Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]Cl>C(O)C>[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)o1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(CCN(C)C)CC4)CO6)cc3)c(C)c2)o1
Yield: 13.1 %

Procedure:
A stirred solution of 5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E17 in WO 96/19477, 500 mg, 0.99 mmole) in ethanol (40 ml) was treated with sodium carbonate (419 mg, 3.9 mmole) and 2-dimethylaminoethyl chloride hydrochloride (287 mg, 1.98 mmole) and heated under reflux for 48 hours. The reaction mixture was concentrated in vacuo and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 0-8% methanol/chloroform to afford the title compound as a yellow/beige solid (75 mg, 13%). This was converted to its hydrochloride salt and crystallised from acetone/ether m.p. 246-248° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13]C=CN=1)=O.CO>C(Cl)Cl>[CH:3]1([CH2:4][CH2:5][CH2:6][NH2:1])[CH2:2][CH2:7][CH2:9][CH2:14][CH2:13]1
Reactant: O=C(c1ccccn1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: NCCCC1CCCCC1
Yield: 335.5 %

Procedure:
Prepared as above from 464.9 mg (1.11 mmol) of the pyridyl ketone and 1.00 g (2.21 mmol) of the Wittig salt. Flash chromatography with 15% MeOH--CH2Cl2 afforded 526.0 mg (92%) of the product (E/Z=~4:1 by 1H NMR): 1H NMR (DMSO) δ8.66 (s, 1H), 8.52(m, 1H), 8.40 (dd, J=4.5, 1.1 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.47 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 6.20 (t, J=7.4 Hz, 1H), 3.57 (br t, J=4.4 Hz, 4H), 3.28 (br dt, J=~6.2, 5.8 Hz, 2H), 2.30 (br s, 6H), 2.02 (m, 4H), 1.63 (br t, J=6.6 Hz, 2H), 1.40 (m, 4H); FDMS 519 (M+1). 97.5% pure by HPLC.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[CH3:6][C:7]([O:10][C:11]([NH:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:12])([CH3:9])[CH3:8].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[N:2]1([C:16](=[O:17])[CH2:15][CH2:14][NH:13][C:11](=[O:12])[O:10][C:7]([CH3:6])([CH3:8])[CH3:9])[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
After adding azetidine hydrochloride (2.96 g) to a solution of triethylamine (4.42 ml) in N,N-dimethylformamide, the mixture was stirred for 10 minutes at room temperature. Boc-beta-ALA-OH (5.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.59 g) and 1-hydroxybenzotriazole (5.35 g) were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated under reduced pressure to provide the title compound (5.99 g, 99.4%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH2:10][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[N:4][O:5][C:6]=1[CH2:7][OH:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[C:3]([O:9][CH2:10][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[N:4][O:5][C:6]=1[CH:7]=[O:8]
Reactant: C[C@@H](COc1noc(CO)c1F)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: C[C@@H](COc1noc(C=O)c1F)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of tert-butyl [(1S)-2-{[4-fluoro-5-(hydroxymethyl)isoxazol-3-yl]oxy}-1-methylethyl]carbamate (164 mg), Dess-Martin periodinane (288 mg) and acetonitrile (3 mL) was stirred at 0° C. for 1 hr, and then at room temperature for 30 min. To the reaction mixture was further added Dess-Martin periodinane (288 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (155 mg).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.C[O:32][C:33]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]([O:46]C)=[C:38]2[C:34]=1[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:61]=[CH:60][C:56]([C:57]([OH:59])=[O:58])=[CH:55][CH:54]=1)[CH2:37]2>O>[CH3:43][O:42][C:41]1[C:33](=[O:32])[C:34]2[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:54]=[CH:55][C:56]([C:57]([OH:59])=[O:58])=[CH:60][CH:61]=3)[CH2:37][C:38]=2[C:39](=[O:46])[C:40]=1[O:44][CH3:45]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)O)cc1)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)O)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
A water (2.0 ml) solution of CAN (1.27 g, 2.32 mmols) was dropwise added to an acetonitrile (8.0 ml) solution of 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoic acid (400 mg, 0.929 mmols), with cooling with ice, and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate) followed by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (200 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.CN(P(N(C)C)(N(C)C)=O)C.C[Si](Cl)(C)C.[O:26]=[C:27]1[CH:44]=[CH:43][O:42][C:29]2([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH2:28]1.[Cl-].[NH4+]>C1COCC1.[Cu](I)I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:43]2[O:42][C:29]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31][CH2:30]3)[CH2:28][C:27](=[O:26])[CH2:44]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C=CO2
Agent: I[Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)CC(c1ccc(F)cc1)O2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 93.6 %

Procedure:
To an oven-dried flask under argon gas was added copper iodide (1.28 g, 6.73 mmol) followed by anhydrous THF (125 mL). The suspension was cooled to −78° C. prior to the dropwise addition of (4-fluorophenyl)magnesium bromide (33.7 mL of 2 M in diethyl ether, 67.3 mmol). The resulting mixture was stirred at −78° C. for 20 minutes. HMPA (23.4 mL, 135 mmol) was added, and the reaction mixture was allowed to further stir at −78° C. for 30 minutes. In a separate flask, TMSCl (17.1 mL, 135 mmol) was slowly added to a solution of tert-butyl 8-oxo-11-oxa-3-azaspiro[5.5]undec-9-ene-3-carboxylate (3.00 g, 11.2 mmol) in THF (10 mL). This solution was then slowly transferred to the reaction mixture at −78° C. The resulting thick opaque white mixture was then allowed to slowly warm to room temperature and stirred overnight. To the obtained grey reaction mixture was added a saturated ammonium chloride (75 mL). The mixture was allowed to stir at room temperature for 5 minutes, and volatiles were removed under reduced pressure. To the remaining ⅓ volume was mixed with ethyl acetate (100 mL) and water (25 mL). The aqueous layer was further extracted with ethyl acetate (2×50 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained yellow oil was purified by column chromatography (20-40% ethyl acetate/hexane) to provide tert-butyl 10-(4-fluorophenyl)-8-oxo-11-oxa-3-azaspiro[5.5]undecane-3-carboxylate (3.81 g). 1H NMR (400 MHz, CDCl3) δ 7.41-7.33 (m, 2H), 7.11-7.03 (m, 2H), 4.83 (dd, J=11.2, 3.1 Hz, 1H), 3.87-3.72 (m, 2H), 3.32 (ddd, J=13.4, 11.5, 3.3 Hz, 1H), 3.09-2.98 (m, 1H), 2.61 (ddd, J=14.0, 3.1, 1.7 Hz, 1H), 2.57-2.47 (m, 2H), 2.39 (dd, J=13.9, 1.8 Hz, 1H), 2.02-1.95 (m, 1H), 1.85 (ddd, J=13.4, 5.8, 3.2 Hz, 1H), 1.68 (ddd, J=13.4, 11.5, 4.8 Hz, 1H), 1.54-1.47 (m, 1H), 1.45 (d, J=6.0 Hz, 9H). ESI-MS m/z calc. 363.18, found 364.0 (M+1)+; Retention time: 1.81 minutes (3 minute run).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:6]
Reactant: C1COCCN1
Reactant: Cc1cccc(C(=O)O)c1Br
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)N2CCOCC2)c1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (2.19 g, 10.18 mmol) in THF (20.37 mL) was treated with N,N′-carbonyldiimidazole (1.98 g, 12.2 mmol). The reaction mixture was stirred at ambient temperature overnight (14 h). Morpholine (3.11 mL, 35.6 mmol) was added in one portion. The resulting solution was stirred for 8 h and then partitioned between EtOAc and water. Organic layer washed with water, dilute HCl, saturated aqueous Na2CO3, water and brine. The solution was then concentrated in vacuo to afford (2-bromo-3-methylphenyl)(morpholino)methanone as a white crystalline solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2)([CH3:3])[CH3:2].[C:18](=O)([O-])[O-:19].[K+].[K+].CI.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]2[O:19][CH3:18])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2cccc(C(C)C)c2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c2cccc(C(C)C)c2n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 700 mg of methyl 8-isopropylquinoline-2-carboxylate. To the resulting solution were added 1.2 g of potassium carbonate and 195 μl of methyl iodide, followed by stirring at 50° C. for one hour. The reaction mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 5% ethyl acetate/n-hexane), whereby 710 mg of the title compound were obtained in the form of a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=O)[CH:18]=[CH:19]N(C)C)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]([NH2:28])=[NH2+:27].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:17]3[CH:18]=[CH:19][N:25]=[C:26]([NH2:28])[N:27]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=[NH2+]
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)nn3ccccc23)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)pyrazolo[1,5-a]pyridine (60 mg, 0.19 mmol), guanidinium hydrochloride (36 mg, 0.38 mmol), and K2CO3 (105 mg, 0.76 mmol) in N,N-dimethylformamide (3 mL) was stirred in a 110° C. oil bath for 8 h. Additional guanidinium hydrochloride (36 mg, 0.38 mmol) was added, and the mixture stirred in a 110° C. oil bath for 16 h. The mixture was cooled to room temperature, and water (20 mL) added. The resulting tan precipitate was collected by filtration, washed with water, air-dried, the dried under high-vacuum to afford the title compound, 0.033 g (57%). 1H NMR (CDCl3) δ 8.57 (d, 1H, J=6.0 Hz), 8.51 (d, 1H, J=8.9 Hz), 7.98 (d, 2H, J=5.7 Hz), 7.64 (m, 2H), 7.46 (m, 1H), 7.22 (m, 2H), 7.04 (m, 1H), 6.47 (d, 1H, J=5.8 Hz), 5.76 (s. 2H). MS (+ve ion electrospray) 306 (100), (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]=[O:27])=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1)[S:6]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])(=[O:8])=[O:7]
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCC=O)cc2)c(C)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(O)cc2Cl)c2ccc(CCCO)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
To a solution of N-(2-chloro-4-hydroxy-benzyl)-2,4,6-trimethyl-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide (0.036 g, 0.08 mmol) in 0.2 mL methanol and 0.2 mL methylene chloride was added sodium borohydride (0.014 g, 0.38 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the aqueous solution was washed with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (40% ethyl acetate/hexanes) afforded 0.018 g of N-(2-chloro-4-hydroxy-benzyl)-N-[4-(3-hydroxy-propyl)-phenyl]-2,4,6-trimethyl-benzenesulfonamide. MS 474.0 (M+1)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH2:9][CH2:8][CH2:7][C:6](=[O:24])[C:5]2=3)[CH:14]=1.FC(F)(F)C(O)=O.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C(OCC)(=O)C.C(#N)C.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:11]3[C:10]3[C:5]2=[C:6]([OH:24])[CH:7]=[CH:8][CH:9]=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(n3C(c3ccccc3)CO2)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cc2c3c(c1)c1c(O)cccc1n3C(c1ccccc1)CO2
Temperature: 90 °C
Yield: 14.5 %

Procedure:
To 5-methyl-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (9.0 g, 28.4 mmol) in ethyl acetate/acetonitrile (150 mL/50 mL) is added trifluoroacetic acid (4 mL) and anhydrous cupric chloride (9.7 g, 56.7 mmol). The mixture is heated to reflux at 90° C. for 7 h. The mixture is poured into methylene chloride (500 mL) and filtered to remove inorganic solids. The filtrates are washed with saturated potassium carbonate solution followed by water, dried over magnesium sulfate and concentrated. The residue is dissolved in DMF (20 mL) to which is added lithium bromide (4.2 g, 56.7 mmol) and lithium carbonate (4.9 g, 56.7 mmol). The mixture is heated at 119° C. for 5 h, then partitioned between water and CH2Cl2. The organic layer is washed twice with brine (30 mL). Column chromatography (200 g silica gel) using EtOAc/hexanes (20/80) as eluent gave 1.3 g (14.5%) of 5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol.
Reaction SMILES: COC(=O)C1C=C(O)C=CC=1CCC.[CH3:15][O:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][C:19]=1[CH3:26]>>[CH3:15][O:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[CH3:26]
Reactant: COC(=O)c1ccc(OC)cc1C
Agent: CCCc1ccc(O)cc1C(=O)OC
Product: COC(=O)c1ccc(O)cc1C
Yield: 77 %

Procedure:
The title compound (77%) is prepared essentially according to the preparation of 5-hydroxy-2-propyl-benzoic acid methyl ester using 4-methoxy-2-methyl-benzoic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.91-7.86 (m, 1H), 6.72-6.67 (m, 2H), 3.86 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[C:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30](O)=[O:31])(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])=[O:15])=[CH:11][CH:12]=1)=[O:31])(=[O:27])[CH3:26]
Reactant: CC(=O)c1cccc(C)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: CC(=O)c1cccc(C)c1C(=O)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Yield: 38 %

Procedure:
N-[(2-Acetyl-6-methylphenyl)carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine was prepared in 38% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-acetyl-6-methylbenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 547.0579. Calcd. mass, 547.0594 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(Br)c2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(C2=CCOCC2)c1
Yield: 89.6 %

Procedure:
A mixture of 4-(3-bromophenyl)tetrahydro-2H-pyran-4-ol (11.17 g, 41.3 mmol) and p-toluenesulfonic acid monohydrate (0.797 g, 4.13 mmol) in toluene (100 mL) is heated to reflux for 30 minutes using a Dean-Stark trap to remove water. The reaction is diluted with water and 5 N NaOH and extracted with EtOAc. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure to afford a residue that is purified on silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (8.85 g, 90%). 1H NMR (400 MHz, CDCl3) δ 2.45-2.50 (m, 2H), 3.92 (t, 2H, J=5.71 Hz), 4.31 (q, 2H, J=3.07 Hz, J=5.71 Hz), 6.12-6.14 (m, 1H), 7.19 (t, 1H, J=7.91 Hz), 7.28-7.32 (m, 1H), 7.36-7.39 (m, 1H), 7.51 (t, 1H, J=1.76 Hz).
Reaction SMILES: N1N=C(C2C=CC=CC=2C([N:14]2[CH2:18][CH:17]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]3[CH2:15]2)=O)NC=1.[CH3:29][C:30]1[N:34]=[C:33]([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37]([OH:39])=O)[O:32][N:31]=1.N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[CH3:29][C:30]1[N:34]=[C:33]([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37]([N:14]2[CH2:18][CH:17]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]3[CH2:15]2)=[O:39])[O:32][N:31]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1noc(-c2ccccc2C(=O)N2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 59 substituting 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated for O21H26N4O4, 398.20; m/z found, 399.2. 1H NMR (500 MHz, CDCl3): 8.12 (d, J=7.8 Hz, 1H), 7.63 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.55 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 3.97-3.86 (m, 1H), 3.76-3.61 (m, 2H), 3.56-3.33 (m, 3H), 3.29-3.15 (m, 1H), 3.08-2.93 (m, 2H), 2.90-2.82 (m, 1H), 2.45 (s, 3H), 1.51-1.41 (m, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccno3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([O:14]C)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>CC(O)=O.O>[CH2:1]([C:8]1[NH:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccnc(Cc2ccccc2)n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccnc(Cc2ccccc2)[nH]1
Temperature: 95 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 2-benzyl-4-methoxypyrimidine (0.675 g, 3.37 mmol) in AcOH (15 mL) was added HBr (2.28 mL, 20.2 mmol; 48 wt % in H2O). The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with H2O. The pH of the reaction mixture was adjusted to 5-6 with 6 M aqueous NaOH and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude yellow solid. Purification of the crude product was achieved by trituration with dichloromethane and diethyl ether. The resulting solid was filtered, washed with diethyl ether, collected and dried under vacuum to yield the desired product (0.531 g, 85%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=6.6 Hz, 1H), 7.31 (m, 4H), 7.23 (m, 1H), 6.10 (d, J=6.6 Hz, 1H), 3.83 (s, 2H). LRMS (ESI pos) m/e 187 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]([CH2:16]Cl)=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH2:16][C:14]([Cl:13])=[CH2:15])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: C=C(Cl)CCl
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cl)COc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrophenol (20.3 g) and 2,3-dichloropropene (11.7 g) was dissolved in N,N-dimethylformamide (200 ml), and potassium carbonate (14.6 g) was added thereto at room temperature, and the resultant mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gelchromatography (eluent: hexane/ethyl acetate=4/1) to give 4-chloro-5-(2-chloro-2-propenyloxy)2-fluoronitrobenzene (14.8 g; yield, 53%).