Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][N:10]=[C:11]([CH3:19])[CH:12]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2cc(C)nc(N)n2)ccn1
Reaction time: 8 h

Procedure:
A mixture of 2.00 g (13.9 mmol) 2-amino-4-chloro-6-methylpyrimidine, 2.48 g (18.1 mmol) 2-picoline-4-boronic acid, 0.43 g (2.8 mmol) tetrakis(triphenylphosphine)palladium(0) and 3.85 g (27.9 mmol) potassium carbonate in 40 mL 1,2-dimethoxyethane and 4 mL water is heated to reflux temperature and stirred overnight. The reaction mixture is concentrated under reduced pressure, water is added and the precipitated product is filtered off and dried in vacuo at 40° C. Yield: 1.94 g (69%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[C:22]([Cl:23])=[C:21]3[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:29])=[C:10]([N+:32]([O-])=O)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C.[Zn]>[NH2:32][C:10]1[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:31]=[CH:30][C:11]=1[O:12][C:13]1[C:22]([Cl:23])=[C:21]2[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]2)=[CH:15][C:14]=1[Cl:29]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Cl
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a mixture of ethyl 7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8-dichlorochroman-4-carboxylate (2.70 g, 5.27 mmol) in 25 mL of THF and 25 mL of saturated ammonium chloride was added zinc dust (3.45 g, 52.7 mmol) under argon. After 1 hour at ambient temperature, the reaction was diluted with ethyl acetate and filtered. The biphasic filtrate was separated and the organic layer was washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in dichloromethane, concentrated onto silica gel and purified by flash column chromatography, eluting with 20% ethyl acetate in hexanes to give ethyl the desired product (2.20 g, 86.5% yield) as a white foam. MS (ESI) m/z=482 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[Si:20]([O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Yield: 97.2 %

Procedure:
A solution of 1H-indazol-5-ol (25 g, 186.38 mmol, 1.00 equiv), imidazole (31.7 g, 466.18 mmol, 2.50 equiv) and tert-butyl(chloro)dimethylsilane (33.8 g, 224.25 mmol, 1.20 equiv) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 2 h. The reaction was quenched by the addition of water/ice (200 mL). The precipitate was collected by filtration and dried in a vacuum oven to give 45 g (97%) of 5-(tert-butyldimethylsilyloxy)-1H-indazole as a brown solid. 1H NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 7.02 (dd, J=9.0 Hz, 2.4 Hz, 1H), 1.03 (s, 9H), 0.24 (s, 6H) ppm. LCMS (method D, ESI): RT=1.66 min, m/z=249.0 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]=[CH2:3].O1[CH2:21][CH2:20][CH2:19][CH2:18]1.C([Li])CCC.C(Cl)/C=C/C>O.CCCCCC>[CH2:1]([C:4]1([CH2:18]/[CH:19]=[CH:20]/[CH3:21])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH2:3]
Reactant: C1CCOC1
Reactant: C=CCC1c2ccccc2-c2ccccc21
Agent: C/C=C/CCl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: C=CCC1(C/C=C/C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
There were put 2.5 g of 9-allylfluorene and 31.3 mL of dry tetrahydrofuran manufactured by Kanto Chemical Co., Inc. in a 100 mL-three necked flask. There were added dropwise thereto at 0° C. over 30 minutes 9 mL of a hexane solution of n-butyllithium (concentration: 1.6 M) manufactured by Kanto Chemical Co., Inc. The resultant mixture was stirred for 2 hours at room temperature, and then 1.4 mL of trans-crotyl chloride manufactured by Aldrich Chemical Company was added dropwise thereto at 0° C. The temperature of the mixture was raised gradually up to room temperature, and then the mixture was stirred for 6 hours at room temperature. Water was added to the reaction mixture, and the obtained mixture was subjected to extraction with ether. The extract was washed with water and with a saline solution in this order. The washed extract was dried over anhydrous magnesium sulfate manufactured by Nacalai Tesque, Inc. The dried extract was subjected to removal of the solvent by distillation, and the resultant liquid was distilled in vacuo, thereby obtaining 2.43 g of 9-allyl-9-((2E)-2-butenyl)-fluorene at 155° C. under 4 mmHg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[B-](F)(F)(F)[F:13].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N.CC(O)=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[C:10]([F:13])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1c[nH]c2nc(Cl)nc(Cl)c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.06 mmol) and SelectFluor (560 mg, 1.58 mmol) in CH3CN (5 mL) and HOAc (1 mL) was stirred at 70° C. for 18 h. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (50 mg).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14].C(=O)(O)[O-].[Na+]>ClCCl>[F:7][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCO)ccc43)ncn2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCF)ccc43)ncn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
(Diethylamino)sulfur trifluoride (DAST, 34 μL, 0.260 mmol) was added at −78° C. to a dichloromethane (5 mL) solution of the tert-butyl 4-[(6-{5-[(2-hydroxyethyl)sulfonyl]indolin-1-yl}pyrimidin-4-yl)oxy]piperidine-1-carboxylate (43.1 mg, 0.0855 mmol) produced in Example 84, and the mixture was stirred at −78° C. for 1 hour and further stirred for 30 minutes with heating to 0° C. To the reaction solution, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate three times. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-7:3, V/V) to obtain the title compound as white foam (17.0 mg, yield: 39%).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH2:24][CH3:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: CCN
Product: CCNC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (10.0 g) and ethylamine gas, the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethylaminoacrylate (9.0 g, white crystals), which is then treated with 60% sodium hydride (1.30 g) as in REFERENCE EXAMPLE 22 to give ethyl 1-ethyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (6.76 g), as pale yellow needles (recrystallized from dichloromethane--n-hexane), m.p. 197°-198° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]=1[CH3:23].[NH3:24]>C(O)C>[NH2:24][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]=1[CH3:23]
Reactant: N
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCCl
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCN

Procedure:
Dissolve N-(2-chloroethyl)-2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline hydrochloride (19.3 g, 50 mmol) in 100 ml ethanol, and bubble in NH3 (8.5 g, 0.50 mol). Heat in a steel bomb 16 hours at 100°. Let cool and partition between ether and water. Extract the ether with 1.0 N HCl. Basify the aqueous with Na2CO3, extract with ether, dry and concentrate. Recrystallize from ether-hexane to give the title compound as a solid product, m.p. 158°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8][C:9](N(C)C)=O.C[O-].[Na+].ClC[C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][CH:43]=1)[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:42]1[CH:43]=[CH:24][CH:25]=[C:26]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])[CH:41]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c(Cl)c1
Reaction time: 12 h
Yield: 35 %

Procedure:
A mixture of methyl [3-chloro-4-[(dimethylamino)carbonylthio]phenyl]acetate (0.80 g), a 28% solution of sodium methoxide in methanol (0.75 g) and methanol (20 mL) was stirred with heating under reflux for 2 hrs. 4-(3-Chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.87 g) was added to the reaction mixture at room temperature and the mixture was further stirred for 12 hrs. The reaction mixture was poured into 0.1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[3-chloro-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetate as a colorless oil (0.48 g, yield 35%), from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=O)([F:4])[F:3].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO.O>[F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)=[N:17][OH:18])([F:4])[F:3]
Reactant: NO
Reactant: O=C(c1ccc2c(c1)OCO2)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Trifluoromethyl(3,4-methylenedioxyphenyl) methanone (1.46 g, 0.0067 mole), hydroxylamine hydrochloride (1.06 g), 0.015 mole) and sodium acetate (0.86 g, 0.010 mole) were dissolved in a mixture of methanol (4 ml) and water (4 ml) and heated to reflux for 4.5 hours. After cooling to room temperature, water (10 ml) was added and the mixture extracted with ether (3×15 ml). The combined extracts were washed with water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the solvent in vacuo the residue was recrystallized from a mixture of dichloromethane and petroleum spirit (40°-60° C.) to give trifluoromethyl(3,4-methylenedioxyphenyl)methanone-oxime (1.2 g), (76.9%) m.p. 96.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([C@H:16]2[CH2:18][C@H:17]2[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[OH:21][CH2:20][CH2:19][C@@H:17]1[CH2:18][C@@H:16]1[CH:13]1[CH2:12][CH2:11][N:10]([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 ml RBF the 6-chloropyridine-3-carbaldehyde (1.907 g, 13.47 mmol) and 2-[(1S,2R)-2-(piperidin-4-yl)cyclopropyl]ethanol (2.28 g, 13.47 mmol) were dissolved in DMF (13.47 ml). Cesium carbonate (13.17 g, 40.4 mmol) was added and the mixture stirred at RT overnight. The mixture was poured into 4:1 water:brine (200 ml), extracted with EtOAc (3×100 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel, Biotage 100M, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 275 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4](C)[CH:3]=1.BrC1C=CC(I)=C([Cl:19])C=1.C[Si](C)(C)C=C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([Cl:19])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1C
Reactant: Clc1cc(Br)ccc1I
Agent: C=C[Si](C)(C)C
Product: C=Cc1ccc(Br)cc1Cl
Yield: 96 %

Procedure:
Using a procedure analogous to that used to prepare 30A, 4-bromo-2-chloro-1-iodobenzene (8 g, 25 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 160° C. for 1 h and worked up in a manner similar as in 30A to yield 61A (5.2 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.41 (d, J=11.86 Hz, 1 H) 7.02 (dd, J=17.36, 11.21 Hz, 1 H) 7.35 (dd, 1 H) 7.41 (d, 1 H) 7.52 (d, J=1.76 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][C:13]1(C)[C:17](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:13]([CH3:17])=[CH2:12])=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cc(N)c(OC)cc1Cl
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzenamine (1.0 g, 3.53 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (889 mg, 5.29 mmol), Pd(PPh3)4 (363 mg, 0.353 mmol), Na2CO3 (1.12 g, 10.6 mmol) in DME (10 mL) and water (3 mL) was stirred at reflux under argon for 6 h. The reaction mixture was allowed to cool to RT and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% petroleum ether/ethyl acetate) to afford the desired product (173 mg, 25% yield) as an off-white solid. ESI-MS m/z: 198.5[M+H]+.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:3][CH:2]=[CH2:1])=[O:26])=[CH:20][CH:19]=1
Reactant: C=CCO
Reactant: O=C(O)Cc1ccc(-c2ccc(O)cc2Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: C=CCOC(=O)Cc1ccc(-c2ccc(O)cc2Cl)cc1

Procedure:
After allyl alcohol (7.0 ml, 103 mmol) and concentrated sulfuric acid (0.1 ml) were successively added to a solution of (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetic acid (1.93 g, 7.35 mmol) obtained in Example (13-1) in benzene (30 ml), the mixture was heated under reflux for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=90/10-65/35) to give allyl (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate as a white powder (1.97 g, yield: 899.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[CH:24][N:25]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=2)=[CH:18][CH:17]=1.[O:41]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[N:42]1.C(OCC)C>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[CH:24][N:25]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:46][C:43]4[CH:44]=[CH:45][O:41][N:42]=4)[CH2:37][CH2:36]3)[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=2)=[CH:20][CH:21]=1
Reactant: O=Cc1ccon1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)CC2)n1
Reaction time: 1.5 h

Procedure:
Sodium triacetoxyborohydride (135 mg, 0.637 mmol) was added to a solution of 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]-N-methylpyrimidin-2-amine (C8) (150 mg, 0.426 mmol) and isoxazole-3-carbaldehyde (49.6 mg, 0.511 mmol) in THF (10 mL). After 90 minutes at room temperature, the reaction was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a thick oil. Purification via silica gel chromatography (Eluants: ethyl acetate followed by 10% methanol in ethyl acetate) provided a viscous oil, which was reconcentrated from diethyl ether to afford the product as a white solid. Yield: 77 mg, 0.18 mmol, 42%. LCMS m/z 434.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.99-2.09 (m, 2H), 2.16-2.22 (m, 4H), 3.03 (m, 2H), 3.05 (d, J=5.1 Hz, 3H), 3.69 (s, 2H), 4.67 (br m, 1H), 5.17 (m, 1H), 6.41 (d, J=5.1 Hz, 1H), 6.41 (d, J=1.7 Hz, 1H), 7.00 (dd, J=8.7, 8.7 Hz, 2H), 7.46 (dd, J=8.7, 5.4 Hz, 2H), 7.77 (s, 1H), 8.16 (br d, J=4.5 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1.NC(N)=[S:13].O1CCCC1>O>[SH:13][C:2]1[S:6][N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=1
Reactant: COC(=O)c1nsc(Cl)n1
Reactant: NC(N)=S
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nsc(S)n1
Reaction time: 6.5 h
Yield: 92.4 %

Procedure:
A mixture of methyl 5-chloro-1,2,4-thiadiazole-3-carboxylate (7.80 g), thiourea (3.32 g), tetrahydrofuran (24 ml) and water (8 ml) was gently boiled for 6.5 hours. The reaction mixture was post-treated according to conventional manner to give yellow powder of methyl 5-mercapto-1,2,4-thiadiazole-3-carboxylate (7.1 g), mp. 126° to 127° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Yield: 49.7 %

Procedure:
The resin-bound 3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as described in above Example 44 was reacted with 3-trifluoromethyl-phenyl boronic acid (57.2 mg, 0.3 mmol) by following as generally described in Example 44 to give title compound (29.2 mg, 50%). LC/MS (m/z): 588 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH:8]=2)[CH2:5][CH:4]([C:24]([NH:26][CH:27]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][C:29]([OH:31])=O)=[O:25])[CH2:3]1.[C:38]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH:8]=2)[CH2:5][CH:4]([C:24]([NH:26][CH:27]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][C:29]([NH:47][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])=[O:31])=[O:25])[CH2:3]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)NCc3ccccc3)c2)C1)c1cccnc1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 3-{(5-oxo-1-(3-{(benzylamino)carbonylamino}phenyl)pyrrolidin-3-yl)carbonylamino}-3-(3-pyridyl)propanoic acid (60 mg, 0.11 mmol), benzenesulfonamide (Aldrich, 18 mg, 0.11 mmol), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (22 mg, 0.11 mmol), and dimethyl-4-pyridylamine (Aldrich, 0.22 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 2 days. A white solid was filtered and further purified by preparative HPLC. The title compound was obtained as a white solid. MS (ES+): 643 (M+H)+; (ES−): 641 (M−H)−.