Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.FC(F)(F)SCl>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:17]=2[S:3][C:2]([F:8])([F:7])[F:1])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)[nH]1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: FC(F)(F)SCl
Solvent: ClCCl
Product: COC(=O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 902.7 %

Procedure:
Trifluoromethanesulfonic acid (0.27 g, 0.001795 mol) is added to a solution of methyl 5-(p-chlorophenyl)pyrrole-2-carboxylate (4.23 g, 0.01795 mol) in methylene chloride (70 mL) at -30° C. This mixture is treated with trifluoromethylsulfenyl chloride (4.0 g, 0.0293 mol), stirred for 30 minutes at -15° C., warmed to room temperature with stirring for three hours, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title product as an off-white solid (5.44 g, mp 133°-137° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH:17]1[CH2:19][CH2:18]1)=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][N:27]=1>>[CH:17]1([C:7]2[N:8]([CH2:12][C:13]3[N:16]=[C:32]([C:30]4[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:24])[F:35])[CH:31]=4)[O:15][N:14]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:19][CH2:18]1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3ccnc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 364A) and 2-(trifluoromethyl)-4-pyridinecarboxylic acid: MS (ES) m/z 478 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:32][CH:33](Br)[CH3:34])(=[O:31])[CH:28]([CH3:30])[CH3:29].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:33]([O:32][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH3:34])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(Br)OC(=O)C(C)C
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(=O)C(C)C)=CCS[C@H]12)c1csc(N)n1

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer) was reacted with 1-bromoethyl isobutyrate in the presence of sodium iodide to give 1-isobutyryloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 120°-125° C. (decompn.).
Reaction SMILES: [BH4-].[Li+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)=[CH:11][C:6]=1[C:7](OC)=[O:8].Cl.N([O-])=O.[Na+]>O1CCCC1.O.C(OCC)(=O)C.CO>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)=[CH:11][C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1OC
Agent: Cl
Agent: O=N[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(-n2cnnn2)cc1CO
Temperature: 0 °C
Yield: 37.6 %

Procedure:
Lithium borohydride (196 mg) was added to a stirred and cooled (ice-water bath) suspension, under nitrogen, of 2-methoxy-5-(tetrazol-1-yl) benzoic acid, methyl ester (1 g) in tetrahydrofuran (15 ml). After 2 min a solution of methanol (288 mg) in tetrahydrofuran (2 ml) was added over 1 min. The cooling bath was removed and the mixture stirred for 86 min. The solution was cooled (ice-water bath) and 3M aqueous hydrochloric acid (1/2-1 ml) was added, forming a thick gel. Water (5 ml) was added, followed by more 3M aqueous hydrochloric acid (5 ml). A solution of sodium nitrite (325 mg) in water (1 ml) was then added. After 11/4 h, water (15 ml) was added and the resulting solution was extracted with ethyl acetate. The organic phase was washed successively with dilute hydrochloric acid and water, and then dried (MgSO4). Evaporation gave a yellow solid which was stirred with ethyl acetate (ca 3 ml). Filtration gave a grey/white solid, which was washed with a mixture of ethyl acetate and petroleum ether (60°-80°) (1:1) and dried to give the title compound (331 mg); nmr, δ(d6 -DMSO), 3.88 (s,3H), 4.58 (d,2H, J=ca 8 Hz), 5.34 (t,1H, J=ca 8 Hz), 7.20 (d,1H, J=ca 10 Hz), 7.75 (dd,1H, J=ca 10 Hz, J=ca 4 Hz), 7.86 (d,1H, J=ca 4 Hz), 10.01 (s,1H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([O:19][CH3:20])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:57][CH2:58][C:59]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:63])[CH2:60][CH2:61][CH3:62]>O1CCCC1>[C:67]([O:66][C:65](=[O:71])[NH:64][C:59]([CH3:63])([CH2:60][CH2:61][CH3:62])[CH2:58][NH:57][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:7][C:8]([O:19][CH3:20])=[CH:9][C:10]=12)=[O:16])([CH3:70])([CH3:69])[CH3:68]
Reactant: COc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
A solution of 170 mg (0.366 mmol, 75% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 163A) in 8 ml of tetrahydrofuran was admixed with 84 mg (0.44 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS: 25952-53-8) and 60 mg (0.44 mmol) of 1-hydroxy-7-azabenzotriazole (CAS: 39968-33-7). The solution was stirred at room temperature for 20 minutes. The reaction mixture was admixed with 0.191 ml (1.01 mmol) of N,N-diisopropylethylamine and 158 mg (0.732 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester (Example 152A). The mixture was stirred at room temperature for a further 18 hours, and the reaction mixture was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed, extracted with a saturated aqueous sodium hydrogencarbonate solution, water and aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The remaining residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:dichloromethane/methanol, gradient 0% to 10%), which gave 120 mg (44% yield, 73% purity) of product.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH2:8]1)[CH3:4].Cl>C(O)C>[CH2:3]([O:5][CH2:6][CH:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH2:8]1)[CH3:4]
Reactant: CCOCC1CC(C(=O)OCC)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCC1CC(C(=O)O)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A 1M solution of sodium hydroxide (5 mL; 5 mmol) was added to the solution of ethyl 5-(ethoxymethyl)-4,5-dihydroisoxazole-3-carboxylate (0.135 g, 0.67 mmol) in ethanol (1 mL). The reaction mixture was stirred at room temperature overnight. The solution was acidified to pH 0-1 by addition of 6N hydrochloric acid and was extracted with ethyl acetate. Combined ethyl acetate extracts were dried over magnesium sulfate and evaporated to provide 0.109 g (94%) of 5-(ethoxymethyl)-4,5-dihydroisoxazole-3-carboxylic acid as a white solid which was directly used in the next step.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.Br[C:21]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH3:33])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>COCCOC.CCOC(C)=O.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>[CH3:33][O:32][C:28]1[C:29]([CH3:31])=[CH:30][C:21]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][N:11]=2)=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(OC)c(C)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(C)cc1-c1ncccn1
Reaction time: 2 h

Procedure:
Pd(PPh3)4 (416 mg, 0.36 mmol) was added to a rt solution of 2-tributylstannylpyrimidine (1.40 g, 3.6 mmol) and methyl 2-bromo-5-methoxy-4-methylbenzoate (1.03 g, 3.96 mmol) in degassed DME (7 mL) and the resulting mixture was irradiated in the microwave at 160° C. for 1 h. To the rxn mixture was added Pd(PPh3)4 (315 mg, 0.27 mmol) and irradiation was continued at 160° C. for another 2 h. The rxn mixture was diluted with EtOAc and H2O, filtered over celite, the org. layer was separated and the aq. layer was re-extracted with EtOAc. The combined org. extracts were dried (MgSO4), filtered, concentrated in vacuo and purified by FC (Biotage SP1: EtOAc/hex 1:9 to 3:7) to yield methyl 5-methoxy-4-methyl-2-(pyrimidin-2-yl)benzoate as a brown solid which was used without further purification. LC-MS A: tR=0.75 min, [M+H]+=258.99.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.C(N(CC)CC)C.CS(C)=O>ClCCl>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1
Reactant: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1ccc2[nH]cc(CCCC=O)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
18 g of 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile and 34 ml of triethylamine are dissolved in 300 ml of dichloromethane and cooled to about 0° C. in an ice/methanol bath. A solution of 39 g of sulfur trioxide/pyridine complex and 140 ml of dimethyl sulfoxide is subsequently metered in at 2 to 5° C. The mixture is stirred at 2 to 3° C. for approximately a further 20 min., then the reaction solution is warmed to 22-23° C. (room temperature) over the course of 2 hrs. The reaction mixture is diluted by addition of a further 200 ml of dichloromethane and then extracted with water, 10% citric acid solution and 10% sodium chloride solution. The organic phase is concentrated to an oily residue in vacuo, then chromatographed on silica gel using a mixture of dichloromethane and MTB ether.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C@@H:3]([CH2:5][CH3:6])[CH3:4].N[C@H](C(O)=O)C(C)C.N[C@@H](C(O)=O)C(C)C.N[C@H](C(O)=O)CC(C)C.N[C@@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CCSC.N[C@@H](C(O)=O)CCSC>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@@H](C)[C@@H](N)C(=O)O
Agent: CC(C)C[C@@H](N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)[C@@H](N)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
replace with: D-Ile, Val, D-Val, Leu, D-Leu, Met, D-Met;
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:32]1[N:33]([C:37]2[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=2[C:39](O)=[O:40])[N:34]=[CH:35][CH:36]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([C:39]([C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[N:33]4[N:34]=[CH:35][CH:36]=[N:32]4)=[O:40])[CH2:14]3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cncc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 30) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H21N7O, 375.44; m/z found 376.1 [M+H]+. 1H NMR (CD3OD): 8.08-7.75 (m, 3H), 7.68-7.37 (m, 4H), 7.33-6.82 (m, 1H), 4.70-3.78 (m, 5H), 3.64-2.97 (m, 3H), 2.43-2.01 (m, 5H).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.Cl.[CH3:26][C:27]1([NH2:30])[CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH3:15][C:3]1[C:2]([NH:30][C:27]2([CH3:26])[CH2:29][CH2:28]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12](=[O:14])[CH3:13])[N:4]=1
Reactant: CC1(N)CC1
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)c1cccc2nc(C)c(NC3(C)CC3)nc12
Temperature: 85 °C

Procedure:
To a 250 mL round-bottomed flask was added 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g) (14.5 g, 71 mmol), DMSO (100 mL), DIEA (27 mL, 156 mmol) and finally 1-methylcyclopropanamine hydrochloride (8.02 g, 92 mmol) (ChemBridge Corporation, San Diego, Calif.). The solution was heated at 85° C. for 7 h. After cooling to RT, the solution was poured into sat NaHCO3 (250 mL) and extracted with EtOAc (3×250 mL). The combined extracts were washed with H2O (3×250 mL) and brine and then dried (Na2SO4) and concentrated to afford 1-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)ethanone (611a) as a purple solid, which was used directly in the subsequent step. m/z (ESI, +ve) 256.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]1.Br[CH:23]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].CCN(C(C)C)C(C)C>C(#N)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:23]([C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=2)[N:1]2[CH2:4][CH:3]([CH:5]([C:10]3[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1cc(F)cc(C(C2CNC2)C(C)(C)F)c1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
The mixture of 4.90 g (16.40 mmol) of ethyl 3-(1-azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorobenzoate, 8.17 g of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 6 mL(34.36 mmol) of DIEA in 40 mL of acetonitrile was refluxed for 4 h, then concentrated in vacuo. The mixture was poured into 150 mL of CH2Cl2 and 30 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Two pairs of racemic compounds were separated by silica gel chromatography. Single diastereomers were separated by a chiral AD column; Mass Spectrum: m/e=523 (M+1, 35Cl), 525 (M+1, 37Cl).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C>O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Yield: 87.4 %

Procedure:
A mixture of 5.0 g of 1-(3-phenoxyphenyl)-4-(4-methoxyphenyl)-4-methylpentane, 30 ml of 47% aq HBr and 30 ml of acetic acid was refluxed with heating for eight hours. The reaction mixture was poured into water and extracted with benzene. The benzene extract was washed with water and dried, and the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: benzene) to give 4.2 g of 1-(3-phenoxyphenyl)-4-(4-hydroxyphenyl)-4-methylpentane.
Reaction SMILES: C([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH2:14][CH:15]3[CH2:19][CH2:18][CH2:17][S:16]3)[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C=C.CC(C)([O-])C.[K+].S(=O)(=O)(O)O>CS(C)=O.C(OCC)(=O)C.[Hg](Cl)Cl>[C:20]1([C:6]2[C:7]3[C:12]([NH:13][CH2:14][CH:15]4[CH2:19][CH2:18][CH2:17][S:16]4)=[N:11][CH:10]=[N:9][C:8]=3[NH:4][C:5]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=CCn1c(-c2ccccc2)c(-c2ccccc2)c2c(NCC3CCCS3)ncnc21
Agent: CC(C)(C)[O-]
Agent: Cl[Hg]Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: c1ccc(-c2[nH]c3ncnc(NCC4CCCS4)c3c2-c2ccccc2)cc1
Temperature: 110 °C

Procedure:
To a solution of (7-allyl-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(tetrahydrothiophen-2-ylmethyl)-amine (Example 3, Step C, 0.20 mmol) in DMSO (1 mL) was added potassium tert-butoxide (50 mg, 0.45 mmol) and the solution was heated to 110° C. for 24 hours. The solution was then cooled, diluted with ethyl acetate, extracted with water (2×25 mL), dried and concentrated under reduced pressure. Acetone (1 mL) was then added, followed by sulfuric acid (1 N, aq., 1 mL) and mercury (II) chloride (250 mg, 1 mmol). The reaction mixture was heated to reflux for 4 hours, cooled, and purified by preparative HPLC (C8 column, water, acetonitrile, 0.1% TFA) to give the title compound. 1H-NMR (CDCl3): 1.95-1.39 (4 H, m), 2.78-2.57 (2 H, m), 3.75-3.42 (4 H, m), 5.91 (1 H, br s), 7.43-7.02 (10 H, m), 8.20 (1 H, s), 13.87 (1 H, br s). Mass Spectrum (ESI) m/e=387 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5]([C:10]2[C:11]([F:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=1.Br.[N:18]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>[F-].[K+].C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5]([C:10]2[C:11]([F:16])=[N:12][CH:13]=[C:14]([C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)[CH:15]=2)[CH:4]=1
Reactant: COc1cc(-c2cccnc2F)c(N)cn1
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2cc(-c3ccc(CN4CCCCC4)cc3)cnc2F)c(N)cn1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
A mixture of 6′-methoxy-2-fluoro-[3,4]bipyridinyl-3′-ylamine (1.0 g, 3.4 mmol), 4-(piperidin-1-ylmethyl)phenylboronic acid hydrobromide (1.7 g, 5.7 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.25 mmol) in 1N aqueous potassium fluoride (8.4 mL) and acetonitrile (12 mL) was heated under microwave irradiation at 100° C. for 25 minutes. The cooled reaction was diluted with water (100 mL) and extracted with DCM (3×50 mL). The combined organic layer was, dried over sodium sulfate, filtered, and purified by flash chromotagraphy (silica, 25 g column, Biotage, 0-10% methanol in (DCM containing 1% 2M ammonia in methanol)) to afford the title compound as a yellow/orange solid (1.0 g, 77%). 1H NMR (DMSO-D6, 500 MHz): 8.59 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.74 (s, 3H), 7.42 (s, 2H), 6.65 (s, 1H), 4.71 (s, 2H), 3.77 (s, 3H), 3.47 (s, 2H), 2.34 (s, 4H), 1.51 (s, 4H), 1.40 (s, 2H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.BrC1C=CC(C(=O)CCC)=CC=1F.FC(F)(F)C(N1C=CN=C1)=O.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46](=O)[CH:47]([CH2:54][CH3:55])[C:48](=O)[C:49]([F:52])([F:51])[F:50])=[CH:42][C:41]=1[F:57].Cl.[NH:59]([C:61]1[CH:62]=[CH:63][C:64]([S:67]([NH2:70])(=[O:69])=[O:68])=[N:65][CH:66]=1)[NH2:60]>O1CCCC1.C(O)C>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:59]([C:61]3[CH:62]=[CH:63][C:64]([S:67]([NH2:70])(=[O:69])=[O:68])=[N:65][CH:66]=3)[N:60]=[C:48]([C:49]([F:52])([F:51])[F:50])[C:47]=2[CH2:54][CH3:55])=[CH:42][C:41]=1[F:57]
Reactant: CCC(C(=O)c1ccc(Br)c(F)c1)C(=O)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)nc1
Agent: CCCC(=O)c1ccc(Br)c(F)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a stirred solution of hexamethyldisilazane (2.5 ml, 11.75 mmol) in tetrahydrofuran (25 ml) was added n-butyllithium (7.5 ml, 11.75 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 30 min. Then cooled to −78° C., to the mixture was added a solution of 1-(4-bromo-3-fluorophenyl)-1-butanone (2.4 g, 9.79 mmol) in tetrahydrofuran (12 ml) dropwise and stirred at rt for 1 h. Then 1-trifluoroacetylimidazole (1.3 ml, 11.75 mmol) was added to the mixture at same temperature, the mixture was stirred at rt for 5 h. This was quenched by water and the pH was adjusted to pH 4-5, extracted with ethyl acetate. The extracts was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:20/1:15) to afford 2.7 g (80.9%) as a yellow oil. A mixture of 1-(4-bromo-3-fluorophenyl)-2-ethyl-4,4,4-trifluoro-1,3-butanedione (1.5 g, 4.40 mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride (1.28 g, 5.72 mmol) in ethanol (60 ml) was stirred at reflux for 3 h. After cooling, the solvent was removed and the residue was diluted with ethyl acetate, washed with water. The extracts was dried (MgSO4), and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:10/1:5/1:4) to afford 1.64 g (75.6%) of the titled compound as a white amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([O:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2)[CH:31]=[N:30][CH:29]=1.[OH-].[Na+]>O1CCOCC1.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([O:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2)[CH:31]=[N:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with (R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (2.5 g, 3.78 mmol) and NaOH (1.513 mL, 7.57 mmol) in p-dioxane (12 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h, then the mixture was diluted with water, and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give the crude (R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate.