Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[CH3:43][O:44][C:45]([C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1)=[O:46].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][C:50]3[CH:51]=[CH:52][C:47]([C:45]([O:44][CH3:43])=[O:46])=[CH:48][CH:49]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Oc3ccc(C(=O)OC)cc3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
(2R,4S)-4-{[3, 5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (170 mg) is dissolved in methylene chloride (3 ml), and thereto are added 4-methoxycarbonylphenylboronic acid (51 mg), copper (II) acetate (52 mg), triethylamine (79 μl) and molecular sieves 4A (170 mg). The mixture is stirred overnight at room temperature. The insoluble materials are removed by filtration and the filtrate is partitioned by adding ethyl acetate and saturated brine. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→3:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-methoxycarbonylphenoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 734 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18]([CH3:26])=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9].N1C=CC=CC=1.[CH:42]([O:45][C:46](Cl)=[O:47])([CH3:44])[CH3:43]>ClCCl>[CH:42]([O:45][C:46]([N:14]1[CH2:15][CH2:16][CH2:17][CH:11]([N:7]([C:8](=[O:10])[CH3:9])[CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=2)[C:12]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([CH3:26])[C:13]1=2)=[O:47])([CH3:44])[CH3:43]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(C)cc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(C)cc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.0210 g, 0.0410 mmol) and pyridine (0.0100 ml, 0.123 mmol) in dichloromethane (1.00 ml) was added 1M isopropylchloroformate (solution in toluene) (0.120 ml), 0.123 mmol) dropwise. The mixture was stirred at room temperature overnight. The solvents were evaporated on a rotavapor (rotary evaporator). Purification by silica gel chromatography (gradient eluent, 0-30% ethyl acetate in hexane) provided the titled compound (0.0180 g, 72%) as white crystalline. MS (ES+): 599 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: Cc1cccc2nc([C@H](C)N)n(-c3ccccc3)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-1-(7-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 1 (100 mg, 0.398 mmol), 6-chloro-9H-purine (65 mg, 0.418 mmol) and DIPEA (77 μL, 0.438 mmol) in n-butanol (2 mL) was stirred at 140° C. for 1 h under microwave irradiation. Volatiles were removed under reduced pressure and the residue was partitioned between DCM and water. The organic phase was then separated, dried and concentrated in vacuo. The resulting crude material was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with IMS affording 110 as a white solid (6.2 mg, 4%) LCMS: RT 3.08 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.12 (1H, bs), 8.07 (1H, s), 7.83-7.75 (1H, m), 7.64-7.37 (7H, m), 7.09 (1H, t, J=7.67 Hz), 6.92 (1H, d, J=7.29 Hz), 5.25 (1H, br), 1.81 (3H, s), 1.54 (3H, d, J=6.84 Hz)
Reaction SMILES: C(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCC(F)(F)C(F)(F)C(F)(F)C(F)F.FC(F)(C(F)(F)C(F)(F)C(F)F)C[NH:34][C:35](=[O:62])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][O:45][C:46](=[O:61])[NH:47]CC(F)(F)C(F)(F)C(F)(F)C(F)F)[CH:39]=1>>[C:46](=[O:61])([O:45][CH2:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][O:36][C:35](=[O:62])[NH2:34])[CH:39]=1)[NH2:47]
Reactant: O=C(NCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCc1cccc(COC(=O)NCC(F)(F)C(F)(F)C(F)(F)C(F)F)c1
Agent: O=C(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Product: NC(=O)OCc1cccc(COC(N)=O)c1
Yield: 98.5 %

Procedure:
The reaction was carried out in the same manner as Example 3 except for using 80.5 g (0.1642 mol) of bis(2,2,3,3,4,4,5,5-octafluoropentyl) carbonate (to be referred to as “BOFC” hereinafter) synthesized in the above Synthesis Example 4 in place of BTFC, and it was confirmed that m-xylylene bis(2,2,3,3,4,4,5,5-octafluoropentyl carbamate) (to be referred to as XDC-4 hereinafter) was generated as the main product (XDA base yield 98.5%). Structural assignment of the product XDC-4 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of XDC-4, 1H-NMR and 19F-NMR were shown in the following.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.C=O.[BH3-][C:17]#N.[Na+]>C(O)(=O)C>[CH3:17][N:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1
Reactant: [BH3-]C#N
Reactant: Brc1cncc(OC[C@@H]2CCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC[C@H]1COc1cncc(Br)c1

Procedure:
A 480 mg sample of the free base of 3-(2-(S)-azetidinylmethoxy)-5-bromopyridine, from Example 67 above, was dissolved in 4 mL of acetic acid treated with 1 mL of 37% HCHO and 500 mg of NaBH3CN at 0° C. for 4 hr. The solvents were removed under reduced pressure The residue was basified with NaHCO3 solution. The mixture was extracted with methylene chloride, the extract was dried over MgSO4, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with 200:1 and 100: 1 chloroform:methanol to give 68 mg of the title compound. MS (DCI/NH3) m/e: 257/259 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.28 (d, J=1.9 Hz, 1H), 8.26 (d, J=2.6 Hz, 1H), 7.38 (dd, J=1.9, 2.6 Hz, 1H), 4.02 (d, J=6.3 Hz, 2H), 3.51-3.44 (m, 1H), 3.43-3.37 (m, 1H), 2.93-2.84 (m, 1H), 2.41 (s, 3H), 2.13-2.03 (m, 2H).
Reaction SMILES: [CH:1]([O:4][Si:5]([CH3:8])([CH3:7])Cl)([CH3:3])[CH3:2].[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Mg]Cl)=[CH:13][CH:12]=1)=[CH2:10].C(C1C=CC(Cl)=CC=1)=C.[Mg]>C1COCC1>[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Si:5]([CH3:8])([CH3:7])[O:4][CH:1]([CH3:3])[CH3:2])=[CH:13][CH:12]=1)=[CH2:10]
Reactant: C=Cc1ccc([Mg]Cl)cc1
Reactant: CC(C)O[Si](C)(C)Cl
Agent: C=Cc1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc([Si](C)(C)OC(C)C)cc1
Temperature: 10 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of isopropoxydimethylchlorosilane (15.2 g, 100 mmole) in dry THF (50 mL) was added dropwise over a 1 hour period to a solution of (4-vinylphenyl)magnesium chloride, prepared from 4-vinylphenyl chloride (13.85 g, 100 mmole) and magnesium (3.0 g, 125 mmole) in dry 100 mL THF. The temperature was maintained at 10° C. during the addition. The reaction mixture was stirred at room temperature for over 18 hours. The desired product distilling at 45°-49° C./0.2 mm was obtained in 45% yield.
Reaction SMILES: [OH:1][C@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.C(#N)C>[OH:1][C@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:12]([F:29])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Yield: 25.4 %

Procedure:
To a solution of (S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 5) (1.25 g, 2.58 mmol, 1 eq) in DMF (26 mL) was added a mixture of Selectfluor (1.187 g, 3.35 mmol, 1.3 eq) in acetonitrile (26 mL). The reaction mixture was irradiated with microwave at 82° C. for 10 minutes and filtered. The filtrate was purified by preparatory LC/MS (30-55% CH3CN in H2O) to give (S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 19) as an off-white solid (331 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.36-3.42 (m, 1H) 3.42-3.51 (m, 1H) 3.59 (s, 3H) 3.63-3.72 (m, 1H) 3.73-3.81 (m, 1H) 4.32 (dd, J=13.14, 3.03 Hz, 1H) 4.79 (br. s., 1H) 5.10 (br. s., 1H) 6.98 (td, J=8.46, 5.31 Hz, 1H) 7.52 (dd, J=8.46, 1.14 Hz, 1H) 7.68 (dd, J=10.36, 1.77 Hz, 1H) 8.51 (s, 1H) 10.24 (d, J=2.27 Hz, 1H). [M+H] calc'd for C17H15F2IN4O4, 505; found, 505.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=1)=O.[NH2:23][C:24]1([CH2:37][CH3:38])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][C:24]([NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=2)([CH2:37][CH3:38])[CH2:29][CH2:28]1)=[O:31])([CH3:34])([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Reactant: CCC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC1(NCc2cn(C(=O)OC(C)(C)C)c3nccc(C(=O)OC)c23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
1-tert-Butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (211 mg, 0.692 mmol) was dissolved in MeOH (10 mL) and tert-butyl 4-amino-4-ethylpiperidine-1-carboxylate (158 mg, 0.692 mmol) were added followed by 2 drops of acetic acid. The solution was allowed to stir at room temperature for 2 h. Then sodium cyanoborohydride (44 mg, 0.692 mmol) was added over the course of 6 h at room temperature. The solution was quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/Hexanes) gave 127 mg of 1-tert-butyl 4-methyl 3-((1-(tert-butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate. [M+H] found 417.
Reaction SMILES: Cl.C1(C[N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[OH:16])[CH2:11][CH2:10]2)C=CC=CC=1.C(O)C.[H][H]>CO.[Pd]>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:29]=[CH:28][C:27]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)([OH:16])[CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:32][CH:31]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of 10.0 grams (0.019 mole) of N-phenylmethyl-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine hydrochloride (prepared as in Steps A and B of Example 12) and 3.0 grams of 5% palladium (catalyst) on charcoal in about 200 mL of 1:1 methanol:ethanol was shaken in a Parr hydrogenator for five to six hours at about 85° C., until the theoretical amount of hydrogen gas was taken up. The mixture was cooled to ambient temperature where it stood for about 18 hours. The mixture was filtered and concentrated under reduced pressure to a residue, which was stirred with ethyl acetate and an aqueous solution saturated with sodium bicarbonate until the residue dissolved. The organic layer was separated and passed through phase-separation paper to remove aqueous material. The organic layer was concentrated under reduced pressure, yielding about 7.0 grams of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[CH2:21][OH:22])[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:23]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[CH2:21][O:22][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:23]=1
Reactant: OC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reaction time: 2.5 h
Yield: 95.6 %

Procedure:
To a stirred solution of {(1R, 2R)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropyl}-methanol (3.712 g, 10.03 mmol) in Et3N (8.5 mL, 61.1 mmol) and anhydrous CH2Cl2 (100 mL ) at 0° C. under N2 was added dropwise CH3SO2Cl (930 uL, 12.02 mmol ). Stirring was continued at 0° C. for 2.5 h. The reaction was quenched with H2O (20 mL). A solution of K2CO3 (4.28 g, 31.01 mmol) in H2O (60 mL) was then added. The resulting mixture was stirred at rt for 15 min, then extracted with CH2Cl2, washed with brine, dried over Na2SO4. Filtration, concentration and drying afforded the desired product (4.301 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13]2[CH:14]=[CH:15][NH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)=[O:11].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13]2[CH2:14][CH2:15][NH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)=[O:11]
Reactant: Cc1cccc(NC(=O)c2cccc3[nH]ccc23)c1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)c2cccc3c2CCN3)c1C
Reaction time: 0.17 h

Procedure:
To compound 11 (0.15 g) was added triethylsilane (0.36 mL) and trifluoroacetic acid (10 mL). After stirring for 10 min. the solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and sodium bicarbonate. The ethyl acetate layer was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the crude product. Trituration with hexane/ethyl acetate 8/2 gave the product. NMR (300 MHz, CDCl3) δ 7.62 (1H, d, J=3 Hz), 7.53 (1H, s), 7.13 (2H, q, J=3 Hz), 7.04 (2H, m), 6.77 (1H, d, J=3 Hz), 3.62 (2H, t, J=3 Hz), 3.39 (2H, t, J=3 Hz), 2.33 (3H, s), 2.21 (3H, s).
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH:13](Br)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1>C(#N)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:3]=[CH:1][S:2][C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Reactant: NC=S
Solvent: CC#N
Product: COc1ccc(-c2ncsc2-c2ccc(OC)cc2)cc1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
An ethereal solution of thioformamide (0.153 mole) was concentrated in vacuo at less than 25°. The residue was slurried with acetonitrile (10 ml.) and cooled in an ice water bath. p-Methoxy-2-bromo-2-(p-methoxyphenyl)acetophenone (4.27 g.; 0.0128 mole) was dissolved in acetonitrile (50 ml.) and added via syringe to the above slurry. After stirring for 15 minutes in ice, the flask was refrigerated at 5°-10° for 16 hours. The solution was then stirred at ambient temperature for 70 hours before work up. The solvent was removed in vacuo and the residue was partitioned with ether and saturated sodium bicarbonate solution. The ether layer was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried (sodium sulfate), and concentrated in vacuo. The residue was chromatographed on silica gel 60 at low pressure with 5% ethyl acetate in benzene. Recrystallization from hexane:benzene (11:1) afforded 2.25 g. (59% yield) of 4,5-bis(p-methoxyphenyl)thiazole.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22])[CH3:5].C1(=O)[NH:28][C:27](=O)C2=CC=CC=C12.[K].CNN>CN(C)C=O.CCOC(C)=O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:28][CH3:27])[S:7]1(=[O:22])=[O:23]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(CCBr)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: CNN
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNCCC(C)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 36.6 %

Procedure:
1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.25 mmol) was dissolved in dimethylformamide (2 mL) in a microwave cuvette and potassium phthalimide (0.06 g, 0.3 mmol) was added. The mixture was irradiated at 100° C. for 3 minutes. Upon cooling the mixture was diluted with EtOAc and washed with water and brine then dried with Na2SO4. Upon concentration, the residue was dissolved in MeOH (5 mL), methyl hydrazine (0.06 g, 1.25 mmol) was added and the mixture heated to reflux for 5 hours. Upon cooling the reaction was concentrated and water (10 ml) added followed by acetic acid (to pH 4). After 1 hour the mixture was filtered and basified to pH 14 with NaOH then extracted with dichloromethane. The organic extracts were washed with water, dried with Na2SO4 and purified via Isco chromatography (Redisep, silica, gradient 0-10% 7M ammonia/MeOH solution in dichloromethane) to afford 32 mg of 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][Sn:5]([C:14]1[S:18][C:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:16][CH:15]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9].[H-].[Na+].I[CH2:30][CH2:31][CH3:32]>CN(C=O)C.O>[CH2:30]([N:19]([C:17]1[S:18][C:14]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:15][N:16]=1)[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:31][CH3:32]
Reactant: CCCI
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(CCC)C(=O)OC(C)(C)C)s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of 2-(N-BOC)-5-(tributylstannyl)thiazole (200 mg, 0.409 mmole) in DMF (2 mL) was added NaH (60% dispersion in mineral oil, 20 mg, 0.500 mmole) at RT. After gas evolution had ceased 1-iodopropane (0.048 mL, 0.490 mmole) was added and the mixture was heated to 60° C. After stirring overnight the mixture was cooled to RT, diluted with H2O, and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-25 g SiO2, 0-10% EtOAc/hexanes) gave the title compound (155 mg, 71%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.33 (s, 1 H); 4.11-4.03 (m, 2 H); 1.79-1.69 (m, 1 H); 1.62-1.52 (m, 18 H); 1.38-1.28 (m, 7 H); 1.13-1.05 (m, 7 H); 0.95 (m, 3 H); 0.93-0.84 (m, 9 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]1=[O:24])[C:5](O)=[O:6].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:62][C:63]1([CH3:75])[O:67][C@H:66]([CH2:68][N:69]2[CH:73]=[CH:72][C:71]([NH2:74])=[N:70]2)[CH2:65][O:64]1>CN(C)C=O.C(OCC)(=O)C>[CH3:62][C:63]1([CH3:75])[O:67][C@H:66]([CH2:68][N:69]2[CH:73]=[CH:72][C:71]([NH:74][C:5](=[O:6])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][CH:15]=4)=[CH:10][C:9]3=[O:24])[CH2:3][CH:2]([CH3:25])[CH3:1])=[N:70]2)[CH2:65][O:64]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3ccccc23)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3ccccc23)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A solution of (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.37 g, 1.11 mmol) in N,N-dimethylformamide (4.27 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.55 mL, 3.33 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.73 g, 1.66 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.24 g, 1.22 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (75 mL) and was washed with a saturated aqueous ammonium chloride solution (1×150 mL), a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 10-30% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.43 g, 76%) as a light orange solid: HR-ES-MS m/z calculated for C29H34N4O5 [M+H]+ 519.2602, observed 519.2604; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.3 Hz, 3H), 0.96 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.41-1.69 (m, 2H), 1.70-1.85 (m, 1H), 3.74 (dd, J=8.3, 5.9 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.11 (t, J=5.6 Hz, 2H), 4.28-4.44 (m, 2H), 4.65-4.77 (m, 2H), 4.90 (dd, J=10.4, 4.7 Hz, 1H), 6.46 (d, J=2.1 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.54-7.67 (m, 4H), 7.91 (d, J=8.2 Hz, 1H), 7.99-8.09 (m, 2H), 10.80 (s, 1H).