Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C1COCC1.[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52](=[O:57])(=[O:56])[N:53]([CH3:55])[CH3:54])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][NH:41][CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C=O>CO>[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52](=[O:56])(=[O:57])[N:53]([CH3:54])[CH3:55])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][N:41]([CH3:1])[CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1CC34CNCC3(COC4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=C(C(=O)N1CC34COCC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A 1M solution of sodium cyanoborohydride in THF (0.15 mL, 0.15 mmol) was added to a solution of 13-cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-(3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-ylcarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 20) (10 mg, 0.015 mmol) and formaldehyde (37 wt. % in water) (0.01 mL, 0.1 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 16 h. The reaction was filtered and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield product 13-cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-((10-methyl-3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (8.5 mg, 10 μmol, 68% yield) as a bright yellow solid. LCMS: m/e 688 (M+H)+. LCMS retention time: 1.91 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min.) 1H NMR (400 MHz, MeOD) δ ppm 8.07 (br s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.54 (br d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.14 (dd, J=8.5, 2.5 Hz, 1H), 7.09 (d, J-2.5 Hz, 1H), 7.06 (s, 1H), 5.23 (br d, J=14.8 Hz, 1H), 4.37-3.06 (in, 10H), 4.25 (br d, J=14.8 Hz, 1H), 3.89 (s, 3H), 2.98 (s, 6H), 2.94-2.76 (m, 4H), 2.15-1.69 (m, 6H), 1.52-1.10 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH:29]=O>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1ccncc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1ccncc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 43 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 4-Methoxy-pyridine-3-carbaldehyde (22.3 mg, 0.163) were reacted to produce 29 mg (43%) of the title compound. mp: 160° C., 1H NMR (300 MHz, DMSO-d6): 12.69 (s, 1H), 9.11 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.07 (s, 1H), 7.74 (s, 1H), 7.27 (d, J=8 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J=9 Hz, 1H), 6.35 (s, 2H), 5.26 (t, J=8 Hz, 1H), 4.02 (s, 3H), 3.38 (q, J=8 Hz, 1H), 3.32 (s, 1H), 2.89 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.26 (d, J=8 Hz, 1H), 1.40 (d, J=8 Hz, 1H), 1.09 (t, J=8 Hz, 1H). MS: 455, 457 (M+H), HPLC: 1.64 min (G method).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C([Li])CCC.[CH:17](=[N:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>C(OCC)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([C@@H:17]([NH:21][S@:22]([C:24]([CH3:25])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: CCCC=N[S@@](=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCC[C@H](N[S@@](=O)C(C)(C)C)c1cccc(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 2-bromo-6-trifluoromethyl-pyridine (480 mg, 2.2 mmol) in anhydrous diethyl ether (20 mL) at −78° C. is added n-butyllithium (1.6 M in hexanes, 1.5 mL, 2.4 mmol) dropwise over 20 min. After stirring at −78° C. for 30 min, (S)-2-methyl-propane-2-sulfinic acid butylideneamide is added. The resultant mixture is stirred at −78° C. for 30 min and is then allowed to warm gradually to room temperature overnight. The reaction mixture is poured into saturated aqueous ammonium chloride solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo to afford (S,S)-2-methyl-propane-2-sulfinic acid 1-(6-trifluoromethyl-pyridin-2-yl)-butylamide as a yellow oil (290 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:11].CO>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:8]=[C:9]([CH3:10])[C:2]([NH2:1])=[C:3]([I:11])[CH:4]=1
Reactant: Cc1cc(C#N)cc(I)c1N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CN)cc(I)c1N
Reaction time: 12 h
Yield: 96.1 %

Procedure:
4-Amino-3-iodo-5-methylbenzonitrile (200 mg, 0.77 mmol) was dissolved in THF at 0° C. After Borane-THF complex (4 eq, 3.10 mmol, 3.10 ml) was slowly added into the reaction mixture, a reaction temperature was heated to reflux. The reaction mixture was stirred for 12 hr with reflux. After confirming the completion of the reaction, MeOH was added. The mixture was stirred for 4 hrs. The reaction solvent was removed in vacuo. A residue was extracted with Ethyl acetate, washed with H2O and brine, dried with Na2SO4 and concentrated in vacuo to yield 4-Aminomethyl-2-iodo-6-methyl-phenylamine (194 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[C:41]3[C:42]([CH3:56])=[C:43]([NH:48][C:49](=[O:55])[CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:44]([CH3:47])=[C:45]([CH3:46])[C:40]=3[O:39][CH2:38]2)=[CH:33][C:32]=1[O:57][CH3:58])(=O)[CH3:29].O>C1(C)C=CC=CC=1>[C:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[C:41]3[C:42]([CH3:56])=[C:43]([NH:48][C:49](=[O:55])[CH2:50][C:51]([CH3:53])([CH3:54])[CH3:52])[C:44]([CH3:47])=[C:45]([CH3:46])[C:40]=3[O:39][CH2:38]2)=[CH:33][C:32]=1[O:57][CH3:58])([CH3:29])=[CH2:1]
Reactant: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1OC
Temperature: 120 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of potassium tert-butoxide (818 mg, 7.29 mmol) in toluene (45 mL) was added methyl triphenylphosphonium iodide (2.94 g, 7.29 mmol) and the resulting mixture was stirred at 120° C. for 1 hour under an argon atmosphere. To the reaction solution was added N-(3-(4-acetyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (2.32 g, 5.48 mmol) obtained in Example 183 and the resulting mixture was stirred at 120° C. for 2 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 1.93 g (yield: 84%) of the title compound. Melting point: 186-187° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7](O)[CH2:8][CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=[O:15])C.[Cl-].[Na+]>O.C(O)(=O)C>[OH:15][CH:3]1[CH2:4][C:5](=[O:6])[C:7]([CH2:8][CH3:9])=[C:2]1[CH3:1]
Reactant: CCC(O)c1ccc(C)o1
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1=C(C)C(O)CC1=O
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixed solution of 28.97 g of the 1-(5-methyl-2-furyl)propanol thus obtained, 0.394 g of 50% aqueous acetic acid, 0.394 g of a 23% (w/v) sodium hydroxide solution in 579.4 g of water was heated and refluxed at the constant pH of 5.70 to 5.85 for 38 hours. After the mixed solution was cooled to the room temperature, a 23% (w/v) sodium hydroxide solution was added to the mixed solution to adjust the pH of the solution to 8.0 to 8.2, and then refluxed for three hours. A 50% acetic acid solution was added to the refluxing solution to adjust the pH to 6.0 to 6.5. The reaction solution was then cooled to the room temperature, mixed with 300 g of sodium chloride, and extracted three times with 500 ml of diethyl ether. The combined ether layer was washed twice with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was distilled, and a distillate fraction of 157° to 162° C. at 19 mmHg was collected to yield 15 g of (RS)-4-hydroxy-3-methyl-2-ethylcyclopent-2-en-1-one. Yield 52% b.p.: 157°-162° C. (19 mmHg)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.Cl>>[O:19]=[C:13]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C1CCC(=O)O1
Reactant: CCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1ccc(C(=O)CCC(=O)O)cc1
Reaction time: 3 h

Procedure:
5 cm3 of ethylbenzene and 2.6 g of aluminum chloride are mixed with magnetic stirring in a 50-cm3 flask. The solution is cooled in an ice bath and 1 g of succinic anhydride is then added. The reaction mixture is stirred for 1 h 30 min at a temperature of 0° C. and then for 3 h at room temperature. It is poured into ice. The resulting mixture is acidified by adding 1N hydrochloric acid (pH 3-4). It is extracted with 3 volumes of ether. The organic phases are washed 3 times with 10% potassium carbonate solution. The aqueous phases are combined and acidified by adding concentrated hydrochloric acid. The precipitate obtained is drained and then recrystallized.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][N:35]([CH3:40])[CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH3:34][N:35]([CH3:40])[CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: CN(C)C1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(dimethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 87 mg of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([NH:30][C:26]4([CH3:25])[CH2:29][O:28][CH2:27]4)=[O:22])[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: CC1(N)COC1
Product: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 81 %

Procedure:
As described for example 163c, 3-((3-(5-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (92 mg, 0.28 mol) was converted, using 3-methyl-3-oxetanamine instead of isopropylamine, to the title compound (90 mg, 81%) which was obtained as a white solid. MS: m/e=401.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCC[C@H](O)c1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a flask containing (S)-1-(4-Bromo-phenyl)-hexan-1-ol in CH2Cl2 at ambient temperature (˜23° C.) was added imidazole and t-butyldimethylsilyl chloride. The reaction mixture was stirred at ambient temperature for a period of time until all starting material was consumed before quenching with a mixture of MeOH and water. The organic layer was washed with deionized water and concentrated under reduced pressure to give the product as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O>C(O)C>[NH2:10][C:3]1[NH:2][C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:12][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=N)N
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C(=O)OC)cc2)[nH]c1N
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
Na metal (1.96 g, 85.3 mmol) was added portion wise to ethanol (210 mL) and stirred for 30 minutes to get clear solution. To this was added ethyl 3-amino-3-imino-propanoate hydrochloride (CAS: 57508-48-2, 14.25 g, 85.6 mmol) and stirred at room temperature for additional 30 minutes. Finally, methyl 4-(2-bromoacetyl)benzoate (11 g, 42.8 mmol) was added to the reaction mixture and stirred for 16-20 h at room temperature. After completion of the reaction (as indicated by TLC and LCMS), reaction mixture was filtered through celite and the residue was washed with MeOH (50 mL×2). The combined filtrate was concentrated under reduced pressure and the residue was purified using silica gel column chromatography (40% EtOAc in hexane) to provide XI-7-I (7 g, 56.7% yield). LCMS; m/z: 289.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH4+:11].[OH-]>COCCOC>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:11])=[O:8]
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: NC(=O)c1cncc(Br)c1
Reaction time: 1.5 h

Procedure:
All of the 5-bromonicotinoyl chloride prepared above was dissolved in 100 ml hot 1,2-dimethyoxyethane and added slowly during about 15 min to 500 ml cold, concentrated NH4OH in a 1 l round-bottom flask. The mixture was then stirred 1.5 hr at -10° C. to about 5° C. followed by filtration to collect white crystalline plates of 5-bromonicotinamide which were dried at 56° C. for 1.0 min to afford 17.79 g (89.2% yield) mp 222°-223° C. (lit. 224°-225° C., Czuba, W., Rec Trav Chim (1963) 82: 988-996; lit 141°-142° C., Morisawa, Y., J Med Chem (1977) 20: 129).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c1O
Yield: 39 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxyphenyl boronic acid in 39% yield using method F; δH [2H6]-DMSO 13.48,(1H, b), 13.38,(1H, b), 8.33,(2H, m), 8.23,(2H, t), 8.17,(2H, d), 8.13,(1H, d), 7.70,(2H, d), 7.37,(1H, t), 7.09,(1H, d), 7.02,(1H, d), 6.94,(1H, t), 3.84,(3H, s); MS 371 (MH)+; HPLC retention time (system 1) 4.03 minutes.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C@@H:18]1[C@@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:21]([OH:34])[CH2:20][C@@H:19]1[OH:35]>C(Cl)(Cl)Cl.O1CCCC1>[CH3:9][O:10][C:11](=[O:36])[CH2:12][CH2:13][CH2:14][CH:15]([Br:1])[CH:16]1[O:35][C@H:19]2[CH2:20][C@@H:21]([OH:34])[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[C:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:18]2[CH2:17]1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1O
Yield: 70.4 %

Procedure:
By proceeding as described in Example 1 but using 800 mg of N-bromosuccinimide and 1.47 g of (5Z,13E)-(9α,11α,15R)-9,11,15-trihydroxy-16,16-dimethylprosta-5,13-dienoic acid methyl ester dissolved in a mixture of 40 ml of chloroform and 4 ml of tetrahydrofuran, there was obtained 1.24 g of the title compound having the following physical characteristics:
Reaction SMILES: N12CCCCC1C=NCCC2.[N+:12]([CH3:15])([O-:14])=[O:13].[C:16]([O:21][CH3:22])(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>CO>[CH3:19][CH:18]([CH2:15][N+:12]([O-:14])=[O:13])[CH2:17][C:16]([O:21][CH3:22])=[O:20]
Reactant: C[N+](=O)[O-]
Reactant: C/C=C/C(=O)OC
Agent: C1=NCCCN2CCCCC12
Solvent: CO
Product: COC(=O)CC(C)C[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 144 h
Yield: 66.2 %

Procedure:
1,5-Diazabicyclo[5,4,0]undec-5-ene (6 ml) is added to a solution of nitromethane (91.5 g) in methanol (500 ml). The resulting mixture is heated to 60° C. and methyl crotonate (100 g, lm) is added under nitrogen. The mixture is then stirred for 6 days at 60° after which it is cooled to room temperature and most of the methanol is removed in vacuo. The residue is treated with ether (500 ml) and washed with 2 N hydrochloric acid (250 ml) and water (250 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give crude product. The crude product is purified by column chromatography on silica gel (500 g, ethyl acetate/hexane 2:98) to give methyl 3-methyl-4-nitrobutanoate (106.6 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (187 mg) in anhydrous DCM (5 ml) and triethylamine (111 ul) was added cyclopropanesulfonyl chloride (65 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature over 4 hours. Aqueous work-up and purification on silica gave 2-chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine (159 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 413. NMR (DMSO): 0.90-0.92 (2H, m), 0.97-1.00 (2H, m), 2.53-2.58 (4H, m), 2.60-2.64 (1H, m), 3.20-3.23 (4H, m), 3.74-3.77 (4H, m), 3.80 (2H, s), 3.88-3.91 (4H, m), 7.08 (2H, br), 7.52 (1H, s), 9.08 (2H, s) MS (ESI+): MH+ 517.22 (50%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(F)cc2F)nc1

Procedure:
In Scheme D, Ra, Ra′, Rc, Rc′, Re, Rg and X are as previously defined. In Scheme D (step 1), the halide can be displaced by either a nucleophilic aromatic substitution or transition metal catalyzed reaction. For example, methyl-6-chloronicotinate and 2,4-difluorophenol is dissolved in a suitable solvent such as DMF. To the reaction mixture is added a suitable base such as potassium carbonate monohydrate and the heated at reflux for a period of 2 to 18 hours to yield [6-(2,4-Difluoro-phenoxy)-nicotinic acid methyl ester. The reaction is concentrated and purified according to techniques well known in the art. These resulting esters formed in Scheme E, Step 1 can be further elaborated to final compounds using the procedures described in Scheme B, step 2 and 3.
Reaction SMILES: [CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[NH:5][S@](C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O)C.Cl.O1CCOCC1>>[CH:1]1([C@@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[NH2:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N[C@H](c1ccc(C(F)(F)F)nc1)C1CC1
Reaction time: 0.5 h

Procedure:
(S)—N—((R)-cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.245 g, 0.000765 mol), ethanol (2.7 g, 0.059 mol), and 4.0 M of hydrogen chloride in dioxane (2.7 mL, 0.011 mol) are combined and stirred for 30 minutes. The mixture is allowed to stir overnight. The solvent is removed and the residue is dissolved in ethanol. After washing with ethanol for 3 times, the mixture is concentrated and the residue is dried under high vacuum overnight to obtain the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CS(C)=O>[C:13]1([C:11](=[O:12])[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:3][CH:4]=2)=[O:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=C(CCC(=O)c1ccc(F)cc1)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(CCC(=O)c1ccc(N2CCCCC2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
1-(4-Fluoro-phenyl)-4-phenyl-butane-1,4-dione (390 mmol, 100 mg) and piperdine (3.9 mmol, 0.34 mL) are dissolved in DMSO (100 uL) in a vial. The vial is capped and allowed to heat/shake at 110° overnight. After which time, the reaction is checked by HPLC. After the reaction cooled to room temperature, 500 uL of water is added. The product precipitates and is filtered. 74 mg is collected and confirmed by LCMS.