Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: Cc1ccc2nc(C(=O)CC(=O)C(F)(F)F)sc2c1
Agent: Cl
Product: Cc1ccc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2c1
Yield: 47 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-methylbenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-methyl-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][NH:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:24]([O:26][CH3:27])=[O:25]>N1C=CC=CC=1.C(Cl)Cl>[CH3:27][O:26][C:24]([N:16]1[C:17]2[CH2:18][CH:19]3[N:11]([S:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)(=[O:9])=[O:10])[CH:12]([CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]3)[C:13]=2[CH:14]=[N:15]1)=[O:25]
Reactant: COC(=O)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CNCC1c1cn[nH]c1C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CC2Cc3c(cnn3C(=O)OC)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
12-(4-Chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene (204 mg, 0.602 mmol) was dissolved in pyridine (1 mL) and cooled to 0° C. Methyl chloroformate (0.139 mL, 1.80 mmol) was added over 15 minutes and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (10 mL), washed with aqueous HCl (5 mL, 1 N) and aqueous NaHCO3 (5 mL), dried (Na2SO4), filtered and concentrated under vacuum to give 275 mg of 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-5,10-dicarboxylic acid dimethyl ester as a brown oil. Retention time (min)=1.704, method [1], MS (ESI) 455.1 (M+H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([OH:13])=O)[CH2:3]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([NH2:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[Br:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:48][C:11](=[O:13])[CH2:10][CH:4]2[CH:5]3[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]3)[CH2:3]2)([CH3:46])[CH3:47])=[CH:43][CH:44]=1
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: CC(C)(N)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)CC1CN2CCC1CC2)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To a solution of 2-(quinuclidin-3-yl)acetic acid hydrochloride (0.97 g, 4.7 mmol) in DMF (30 mL) was added HATU (1.79 g, 4.72 mmol), 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7 mmol), and triethylamine (3.9 mL, 28 mmol). The resulting mixture was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1) to obtain N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide as a yellow solid (1.3 g, 76%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][OH:5].C(N(C(C)C)CC)(C)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:6]1([CH:3]2[CH2:4][O:5][C:22](=[O:24])[NH:1][CH2:2]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCC(CO)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cooled (0° C.) solution of 3-amino-2-phenylpropan-1-ol (245 mg, 1.62 mmol) in CH2Cl2 (10 mL) was treated with diisopropylethylamine (1.65 mL, 9.72 mmol) and triphosgene (241 mg, 0.81 mmol), under an atmosphere of nitrogen. The reaction was stirred at 0° C. for an additional 2 h. The reaction was quenched with sat. NaHCO3 (2 mL) and then extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a colorless oil. LCMS=178.2 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]1.C(N(CC)CC)C>CO.[Pt]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2F)CCN1C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N)cc2F)CCN1C(=O)OC(C)(C)C
Reaction time: 2.75 h

Procedure:
1,1-Dimethylethyl (2S)-4-[(2-fluoro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D65) (2.05 g, 5.801 mmol) was taken up in methanol (50 mL) and wet (50% w/w water) 5% platinum on carbon (2 g) and triethylamine (8 mL, 58.01 mmol) were added. The mixture was hydrogenated at atmospheric pressure and room temperature for 2.5-3 h. The mixture was filtered and the filtrate concentrated to give the crude product which was purified by column chromatography. Elution with EtOAc/pentane yielded the title compound as an almost colourless gum (1.15 g). δH (CDCl3, 400 MHz) 7.11 (1H, t), 6.42 (1H, dd), 6.35 (1H, dd), 4.17 (1H, br.s), 3.79 (1H, d), 3.72 (2H, s), 3.43 (2H, m), 3.07 (1H, td), 2.74 (1H, m), 2.58 (1H, d), 2.14 (1H, dd), 1.99 (1H, m), 1.45 (9H, s), 1.20 (3H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:5]2O.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:5]2[CH2:26][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(cc1C)C(O)N(c1ccc(F)cc1)C2=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1ccc(F)cc1
Yield: 32.8 %

Procedure:
The product of above-mentioned (1-b) (0.90 g, 3.3 mmol) and (carboethoxymethylene)triphenylphosphorane (1.4 g, 3.9 mmol) was heated under reflux in toluene (15 ml) under an argon atmosphere for 3.5 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform methanol=50:1) to give 0.37 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-ethoxycarbonylmethylisoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetate].
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C@:13]([CH3:49])([CH2:47][OH:48])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]1[S:42][C:41]([CH3:43])=[N:40][CH:39]=1)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([CH2:7][S:8]([O:48][CH2:47][C@:13]([OH:12])([CH3:49])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]2[S:42][C:41]([CH3:43])=[N:40][CH:39]=2)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)Cc1ccccc1

Procedure:
Prepared according to procedures described above, by reacting phenylmethanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C32H40N4O10S2 m/z: 705 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=O)=[C:4]([F:12])[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[S:22])[NH:8][CH3:9])=[C:4]([F:12])[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1ccc(Br)cc1F
Solvent: Cc1ccccc1
Product: CNC(=S)c1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 104.8 %

Procedure:
A mixture of 4-bromo-2-fluoro-N-methylbenzamide (500 mg, 2 mmol) and Lawesson reagent (872 mg, 2.16 mmol) in toluene (10 mL) was heated to 100° C. and stirred for 4 hours. The reaction was cooled to room temperature, diluted with toluene, and filtered. The filtrate was concentrated and purification of the residue by flash column chromatography (0-20% ethyl acetate/heptanes) gave the title compound (520 mg, 97%) as a yellow solid. +ESI (M+H+1) 250.1; 1H NMR (400 MHz, CDCl3, δ): 8.09 (t, J=8.58 Hz, 1H), 8.03 (br. s., 1H), 7.35 (dd, J=8.19, 2.15 Hz, 1H), 7.27 (dd, J=11.41, 1.85 Hz, 1H), 3.36 (dd, J=4.88, 0.78 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(CCCO)C1CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
230 mg (1.79 mmol) of 1-cyclopropyl-4-hydroxy-1-butanone was dissolved in 7 ml of dichloromethane, and 580 mg (2.69 mmol) of pyridinium chlorochromate was added thereto, followed by stirring for 1 hour at room temperature. To the reaction solution was added diethyl ether, the mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; diethyl ether alone) to give 176 mg of the title compound as a pale yellow oil (yield: 78%).
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:8]3[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:32]([Cu])#[N:33]>CN(C=O)C>[C:32]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]3[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[CH:30][CH:31]=1)#[N:33]
Reactant: N#C[Cu]
Reactant: Brc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Yield: 33.6 %

Procedure:
3-(4-Bromobenzyl)-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (300 mg, 0.61 mmol) in DMF (5 mL) was treated with CuCN (135 mg) at reflux for 3 h. The cooled reaction mixture was extracted with EtOAc (3×50 mL), with water (50 mL) washing. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the product (90 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][O:12][CH2:13]4.[CH2:20](Br)[CH:21]=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[CH2:10][CH2:11][O:12][CH2:13]3)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCOC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(OC)cc13

Procedure:
A mixture of 3-methoxy-6-oxamorphinan (VIII) (0.005 m), allyl bromide (0.006 m) and potassium carbonate (2 g) in 20 ml acetonitrile is heated at reflux for 18 hours. The mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:26]>CN(C=O)C>[Br:26][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: Oc1ccnc2ccc(C(c3ccc(Cl)cc3)c3nccs3)cc12
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: Clc1ccc(C(c2ccc3nccc(Br)c3c2)c2nccs2)cc1

Procedure:
6-((4-chlorophenyl)(thiazol-2-yl)methyl)quinolin-4-ol (500 mg, 1.417 mmol, 1 equip) was dissolved in DMF (4 mL) and phosphorus tribromide (766 mg, 2.834 mmol, 2 equip) was added dropwise. A red-brown precipitate formed immediately and was collected to yield 2-((4-bromoquinolin-6-yl)(4-chlorophenyl)methyl)thiazole which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a red solid (118 mg).
Reaction SMILES: [CH3:1][C:2]([NH2:11])([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].O>C(Cl)(Cl)Cl>[CH3:3][C:2]([NH2:11])([CH3:1])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)(N)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of phentermine (1.0 g) in chloroform (20 ml) was added dropwise to sulfuric acid (3.57 ml) at 0° C.; then fuming nitric acid (specific gravity=1.52; 2.8 ml) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2 h, made alkaline with water and a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1) to give 367 mg of the titled compound (yield, 28%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[S:5][CH:6]=1.[Cu](C#N)[C:17]#[N:18].N>CN(C)C=O.CCOCC>[Si:9]([O:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:17]#[N:18])[CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)cs1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(C#N)cs1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of [(4-bromo-2-thienyl)methoxy]t-butyldimethylsilane (9.0 g, 29 mmol) [reference literature: J. Med. Chem., vol. 45, 5005 (2002)] in N,N-dimethylformamide (20 ml) was added copper cyanide (4.7 g, 53 mmol) with stirring, and the resulting mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ether (80 ml), and after adding a 28% aqueous solution of ammonia (50 ml), the resulting mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was extracted with ether, and the extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:50 to 1:4) as the eluent to afford the title compound (4.3 g) in a yield of 58% as a colourless oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[N:9][N:10]=[C:4]2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C1C=CC=CC=1.BrN1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[N:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn2nnnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: BrCc1ccn2nnnc2c1

Procedure:
7-Methyl tetrazolo [1,5-a]pyridine [Boyer, et al., J. Am. Chem. Soc., 82, 2218 (1960] (23 g. 173 mmole), benzene N-bromosuccinimide (30.6 g. 173 mmole) and benzoyl peroxide (100 mg) in 1.5 liters of benzene is refluxed overnight. More N-bromosuccinimide (15.3 g. 86.5 mole) is added and the reflux is maintained for several hours. The mixture is cooled and washed with 100 ml 20% sodium hydroxide and then with water. It is dried over calcium chloride, evaporated to dryness to yield 36.4 g of a mixture of 7-bromomethyltetrazolo [1,5-a]pyridine (63%) 7-dibromomethyltetrazolo [1,5-a]pyridine (24%) and 7-methyltetrazolo [1,5-a]pyridine (13%). Two triturations of this mixture with 500 ml of ether-hexane 1:1 (v/v) affords 25 g of a mixture consisting of 82% monobromo derivative, 13% dibromo derivative and 5% of starting material. This mixture is used for the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 75. Step 1. LC-MS Method 2 tR=0.976 min, m/z=463.8; 1H NMR (CDCl3) 1.09 (d, 6H), 1.49 (d, 3H), 2.16 (m, 4H), 2.35 (m, 1H), 2.56 (d, 3H), 2.85 (m, 1H), 5.65 (m, 1H), 6.94-7.05 (m, 4H), 7.17-7.26 (m, 4H), 7.34 (d, 2H), 8.47 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[N:30]=[C:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=3[F:44])=[C:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:30]=2)[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: COc1ccc(F)c(-c2ccc(CBr)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CN(CC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 2-(ethyl(3-hydroxyphenyl)amino)acetate (122 mg) in DMF (5.0 mL) were added potassium carbonate (75 mg) and 6-(bromomethyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (100 mg), and the mixture was stirred at 80° C. for 1 hr. The mixture was allowed to cool to room temperature, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (107 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:10]1[C:11]([CH:16]=O)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][C:33]2[C:38]([CH3:39])=[CH:37][C:36]([Cl:40])=[CH:35][N:34]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][CH:28]([N:31]([CH2:32][C:33]2[C:38]([CH3:39])=[CH:37][C:36]([Cl:40])=[CH:35][N:34]=2)[CH2:16][C:11]2[C:10]([C:2]([CH3:1])([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:3])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(c1ccccc1)c1cccnc1C=O
Reactant: Cc1cc(Cl)cnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 3-(1-methyl-1-phenyl-ethyl)-pyridine-2-carbaldehyde, 4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave 4-{(5-Chloro-3-methyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid. 1H NMR (CDCl3): δ 1.13 (q, 2H, J=11.1 Hz), 1.44 (s, 9H), 1.50 (br, 2H), 1.62 (s, 6H), 2.28 (s, 3H), 2.43 (m, 3H), 3.34 (s, 2H), 3.61 (s, 2H), 3.98 (br, 2H), 6.98 (m, 2H), 7.17 (m, 4H), 7.35 (s, 1H), 7.85 (d, 1H, J=7.2 Hz), 8.20 (s, 1H), 8.48 (d, 1H, J=3.9 Hz). Deprotection with TFA using General Procedure F gave (5-Chloro-3-methyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:10][O:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cl)c(O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)ccc1Cl
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 3-hydroxy-4-chlorotoluene (25 g, 0.175 mol) in 400 ml of acetone was added 30.11 g (0.22 mol) of milled potassium carbonate and 31.22 g (0.22 mol) of methyl iodide, and the mixture was refluxed with stirring for 16 hours. The mixture was cooled, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in ether, washed with water, and the organic layer was dried over sodium sulfate and concentrated in vacuo to afford 25.6 g of 3-methoxy-4-chlorotoluene as a solid.