Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH:26]=[O:27].C(O)(C)C>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]([C:25]2[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)[OH:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(OC)cc(C(O)c2cccc(OCc3ccccc3)c2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
A stirred mixture of 1-benzyloxy-3-bromo-benzene (10.56 g, 40.1 mmol) and dry THF (35 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (17.7 mL, 44.1 mmol) and stirred for 20 min. Then a mixture of 3,5-dimethoxy-benzaldehyde (7.34 g, 44.1 mmol) in dry THF (30 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (18.5 mL, 241 mmol) and added water (30 mL). The mixture was extracted with EtOAc (3×80 mL). The combined organic phases were washed with water (2×80 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3-benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as an oil (11.54 g, 82% yield): 1H NMR (CDCl3) δ 2.21 (d, J=4 Hz, 1H, OH), 3.76 (s, 6H, 2OCH3), 5.04 (s, 2H, CH2), 5.72 (d, J=4 Hz, 1H, CH), 6.36 (t, J=2 Hz, 1H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.85-7.04 (m, 3H, Ar), 7.21-7.43 (m, 6H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:22][C@H:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][OH:25].C(N1C2=NC=C(C(N[C@H](C3C=CC=CC=3)CO)=O)C(NC3CCOCC3)=C2C=N1)C>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:22][C@H:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:24][OH:25])=[O:21])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Agent: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)Cc3ccccc3)cnc21

Procedure:
Intermediate 45 was prepared from Intermediate 17 and (2R)-2-amino-3-phenyl-1-propanol (commercially available from Aldrich) using an analagous method to that for Intermediate 42. LCMS showed MH+=424; TRET=2.59 min.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([OH:10])[CH2:8][OH:9].[CH3:11][C:12]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:25][O:26][CH3:27])[CH:23]=O>[Cl-].[Na+].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:27][O:26][N:25]=[C:22]([CH:23]1[O:10][CH2:7][CH2:8][O:9]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:13]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:12]=1[CH3:11]
Reactant: OCCO
Reactant: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CON=C(c1ccccc1COc1cc(C)ccc1C)C1OCCO1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Benzene (4 ml), ethylene glycol (0.12 g, 2.0 mmol) and p-toluenesulfonic acid monohydrate (0.01 g, 0.05 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.3 g, 1.0 mmol), and the mixture was subjected to azeotropic dehydration for 2 hours. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetatein-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1,3-dioxolan-2-yl ketone O-methyloxime (0.30 g, yield 87.9%) as colorless crystals. mp 136-137° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N:10]([O-])=O.[Na+].[O:14]=[C:15]1[O:21][C@H]([C@H](CO)O)C(O)=[C:16]1[OH:17]>O>[Br:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]([C:16](=[O:17])[C:15]([OH:21])=[O:14])[NH2:10]
Reactant: O=N[O-]
Reactant: Nc1ccccc1Br
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NN(C(=O)C(=O)O)c1ccccc1Br
Temperature: -1 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a 250 ml flask under a nitrogen atmosphere, concentrated HCl (50 ml, 32%, 0.51 moles) was charged and cooled down to −2 to 0° C. 2-Bromoaniline (10 g, 0.058 moles) was added in one portion as a solid. The acidic suspension was re-cooled to −2 to 0° C. and sodium nitrite (4.8 g, 0.070 moles) dissolved in water (10 ml) was added dropwise to the acidic mixture through an addition funnel over a period of 40 minutes at −2 to 0° C. The resulting mixture (yellow suspension) was stirred for 1 hour at −2 to 0° C. L-Ascorbic acid (10.3 g, 0.058 moles) was then added in portions as a solid at −2 to 0° C. over a period of 45 minutes. The reaction mixture (orange suspension) was allowed to come to room temperature (18-20° C.), then heated to 40° C. and stirred for 3 hours at this temperature. A red suspension was formed. The reaction mixture was cooled and stirred for 2 hours at 0-5° C. The slurry was filtered, washed with water and dried to constant weight to afford 14.3 g of crude 2-bromophenylhydrazido oxalic acid as an orange crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.C(Cl)CCl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:21][C:31](=[O:32])[CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:34])([F:22])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(NC(=O)Cc2cccc(C(F)(F)F)c2)ccc1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 3-methyl-4-(3-pyrimidin-4-yl-pyridin-2-yloxy)-phenylamine (30 mg, 0.11 mmol), (3-trifluoromethyl-phenyl)-acetic acid (27 mg, 0.13 mmol), and EDC (41 mg, 0.22 mmol) was added CH2Cl2 (2.0 mL). The mixture was stirred for 6 h at RT, concentrated, diluted with EtOAc, and extracted with saturated NaHCO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to yield N-(3-Methyl-4-((3-(4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide. MS m/z=465 [M+1]+. Calc'd for C25H19F3N4O2: 464.45.
Reaction SMILES: C1(C[NH:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([B:13]3[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]3)[CH:12]=2)CC1.C(S(N1CC[CH:30](C2C3C(=C(C(N)=O)C=C(C4C=NC=C(CNC(C)C)C=4)C=3)NC=2)[CH2:29][CH2:28]1)(=O)=O)C.C(N)(C)C.CC1(C)C(C)(C)OB(C2C=C(C=O)C=NC=2)O1.[BH3-]C#N.[Na+]>CO>[CH3:28][CH:29]([NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH:12]=1)[CH3:30]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNC(C)C)c4)cc23)CC1
Reactant: CC1(C)OB(c2cncc(CNCC3CC3)c2)OC1(C)C
Agent: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)N
Solvent: CO
Product: CC(C)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The (cyclopropyl methyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine used to prepare 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-pyridinyl)-1H-indole-7-carboxamide was prepared as follows: isopropylamine (0.011 mL, 0.129 mmol) was added to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol) in MeOH (1 mL) in a 2-dram vial. NaCNBH3 (16 mg, 0.258 mmol) was then added, the vial was capped and the reaction was stirred at room temperature for 24 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 22 mg of crude (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(OCCOCC)C>CCOC(C)=O.CCO>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: CCOCCOCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N2CCOCC2)c(Cl)cc1[N+](=O)[O-]
Yield: 54 %

Procedure:
1,2-Dichloro-4-methyl-5-nitrobenzene (R.J. De Lang, et al. Tetrahedron (1998), 54(12), 2953-2966.) (1 g; 4.8 mmol), morpholine (1 ml) and 1,2-diethoxyethane (1 ml) were heated in a microwave oven at 160° C. for 2 h. The reaction mixture was poured on water/2N HCl 10/1 (50 ml) and extracted with TBME three times. The combined organic phases were dried over Na2SO4, evaporated and recrystallised from hot TBME to yield the title compound as yellow crystals (670 mg; 54%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:45])[NH:12][C:13]2[CH:14]=[C:15]([CH:42]=[CH:43][CH:44]=2)[O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][C@H:30]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:46]>O1CCOCC1.ClCCl>[ClH:46].[ClH:46].[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:12][C:13]2[CH:44]=[CH:43][CH:42]=[C:15]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][C@H:30]5[CH2:34][CH2:33][NH:32][CH2:31]5)=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:14]=2)=[O:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Yield: 67 %

Procedure:
A solution of (S)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazol-3-yl)ureido)phenoxy)-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate from the previous step (35 mg, 0.0566 mmol) and hydrochloric acid (0.1 mL of a 4N solution in 1,4-dioxane, 0.40 mmol) in dry dichloromethane (0.01 mL) was stirred at room temperature for 2 h. Concentrated under reduced pressure to afford (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)urea dihydrochloride as a colorless solid (22 mg, 67%), which did not require further purification. 1H NMR (300 MHz, MeOH-d4) δ 9.02 (brs, 1H), 7.82 (s, 1H), 7.73 (brs, 1H), 7.54 (s, 1H), 7.41 (m, 1H), 7.29 (m, 1H), 7.06 (m, 1H), 6.32 (s, 1H) 5.56 (brs, 1H), 4.04 (s, 3H), 3.50-3.85 (m, 5H), 2.50-2.60 (m, 2H), 1.35 (s, 9H); LC-MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:15]([C:12]1[CH:11]=[C:10]([CH3:14])[C:3]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[C:2]([CH3:1])[CH:13]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)COc1c(C)cccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COC(=O)COc1c(C)cc(C(C)=O)cc1C

Procedure:
7 Grams of methyl 2,6-dimethylphenoxyacetate, 3.4 ml of acetic anhydride and 100 ml of carbon disulfide were mixed at 0° C., and to the mixture was added 17.9 g of aluminum chloride, and the resulting mixture was heated until gas was evolved. After the gas-evolution was ceased, the reaction mixture was refluxed for 30 minutes under heating. Then water was added to the solution. The resulting mixture was extracted with di-isopropyl ether, washed with water, dried over anhydrous magnesium sulfate. The oily solution was concentrated to obtain an oily substance. The oily substance was chromatographed on silica gel to obtain 6.1 g of methyl 4-acetyl-2,6-dimethylphenoxyacetate, nD21.6 1.5165.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[Br:13]NC(=O)CCC(N)=O>C(#N)C>[Br:1][C:2]1[S:3][C:4]2[C:10]([Br:13])=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: COc1cccc2sc(Br)nc12
Solvent: CC#N
Product: COc1ccc(Br)c2sc(Br)nc12
Yield: 119.4 %

Procedure:
Starting from 2-bromo-4-methoxybenzothiazole (1.6 g), N-bromosuccinamide (0.91 g) and acetonitrile (100 ml). Purification by flash chromatography (eluent 20% ethylacetate/hexane) yielded the title compound as an off-white solid (1.8 g). TLC Rf 0.31 (20% ethyl acetate in heptane).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20]SC)[CH:12]=3)=[CH:6][C:5]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])=[C:4]([F:36])[CH:3]=1.[CH:37]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:48][S:49]([O-:51])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:7]([C:8]2[C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][S:49]([CH3:37])(=[O:51])=[O:48])[CH:12]=3)=[CH:6][C:5]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])=[C:4]([F:36])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(NCCSC)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(NCCS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a suspension of 1-(4-bromo-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.18 g, 0.31 mmol) in DCM (25 mL) was added 70-75% mCPBA (0.14 g, 0.63 mmol) and the suspension was stirred at RT for 15 minutes. The mixture was diluted with a 10% Na2SO3 solution (30 mL), the layers were separated, and the organic layer was washed with satd. NaHCO3 solution, then brine, dried (Na2SO4), and concentrated. The crude product was purified by silica gel chromatography (MeOH/DCM) to afford 1-(4-bromo-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (115 mg, 61% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J=10.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.28-7.24 (m, 3H), 6.96 (t, J=7.6 Hz, 1H), 6.42 (s, 1H), 4.12 (q, J=6.8 Hz, 2H), 3.77 (q, J=6.4 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 3.02 (s, 3H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 602.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=[O:11])[CH:3]=1.C[Si](C)(C)[O-].[K+].Cl.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(N)c(Cl)c(Cl)n1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)nc(Cl)c1Cl
Yield: 98.5 %

Procedure:
The compound prepared in Example 405 (2.438 g) and potassium trimethylsilanolate (2.971 g) were suspended in tetrahydrofuran (100 mL) and stirred at reflux for 4 hours. The reaction mixture was dissolved in water and added to 1 N hydrochloric acid. Ethyl acetate was added and the system stirred at room temperature. The organics were dried, magnesium sulfate and concentrated under reduced pressure to furnish the title compound (2.250 g), which was used without further purification, possessing the following physical data.
Reaction SMILES: [CH3:1][P:2](=[O:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[C:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1.O>[CH3:1][P:2]1(=[O:7])[CH2:5][CH2:6][N:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=CP(C)(=O)C=C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCP(C)(=O)CC2)CC1
Yield: 46.5 %

Procedure:
A solution of methyl divinyl phosphine oxide (140 mg, 1.21 mmol) and 1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1 THF/water (3 mL) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired compound as a white solid (178 mg, 38% yield).
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.Cl.[F:11][C:12]([F:46])([F:45])[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:16]=[C:15]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=3)[CH:30]=2)[N:14]=1>C1COCC1>[CH3:3][NH:5][S:41]([C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([C:31]2[CH:30]=[C:29]([C:15]3[N:14]=[C:13]([C:12]([F:46])([F:45])[F:11])[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[N:16]=3)[CH:34]=[CH:33][N:32]=2)[CH:36]=1)(=[O:43])=[O:42]
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of methylamine solution (2M in THF) (1.5 ml, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.46 g, 92%). MS (ISP) 538.8 [(M+H)+]; mp 174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:10][C:11]=2[C:12]#[N:13])=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:10][C:11]=2[C:12]2[NH:24][N:23]=[N:22][N:13]=2)=[CH:20][CH:21]=1
Reactant: N#Cc1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2nnn[nH]2)cc1
Yield: 4.7 %

Procedure:
To a solution 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carbonitrile (167 mg, 0.536 mmol) in DMF (3.5 mL) was added sodium azide (104 mg, 1.61 mmol) and ammonium chloride (86 mg, 1.61 mmol) and the resulting mixture was heated at 100 degrees overnight. The reaction was cooled and taken up in ethyl acetate and water. The aqueous layer was concentrated in vacuo, and the residue was purified by silica gel chromatography (MeOH/DCM=0/100→10/90) to give 9 mg (5% yield) of the title compound. LC/MS (FA) ES+ 355, 357. 1H NMR (400 MHz, DMSO-d6) δ: 8.74-8.73 (m, 2H), 7.93-7.92 (m, 2H), 7.38-7.32 (m, 4H), 4.62 (s, 2H).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:8])=[O:7])=[CH:4][CH:3]=1.C(OC(=O)[N:19]([CH3:49])[C@H:20]([C:22](=[O:48])[NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]2[C:42]3[C:37](=CC=C[CH:41]=3)[CH:36]=[CH:35][C:34]=2[CH3:43])[C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=2[NH:26][CH2:25]1)[CH3:21])(C)(C)C>>[ClH:8].[ClH:8].[CH3:49][NH:19][C@@H:20]([CH3:21])[C:22]([NH:23][C@H:24]1[CH2:25][N:26]([C:1](=[O:11])[C:2]2[CH:10]=[CH:9][C:5]([C:6]([N:26]3[C:27]4[CH:47]=[CH:46][CH:45]=[CH:44][C:28]=4[N:29]([CH2:32][C:33]4[C:42]5[C:37](=[CH:1][CH:2]=[CH:3][CH:41]=5)[CH:36]=[CH:35][C:34]=4[CH3:43])[C:30](=[O:31])[C@@H:24]([NH:23][C:22](=[O:48])[C@@H:20]([NH:19][CH3:49])[CH3:21])[CH2:25]3)=[O:7])=[CH:4][CH:3]=2)[C:27]2[CH:47]=[CH:46][CH:45]=[CH:44][C:28]=2[N:29]([CH2:32][C:33]2[C:42]3[C:37](=[CH:4][CH:5]=[CH:6][CH:41]=3)[CH:36]=[CH:35][C:34]=2[CH3:43])[C:30]1=[O:31])=[O:48]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Product: CN[C@@H](C)C(=O)N[C@H]1CN(C(=O)c2ccc(C(=O)N3C[C@H](NC(=O)[C@H](C)NC)C(=O)N(Cc4c(C)ccc5ccccc45)c4ccccc43)cc2)c2ccccc2N(Cc2c(C)ccc3ccccc23)C1=O
Product: Cl
Yield: 32.6 %

Procedure:
In a similar manner to that described for Example 22, terephthaloyl chloride (60 mg, 0.296 mmol) and methyl-{(S)-1-[(S)-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (Intermediate 15) (305.37 mg, 0.591 mmol) were converted to the title compound (50 mg) as an off white solid. LC-MS: 963.6 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[C:20]([NH:21][C:22](=O)[CH:13]2[CH2:12]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:33][C:34]([F:39])([F:38])[C:35](O)=[O:36].Cl>ClCCl.C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[C:20]([N:21]([C:35](=[O:36])[C:34]([F:39])([F:38])[F:33])[CH2:22][CH:13]2[CH2:12]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC12
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN2c3ccccc3N(C(=O)C(F)(F)F)CC2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 2 ml portion of THF solution containing 100 mg (0.30 mmol) of 3-benzyloxycarbonyl-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one was cooled to 0° C., mixed with 59 μl (0.59 mmol) of borane-dimethyl sulfide complex and stirred overnight at room temperature. The reaction solution was mixed with ice water, stirred for 30 minutes and extracted with ethyl acetate. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure, and the thus obtained residue was recrystallized from ethyl acetate-hexane to obtain crude crystals. A 97 mg portion of the crude crystals were dissolved in 2 ml of dichloromethane, and the solution was mixed with 125 μl (0.90 mmol) of triethylamine and 64 μl (0.45 mmol) of anhydrous trifluoroacetic acid and stirred overnight at room temperature. The reaction solution was poured into ice water, acidified by adding 1 N hydrochloric acid and then extracted with ethyl acetate. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure, and the thus obtained residue was purified by a silica gel chromatography (30 cc; elution by ethyl acetate-hexane=1:5) to obtain 94 mg (74% in yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][C@@H:19]1[CH2:24][O:23][C@@H](C2C=CC=CC=2)[O:21][CH2:20]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: Cl
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1cc(F)ccc1F

Procedure:
In the same manner as that described in Example 7(vi) above, 5.0 g of crude (2R,3 R)-2-(2,5-difluorophenyl)-3-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 8(v) above] were treated with hydrochloric acid and the product obtained was purified by chromatography on a silica gel (50 g) column using a 3:100 mixture of methanol and ethyl acetate as the eluant to afford 3.17 g [overall yield from Step 8(v) 83%] of the of the title compound as an oil.