Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:9]=1[NH2:10]>Cl.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:9]=1[N:10]=[C:3]([CH3:4])[CH:2]=[CH:1]2
Reactant: COc1ccc(Cl)c(N)c1
Reactant: C/C=C/C=O
Agent: Cl
Solvent: O
Product: Cc1ccc2c(O)ccc(Cl)c2n1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Crotonaldehyde (17.5 mL, 0.21 mol) was added dropwise to a refluxing solution of 2-chloro-5-methoxyaniline hydrochloride (10.36 g, 53.4 mmol) in 5 N hydrochloric acid (450 mL) and reflux continued for a further 0.5 h. The reaction mixture was cooled and diluted with water (500 mL), then extracted with ether (400 mL). The aqueous layer was separated and basified using 50% aqueous NaOH (pH 14), and then extracted into dichloromethane (3×300 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a dark oil which was purified by chromatography on silica gel (˜200 g) eluting with 20% ethyl acetate in hexane to give a brown oil (5.17 g) which was heated at reflux in a mixture of acetic acid (30 mL) and 48% hydrobromic acid (30 mL) for 66 h. Reaction mixture was evaporated in vacuo and the residue suspended in sat. NaHCO3 (aq), then extracted into dichloromethane (3×50 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a brown solid (2.90 g, 28%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH2:16]1)(=[O:14])=[O:13].[F:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[C:38]1[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[S:12]([N:15]3[CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH2:16]3)(=[O:14])=[O:13])=[CH:28][C:23]=2[F:22])=[CH:39][N:40]=1
Reactant: O=C1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3S(=O)(=O)N3CCNC(=O)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-((2-bromo-5-(trifluoromethyl)phenyl)-sulfonyl)-piperazin-2-one and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine. MS (ESI): mass calcd. for C21H17F4N5O3S, 495.10; m/z found, 496.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.70-8.61 (d, J=1.2, 2H), 8.40 (s, 1H), 8.10-8.03 (d, J=157.7, 1H), 7.71-7.64 (d, J=7.9, 1H), 7.64-7.58 (m, 1H), 7.39-7.37 (m, 1H), 7.36 (s, 1H), 3.34 (s, 2H), 3.22-3.17 (m, 2H), 3.17-3.12 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[NH:17][C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C@H:27]2[C:33]3[N:34]=[CH:35][S:36][C:32]=3[C@@H:31]([NH:37]C(OC(C)(C)C)=O)[C@H:30]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[F:52])[CH2:29][CH2:28]2)=[O:25])[CH2:20][CH2:19]1>C(Cl)Cl>[O:8]=[C:9]1[NH:17][C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]1[CH:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C@H:27]2[C:33]3[N:34]=[CH:35][S:36][C:32]=3[C@@H:31]([NH2:37])[C@H:30]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[F:52])[CH2:29][CH2:28]2)=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2scnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1c2scnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
A mixture of trifluoroacetic acid (0.986 mL, 12.80 mmol) and (4R,7S,8S)-8-(tert-butoxycarbonylamino)-7-(2,3-difluorophenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-4-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (16.4 mg, 0.026 mmol) in methylene chloride (10 mL) was stirred at rt from for 2.5 h. The solvent was removed under vacuum and the crude product was taken up in ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography, eluting with methanol in methylene chloride from 0 to 10% gave the desired product (13 mg, 89%) as a white solid: LCMS (M+H=541.40); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.98 (1H, br. s), 8.64 (1H, s), 8.08 (1H, d, J=4.8 Hz), 7.31-7.64 (1H, m), 6.94-7.19 (4H, m), 6.11-6.21 (1H, m), 4.42 (4H, m), 3.23-3.43 (1H, m), 2.85-3.16 (2H, m), 2.24 (6H, m), 1.83-1.98 (2H, m), 1.56 (2H, br.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9].CCN(CC)CC.Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[C:16]([N:13]1[CH2:14][CH2:15][C@H:12]1[CH2:11][O:10][C:5]1[CH:6]=[N:7][C:8]([Cl:9])=[C:3]([CH2:2][NH:1][C:31]([O:33][CH3:34])=[O:32])[CH:4]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
5-Aminomethyl-3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine (0.23 g, 0.70 mmol) from Example 92b in CH2Cl2 (5 mL) at 0° C. was treated with NEt3 (0.2 mL, 1.40 mmol) and methyl chloroformate (0.061 mL, 0.80 mmol). The mixture was allowed to warm to room temperature and stir for 1 h. The volatile components were evaporated and the residue was chromatographed (silica gel; MeOH/CH2Cl2, 1:19) to afford the title compound as a yellow oil (0.22 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.28-2.35 (m, 2H), 3.71 (s, 3H), 3.89 (t, J=7.5 Hz, 2H), 4.10 (dd, J=3.0, 10.0 Hz, 1H), 4.36 (m, 1H), 4.40 (d, J=6.5 Hz, 2H), 4.54 (m, 1H), 7.35 (d, J=3.5 Hz, 1H), 8.01 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 386 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:5]([NH:6][CH3:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.C1CCCCC=1.C(=O)([O-])[O-].[Na+].[Na+].[N:28]([C:31]1[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=1[CH3:39])=[C:29]=[S:30]>C(O)C.[Pd]>[NH2:10][C:8]1[C:5]([NH:6][CH3:7])=[C:4]([NH:13][C:29]([NH:28][C:31]2[C:32]([CH3:39])=[CH:33][C:34]([CH3:38])=[CH:35][C:36]=2[CH3:37])=[S:30])[CH:3]=[C:2]([F:1])[CH:9]=1
Reactant: CNc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CNc1c(N)cc(F)cc1NC(=S)Nc1c(C)cc(C)cc1C
Yield: 32.4 %

Procedure:
In 75 mL of ethanol was mixed 1.30 g (6.04 mmol) of 4-fluoro-N-methyl-2,6-dinitroaniline, 3.7 mL (36 mmol) of cyclohexene and 5.1 g (2.4 mmol, 40 mol %) of 10% palladium on carbon (50% water, Degussa type). The mixture was refluxed for 2.5 h and filtered into a flask containing 0.77 g (7.3 mmol) of sodium carbonate and 1.07 g (6.04 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The resulting slurry was refluxed for 4 h, concentrated and slurried in dichloromethane. The slurry was filtered, concentrated and purified by flash chromatography eluting with a 70% hexanes/ethyl acetate mixture to give 0.65 g (32%) of the title compound as an off-white solid.
Reaction SMILES: CN(C)C=O.[OH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8].[H-].[Na+].[C:34]1(C)[CH:39]=[CH:38][C:37](S(OCCCCCC)(=O)=O)=[CH:36][CH:35]=1>O>[CH2:38]([O:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[CH3:8])[CH2:39][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OCCCCCC)cc2)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Into 20 ml of anhydrous dimethylformamide were dissolved 1.78 g (5 millimole) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)] 70, and then 0.24 g (6 millimole) of 60% sodium hydride was added thereto, followed by stirring at 40° C. for 1 hour. Subsequently, 1.79 g (7 millimole) of hexyl p-toluenesulfonate were added thereto, to subject to reaction at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, extracted with 200 ml of toluene, followed by separation thereof, and the organic phase was washed with water sufficiently, followed by drying over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate) to obtain 1.81 g (yield: 82%) of (+)-2-{4-(1-hexyloxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH2:33]([NH2:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:24])([F:25])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:34]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), ethanamine-HCl (8.51 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention 12.1=min) to provide (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (25 mg, 0.049 mmol, 69.8% yield): LCMS=459.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14 (2 H, d, J=8.36 Hz), 7.48-7.85 (7 H, m), 5.10 (1 H, s), 3.28 (2 H, dd, J=7.15, 0.99 Hz), 1.14 (3 H, t, J=7.26 Hz); HPLC peak RT=9.2 min (Method A).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:26]([O-])(=[O:28])C.[Na+]>CN(C)C=O>[CH3:6][N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([CH:26]=[O:28])=[CH:10][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: CCCCOC(=O)CCCCCN(C)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)CCCCCN(C)c1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Phosphorus oxychloride (18.4 g, 0.12 mol) was added dropwise with stirring, at 5° C., under nitrogen, to N,N-dimethylformamide (DMF, 50 mL). The resulting orange solution was stirred for 2 hours, then 27.6 g (0.81 mol) of butyl 6-(N-methyl-N-phenylamino)hexanoate was dropwise. The reaction mixture was stirred at 5° C. for 1 hour and then was heated in a water bath to 90° C., for 4 hours. After cooling the hot solution was poured over 200 g of crushed ice and naturalized to pH 6 by a slow addition of solid sodium acetate with vigorous stirring. The mixture was extracted with three portions of 200 mL dichloromethane. The combined organic extracts were washed three times with water, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was distilled in vacuo yielding 23.4 g (76.8%) of pale yellow oil bp 151°-153° C. (3×10-4 mm).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)C.[NH3:30]>C(O)C>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][C:15]2[N:11]([C:9]3[S:10][C:6]([C:4]([NH2:30])=[O:3])=[C:7]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:8]=3)[CH:12]=[N:13][C:14]=2[CH:19]=1
Reactant: N
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Solvent: CCO
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(N)=O)s3)c2cc1OC
Yield: 36 %

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid amide was prepared from 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (80 mg, 0.20 mmol) and ammonia in ethanol (29 molar) as described above in the general amide formation procedure. The product was isolated by preparative HPCL: 7.7 mg, 36% yield. 1H-NMR (DMSO-D6) 8.78 (s, 1H); 7.80-7.90 (m, 4H); 7.789s, 1H); 7.40-7.55 (m, 3H); 7.38 (s, 1H); 3.84 (s, 3H); 3.83 (s, 3H). MS M/z 381 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].O.[CH3:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.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:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:3]2[C:2]([C:35]3[C:30]([O:29][CH3:28])=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=2)=[CH:15][CH:16]=1
Reactant: COc1ncccc1B(O)O
Reactant: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2)cc1F
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: C1COCCO1
Product: COC(=O)c1cc(-c2cccnc2OC)c(Oc2ccc(Cl)cc2)cc1F
Temperature: 50 °C
Yield: 179.6 %

Procedure:
To a stirred solution of methyl 5-bromo-4-(4-chlorophenoxy)-2-fluorobenzoate (Preparation 32, 199 mg, 0.55 mmol) in dioxane (10 mL) and water (0.5 mL) was added potassium carbonate (158 mg, 1.14 mmol) and 2-methoxypyridin-3-ylboronic acid mono hydrate (147 mg, 0.86 mmol). The reaction was degassed three times followed by the addition of tetrakis(triphenylphosphine)palladium(0) (13.2 mg, 0.012 mmol). The reaction was degassed three times and heated at 50° C. overnight under a nitrogen atmosphere. The reaction was cooled to room temperature, concentrated in vacuo to afford a brown residue. The residue was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford brown oil (383 mg). The oil was then purified by flash column chromatography using the Biotage System™ (50 g silica column, eluting with DCM). Fractions containing product were combined and concentrated in vacuo to afford the title compound as a grey oil (194 mg, 91%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].CO[CH2:12][CH2:13][C:14](OC)(OC)[CH3:15]>[Cl-].[Zn+2].[Cl-].C(O)C>[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[CH:12][CH:13]=[C:14]2[CH3:15]
Reactant: Nc1ccccc1Cl
Reactant: COCCC(C)(OC)OC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1ccnc2c(Cl)cccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Commercially available 2-chloroaniline (200 g, 1.56 mol) was dissolved in 600 ml ethanol, and dry HCl gas was bubbled through for 10 minutes to give 2-chloroaniline hydrochloride. A new flask was charged with 2-chloroaniline hydrochloride (130 g, 0.793 mol), ferric chloride hexahydrate (25.7 g, 0.095 mol), anhydrous zinc chloride (10.9 g, 0.0799 mol) and 500 ml 2B ethanol. The mixture was heated to 60° C. for 10 minutes and 1,3,3-trimethoxy butane was added dropwise over a period of one hour. The mixture was then refluxed for two hours and allowed to stand overnight at room temperature. Most of the alcohol was removed by distillation and the residue was made alkaline with 25% sodium hydroxide solution. The reaction was cooled, filtered, and the filter pad washed with toluene. The toluene was concentrated to dryness. The product was recrystallized from dichloromethane/pentane to obtained a spectroscopically pure sample (mp: 110° C., 37.0 g, 25% overall yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[CH:4][CH:3]=1.[BrH:14].C(O)(=O)C.O>C(O)(=O)C>[Br:14][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-c2csc(Br)n2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-oxoethyl thiocyanate (3.70 g, 19.0 mmol) in acetic acid (35 ml) was added a 25% hydrogen bromide/acetic acid (35 ml) solution, and the mixture was stirred at 130° C. for 2 hours and at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethanol and water to give the desired product (4.50 g, 91.9%) as a solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6]Cl)=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([OH:36])[CH:33]([F:35])[F:34])=[CH:28][CH:27]=2)[CH:12]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:35][CH:33]([F:34])[C@@H:32]([C:29]1[CH:30]=[CH:31][C:26]([C:11]2[CH:12]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:14]=[C:9]([N:8]3[CH2:6][CH2:5][O:4][C:2]3=[O:3])[CH:10]=2)=[CH:27][CH:28]=1)[OH:36]
Reactant: Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1OCCN1c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloroethyl chloroformate (12.58 μL, 0.122 mmol) was slowly added to a stirred, cooled (0° C.) mixture of (1R)-1-(3′-amino-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)-2,2-difluoroethanol (40 mg, 0.097 mmol) and potassium carbonate (33.7 mg, 0.244 mmol) in acetonitrile (0.5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then heated and stirred at 80° C. for 3 hours, then allowed to cool to room temperature. The mixture was diluted with ethyl acetate and concentrated in vacuo. Purification via silica gel column chromatography (20-80% ethyl acetate in hexanes) to give 3-(4′-[(1R)-2,2-difluoro-1-hydroxyethyl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-oxazolidin-2-one as a colorless solid. MS ESI calc'd. for C22H18F5N4O3 [M+H]+ 481, found 481. 1H NMR (500 MHz, DMSO-d6): δ 10.39 (s, 1H); 8.85 (d, J=4.9 Hz, 1H); 8.01 (s, 1H); 7.88 (s, 1H); 7.64 (d, J=7.8 Hz, 2H); 7.55 (t, J=8.9 Hz, 3H); 7.31 (d, J=4.8 Hz, 1H); 6.27 (d, J=4.8 Hz, 1H); 6.07 (td, J=55.5, 3.9 Hz, 1H); 4.83 (s, 1H); 4.48 (t, J=7.8 Hz, 2H); 4.13 (t, J=7.9 Hz, 2H).
Reaction SMILES: [Cl:1]/[C:2](=[N:7]/[C:8]1[C:9]([CH3:26])=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])/[C:3]([F:6])([F:5])[F:4].[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:26][C:9]1[C:8](/[N:7]=[C:2](/[Cl:1])\[C:3]([F:5])([F:4])[F:6])=[CH:25][CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(/N=C(/Cl)C(F)(F)F)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(F)cc1Oc1cccc(/N=C(/Cl)C(F)(F)F)c1CBr

Procedure:
A mixture of EXAMPLE 215B (1.4 g), N-bromosuccinimide (0.671 g), and benzoyl peroxide (0.044 g) in CCl4 (20 mL) was heated under reflux for 4 hours. After cooling, the solid was filtered off. The filtrate was then concentrated. The residue was purified by flash chromatography on silica gel eluting 1:20 ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1>O>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][N:40]2[C:17](=[O:19])[CH2:18][CH:13]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])[C:14]2=[O:16])=[O:38])[CH:25]=[C:24]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]=1[OH:30])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CC(C)CCCCCCCC=CC1CC(=O)OC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCCCCCCC=CC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 102.8 %

Procedure:
A mixture of 2-isododecenylsuccinic anhydride (31.2 g, 111 mmol), 3-(3,5-di-t-butyl-4-hydroxy-phenyl)propanoic acid hydrazide (32.6 g, 111 mmol) and 60 ml of toluene was refluxed for 90 minutes under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The bulk of the solvent was distilled off followed by vacuum stripping of the hot (135° C.) melt for 25 minutes to remove last traces of solvent. After cooling to room temperature, the vacuum was removed. Additional cooling in an acetone/dry ice bath allowed for easy removal of the thermally fractured solid from the vessel. 61.7 g of an amber solid was obtained having a melting range of 62°-68° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]#[C:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=O)C.[NH2:26][NH2:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:27]([C:14]3[CH:15]=[CH:16][C:11]([CH3:9])=[CH:12][CH:13]=3)[N:26]=[C:7]([CH2:6][CH:5]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[C:4]([OH:3])=[O:25])[CH:8]=2)=[CH:16][CH:15]=1
Reactant: NN
Reactant: CCOC(=O)C(CC#CC(=O)c1ccc(Br)cc1)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 121.8 %

Procedure:
3-[5-(4-Bromo-phenyl)-1-β-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester. To a solution of 6-(4-bromo-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester (7.5 g, 19 mmol) in THF (40 mL) was added hydrazine (4.5 g, 28 mmol, 1.5 equiv) and Cs2CO3 (9.0 g, 28 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (30 mL), and a satd aq solution of cesium carbonate (50 mL) was added. The resulting aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with satd aq NaHCO3 (50 mL) then brine (50 mL), and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (5.5 g, 58%). TLC (silica gel, 3:7 EtOAc/hexanes): Rf=0.35. MS (ESI): mass calculated for C28H27BrN2O2, 502.13; m/z found, 503/505 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=10.7 Hz, 2H), 7.25-7.01 (m, 10H), 6.17 (s, 1H), 4.19-4.03 (m, 3H), 3.52 (dd, J=14.7, 9.6 Hz, 1H), 3.09 (dd, J=14.7, 6.0, 1H), 2.35 (s, 6H), 1.19 (t, J=7.1 Hz, 3H).