Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 88.1 %

Procedure:
To a solution of acid 1-6 (0.88 g, 3.5 mmol) in DMF (8 mL) was added K2CO3 (1.44 g, 10 mmol) followed by iodomethane (0.43 mL, 6.95 mmol). The reaction was heated to 60° C. for 17 h then DMF was removed under reduced pressure to give an orange gum. H2O (20 mL) was added and the solution was acidified to pH 1 with a 10% HCl solution. The aqueous solution was then extracted with EtOAc (30 mL) and washed with H2O and brine. After drying over Na2SO4 the reaction was filtered and concentrated to afford 1-7 as an orange gum (0.82 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 31-1), 7.69 (s, 1H), 10.85 (br s, 1H).
Reaction SMILES: CI.[CH3:3][C:4]1[N:8]=[C:7]([CH2:9][C:10](=[O:12])[CH3:11])[O:6][N:5]=1.[C:13](=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CCCCCCC>[CH3:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:13])[C:10](=[O:12])[CH3:11])[O:6][N:5]=1
Reactant: CC(=O)Cc1nc(C)no1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CI
Product: CC(=O)C(C)c1nc(C)no1
Temperature: 20 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
Methyl iodide (0.375 ml, 6 mmol) was added to a mixture of 1-(3-methyl-[1,2,4]oxadiazol-5-yl)-propan-2-one (0.84 g, 6 mmol) and potassium carbonate (4.15 g, 30 mmol) in acetoniotrile (8 mL), and the mixture was stirred at 20° C. for 12 h. Insoluble material was filtered off and the filtrate was diluted with dichloromethane. The solution was washed with 1 N hydrochloric acid and with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual oil was subjected to column chromatography on silica gel. Heptane/0-20% ethyl acetate eluted successively the title compound 3-methyl-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (181 mg, 18%), obtained as colorless oil, Rf 0.4 (SiO2, ethyl acetate/heptane 1:1), MS ISP (m/e): 169.1 [(M+H)+]; 3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (296 mg, 3 2%), obtained as colorless oil, Rf 0.2 (SiO2, ethyl acetate/heptane 1:1), MS ISP (m/e): 155.1 [(M+H)+]; and 3-hydroxy-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (204 mg, 20%), obtained as colorless oil, Rf 0.1 (SiO2, ethyl acetate/heptane 1:1),
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[O:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=2)[CH:14]=1>C(C#N)(C)=O.O=[Mn]=O>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][O:7][C:8](=[O:23])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[O:17][C:18]([CH:21]=[O:22])=[CH:19][CH:20]=2)[CH:14]=1
Reactant: O=C(Nc1cnn(Cc2ccc(CO)o2)c1)OCc1ccccc1Cl
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: O=Cc1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(5-hydroxymethyl-furan-2-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (300 mg, 0.83 mmol) in AcCN (8.0 mL) was treated at rt with MnO2 (400 mg, 4.15 mmol). The reaction mixture was stirred at rt overnight before being filtered through Celite and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.90 min; [M+H]+=360.28. 1H NMR (400 MHz, CDCl3) δ 5.32 (s, 5H), 6.47 (s, 1H), 6.64 (s, 1H), 7.20 (s, 1H), 7.30 (s, 1H), 7.37-7.45 (m, 1H), 7.45 (s, 2H), 7.79 (s, 1H), 9.63 (s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2.IC1C=C2C(=CC=1)[NH:24][CH:23]=C2>>[C:23]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2)#[N:24]
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1

Procedure:
When the product of Step B was substituted for 5-iodoindole in Example 7, Step A, the similar process afforded the title compound in 85%, as colourless solid, after purification by FCC (SiO2; CH2Cl2). 1H-NMR (CDCl3) 1.49 (s, 9H); 4.56-4.72 (m, 4H); 7.32-7.37 (m, 1H); 7.49-7.56 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16].[OH-].[K+].O>CC1CCCCC1.CCOC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH:16]=[CH:6][C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc[nH]1
Reactant: CC(=O)c1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccc[nH]1)c1ccccc1Br
Temperature: 45 °C
Yield: 75 %

Procedure:
A mixture of 20.0 g of (0.21 moles) 2-pyrrolecarboxaldehyde, 71.4 mL of (0.52 moles) o-bromoacetophenone, 72 mL of 1N potassium hydroxide and 800 mL of water was placed in a flask under nitrogen and heated to 45° C. for 72 hr. The reaction was cooled in an ice bath until a solid formed. The solid was taken up in methylcyclohexane/EtOAc, dried over 4A sieves and allowed to cool. The resulting solid was recrystallized from methylcyclohexane/EtOAc to give 43.5 g of 1-(2-bromophenyl)-3-(1H-pyrrol-2-yl)-2-propen-1-one as a yellow solid (75%), mp 76°-78° C.
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]#[N:15]>C(Cl)(Cl)(Cl)Cl>[NH2:3][C:4]1[C:5]([C:14]#[N:15])=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[Cl:1]
Reactant: ClCl
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(C(F)(F)F)cc(Cl)c1N

Procedure:
Chlorine gas was passed through a stirred solution of 4-amino-3-cyanotrifluoromethyl-benzene (5 g) in carbon tetrachloride (75 ml) until the absence of starting material was confirmed by gas liquid chromatography. Flow of the gas was then stopped and evaporation of the solvent under reduced pressure gave 4-amino-3-chloro-5-cyano-trifluoromethyl benzene as an orange solid (5.5 g).
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3].C(N(CC)CC)C.[CH2:40]([NH:43][CH2:44][CH2:45][CH3:46])[CH2:41][CH3:42]>CN(C)C=O.C(OC(=O)C)C>[N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([N:43]([CH2:44][CH2:45][CH3:46])[CH2:40][CH2:41][CH3:42])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[N+:2]=[N-:3]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Reactant: CCCNCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CCC)C1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl 6-azido-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (0.1 mmol) in anhydrous dimethylformamide (1 ml) is cooled in an ice-bath and stirred while triethylamine (0.2 mmol) and dipropylamine (0.12 mmol) are added. The resulting solution is allowed to warm to room temperature and kept there overnight. The solution is diluted with ethylacetate, washed with water, pH 3 phosphate buffer, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to afford benzyl 6-azido-3-dipropylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O.N>C(OCC)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:20][CH:19]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC/C=C/c1ccc(Br)cc1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc(/C=C/CO)cc1
Temperature: 155 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A mixture of 4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one (1.10 g, 5.0 mmol), (2E)-3-(4-bromophenyl)-2-propen-1-ol (1.28 g, 6 mmol), cuprous iodide (476 mg, 3 mmol), potassium carbonate (829 mg, 6 mmol) and DMF (20 mL) was stirred overnight at 155° C. The reaction liquid was cooled to room temperature, then poured into ammonia water, and ethyl acetate was added for extraction. The organic layer was washed with water and saturated saline, and dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, followed by purification by flash column chromatography (KP-Sil, hexane:ethyl acetate=1:1 to 0:1) to obtain the entitled compound (881 mg).
Reaction SMILES: [CH3:1]CN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:24]1([N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:38][C@H:37]3[C:39]3[CH:47]=[CH:46][C:42]([C:43]([NH2:45])=[O:44])=[CH:41][CH:40]=3)=[O:35])[CH2:30][C@H:29]2[CH3:48])[CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:38][C@H:37]3[C:39]3[CH:40]=[CH:41][C:42]([C:43]([NH2:45])=[O:44])=[CH:46][CH:47]=3)=[O:35])[CH2:30][C:29]2([CH3:1])[CH3:48])[CH2:25][CH2:26][CH2:27]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1CN(C(=O)[C@@H]2C[C@H]2c2ccc(C(N)=O)cc2)CCN1C1CCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)CN(C(=O)[C@@H]2C[C@H]2c2ccc(C(N)=O)cc2)CCN1C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
Intermediate 14 (282 mg, 1.38 mmol) was dissolved in DMF (15 mL). DIPEA (1.201 mL, 6.88 mmol) was added, followed by HOBT (279 mg, 2.06 mmol), EDC (395 mg, 2.06 mmol) and Intermediate 2 (278 mg, 1.65 mmol). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure. The residue was redissolved in DCM, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure to give 632 mg of crude as an orange oil. The crude material was purified on preparative HPLC UV using the long high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 30 min run) on XBridge Prep C18 OBD, 50×250 mm, 10μ, Waters reverse phase column, providing 151 mg title compound (30.9%) as a solid (enantiomeric mixture). 1H NMR (400 MHz, CD3OD) δ ppm 1.01 (s, 2H) 1.08 (s, 4H) 1.34-1.43 (m, 1H) 1.55-1.70 (m, 4H) 1.96-2.12 (m, 5H) 2.25-2.37 (m, 1H) 2.40-2.48 (m, 1H) 2.61 (br. s., 2H) 3.45 (br. s., 2H) 3.75 (br. s., 1H) 7.26 (dd, J=8.20, 5.08 Hz, 2H) 7.80 (dd, J=8.40, 2.93 Hz, 2H); HRMS m/z calcd for C21H30N3O2 356.23325 [M+H]+, found 356.23286.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N.CO>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Methylbenzenesulfonyl chloride (19 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (4.9 mg). MS m/z 343 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][CH3:35])[C:11](=[CH2:33])[C:12](NCC2C=CN=C(C3C=CC(OC(F)(F)F)=CC=3)C=2)=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:47]1([C:52]2[CH:57]=[C:56]([CH2:58][NH2:59])[CH:55]=[C:54]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=3)[N:53]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:34][CH3:35])[C:11](=[CH2:33])[C:12]([NH:59][CH2:58][C:56]2[CH:55]=[C:54]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:67])[F:68])=[CH:62][CH:61]=3)[N:53]=[C:52]([N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[CH:57]=2)=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Reactant: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)N(CC)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Acid 7 (295.76 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (1.1 equiv., 353.47 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded 150 mg of a pale yellow solid. Yield=25% 1HNMR (DMSO, 200 MHz) δ 1.07 (3H, t), 1.94 (4H, m), 3.41 (6H, m), 4.37 (2H, d), 5.39 (1H, s), 6.21 (1H, s), 6.31 (1H, s), 7.20 (1H, s), 7.34 (1H, d, J=4.2 Hz), 7.57 (1H, d, J=4 Hz), 7.91 (2H, d), 8.48 (2H, d), 8.75 (1H, bt) [M+1] 599.9 (C26H26ClF3N4O3S2 requires 599.09).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>CCO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:23][C:22]3[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Solvent: CCO
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccc(N(C)C)cc1
Temperature: 25 °C

Procedure:
A slurry composed of 1-(4-carboxyphenyl)-3-methyl-2-pyrazolin-5-one (21.8 gm, 0.10 mol), 4-dimethylaminobenzaldehyde (14.9 gm, 0.10 mol) and EtOH (250 ml) was heated at reflux for two hours. The reaction mixture was cooled to RT resulting in a crude orange product which was isolated by filtration. The product was then washed with ether and dried. The product was purified further by making a slurry of the solid in EtOH (700 ml) at refluxing temperature and filtering the slurry to recover the dye. The treatment was repeated. The mp of the product was above 310° C. The NMR and IR spectra were consistent with the structure assigned. The C,H, and N elemental analyses were in agreement with those calculated for the empirical formula.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24](C)[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24]([C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Solvent: Cc1ccccc1
Product: O=C(C1CC1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 3.7 g (0.011 mol) of (-)-3-phenoxy-N-methylmorphinan in 50 ml of toluene, 5.8 g of cyclopropane carboxylic acid chloride in 25 ml of toluene was added dropwise at 5°. The mixture was allowed to warm to room temperature and was then refluxed for 15 hours. The solvent was removed in vacuo and the residue partitioned between ether and dilute hydrochloric acid. The ether solution was washed with water and dried. Removal of the solvent in vacuo afforded 4.2 g (99%) of (-)-3-phenoxy-N-cyclopropylcarbonylmorphinan. For analysis, a sample of this compound was distilled, bp 230°-240°/0.05 mmHg, [α]25D-173.45° (c 0.99, MeOH).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ncccc1CCl
Reaction time: 2 h
Yield: 47 %

Procedure:
Prepared essentially according to the procedure of I. M. Bell et al., J. Med. Chem. 41, 2146–2163 (1998). To a stirred solution of the 3-hydroxymethyl-2-methyl-pyridine of Step A (2.5 g, 20.3 mmol) in dichloromethane (100 mL) was added thionyl chloride (15 mL, 206 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was repeatedly extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.35 g of the title compound as an orange oil which was immediately used in the next step.
Reaction SMILES: ClCCCl.[Br:5]CC1C=C2C(=CC=1)N=CC=N2.[CH3:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[N:20]=[CH:21][CH:22]=[N:23]2.BrN1C(=O)CCC1=O>C(O)(=O)C.C(Cl)Cl>[Br:5][CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[N:20]=[CH:21][CH:22]=[N:23]2
Reactant: BrCc1ccc2nccnc2c1
Reactant: Cc1cccc2nccnc12
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: BrCc1cccc2nccnc12

Procedure:
In polar solvents, such as 1,2-dichloroethane, a good yield of 6-(bromomethyl)-quinoxaline was observed and consequently other hydrochlorocarbons (for example, methylene chloride) would be expected to be good as well. However, these solvents are less preferred due to their high toxicity and volatility. In other polar solvents, such as acetic acid, 5-(methyl)-quinoxaline reacted with N-bromosuccinimide almost quantitatively to give 5-(bromomethyl)-quinoxaline. However, the 6-isomer reacted to give 6-(bromomethyl)-quinoxaline that quickly decomposed to give a black tar. Therefore, benzylic bromination with N-bromosuccinimide in acetic acid can only apply to one isomer (the 5-isomer) but not to the mixtures of 5- and 6-methylquinoxalines obtained from ortho-toluene diamine. In acetonitrile, the 5-isomer reacted with N-bromosuccinimide to give 5-(bromomethyl)-quinoxaline in a good yield (>90%) but the 6-isomer did not react. Therefore, benzylic bromination with N-bromosuccinimide in acetonitrile can only apply to one isomer (the 5-isomer) but not to the methylquinoxalines mixtures obtained from ortho-toluene diamine. An acceptable yield was obtained for the benzylic chlorination of 6-methyl-quinoxaline using N-chlorosuccinimide in acetonitrile (conversion=60% and selectivity=80%) but the reaction was very slow requiring 8 to 12 hours reflux (Example 15).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([O:6][CH2:10][CH2:2][CH2:3][CH3:4])=[O:5]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)O)c(Cl)cc1F
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCOC(=O)c1cc(-n2c(OC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
A suspension of 1.90 g of 2-chloro-4-fluoro-5-[2-methoxy-6 -oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoic acid in 10 ml of benzene and 1.85 g of thionyl chloride is heated for 4 hours while stirring until a solution forms. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in 20 ml of methylene chloride and the solution is treated at room temperature with 5 ml of n-butanol and 0.50 g of pyridine while stirring. The reaction mixture is stirred for 3 hours and evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of ethyl acetate, the solution is washed three times with 50 ml of water each time, the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The resinous residue is purified by chromatography on silica gel using diethyl ether/n-hexane (1:3) as the eluent. There is obtained n-butyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate. 1H-NMR (CDCl3 : 400 MHz): 7.84 ppm (d,1H), 7.40 ppm (d,1H), 6.63 ppm (s,1H), 4.34 ppm (m,2H), 4.02 ppm (s,3H), 1.75 ppm (m,2H), 1.46 ppm (m,2H), 0.97 ppm (t,3H),
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si](C(C)(C)C)(C)C)[C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:21](=O)(O)[O-:22].[Na+]>CO>[OH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:3]([CH2:2][O:22][CH3:21])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])O
Reactant: COC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(O)c1C(=O)OC

Procedure:
A solution of methyl 2-bromomethyl-6-(tert-butyldimethylsilyloxy)benzoate (Intermediate 12, 4.26 g) in methanol (63 mL) was stirred and heated at reflux overnight. After cooling, the mixture was basified by addition of solid sodium bicarbonate and then evaporated to dryness. The residue was triturated with DCM and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give methyl 2-hydroxy-6-methoxymethylbenzoate (1.46 g) as a white crystalline solid.