Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:49])([F:48])[CH:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:30]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:37])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([C:16]([NH:47][CH:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:39]([F:38])([F:48])[F:49])=[O:17])[CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Reactant: NC(c1ccccc1)C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)NC(c2ccccc2)C(F)(F)F)c1)S(C)(=O)=O
Reaction time: 4 h

Procedure:
To a solution of 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI, 10.0 mg, 0.019 mmol) and (2,2,2-trifluoro-1-phenylethyl)amine (7.6 mg, 0.056 mmol) in DMF (500 μL) were added BOP reagent (10.0 mg, 0.022 mmol), ethyl(diisopropyl)amine (5.0 μL, 0.028 mmol). After sitting at rt for 4 hr, the reaction was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl {1-benzyl-1-methyl-2-[(3-[(methylsulfonyl)(propyl)amino]-5-{[(2,2,2-trifluoro-1-phenylethyl)amino]carbonyl}benzyl)oxy]ethyl}carbamate which was taken up in HCl(g) saturated EtOAc (1 mL). After 15 hr, it was purified by preparative HPLC (5->95% CH3CN/H2O, 0.1% added TFA, C18 PRO YMC 20×150 mm) to provide 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(methylsulfonyl)(propyl)amino]-N-(2,2,2-trifluoro-1-phenylethyl)benzamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.90 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.61-7.55 (m, 2H), 7.46-7.40 (m, 3H), 7.34-7.24 (m, 3H), 7.20-7.15 (m, 2H), 6.04-5.96 (m, 1H), 4.72 (A of AB, d, J=13.8 Hz, 1H), 4.68 (B of AB, d, J=13.8 Hz, 1H), 3.71 (t, J=7.1 Hz, 2H), 3.45 (A of AB, d, J=10.0 Hz, 1H), 3.40 (B of AB, d, J=10.0 Hz, 1H), 3.08 (A of AB, d, J=13.4 Hz, 1H), 2.96 (s, 3H), 2.87 (B of AB, d, J=13.4 Hz, 1H), 1.51-1.41 (m, 2H), 1.25 (s, 3H), 0.90 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([C:15]1([S:18]([NH:21]C(=O)OC(C)(C)C)(=[O:20])=[O:19])[CH2:17][CH2:16]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14]>O>[CH2:8]([C:15]1([S:18]([NH2:21])(=[O:19])=[O:20])[CH2:17][CH2:16]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCCCCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C=CCCCCCC1(S(N)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
4.0M HCl in dioxane (4.285 mL, 17.14 mmol) was added to tert-butyl 1-(hept-6-enyl)cyclopropylsulfonylcarbamate (544 mg, 1.714 mmol) and stirred at r.t. for 3 h. Poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated in vacuo. The residue was purified by Biotage column, eluted with gradient 5%˜60% EtOAc-Hexane to afford the desired product 1-(hept-6-enyl)cyclopropane-1-sulfonamide (350 mg, 1.578 mmol, 92% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.82-0.94 (m, 2 H) 1.28-1.53 (m, 8 H) 1.84-1.97 (m, 2 H) 2.06 (q, J=6.94 Hz, 2 H) 4.49 (b, NH2) 4.89-5.07 (m, 2 H) 5.70-5.90 (m, 1 H).
Reaction SMILES: [CH2:1]([C:4]1[C:17]([Br:18])=[CH:16][C:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:14]([Cl:28])[C:5]=1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH:2]=[CH2:3].CSC.B.[OH-:33].[Na+].OO>C1COCC1.O>[Br:18][C:17]1[C:4]([CH2:1][CH2:2][CH2:3][OH:33])=[C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[C:14]([Cl:28])=[C:15]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:16]=1
Reactant: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cc2cc(Br)c(CCCO)c(O[Si](C)(C)C(C)(C)C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of bromide 186 (2.57 g, 5.33 mmol) in THF (35 mL) was added borane dimethylsulfide complex (10M in THF, 0.18 mL, 1.76 mmol) at 0° C. The mixture was stirred at rt for 1 hr. The mixture was cooled to 0° C. and H2O (0.5 mL), aq. 3N NaOH solution (1.1 mL), 35% H2O2 (0.65 mL) were added to the mixture.) The mixture was stirred at 50° C. for 30 min and cooled to rt. The mixture was extracted with EtOAc/aq. 50% NaCl solution (100 mL/100 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 187 (1.73 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][C:29]([OH:31])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([N:39]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN>CN(C)C=O.O1CCCC1.O>[CH2:32]([C:11]1[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:19]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:27][CH2:28][C:29]([NH:39][CH3:37])=[O:31])[CH:17]=2)[N:12]=1)[CH:33]([CH3:34])[CH3:35]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC(=O)O)cc23)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)COc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
To a solution of {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetic acid (0.48 g, 1.0 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2 mmol), 1-hydroxy-1H-benzotriazole (0.16 g, 1.2 mmol) and 1.0 M solution of methylamine in tetrahydrofuran (2 ml) and the mixture was stirred at room temperature for 12 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl {[2-isobutyl-6-[2-(methylamino)-2-oxoethoxy]-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.27 g, yield 55%) as pale-yellow crystals.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C=O.[NH:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[C:8]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](O)(=O)C>C(O)C>[CH2:19]([O:18][C:16]([C:8]1[NH:7][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]=1[CH2:2][N:3]([CH3:21])[CH3:4])=[O:17])[CH3:20]
Reactant: CNC
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ncccc2c1CN(C)C
Temperature: 85 °C
Yield: 76.8 %

Procedure:
In a 50 mL round-bottomed flask, dimethylamine hydrochloride (4.91 g, 60.3 mmol, Eq: 6) was added to 37% aqueous formaldehyde (4.49 mL, 60.3 mmol, Eq: 6). Ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.91 g, 10.0 mmol, Eq: 1.00) in ethanol (50 mL) was added followed by acetic acid (5.00 mL, 87.3 mmol, Eq: 8.7). The reaction mixture was heated to 85° C. and stirred over the weekend. The crude reaction mixture was filtered through a pad of Celite, concentrated in vacuo to ˜20% of its original volume, water (100 mL) was added, and this was then washed with DCM (50 mL). The aqueous layer was cooled, basified to pH 11 through the addition of 3 M aqueous NaOH and extracted with DCM. The organic layers were dried over Na2SO4 and concentrated in vacuo to give 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester as light yellow solid (1.9 g), m/z=248 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.[Br:21][CH2:22][CH2:23][CH2:24]O>>[Br:21][CH2:22][CH2:23][CH2:24][N:8]1[CH2:7][C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Reactant: OCCCBr
Product: O=S1(=O)N(CCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 71.9 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.51 g, 1.7 mmol) was reacted with 3-bromopropanol (0.25 mL, 2.8 mmol) to afford 3-(3-bromopropyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.51 g, 71%) as a white solid:
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20].O>[Pd].C1(OC)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:29])[C@@H:19]([NH:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: O
Solvent: COc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
A stirred mixture of 92 g (0.45 mol) 2-benzoyl-cyclohexanone, (Denny, W. A. et. al. J. Med. Chem. 1978, 21(5), 430-7) 78 g (0.40 mol) L-Tyrosine methyl ester, 17.0 g Palladium on activated carbon (10%) was refluxed for 2 h in 1 L anisole while the resulting water was removed by a Dean-Stark apparatus. The mixture was cooled to 80° C. and the Pd/C was filtered, and washed with 50 mL anisole three times. The mixture was cooled to 40° C., 1 L hexane was added and kept at −20° C. for 48 h. The solid was filtered, washed with 200 mL hexane five times to yield 89.0 g crude (S)-2-(2-Benzoyl-phenylamino)-3-(4-hydroxy-phenyl)-propionic acid methyl ester. This solid was mixed with 220 mL of MeOH, and the slurry was refluxed for 30 min. The mixture was cooled to 0° C., the product was filtered and washed with 50 mL cold (−20° C.) MeOH twice, then dried under reduced pressure to yield 67.4 g the of the title compound. mp 185-6° C.; low resolution MS (ESP+) m/e 376 (MH+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])/[C:9]1=[O:37])=O)(C)(C)C.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:54])=[C:43]([CH:45]=[N:46][C:47]([O:49][Si](C)(C)C)=[CH2:48])[CH:44]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:37])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:48][C:47](=[O:49])[NH:46][CH:45]3[C:43]3[CH:44]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=3[CH3:54])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNC(=O)OC(C)(C)C)C12C(=O)Nc1cc(Cl)ccc12
Yield: 9 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-3-[2-(2-tert-butoxycarbonylamino-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (8 g, 14.6 mmol) prepared in Example 32d was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (43.8 mmol) in toluene (22 mL) to give the title compound as a white solid (830 mg).
Reaction SMILES: Cl.[N:2]1([C:8]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:10]([C:11]([NH:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[O:12])[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1CCNC[CH2:27]1.[Cl:32]C1C2C(=CC=CC=2)N=C([C:36](NC2NN=NN=2)=[O:37])C=1>>[ClH:32].[CH3:36][O:37][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:10]([C:11]([NH:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1)=[O:12])[CH:9]=[C:8]2[N:2]1[CH2:3][CH2:4][N:5]([CH3:27])[CH2:6][CH2:7]1
Reactant: O=C(Nc1nnn[nH]1)c1cc(N2CCNCC2)c2ccccc2n1
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Reactant: C1CNCCN1
Agent: Cl
Product: COc1ccc2nc(C(=O)Nc3nnn[nH]3)cc(N3CCN(C)CC3)c2c1

Procedure:
4-Piperazino-N(1H-tetrazol-5-yl)quinaldamide hydrochloride, m.p. 320° (d), was prepared in a similar way from piperazine and 4-chloro-N(1H-tetrazol-5-yl)quinaldamide.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:31][CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[CH:33]=O)=[CH:21][CH:20]=1.CC[O:37][CH2:38][CH3:39]>O>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH2:31][CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[CH:33]=[CH:39][CH:38]=[O:37])=[CH:23][CH:24]=1
Reactant: CCOCC
Reactant: O=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Solvent: O
Product: O=CC=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 0°-5° C. solution of LDA (26.5 mmoles) in 25 ml anhydrous ether was added ethylidenecyclohexylamine (Org. Syn. 50 66) (3.32 g, 26.5 mmoles) in 25 ml anhydrous ether. The solution was stirred for 10 minutes, cooled to -70° C. and 3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-ene-2-carboxaldehyde (5.55 g, 24.1 mmoles) in 25 ml ether was added. The solution was stirred for 60 minutes, warmed to 0°-5° C., stirred for 90 minutes and diluted with water. The organic layer was washed with water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by HPLC using 3% ethyl acetate in hexanes as the eluent. Concentration in vacuo of the product rich fractions provided 2.53 g of the product as an orange oil.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH3:14].CCCCCC.C[O:22][B:23]([O:26]C)[O:24]C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH2:10][O:11][CH3:12])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:22][B:23]([OH:26])[OH:24]
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Reactant: COB(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Under cooling in an dry ice-acetone bath in nitrogen flow, to a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (20.0 g, 76.6 mmol) in tetrahydrofuran (200 mL) was added a solution (50.9 mL, 80.4 mmol) of 1.58Mn-butyllithiumin hexane, and the reaction mixture was stirred for 30 minute. Then, to the reaction mixture was added a solution of trimethoxyborane (8.75 g, 84.2 mmol) in tetrahydrofuran (20 mL), and the reaction temperature was raised up to 0° C. under stirring. To the reaction mixture was added 1N hydrochloric acid (200 mL), and the reaction mixture was stirred for 30 minutes at room temperature. After the reaction, to the reaction mixture was added toluene (200 mL) and an organic layer was separated, then, the remaining aqueous layer was further extracted with toluene (100 mL). Combined organic layers were washed with water (100 mL), and the solvent was concentrated under reduced pressure. The resulting residue was dissolved in t-butyl methyl ether (75 mL), the reaction mixture was stirred for 30 minutes. Then, to this was added heptane (223 mL), and the mixture was further stirred for 2 hours. A precipitate was filtrated, and the precipitate was washed with a t-butyl methyl ether-heptane mixed solution (1:3, 3.75 mL), and dried at 40° C. for 24 hours to obtain 12.4 g of a title compound (yield: 71.8%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(N)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(N)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 64.3 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0 mmol), K2CO3 (2.0 g) and 4-(3-bromopropoxy)-3-methoxybenzamide (2.32 g, 8.0 mmol) in acetonitrile (80 ml) was heated at reflux for 5 hours. At the end of the reaction the solvent was evaporated. The residue was extracted into dichloromethane. The inorganic insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was purified by flash chromatography over a silica gel column (55 g, SiO2; eluted with 1% methanol in dichloromethane, 1 l; 2% methanol in dichloromethane, 1). The material thus obtained weighed 2.93 g (84%) as white crystals. Recrystallization from hot ethanol (60 m1) gave 2.2 g of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide as white crystals, m.p.=163°-164° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1>>[CH:29]([OH:31])=[O:30].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([O:22][CH:21]([F:32])[F:20])=[CH:28][N:27]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 5-difluoromethoxy-pyridine-2-carboxylic acid (prepared according to Y. Suzuki et al., Int. Patent Appl. No. WO2009091016) yielded the title compound as a pale yellow solid. MS (ISP): m/z=545.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:31]([NH2:33])[CH3:32])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:33]([CH:31]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])=[C:17]([Cl:16])[CH:18]=3)[CH3:32])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1cnc(OCC(F)(F)C(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 53 %

Procedure:
The title compound is prepared in 53% yield (420 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (580 mg, 1.8 mmol, Amine-60, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: O.S(O)(O)(=O)=O.[CH3:7][S:8][C:9](=[NH:11])[NH2:10].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:7][S:8][C:9](=[NH:10])[NH:11][S:20]([CH2:19][Cl:18])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)CCl
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSC(=N)NS(=O)(=O)CCl
Yield: 90.6 %

Procedure:
Water (250 ml) is added with stirring to a slurry of S-methylisothiourea sulfate (77.3 g, 0.556 mol) and sodium carbonate (273 g, 2.58 mol) in methylene chloride (1100 ml). Chloromethanesulfonyl chloride (85% pure, 94.8 g, 0.542 mol) is then added slowly with stirring at such a rate as to maintain gentle reflux of the solvent. The mixture is then stirred at room temperature for 16 hr, and the organic solution is decanted from the inorganic residue. The residue is washed with additional methylene chloride (500 ml), and the combined organic solutions are dried with magnesium sulfate, filtered, and concentrated to leave crude II as a yellow oil (99.5 g, 90%). This crude material is adequate for preparing the thiadiazole compounds of the invention (e.g., see Example 4, below). Purification by chromatography on silica gel (2.5% ethyl ether in methylene chloride as eluant) provides the title compound as a colorless solid, mp 60°-62° C. (72 g, 65%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:27][S:28]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])[CH2:13][CH2:12]1)=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(Cl)[Cl:63]>>[ClH:63].[ClH:63].[NH2:8][C@@H:9]([CH2:27][SH:28])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])[CH2:13][CH2:12]1
Reactant: Cc1cccc(C(=O)N2CCN(C[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)CC2)c1C
Reactant: ClCCl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)N2CCN(C[C@@H](N)CS)CC2)c1C
Product: Cl
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
The product from step D and triethylsilane (0.54 mL, 3.4 mmol) were dissolved in methylene chloride (6 mL). To this solution was added trifluoroacetic acid (3 mL) and the reaction stirred at 20° C. for 30 min. The reaction was evaporated to dryness and partitioned between hexane and water. The aqueous phase was injected onto a 40×100 mm Waters PrepPak® reverse phase HPLC column (Delta-Pak™ C18 15 μm, 100 Å), and pure product isolated by gradient elution using 100% Solvent A (0.1% trifluoroacetic acid in water) to 50% Solvent A/50% Solvent B (0.1% trifluoroacetic acid in acetonitrile) over 50 min at a flow rate of 40 mL/min. Combined fractions were evaporated, dissolved in water and passed through a Biorad AG® 3×4 ion exchange resin column (100-200 mesh, Cl-form). The column eluant was lyophilized to give the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:5](OC)=O.[H-].[Na+].[C:15]([O:18][CH3:19])(=[O:17])[CH3:16].[CH3:20][O:21]CCOC>>[CH3:12][C:10]1[CH:9]=[C:4]([CH2:5][C:20](=[O:21])[CH2:16][C:15]([O:18][CH3:19])=[O:17])[CH:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: COC(=O)c1cc(C)cc(C)c1
Reactant: COCCOC
Reactant: COC(C)=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(=O)Cc1cc(C)cc(C)c1
Yield: 50 %

Procedure:
A solution of methyl 3,5-dimethylbenzoate (50 g; 300 mmol) in DME (80 ml) was added to a suspension of NaH (26.8 g; 60% in oil; 670 mmol) in DME (80 ml) under argon. The mixture was heated to reflux and a solution of methyl acetate (45 g; 610 mmol) in DME (40 ml) added dropwise. The mixture was heated for a further 4 h under reflux. The mixture was cooled and the excess of NaH destroyed by the dropwise addition of MeOH (40 ml). The mixture was poured into dilute HCl (2N), extracted with Et2O and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with Et2O/hexanes (10% Et2O) to give methyl 4-(3′,5′-dimethylphenyl)acetoacetate as a yellow oil (31 g).