mmol) in N,N-dimethylformamide (20 mL) and add 95% sodium hydride (0.83 g, 33.0 mmol) at ambient temperature. After 40 min., add 1,3-difluoro-5-nitro-benzene (5.0 g, 31.43 mmol), stir and heat at 65° C. After 2 hr., cool to ambient temperature and pour slowly into water (100 mL). Extract the reaction mixture with ethyl acetate (3×150 mL), wash the combined organic layers with aqueous NaCl solution (100 mL), dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain of the title compound (2.76 g, 35%). 1H NMR (CDCl3): 7.6 (s, 1H), 7.5 (d, 1H), 7.0 (d, 1H), 4.4 (m, 1H), 2.7 (m, 2H), 2.4 (m, 5H), 2.0 (m, 2H), 1.9 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1F.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([Cl:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1F
Solvent: CO
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1Nc1ccccc1
Temperature: 0 °C
Reaction time: 19 h
Yield: 84.4 %

Procedure:
4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a (2.20 g, 8.84 mmol) is suspended in MeOH (9.4 mL) and aniline (3.22 mL, 35.4 mmol) is added. The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 19 hours, the reaction is complete. Distilled water (3.22 mL) is added to the reaction mixture and refluxing is continued for one hour. The reaction mixture is cooled to 0° C. in an ice bath for 20 minutes. The reaction mixture is filtered and washed with 3:10 distilled water/MeOH (65 mL total) and then with MeOH. The solid is dissolved with CH2Cl2 and concentrated under reduced pressure to give 2.40 g (84%) of pure desired product. MS APCI (−) m/z 320.3 (M−1) detected.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[O:1][CH:5]=[CH:4][N:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: c1cocn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of 1.00 g (14.5 mmol) oxazole in 25 ml dry THF under argon at −78° C. was added 9.14 ml (14.6 mmol) n-butyllithium solution (1.6M in hexane) and stirring continued for 30 minutes at −78° C. 3.91 ml (14.5 mmol) tributyltin chloride was then added dropwise and stirring continued for 15 minutes at −78° C. and for 1 hour at room temperature. The reaction mixture was then concentrated in vacuo and the residue resuspended in 50 ml hexane. The insoluble lithium salts were removed by filtration and the filtrate was concentrated in vacuo to afford 4.90 g (95%) 2-tributylstannanyl-oxazole as a light yellow liquid which was used in the next step without further purification. 1H NMR 6 (CDCl3, 250 MHz): 7.84 (1H, s), 7.18 (1H, s), 1.67-1.53 (6H, m), 1.42-1.29 (6H, m), 1.20 (6H, t, J=8 Hz), 0.89 (9H, t, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]CC4C=CC=CC=4)[CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](CN3CCCC3)=[C:28]([O:38][CH3:39])[CH:27]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+:43]>C1COCC1.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:43]3[CH2:4][CH2:3][CH2:2][CH2:7]3)=[C:28]([O:38][CH3:39])[CH:27]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1cc(Cc2c(-c3ccc(N)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Solvent: C1CCOC1
Product: COc1cc(Cc2c(-c3ccc(N)cc3)sc3cc(O)ccc23)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
2-(4-Aminophenyl)-6-benzyloxy 3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]benzo[b]thiophene (103 mg) in THF (4.0 mL) was treated with a solution of ammonium formate (25% in H2O, 2.0 mL) and 10% palladium on carbon (100 mg) sequentially at ambient temperature. The resulting mixture was stirred at ambient temperature under argon for 21 h before filtered through diatomaceous earth followed by rinsing with dichloromethane and methanol. The filtrate was extracted with dichloromethane (20 mL×3) from water (30 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:10:85) afforded the product (80 mg).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2ncccc2C12Cc1cc3ccc(O)nc3cc1C2
Product: O=C1Nc2ncccc2C12Cc1cc3ccc(Cl)nc3cc1C2

Procedure:
A solution of (±)-2-hydroxy-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (3.00 g, 9.89 mmol) in POCl3 (30 mL) was stirred at 80° C. for 2 h, then concentrated to dryness under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (200 mL) and CH2Cl2 (500 mL). The aqueous layer was extracted further with CH2Cl2 (200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=322 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([F:4])([F:3])[F:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)[Cl:13].C([O-])([O-])=O.[K+].[K+]>>[Cl:13][CH2:12][CH:14]([OH:16])[CH2:15][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([F:3])([F:2])[F:4])[CH:6]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC(CCl)COc1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of m-CF3C6H4OH (48.6 g, 0.30 mol), epichlorohydrin (138.8 g, 1.50 mol) and K2CO3 (20.7 g, 0.15 mol) was stirred at 70° C. for 2 h. Epichlorohydrin was evaporated in vacuo. Water (250 mL) was added and the resulting mixture was extracted with CH2Cl2 (2×50 mL). The combined organic extract was stirred with 32% HCl (50 mL) for 0.5 h at rt. The organic layer separated, dried over Na2SO4, filtered and concentrated in vacuo to give 76.2 g of crude 1-chloro-3-[3-(trifluoromethyl)phenoxy]-2-propanol which was used in next step without additional treatment.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:14])[CH3:13])[CH:7]=1)=[O:4].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1>>[N:15]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:14])[CH3:13])[CH:7]=2)=[O:4])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CN(C)c1cccc(NC(=O)CBr)c1
Product: CN(C)c1cccc(NC(=O)Cn2cnc3ccccc32)c1

Procedure:
Part B: The title compound was synthesised according to the procedure described in Example 94, from 2-bromo-N-(3-dimethylamino-phenyl)-acetamide and 1H-benzoimidazole. Calculated for C17H18N4O m/z: 294.3, found 295.3 [M+H]+.
Reaction SMILES: [C:1](O[K])(C)(C)C.[CH3:7][O:8][C:9]1[CH:10]=[N:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH:19]=O)[C:17]=2[N:18]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[CH3:7][O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17](=[C:16]([CH:19]=[CH2:1])[CH:15]=[CH:14][CH:13]=2)[N:18]=1
Reactant: COc1cnc2cccc(C=O)c2n1
Reactant: CC(C)(C)O[K]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1cccc2ncc(OC)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (22.78 g) in THF (200 mL) was treated with tBuOK (7.15 g) and further stirred at rt for 1 h. The mixture was cooled to 0° C. and treated with a solution of 3-methoxy-5-quinoxalinecarboxaldehyde (10.0 g; prepared according to WO 2006/021448) in THF (100 mL). The mixture was further stirred at rt for 3 h, diluted with ether and washed with water and an aq. sat. NH4Cl solution. The org. phase was dried over MgSO4 and concentrated under reduced pressure. The residue was crystallized from ether and the crystals were filtered off. The mother liquor was purified by CC (Hex/EA 1:1), affording a light orange solid (8.70 g; 88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:18][CH:17]=3)[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(COc3ccccc3)co2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(-c2nc(COc3ccc(S(=O)(=O)Cl)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
950 mg 2-(4-Methoxy-phenyl)-4-phenoxymethyl-oxazole were dissolved in 9 ml dichloromethane. At −20° C. 0.90 ml chlorosulfonic acid were added dropwise. The cooling bath was removed and the reaction mixture stirred at room temperature for two hours. The reaction mixture was cooled to 0° C., then 20 ml ice water were added and the reaction mixture extracted five times with portions of 50 ml dichloromethane. The combined organic layers were washed with water and then dried over MgSO4. The solvent was then removed in vacuo to obtain 580 mg 4-[2-(4-Methoxy-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl chloride.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:36][CH:35]=1
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Br-]
Product: O=C(O)CCCCCCCCCCc1ccc(Br)cc1

Procedure:
By the similar procedure of synthesis of B10, compound B2 (330 mg, 0.643 mmol) and 4-bromobenzaldehyde (91.5 mg, 0.495 mmole) were used as starting materials to afford B18 (98.0 mg, 0.287 mmol, 58%) as off-white solids. mp: 91° C. 1H-NMR (CDCl3, 400 MHz) δ 7.37 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 1.52-1.63 (m, 4H), 1.20-1.37 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 179.94, 141.79, 141.79, 131.22, 130.14, 119.22, 35.31, 34.11, 31.27, 29.44, 29.38, 29.36, 29.19, 29.12, 29.03, 24.68. HRMS (ESI) calculated C17H26BrO2 [M+H]+: 341.1116, found: 341.1111.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[C:30]([CH3:36])=[CH:31][C:32]([Cl:35])=[N:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:29]1[CH:34]=[N:33][C:32]([Cl:35])=[CH:31][C:30]=1[CH3:36]
Reactant: CN(C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1)c1ccccc1O
Reactant: Cc1cc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ncc1-c1cc(C(=O)N(C)c2ccccc2O)ccc1Cl
Temperature: 100 °C
Yield: 119.2 %

Procedure:
A mixture of 4-chloro-N-(2-hydroxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (100 mg, 0.26 mmol, Step 8A), 5-bromo-2-chloro-4-methyl-pyridine (200 mg, 0.52 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), K2CO3 (180 mg, 1.3 mmol) in dioxane (2.5 mL), was heated at 100° C. for 12 hrs. The mixture was dried in vacuo in the presence of silica gel and directly chromatographed on silica gel (eluent: ethyl acetate/hexane (1/4 up to 2/3)) to yield 4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (120 mg). MS [M+H]+: 387.0; tR=2.27 min. (method 1)
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18](O)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:55]([O:57][C:58](=[O:77])[CH2:59][CH:60]([C:67]1[CH:76]=[C:75]2[C:70]([CH2:71][CH2:72][NH:73][CH2:74]2)=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][N:64]=[CH:63][CH:62]=1)[CH3:56]>CN(C)C=O>[CH2:55]([O:57][C:58](=[O:77])[CH2:59][CH:60]([C:61]1[CH:62]=[CH:63][N:64]=[CH:65][CH:66]=1)[C:67]1[CH:76]=[C:75]2[C:70]([CH2:71][CH2:72][NH:73][CH:74]2[C:18](=[O:19])[CH2:17][C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:21])[O:9][C:10]=3[CH:16]=2)=[CH:69][CH:68]=1)[CH3:56]
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: CCOC(=O)CC(c1ccncc1)c1ccc2c(c1)CNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1ccncc1)c1ccc2c(c1)C(C(=O)Cc1ccc3nc(Nc4ccccc4C)oc3c1)NCC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-o-tolylaminobenzoxazole-6-acetic acid (0.124 g) and diisopropylethylamine (0.17 g) in dimethylformamide (2 mL) was treated with a solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.183 g) in dimethylformamide. After 10 minutes at room temperature this yellow solution was added dropwise to a rapidly stirred solution of 3-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-3-(pyrid-4-yl)-propionic acid ethyl ester, enantiomer A {0.219 mmoles, Reference Example 17(a)} in dimethylformamide. After stirring at room temperature for 2.5 hours the reaction mixture was evaporated. The residual oil was dissolved in a mixture of acetonitrile, water and trifluoroacetic acid (25:75:0.1) and treated with dimethylformamide and trifluoroacetic acid to bring to pH2. This mixture was subjected to preparative HPLC {Hypersil Elite C18 column, 10 cm×2.1 cm, using a mixture of acetonitrile, water and trifluoroacetic acid (25:75:0.1) as the mobile phase followed by a 1% acetonitrile/minute gradient) to give the title compound. LC-MS:MS (ES)=575 (M+H)+, 573 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH2:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH:24][C:31](=[O:33])[CH3:32])=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(N)cc12
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of tert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (synthesized according to the method similar to that in Example 82 (2)) (0.21 g, 0.5 mmol) and acetyl chloride (0.04 ml, 0.6 mmol) in N,N-dimethylacetamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{6-(acetylamino)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.19 g, 80.8%) as crystals.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1(/[C:7](/[N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:6]\[C:5]2[CH:13]=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: C(=C(\c1ccccc1)n1c2ccccc2c2ccccc21)\c1ccccc1

Procedure:
N-Phenylbenzaldimine (1.35 g, 0.0075 mol) and 9-benzylcarbazole (1.29 g, 0.0077 mol) were heated at 75° C. for 30 min in dimethylformamide (dry), 50 mL, and potassium tert-butoxide (0.10 g, 0.00089 mol). Based on reversed-phase HPLC results, the reaction was complete after 3 min. Aqueous work-up as above and recrystallization of the precipitate from methanol gave needles mp 160°-2° C. (81%). 1H NMR (200 MHz, CDCL3) δ(assignment): 6.85-7.09 (m, 2 H, aromatic). MS [m/e (70 eV, % of base peak)]C26H19N 345 (M+·, 100), 267 (M+· --PhH, 25.8), 178 PhCCPh+·, 47.5), 167 (carbazole+·, 63.6). HRMS (m/z) for C26H19N (M+·) calcd. 345.1517 found 345.1513. FTIR (CDCl3): 3083, 3064, 3027, 1624, 1598, 1493, 1479, 1450, 1384, 1335, 1314, 1232 cm-1 . Analysis: calcd. for C26H19N: C 90.40, H 5.54, N 4.05%; found: C 90.25, H 5.66, N 4.20%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1F.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:24]1[CH2:23][CH2:22][CH:21]([N:18]2[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]2)[CH2:26][CH2:25]1
Reactant: COc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1,2-Difluoro-4-methoxy-5-nitrobenzene (INTERMEDIATE 52) (1.0 g, 5.3 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (1.066 g, 5.8 mmol) were added in a 50 mL round-bottomed flask. DMSO (6 mL) was added. The reaction was stirred at 90° C. for 1 h. After it was cooled to RT, sat. NaHCO3 (20 mL) was added. After the mixture was stirred at RT for 10 min, filtration afforded the title product as an orange solid (1.7 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[S:17][C:18]=1[Cl:19]>>[Br:13][C:14]1[CH:15]=[C:16]([S:20]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[N:8]=2)(=[O:22])=[O:21])[S:17][C:18]=1[Cl:19]
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1cc(Br)c(Cl)s1

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (34.2 mg) with purity >90%: MS (pos) m/z 457.1, 477.1, 479.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([NH2:14])[CH2:13][CH2:12]1.O>CS(C)=O>[CH:11]1([NH:14][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1NC1CC1
Yield: 49.7 %

Procedure:
1-fluoro-2-nitrobenzene (1.85 mL, 175 mmol) and cyclopropanamine (2.43 mL, 35 mmol) were stirred in DMSO for 3 hours. Water was added (250 mL) and the mixture was extracted with ether (2×250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to afford title compound 380 (3.1 g, 99%) as an orange oil. MS (m/z): 178.9 (M+H). 1H NMR (CDCl3) δ (ppm): 8.15 (dd, J=8.6, 1.6 Hz, 1H), 8.09 (s, 1H), 7.49-7.45 (m, 1H), 7.32 (dd, J=8.6, 1.4 Hz, 1H), 6.72-6.67 (m, 1H), 2.60-2.58 (m, 1H), 0.94-0.89 (m, 2H), 0.68-0.64 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:14].ClN1C(=O)CCC1=O>CCOC(C)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:14][CH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2ccon2)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: ClCc1ccc(-c2ccon2)cn1
Reaction time: 4 h
Yield: 34 %

Procedure:
To a stirring mixture of 3-(6-methylpyridin-3-yl)isoxazole (76 mg, 0.474 mmol) and 6 mL carbon tetrachloride, was added N-chlorosuccinimide (69.7 mg, 0.52 mmol), followed by 3 mg benzoyl peroxide. The reaction mixture was refluxed. Additional N-chlorosuccinimide (40 mg, 0.30 mmol) was added in two portions after stirring 2 h and 4 h. After refluxing for a total of 13 h the reaction mixture was diluted with EtOAc, then washed sequentially with 1 N aq. NaOH solution, water and brine. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to isolate 31 mg (34%) of the title compound as a white solid. HPLC/MS: retention time=1.77 min, [M+H]+=195.