Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH2:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2)[CH3:2]>CO.[Pd]>[CH2:1]([CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2)[CH2:12]1)[CH3:2]
Reactant: CCC1=Cc2ccc(OC)cc2CC1
Agent: [Pd]
Solvent: CO
Product: CCC1CCc2cc(OC)ccc2C1
Reaction time: 18 h

Procedure:
To a solution of 3-ethyl-7-methoxy-1,2-dihydronaphthalene (2.6 g, 13.8 mmol) in MeOH (20 mL) is added 10% Pd/C (200 mg) and the mixture is stirred at 1 atm for 18 h. The mixture is filtered through Celite, and the filtrate is concentrated to give the title compound: 1H NMR (CDCl3) δ 0.87 (t, J=7 Hz, 3H), 1.19-1.32 (m, 3H), 1.49-1.50 (m, 1H), 1.80-1.82 (m, 1H), 2.19-2.23 (m, 1H), 2.72-2.67 (m, 3H), 3.67 (s, 3H), 6.52 (d, J=2.5 Hz, 1H), 6.57 (dd, J=2.5, 8 Hz, 1H), 6.83 (d, J=8 Hz, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][CH2:13][CH2:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:22][C:23]=2[OH:25])[N:18]([CH3:34])[CH:17]([CH3:35])[CH2:16]1.C(Cl)(Cl)Cl>C(O)(=O)C>[OH:12][CH2:13][CH2:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[O:9])=[CH:22][C:23]=2[OH:25])[N:18]([CH3:34])[CH:17]([CH3:35])[CH2:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCSCCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCS(=O)CCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Equimolar amounts of m-chloroperbenzoic acid and dl-4-(2-hydroxyethyl)-5-hydroxy-1,2-dimethyl-7-(4-thiaoctyl)-1,2,3,4-tetrahydroquinoline are added to a mixture of chloroform and acetic acid (2:1 v/v) and the mixture stirred at room temperature for one hour. The mixture is washed with water, the organic phase dried (MgSO4) and evaporated to dryness at reduced pressure to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22]2=[O:30])[CH2:17][CH2:16]1.CO>C1C=CC=CC=1>[O:30]=[C:22]1[N:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:13][CH3:14])[CH2:20][CH2:19]2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23]1
Reactant: COc1cc(F)ccc1C(=O)N1CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 8 parts of 1-(4-fluor-2-methoxybenzoyl)-aziridine, 3.8 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and 90 parts of benzene are added. The whole is washed with water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 4 parts of N{2-[4-(2,3-dihydro-2-oxo-lH-benzimidazol-1-yl)-1-piperidinyl] ethyl}-4-fluoro-2-methoxybenzamide; mp. 197.3° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)#[N:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(C#N)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-cyanobenzoic acid
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[O:12])=[CH:3][N:2]=1.B.CSC>C1COCC1>[OH:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=[N:2][CH:3]=1
Reactant: O=Cc1cncc2ccccc12
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1cncc2ccccc12

Procedure:
4-Isoquinolinecarboxaldehyde (1 mmole) (prepared by the method of: J. B. Wommack, T. G. Barbee, Jr., D. J. Thoennes, M. A. McDonald and D. E. Pearson, J. Heterocyclic Chem., 1969, 6, 243-245.) is dissolved in anhydrous THF (50 mL) and treated with borane-methyl sulfide (0.3 mmoles) (as described in: E. Mincione, J. Org. Chem., 1978, 43, 1829-1830) at 0° C. for 0.5-1 h and worked up in the usual way to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])=[CH:28][CH:27]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1.C(O)(C(F)(F)F)=O.[ClH:83]>>[ClH:83].[ClH:83].[NH2:13][C:9]1[C:8]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:7]([O:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[O:37])=[CH:3][C:4]=2[F:24])[CH:12]=[CH:11][N:10]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(N)c2C#Cc2ccccn2)c(F)c1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)c1C#Cc1ccccn1
Yield: 40 %

Procedure:
The title compound was prepared from 4-(4-amino-2-fluorophenoxy)-3-(2-(pyridin-2-yl)ethynyl)pyridin-2-amine (25 mg, 0.078 mmol) and a 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.26 mL, 0.078 mmol) in the same manner as Step E of Example 11. The crude product was prepared by preparative HPLC (Column B). The TFA salt was converted to the hydrochloride in the same manner as in Step E of Example 36 to give the title compound (18 mg, 40%) as a brown solid. 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.63 (s, 1H), 8.62 (d, 1H, J=4.6 Hz), 8.23 (s, 1H), 7.99 (d, 1H, J=7.1 Hz), 7.94-7.84 (m, 3H), 7.87-7.76 (m, 1H), 7.51-7.42 (m, 3H), 7.39-7.32 (m, 2H), 7.21-7.13 (m, 2H), 6.30 (d, 1H, J=7.1 Hz), 3.74 (s, 2H) MS(ESI+): m/z 498.11 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>CN(C)C=O>[S:9]1[CH:10]=[CH:11][C:7]([C:4]2[N:3]=[C:2]([N:15]3[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]3)[S:6][N:5]=2)=[CH:8]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(-c2ccsc2)ns1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccsc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 5-chloro-3-(3-thienyl)-1,2,4-thiadiazole (2.47 g, 12.2 mmol) and tert-butyl piperazine-1-carboxylate (2.27 g, 12.2 mmol) in dimethylformamide (25 ml) was added triethylamine (6.8 ml, 48.8 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1) to give 3.72 g (86.5%) of the desired product as a solid.
Reaction SMILES: [CH3:1]COCC.C[Mg]Br.[O:9]=[C:10]1[CH2:14][O:13][CH2:12][CH:11]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C>O1CCCC1>[OH:9][C:10]1([CH3:1])[CH2:14][O:13][CH2:12][CH:11]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(NC1COCC1=O)OCc1ccccc1
Reactant: CCOCC
Agent: C
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)COCC1NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A 3 M ether solution of methylmagnesium bromide (4.07 mL, 12.20 mmol) was added dropwise to a solution of benzyl 4-oxotetrahydrofuran-3-ylcarbamate (1.305 g, 5.55 mmol, from Step 3) in tetrahydrofuran (50 mL) at 0° C. Gas evolution was observed during the addition, indicating formation of methane. After 1 h at 0° C., the mixture was quenched with saturated ammonium chloride (75 mL) and extracted with ethyl acetate three times. The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 20-70% ethyl acetate in hexanes, gave impure material. 1H NMR showed presence of the desired product. The impure material was combined with the material from another run (from 2.18 g of ketone starting material) and taken to the next reaction without purification.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]([NH2:34])([CH3:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[N:23]=1.Br>>[F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([NH:34][C:27]([C:24]3[N:23]=[C:22]([CH3:21])[O:26][N:25]=3)([CH3:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:14])=[N:10][CH:11]=2)[CH2:3][O:4][CH2:5]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)COC2)cn1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3(F)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 131b) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (35 mg, 42%); MS (ESI, m/z): 497.6 (M+H+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH3:9][CH:10]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]1=[O:17].N1C=CC=CC=1>C(Cl)Cl>[C:1]([N:14]1[CH2:15][CH2:16][CH:10]([CH3:9])[C:11](=[O:17])[CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCNCCC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(=O)C(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
Acetic anhydride (0.437 mL, 4.62 mmol) was added at 0° C. to a solution of 5-methyl-azepan-4-one hydrochloride (0.740 g, 3.08 mmol) in DCM (20 mL) and pyridine (0.25 mL, 3.08 mmol). The reaction mixture was stirred at RT for 8 hours before being partitioned between DCM and H2O. The organic layer was dried (Na2SO4), filtered, and evaporated. The crude residue was purified by SiO2 chromatography (100% EtOAc) to give 0.220 g of 1-acetyl-5-methyl-azepan-4-one (42% yield).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:30]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH:36]=O)[CH3:31].C([BH3-])#N.[Na+]>C(O)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:36][C:35]3[CH:38]=[CH:39][C:40]([CH3:41])=[C:33]([O:32][CH2:30][CH3:31])[CH:34]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1
Reactant: Clc1nccc(NC2CCNCC2)n1
Reactant: CCOc1cc(C=O)ccc1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3ccnc(Cl)n3)CC2)ccc1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 4.4 %

Procedure:
To a solution of (2-chloro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (42.9 mg, 0.15 mmol, 1.0 equiv; intermediate C1) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate D10, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.4 mg (4%) of the title compound. MS (ISP): 361.3 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:31])=[C:11]([CH:17](C2N(C)N=C(C3C=CC=CC=3)N=2)[OH:18])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.CS(OS(C)(=O)=O)(=O)=O.C(OC(N(C(OC(C)(C)C)=O)C1C2C(=CC(N)=CC=2)C=CN=1)=O)(C)(C)C>C(#N)C>[Si:1]([O:8][C:9]1[C:10]([F:31])=[C:11]([CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)[CH:17]=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)nn2C)c1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 139.5 %

Procedure:
To a solution of Intermediate 368.3 (440 mg, 1 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.35 mL, 2 mmol) in ACN (30 mL) at −15° C. was added methanesulfonic anhydride (279 mg, 1.6 mmol). The mixture was stirred for 1 h as the temperature was raised to 23° C. 1-(di-(tert-butyloxycarbonyl)amino)-6-aminoisoquinoline (359 mg, 1 mmol) was added as a solid and the mixture stirred 18 h at 50° C. The mixture was concentrated and purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 394 mg of Intermediate 368.2. 1H NMR (400 MHz, CDCl3) δ ppm 0.04-0.20 (s, 6H) 0.77-1.02 (m, 12H) 1.08-1.37 (s, 18H) 1.09-1.32 (s, 9H) 2.35 (q, J=7.47 Hz, 2H) 3.82 (s, 3H) 5.96-8.33 (m, 13H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([CH3:23])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH:11]=1.C1C(=O)N([Br:36])C(=O)C1.C(OC(Cl)=O)C(C)C.C[N:46]1[CH2:51]COCC1.CN>ClCCl.O1CCOCC1.C1COCC1>[Br:36][C:11]1[C:10](=[O:12])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:46][CH3:51])=[O:19])=[CH:16][CH:15]=2)[C:8]([CH3:23])=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: CN1CCOCC1
Reactant: Cc1nc(OCc2ccc(F)cc2F)cc(=O)n1Cc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1ccc(Cn2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a suspension of 4-{[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]methyl}benzoic acid (0.18 g, 0.00047 mol, from step 4) in dichloromethane (3.0 mL) and dioxane (1.0 mL) is added NBS (0.09 g, 0.0005 mol). The resulting reaction mixture is stirred at room temperature for 3 hours, concentrated to dryness, and the residue is then dried in a desiccator for 2 h. This residue is dissolved in dimethylacetamide (2.5 mL), isobutylchloroformate (0.08 mL, 0.00062 mol) is added, N-methylmorpholine (0.0.08 mL, 0.00073 mol) is then added, and the reaction mixture is stirred at 0° C. for 5 min under argon. The reaction mixture is then stirred at room temperature for 30 min, it is recooled to 0° C., a solution of N-methylamine in THF (1.1 mL of 2M in THF) is then added, and the resulting reaction mixture is stirred at 0° C. for 30 min. The resulting mixture is concentrated to dryness under reduced pressure and the residue is purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=478) are combined and concentrated to a small volume (˜25 mL), cooled added 5% NaHCO3 solution (5.0 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts are dried (Na2SO4), filtered and concentrated to dryness to afford the title compound (0.14 g, 64%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.77 (d 2H, J=8.4 Hz), 7.58 (m, 1H), 7.26 (d, 2H, J=8.4 Hz), 7.01 (m, 2H), 5.49 (s, 2H), 5.42 (s, 2H), 2.89 (s, 3H), and 2.48 (s, 3H); ES-HRMS m/z 478.0596 (M+H calcd for C21H19N3O3F2Br requires 478.0572). 19F NMR(CD3OD/400 MHz) −111.99 (m) and −115.99 (m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH2:13][CH2:14][O:15][CH2:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C2=CCOCC2)C1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CC(C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 92.2 %

Procedure:
A mixture of 3-(3,6-dihydro-2H-pyran-4-yl)azetidine-1-carboxylic acid tert-butyl ester (28.6 g, 0.12 mol) and 10% palladium on charcoal (5.0 g) in IMS (500 mL) was stirred under hydrogen (4 bar) at room temperature for 36 hours. The reaction mixture was filtered through a bed of Celite® which was washed with IMS. The filtrates were combined and concentrated to give a residue which was reacted as above for 18 hours. The reaction mixture was worked up as above to give a residue which was dried under reduced pressure to give 3-(Tetrahydropyran-4-yl)azetidine-1-carboxylic acid tert-butyl ester as a beige solid (26.7 g, 92%). 1H NMR (300 MHz, CHCl-d): δ 4.03-3.90 (m, 4H); 3.63 (dd, J=8.6, 5.7 Hz, 2H); 3.37 (td, J=11.8, 2.0 Hz, 2H); 2.32-2.19 (m, 1H); 1.63-1.48 (m, 3H); 1.44 (s, 9H); 1.29-1.12 (m, 2H).
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[C:7]([C:14]([OH:16])=[O:15])=[CH:6][C:5]=1[S:17](Cl)(=[O:19])=[O:18]>O>[CH3:2][O:3][C:4]1[C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[C:7]([C:14]([OH:16])=[O:15])=[CH:6][C:5]=1[S:17](=[O:19])(=[O:18])[NH2:1]
Reactant: COc1c(S(=O)(=O)Cl)cc(C(=O)O)c2c1OCCO2
Reactant: N
Solvent: O
Product: COc1c(S(N)(=O)=O)cc(C(=O)O)c2c1OCCO2
Yield: 79.2 %

Procedure:
300 g of 34% ammonia were introduced into a balloon flask provided with an agitator and a thermometer and then 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in portions, the temperature being maintained at from 0°-5° C. The mixture was agitated and then the precipitate was dissolved in water. The solution was filtered and treated with 280 cm3 of concentrated hydrochloric acid. The precipitate was dried off, washed and dried. 118 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 247°-248° C.; yield: 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9]>CO.[C].[Pd]>[NH2:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: COc1ccc([N+](=O)[O-])c(C(N)=O)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
To a solution of 5-methoxy-2-nitrobenzamide (9.70 g, 49.4 mmol) in methanol (250 mL) was added 10% palladium carbon (2.00 g), and the mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 6 hr. The insoluble material was filtered off, and the filtrate was concentrated to give 2-amino-5-methoxybenzamide as a pale-yellow powder (8.20 g, 99%).
Reaction SMILES: [CH2:1]([C:8]1[NH:12][N:11]=[C:10]([C:13]2[S:17][C:16]([C:18]([O:20]CCCC)=[O:19])=[C:15]([CH3:25])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[CH2:1]([C:8]1[NH:12][N:11]=[C:10]([C:13]2[S:17][C:16]([C:18]([OH:20])=[O:19])=[C:15]([CH3:25])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)c1sc(-c2n[nH]c(Cc3ccccc3)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)O
Temperature: 0 °C
Yield: 94 %

Procedure:
A mixture of butyl 5-(5-benzyl-1H-1,2,4-triazol-3-yl)-3-methylthiophene-2-carboxylate (0.23 g, 0.64 mmol) and 1 N aqueous sodium hydroxide (3.8 mL, 3.8 mmol) in ethanol (7.6 mL) was stirred at reflux for 1 h. The reaction mixture was cooled to 0° C. and acidified with glacial acetic acid to pH 5-6, and diluted with water (25 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless solid (0.18 g, 96%): 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br s, 1H), 7.45 (s, 1H), 7.37-7.20 (m, 6H), 4.12 (s, 2H), 2.47 (s, 3H); MS (ES+) m/z 300.21 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.CCCCCC.Cl[C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:17]=1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:17]=2)=[CH:3][CH:4]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: Brc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
1,4-Dibromobenzene 2.64 g (11.2 mmol) was dissolved in 30 mL of dried tetrahydrofuran and cooled down to −70° C. A hexane solution (1.6M) 7.4 mL (11.8 mmol) was dropwise added slowly to the above solution and stirred at −70° C. for 30 minutes. A tetrahydrofuran solution of 2-chloro-4,6-diphenyl-1,3,5-triazine 3.00 g (11.2 mmol) was dropwise added to the above mixture at −70° and stirred at −70° C. for 30 minutes, and then the solution was heated slowly up to room temperature and stirred further for 1.5 hour. The mixture thus obtained was extracted with ethyl acetate, and the organic layer was washed in order with water and a saturated saline solution and dried on anhydrous magnesium sulfate. Then, the solvent was removed by distillation, and the residue was refined by silica gel chromatography to thereby obtain 1.48 g (yield: 34%) of 2-(4-bromophenyl)-4,6-diphenyl-1,3,5-triazine.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[C:18](=O)[CH2:17][CH2:16][CH2:15]2.[CH3:21][O:22][C:23](=[O:26])[CH2:24]Br.Cl.C1C[O:31]CC1>>[Br:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]([CH2:24][C:23]([O:22][CH3:21])=[O:26])[C:17](=[O:31])[CH2:16][CH2:15]2
Reactant: COC(=O)CBr
Reactant: C1CCOC1
Reactant: O=C1CCCc2cccc(Br)c21
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Product: COC(=O)CC1C(=O)CCc2cccc(Br)c21
Reaction time: 18 h

Procedure:
33 ml of 2M lithiumdiisopropylamide were added to a solution of 13.5 g (60 mmol) of 8-bromotetralone in 470 ml of THF at −30° C. under a protective gas atmopshere and, after stirring, a solution of 11 g (72.mmol) of methylbromoacetate in 100 ml of THF was added dropwise. The mixture was worked up after 18 h at room temperature by adding 10 ml of concentrated hydrochloric acid at 0° C. The solvent was removed in vacuo, and the residue was taken up in water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated; the residue was purified by column chromatography (silica gel, mobile phase: methylene chloride).