Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][CH2:14][CH:13]([NH:18][C:19]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:25])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CCCO)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Methanesulfonyl chloride (0.511 mL, 6.60 mmol) was added dropwise to tert-butyl 1-(4-chlorophenyl)-4-hydroxybutylcarbamate (Intermediate 55) (1.80 g, 6.00 mmol) and triethylamine (1.004 mL, 7.20 mmol) in DCM (30.0 mL) at 25° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was evaporated to dryness and the residue was suspended in DCM, filtered and the filtrate purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(tert-butoxycarbonylamino)-4-(4-chlorophenyl)butyl methanesulfonate (2.270 g, 100%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:30]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Reactant: COCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc(C2CCN(CCc3ccc(OC)c(S(N)(=O)=O)c3)CC2)oc1-c1ccc(F)cc1
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of 4-[5-(4-fluoro-phenyl)-4-methoxymethyl-oxazol-2-yl]-piperidine (0.3 g; 1.03 mmol) in dry dioxane (7 ml) is treated with 5-(2-chloroethyl)-2-methoxy-benzenesulfonamide (0.52 g; 2.06 mmol), sodium iodide (0.31 g; 2.06 mmol) and diisopropylethylamine (0.72 ml; 4.12 mmol) and heated to 100 C. for 16 hours. The reaction mixture is partitioned between ethyl acetate (50 ml) and dilute sodium bicarbonate (20 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol/ethyl acetate gradient (5%-20%) is followed by a second chromatography using a methanol/dichloromethane gradient (5%-15%). Crystallization from dichloromethane/ethyl acetate afforded the product as a white solid (0.20 g; 40%). HNMR (CDCl3): 7.72 (d, 1H, J=2.1 Hz), 7.62 (m, 2H), 7.35 (dd, 1H, J=8.6; 2.1 Hz), 7.13 (t, 21H, J=8.6 Hz), 6.96 (d, 1H, J=8.6 Hz), 5.64 (broad s, 2H), 4.44 (s, 2H), 3.97 (s, 3H), 3.44 (s, 3H), 2.96 (m, 2H), 2.80 (m, 1H), 2.75 (m, 2H), 2.53 (m, 2H), 2.10 (m, 4H), 1.90 (m, 2H). Mass spectrum: m/e calculated (MH+)=504; observed (MH+)=504.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[Cl-].C[Zn+].[CH3:28]COC(C)=O.O>C1COCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[CH3:28]
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg) and Pd(PPh3)4 (15 mg) in THF (1.0 ml), was added a solution of methylzinc chloride in THF (2.0M, 0.75 ml). The mixture was stirred at 25° C. for 7.5 hours and then heated at 60° C. for 1.5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was crystallized form MeOH-IPE and dried in vacuo to give 5-(5-amino-6-methyl-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (95 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[CH:32][CH:31]=4)([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:42])=[N:3]1.[OH-].[Na+].C(O)(=O)C>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=4)([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:42])=[N:3]1
Reactant: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(CCC(=O)O)cc4)c3)c2)n(C)n1
Yield: 70.8 %

Procedure:
A solution of Methyl 3-{4-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}propanoate (0.075 g, 0.129 mmol) in THF (3 mL) was cooled to 0° C. and slowly treated with 0.5M NaOH (1.29 mL, 0.643 mmol). The reaction mixture was allowed to slowly come to room temperature. Once the reaction was done by TLC, the reaction was acidified with acetic acid and then extracted with EtOAc (20 mL) and H2O (20 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered, and concentrated to give the title compound (0.052 g, 71%)
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:15][CH:14]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C[N:26](C=O)C>>[C:5]([O:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([NH2:26])=[O:24])=[CH:15][CH:14]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccc(CCCC(N)=O)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Thionyl chloride (0.22 mL, 3.01 mmol) was added slowly to a solution of 4-[4-(t-Butoxycarbonylamino)phenyl]butanoic acid (100) (0.70 g, 2.51 mmol) in DMF (5 mL) cooled at −5° C. The mixture was stirred for an additional 1 h at −5° C. Excess ammonia (freshly distilled from its aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 h. Ethyl acetate (50 mL) was added to the mixture, which was washed with brine (2×50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified by silica gel column chromatography (dichloromethane:acetone, 9:1) to give 4-[4-(t-Butoxycarbonylamino)phenyl]butanamide (99) (0.57 g, 82%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[Cl:10].CC1(C)C(C)(C)OB([C:19]2[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])O1.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1(C)C(C)(C)OB(C2C=CC=CC=2C(OCC)=O)O1>[Cl:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccc(OC)cc1Cl
Temperature: 120 °C
Reaction time: 7 h
Yield: 116.4 %

Procedure:
Under an argon atmosphere, 1-bromo-2-chloro-4-methoxybenzene (44.3 g) was dissolved in toluene (220 ml), ethyl 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoate (60.8 g), water (132 ml), sodium hydrogen carbonate (33.6 g) and dichlorobis(triphenylphosphine)palladium(II) (2.8 g) were added, and the mixture was stirred at an oil bath temperature of 120° C. for 7 hr. To the reaction mixture was added ethyl 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoate (5.2 g), and the mixture was further stirred for 2 hr. The reaction mixture was cooled to room temperature, toluene (100 ml) and water (200 ml) were added, and the mixture was stirred overnight. To the reaction mixture was added activated carbon (3 g), and the mixture was further stirred for 1 hr. The insoluble material was filtered off through celite, and the insoluble material was washed with toluene (100 ml) and water (200 ml). The obtained filtrates were combined to allow for layer separation. The obtained organic layer was washed with water (100 ml), and the solvent was evaporated to give the title compound (67.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:19]3[CH2:18][O:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Pd]>[CH2:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[C:19]=2[CH2:18][O:17]1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c2COC3)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2cccc3c2COC3)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 4-[(4-nitrophenyl)oxy]-1,3-dihydro-2-benzofuran (Intermediate 4, 208 mg), hydrazine hydrate (0.051 ml, 1.618 mmol) and Pd/C (172 mg, 0.162 mmol) in ethanol (6 ml) was stirred under argon at 90° C. After 1.5 hour the mixture was cooled to room temperature and then filtered over celite. The celite was washed with methanol. The organic phase was concentrated to afford title compound (136 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CO.[Pd]>[F:1][C:2]1[CH:14]=[C:13]([CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[NH2:15]
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-fluoro-4-nitrobenzyl)morpholine (14.80 g, 62 mmol) in MeOH (100 mL) was added Pd/C (4.0 g). The reaction mixture was stirred at rt under H2 overnight and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a claybank solid (11.27 g, 87%).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20](O)=[O:21])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:21])[NH:43][CH2:42][C:41]3[CH:44]=[CH:45][C:38]([F:37])=[CH:39][CH:40]=3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: NCc1ccc(F)cc1
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NCc1ccc(F)cc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 46 %

Procedure:
The title compound (27 mg, 46%) was obtained from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and 4-fluorobenzyl amine as in Example 1, Part C. HPLC: RT=10.66 min. MS (ESI−): mass calcd. for C29H21Cl3FN5O4S2, 693.00; m/z found, 690/692 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.55 (s, 1H), 8.38 (dd, J=7.0, 0.8, 1H), 8.21 (dd, J=8.8, 0.6, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.68 (d, J=1.9, 1H), 7.35-7.32 (m, 1H), 7.30-7.25 (m, 2H), 7.12-7.07 (m, 2H), 7.05-6.99 (m, 5H), 6.94 (dd, J=8.4, 1.9, 1H), 6.88-6.81 (m, 1H), 5.79-5.72 (m, 1H), 4.67-4.59 (m, 1H), 4.47-4.40 (m,1H), 4.29-4.25 (m, 1H), 3.15-3.11 (m, 1H), 3.00-2.96 (m, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][CH:56]=[C:57]2[C:61]=1[NH:60][C:59]([C:62](O)=[O:63])=[CH:58]2)=[O:51])([CH3:48])[CH3:47].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:59]2[NH:60][C:61]3[C:57]([CH:58]=2)=[CH:56][CH:55]=[CH:54][C:53]=3[NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
HATU (0.055 g, 0.145 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.030 g, 0.096 mmol), 7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.026 g, 0.096 mmol) and DIPEA (0.025 mL, 0.145 mmol) in DMF (1 mL). The mixture was stirred at RT overnight then extracted with water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.027 g, 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (s, 1H), 9.32 (s, 1H), 9.07 (t, 1H), 7.81 (s, 1H), 7.67-7.77 (m, 1H), 7.44-7.57 (m, 3H), 7.39 (t, 1H), 7.27 (d, 1H), 7.17 (d, 1H), 6.96 (t, 1H), 4.57 (d, 2H), 1.5 (s, 9H). MS: m/z 569 (M).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][SH:9])[NH2:7])[CH3:3].[Na].Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].P([O-])(O)(O)=O.[Na+]>C(O)C.CS(C)=O>[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH2:8][S:9][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH2:7])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)CCCCSC[C@H](N)C(=O)OCC
Reaction time: 8 h

Procedure:
L-Cysteine ethyl ester hydrochloride (18.6 g; 0.10 mole) was added to a solution of sodium (4.6 g; 0.20 g.a) in ethanol (320 ml, absolute), stirred 15 minutes and then the solvent removed in vacuo. To a solution of the residual sodium salts in dry dimethylsulphoxide (200 ml) was added ethyl 5-bromovalerate (21.0 g; 0.10 mole) in a single portion with stirring. The reaction mixture was allowed to stand at room temperature overnight, warmed on a steam bath for 5 mins. and then poured onto water (300 ml) containing sodium dihydrogen phosphate (1 g). The oil was extracted with ether (3×), the combined extracts washed with water and dried over MgSO4. The solvent was removed in vacuo yielding the product as a pale yellow oil which was used in Example 70.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.C([O:16][CH2:17][C:18]([OH:20])=O)(=O)C.[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31]([NH:33][C:34]3[CH:39]=[C:38]([C:40](=[NH:43])[NH:41]O)[CH:37]=[CH:36][C:35]=3[CH3:44])=[O:32])=[CH:29][N:30]=2)[CH:27]=1.O.[OH-].[Li+]>CN1C(=O)CCC1.C1COCC1.CO.O>[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([C:31]([NH:33][C:34]3[CH:39]=[C:38]([C:40]4[N:41]=[C:18]([CH2:17][OH:16])[O:20][N:43]=4)[CH:37]=[CH:36][C:35]=3[CH3:44])=[O:32])=[CH:29][N:30]=2)[CH:27]=1
Reactant: Cc1ccc(C(=N)NO)cc1NC(=O)c1cnc2ccc(Br)cn12
Reactant: CC(=O)OCC(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)c1cnc2ccc(Br)cn12
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
Carbonyl diimidazole (CDI) (2.3 g, 14.24 mmol) was added to a stirred solution of 2-acetoxyacetic acid (1.68 g, 14.24 mmol) in NMP (10 mL). After 30 minutes, 6-bromo-N-(5-(N-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (50f) (1.38 g, 3.56 mmol) was added in one portion and the resulting solution was stirred for 30 minutes before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was hydrolyzed by lithium hydroxide monohydrate (897 mg, 21.36 mmol) in THF/MeOH/H2O (3:2:1). After removal of all solvents 2M NaHCO3 (10 mL) was added. The precipitate was filtered and dried in air to afford 6-bromo-N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (142). 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 9.64 (d, J=1.2 Hz, 1H), 8.60 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.79 (dd, J=0.8, 9.6 Hz, 1H), 7.67 (dd, J=2.0, 9.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 6.09 (s, 1H), 4.81 (s, 2H), 2.37 (s, 3H). MS m/z 427.9, 429.9 (M+1)+.
Reaction SMILES: [Br-].[NH+]1C=CC=CC=1.C[O:9][C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[CH:11]=1.[O:25]([C:27]#[N:28])[Na].Cl>C1(C)C=CC=CC=1.O>[CH:23]1[CH:22]=[CH:21][C:13]2[N:14]([C:27]([NH2:28])=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10](=[O:9])[CH2:11][C:12]=2[CH:24]=1
Reactant: N#CO[Na]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 89 °C
Yield: 58 %

Procedure:
The carbamoylation reaction was performed as in Example 1. After about 7–8 hours of stirring the carbamoylation reaction mixture (containing pyridinium bromide, 10-methoxy-5H-dibenz[b,f]azepine, water, toluene, and NaOCN) at room temperature (22° C.), the mixture was heated to 55–60° C., and 500 ml of 10% HCl was added drop-wise and carefully. The reaction mixture was warmed to reflux (89° C.) for 3–4 hours, and then worked up and purified as in Example 1. 32.8 g (58% yield) of crude oxcarbazepine was obtained. The crude afforded 24.9 g (44% overall yield) of pure oxcarbazepine.
Reaction SMILES: [CH3:1][CH:2]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:3]([O:5]CC)=O.[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][CH2:24][NH2:25]>>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][CH2:24][NH:25][C:3](=[O:5])[CH:2]([CH3:1])[N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]
Reactant: C[C@@H]1CCC[C@H](C)N1CCCN
Reactant: CCOC(=O)C(C)N1CCCC1=O
Product: CC(C(=O)NCCCN1[C@H](C)CCC[C@@H]1C)N1CCCC1=O

Procedure:
From 9.25 g. of ethyl α-methyl-2-oxo-1-pyrrolidineacetate and 10.5 g. of cis-3-(2,6-dimethyl-1-piperidinyl)propylamine, following the procedure of Example 21, there is obtained cis-(±)-N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-α-methyl-2-oxo-1-pyrrolidineacetamide; b.p. 165°-170° C./0.1 mm.
Reaction SMILES: C([O:8][CH2:9][C:10]1([Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]2[CH:21]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][C:13]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:14][CH:15]=2)C1C=CC=CC=1.C1COCC1>[Pd].CCO>[C:23]([C:20]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:27]([CH3:29])([CH3:30])[CH3:28])=[CH:14][CH:15]=3)[C:10]([Si:31]([CH3:34])([CH3:33])[CH3:32])([CH2:9][OH:8])[C:22]=2[CH:21]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc2c(c1)C(COCc1ccccc1)([Si](C)(C)C)c1cc(C(C)(C)C)ccc1-2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1ccc2c(c1)C(CO)([Si](C)(C)C)c1cc(C(C)(C)C)ccc1-2
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 4.0 g of 2,7-di-tert-butyl-9-trimethylsilyl-9-fluorenylmethyl benzyl ether in 20 mL of freshly distilled THF and 80 mL of 100% EtOH was added 0.8 g of 5% palladium on charcoal. The heterogeneous mixture was shaken under hydrogen at a pressure of 45 psi in a Parr apparatus for 2 hours. The catalyst was removed by filtration and rinsed with ether (2×10 mL). The filtrate was evaporated under reduced pressure to give 3.23 g (100%) of the crude alcohol as a yellow oil which was chromatographed on silica gel (230-400 mesh, 4×45-cm packed column) with an eluant consisting of Skelly B--ether (3:1), to give 3.12 g (96.4%) of the alcohol as a white solid. Recrystallization from Skelly B gave 2.57 g (79.44%) of the pure alcohol as white needles, m.p. 131°-132° C.; IR (KBr): 3545, 3495 cm-1 (OH); 1H NMR (CDCl3): δ -0.18 (s, 9H, SiMe3), 1.20 (b, 1H, OH), 1.39 (s, 18H, t-Bu), 4.50 (s, 2H, CH2), 7.20-7.90 (m, 6H, aryl).
Reaction SMILES: Cl.[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32]CC2C=CC=CC=2)=[C:26]([NH:28][C:29]([NH2:31])=[O:30])[CH:27]=1)[OH:21].CO.C(Cl)(Cl)[Cl:43]>CO.[Pd]>[ClH:43].[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([NH:28][C:29]([NH2:31])=[O:30])[CH:27]=1)[OH:21]
Reactant: NC(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1O

Procedure:
According to the procedures as given in Example 2, the compound of Example 20 (in a solution of 40 mg of the compound in 5.3 ml of methanol) was subjected to a hydrogenolysis using 10% palladium/carbon black (25 mg), whereby the above-identified compound (29.8 mg) was obtained. Rf=0.08 (methanol/chloroform of 1/10).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]O)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][Br:2])=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CCBr)cc1

Procedure:
Phosphorus tribromide (14 g) was added, over 2 minutes, to a solution of 2-(4-fluorophenyl)ethanol (14 g) in carbon tetrachloride (80 ml). The mixture was heated under reflux for 2 hours then cooled in an ice bath. 10% Aqueous sodium carbonate solution was added until all of the solid has dissolved. The mixture was transferred to a separating funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (50 ml) and the organic solutions were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 1:1 hexane/dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil, 10 g.