Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[O:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[K+].[Br-]>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH:24]4[CH2:25][CH2:26][CH2:27][O:23]4)[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: C1COC(CN2CCNCC2)C1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(CC2CCCO2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(tetrahydrofuran-2-ylmethyl)-piperazine, yield 23%. White crystals, m.p. 98-100° C.; IR (KBr): ν 1731 (C═O) cm−1.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:22]1[CH:35]=[C:34]2[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]([C:49]4[C:50]([F:55])=[N:51][CH:52]=[CH:53][CH:54]=4)=[CH:31][C:32]=3[C@@:33]32[N:40]=[C:39]([NH:41]C(OC(C)(C)C)=O)CO[CH2:36]3)=[CH:24][CH:23]=1)(=O)=O.[C:58](=[O:61])([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[O:1]1[CH2:2][CH:3]=[C:4]([C:22]2[CH:35]=[CH:34][C:25]3[O:26][C:27]4[C:32](=[CH:31][C:30]([C:49]5[C:50]([F:55])=[N:51][CH:52]=[CH:53][CH:54]=5)=[CH:29][CH:28]=4)[C@:33]4([N:40]=[C:39]([NH2:41])[CH2:58][O:61][CH2:36]4)[C:24]=3[CH:23]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(COC1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1ccc(-c3cccnc3F)cc12
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC1=N[C@]2(COC1)c1cc(C3=CCOCC3)ccc1Oc1ccc(-c3cccnc3F)cc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
In a microwave vial, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.062 g, 0.297 mmol), (S)-5-(tert-butoxycarbonylamino)-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (0.145 g, 0.238 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.027 g, 0.024 mmol) were taken up in DMF (3 mL). Aqueous sodium carbonate (1.0 M, 0.714 mL, 0.714 mmol) was added. Argon was blown through the vessel which was sealed and placed in an 85° C. oil bath. After 3 h, the reaction was concentrated. The residue was diluted with water (15 mL) and the aqueous phase was extracted with 3% MeOH/DCM (3×25 mL). The organics were combined, washed with brine (7 mL), dried over sodium sulfate and concentrated. The residue was transferred to a microwave vial with 3 mL of DCMm and tfa (0.275 mL, 3.57 mmol) was added. The vial was sealed and the reaction was stirred in a 65° C. oil bath for 2 h. The reaction was concentrated. The residue was neutralized with 0.5 M Na2CO3 (13 mL). The aqueous phase was extracted with 5% MeOH/DCM (3×25 mL). The organics were combined, washed with dilute brine (8 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (7%-8% MeOH/DCM) to afford (R)-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (65 mg, 0.146 mmol).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:11]([Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])#[CH:12].C(N(CC)CC)C>O1CCOCC1.[Cu]I.Cl[Pd]Cl>[CH:17]([Si:13]([C:11]#[C:12][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1)([CH:14]([CH3:16])[CH3:15])[CH:20]([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: Ic1ccn2ccnc2c1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1ccn2ccnc2c1)(C(C)C)C(C)C
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
Combine 7-iodo-imidazo[1,2-a]pyridine (2.64 g, 10.82 mmol), ethynyl-triisopropyl-silane (3.61 mL, 16.23 mmol), copper (I) iodide (0.103 g, 0.541 mmol) and triethylamine (7.54 mL, 54.09 mmol) in 1,4-dioxane (50 mL). Bubble nitrogen through the mixture for five minutes. Add [1,1′-Bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (0.442 g, 0.541 mmol, 1:1 complex with dichloromethane). Attach a reflux condenser, and heat the mixture to 85° C., stir overnight (15 hours), and cool to room temperature. Filter the mixture through Celite® 521. Concentrate the solution in vacuo to a dark brown oil and use as is. MS(ES), m/z 299 (M+1).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(O)nc1Cc1ccccc1
Product: CCOC(=O)c1cnc(Cl)nc1Cc1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared as described in Example 7, but employing a solution of ethyl 2-hydroxy-4-benzylpyrimidine-5-carboxylate (1.1 g, 4.3 mmol) and POCl3 (16 g, 107 mmol) resulting in a 37% yield (0.44 g); 1HNMR (DMSO-d6) δ 9.00 (s, 1H), 7.6-7.4 (m, 5H), 4.55 (s, 2H), 4.25 (q, 2H), 1.14 (t, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H][H].C1(C)C=CC=CC=1>CO.Cl>[OH:1][C@H:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CCCC(=O)CC(=O)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC[C@@H](O)CC(=O)OC

Procedure:
Methyl 3-ketohexanoate (44.7 g, 310 mmol) was diluted with methanol (75 mL) and 0.2N HCl (2 mL). Et2NH2 +Ru2Cl5- (BINAP)2 (200 mg) was added and the mixture was heated at 60° under 100 psi of hydrogen for 2 hours. Toluene (100 mL) was added and the mixture was concentrated to an oil weighing 75 g.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(OC(F)(F)F)cc4)cc3CC[C@@H]12
Reaction time: 24 h
Yield: 54.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-trifluoromethoxyphenylboronic acid (161 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was healed at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 137 mg (56%) of the title compound as a waxy solid. FDMS: m/e=389. α[D]589 =+48.95 (c=0.96, chloroform).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[OH-].[Li+].CS(C)=O>O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1

Procedure:
2-Chloro-5-nitropyridine (9.5 grams), 2,2,2-trifluoroethanol (6.0 grams), and lithium hydroxide (4.0 grams) were mixed in 50 ml. of DMSO and stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product was separated by filtration. It was crystallized from ethyl acetate-hexanes, yield 5.0 grams, m.p., 35°-37° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[CH3:32][O-:33].[Na+]>CO>[CH3:32][O:33][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 76.4 %

Procedure:
A solution of 0.55 g (1.2 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 10 ml of MeOH was treated with 2.25 ml (12.2 mmol) of a sodium methoxide solution (5.4 molar in MeOH) and the reaction mixture was heated up to reflux. After 18 hours, it was poured into crashed ice and extracted three times with CH2Cl2/2-propanol 4:1; the organic phases were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.41 g (76%) of the title compound as light yellow oil. MS: 448.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][C:15](=O)[NH:16][C:17]=4[CH:18]=[CH:19][CH:20]=3)[C:12]2=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][CH2:15][N:16]([CH3:25])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(=O)n3c4c(cccc42)NC(=O)C3)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CN3CCN(C)c4cccc2c43)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-[(4-methylphenyl)sulfonyl]-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione from Step D (1.16 g, 3.38 mmol) in DMF (40 mL) was added potassium carbonate (467 mg, 3.38 mmol) and the resulting mixture was stirred at ambient temperature for 10 min. Iodomethane (480 mg, 3.38 mmol) was added dropwise and the reaction mixture was stirred for 18 h, then poured into H2O (50 mL). The resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=358 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.[OH:17][CH2:18][C:19](O)=[O:20].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(#N)C>[OH:20][CH2:19][C:18]([N:9]1[CH2:10][CH:11]2[CH2:15][C:14](=[O:16])[CH2:13][CH:12]2[CH2:8]1)=[O:17]
Reactant: O=C(O)CO
Reactant: O=C1CC2CNCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1CC2CN(C(=O)CO)CC2C1
Yield: 64 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (764.8 mg, 3.2 mmol) and 2-hydroxyl ethanoic acid (267.5 mg, 3.52 mmol) were dissolved in 10 mL of acetonitrile. Upon cooling by an ice-water bath, hydroxyacetic acid (1.3 g, 9.6 mmol), 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (1.23 g, 6.4 mmol) and triethylamine (1.3 mL, 9.6 mmol) were added. The ice-water bath was removed and the reaction mixture was reacted overnight at 25° C. The mixture was concentrated and diluted with 20 mL of ethyl acetate. The mixture was filtered under reduced pressure and the filtrate was washed with 20 mL of water. The organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(2-hydroxy-acetyl)-hexahydro-cyclopenta[c]pyrrol-5-one 3a (0.375 g, yield 64%) as a colorless oil.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([O-:9])=[O:8].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[C:28]([NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)(=[O:32])[CH:29]([CH3:31])[CH3:30].[N+](C1C=CC=CC=1N)([O-])=O.N1C=CC=CC=1>C(OCC)(=O)C>[N+:7]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])=[CH:42][CH:41]=1)([O-:9])=[O:8]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(C)C(=O)Nc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(2'-Nitrophenyl)-4-isobutyrylaminobenzamide is prepared under the reaction conditions given in Example 5: after the addition of pyridine/o-nitroaniline, the reaction solution is stirred for 15 hours at ambient temperature and for 5 hours at boiling temperature, the following components being used: 54.6 g (74.68 mMole) dimethylformamide, 1.5 L dry ethyl acetate, 37.3 g (29.42 mMole) oxalyl chloride, 47 g (22.63 mMole) 4-isobutyrylaminobenzoic acid, 34.4 g (24.89 mMole) o-nitroaniline, and 25.6 g (32.36 mMole) pyridine. The product is recrystallized from ethyl acetate. Yield 13.3 g (18% of theory); m.p. 237.6° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([C:21]([O:23][CH3:24])=[O:22])[CH:5]=1.S(OC)(O[CH3:29])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([N:8]([CH3:29])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([C:21]([O:23][CH3:24])=[O:22])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1N(C)S(=O)(=O)c1ccc(C)cc1
Yield: 85.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.43 g (10.8 mmol)) in DMF (10.0 ml), 4′-chloro-2′-methoxycarbonyl-p-toluenesulfonanilide (3.33 g (9.80 mmol)) was added under cooling with ice and with stirring. After 15 minutes' stirring under cooling with ice, dimethyl sulfate (1.02 g (10.8 mmol)) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. Then, resulting reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 2.95 g (85%) of 4′-chloro-2′-methoxycarbonyl-N-methyl-p-toluenesulfonanilide as white crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.O>C(OCC)C>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]([C:7]2[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[S:10][CH:11]=2)([OH:23])[CH2:19][CH2:18]1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1csc2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CN1CCC(O)(c2csc3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
13.5 g (0.21 mole) of n-butyllithium in 145 ml of absolute diethyl ether is precooled to -70° to -80°. To this solution there is then added dropwise within 30 minutes, at a temperature of -70°, a solution of 42.6 g of 3-bromobenzo[b]thiophene in 250 ml of absolute diethyl ether. The solution is thereupon stirred for a further 30 minutes at -70°. An addition is then made dropwise, in the course of 30 minutes, of a solution of 23.5 g of 1-methyl-4-piperidone in 100 ml of absolute diethyl ether; the reaction temperature is held by external cooling at -70°, and the reaction solution is subsequently stirred for a further 10 hours at -70°. The reaction solution is thereupon heated to -5°, and 300 ml of water is added dropwise. The organic phase is separated, and the aqueous phase is extracted twice with 400 ml of ethyl acetate. The organic phases are combined, dried with sodium sulphate, filtered off with suction and concentrated by evaporation. The residue is dissolved in 500 ml of 2N hydrochloric acid, and the acid solution is washed with ether. The aqueous solution is then adjusted be addition by 10% sodium hydroxide solution to have a pH-value of 12, and extracted with one litre of chloroform. The chloroform solution is dried with sodium sulphate, filtered off with suction and concentrated by evaporation to obtain crude 1-methyl-4-(benzo[b]thien-3-yl)-4-piperidinol. The free base melts at 150°-151° after recrystallisation from acetone.
Reaction SMILES: CS[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[OH:8][S:9]([O-:12])(=O)=O.[K+].[CH3:14]O>O>[CH3:14][S:9]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])(=[O:12])=[O:8]
Reactant: CSCCCCO
Reactant: O=S(=O)([O-])O
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
4-(Methylthio)butan-1-ol (721 mg, 6.0 mmol) was dissolved in methanol (15 mL) and cooled to 0° C. in an ice bath. 2KHSO5.KHSO4.K2SO4 (4057 mg, 6.60 mmol), dissolved in water (15 mL), was added dropwise over a 10 minute period. Upon completion of addition, the reaction mixture was removed from the ice bath and warmed to room temperature and stirred for one hour. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (50 mL). The aqueous layer was concentrated to dryness, and the residue was diluted with dichloromethane, stirred 30 minutes and filtered. The filtrate was concentrated to give the title compound as a clear oil (825 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH3:19][O:20][C:21]1[C:26]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:3]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: COc1ncccc1B(O)O
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1ncccc1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-methoxypyridin-3-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 337.0 (M+H)+, retention time 1.24 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]([NH2:16])=O.C([O-])(O)=O.[Na+]>>[N+:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[NH:16][CH:14]=[N:1]2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: NC=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Temperature: 150 °C
Yield: 70.4 %

Procedure:
A mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 27.5 mmol) and formamide (8.0 ml, 201.5 mmol) in a microwave reaction vessel was heated in a microwave reactor at 150° C. for 1 hr. The slurry was cooled to rt, stirred with aq. NaHCO3, filtered, washed with water followed by ether and dried in vacuum oven to provide 3.7 g of 7-nitroquinazolin-4(3H)-one (Compound 98-1).
Reaction SMILES: [N:1]1([C:10]2[O:11][C:12]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([C:10]2[O:11][C:12]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A mixture of methyl 3-{2-(1H-benzimidazol-1-yl)-4-[4-(trifluoromethyl)phenyl]-5-oxazolyl}propionate (1.00 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, dried and recrystallized from tetrahydrofuran-ethanol to give 3-{2-(1H-benzimidazol-1-yl)-4-[4-(trifluoromethyl)phenyl]-5-oxazolyl}propionic acid (1.00 g, yield 83%) as pale-yellow prism crystals. melting point: 224–226° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)=[CH:8][CH:9]=1
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Reactant: c1ccc2cnccc2c1
Product: [Br-]
Product: c1ccc(-c2ccc(CCCCC[n+]3ccc4ccccc4c3)cc2)cc1
Temperature: 65 °C
Yield: 61 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (322 mg, 1.06 mmol) and isoquinoline (1 mL) was heated at 60-70° C. for 12 hrs. The resulted mixture was washed with diethyl ether and then dissolved in water (30 mL). The aqueous solution was extracted with ethyl acetate (30 mL×5). Water was removed by lyophilization to afford 278 mg of the title compound. Yield: 61%. 1H NMR (300 MHz, CDCl3) δ 1.47 (m, 2H), 1.70 (m, 2H), 2.17 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 5.07 (t, J=7.5 Hz, 2H), 7.14-7.55 (m, 9H), 7.86 (m, 1H), 8.05 (m, 2H), 8.33 (d, J=6.9 Hz, 1H), 8.70 (d, J=8.1 Hz, 1H), 8.79 (dd, J=6.9, 0.6 Hz, 1H), 10.93 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 25.7, 30.7, 31.7, 35.2, 61.5, 126.3, 126.8, 126.9, 127.0, 127.7, 128.7, 128.8, 131.15, 131.22, 134.4, 136.9, 137.2, 138.5, 140.8, 141.0, 150.1 ppm.
Reaction SMILES: [O:1]=[O+][O-].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]([OH:16])[CH2:13][CH:14]=C)[CH:5]=1>CO>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][OH:1])[CH:5]=1
Reactant: C=CCC(O)CCc1cccnc1
Reactant: O=[O+][O-]
Solvent: CO
Product: OCCC(O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of ozone in air was passed through a solution of (±)-6-(3-pyridyl)-hex-1-en-4-ol (1.38 g) in methanol (70 ml) at 0° C. for 2 hours. The solution was flushed with nitrogen for 1 hour then sodium borohydride (2 g) was added portionwise. The mixture was stirred at room temperature for 20 hours and then concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with methanol:dichloromethane (1:19) and the required fractions concentrated under reduced pressure. Ethyl acetate (25 ml) and aqueous potassium tartrate solution (1 M, 25 ml) were added to the residue and the mixture stirred rapidly for 2 hours. The phases were separated and the aqueous phase extracted with ethyl acetate (10×25 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as an oil (1.20 g).