Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[S:61][CH:62]=2)=[N:56]\[OH:57])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:91][CH2:92][C:93]([O:95][C:96]1[CH:97]=[C:98]([CH:102]=[C:103]([O:110][C:111](=[O:114])[CH2:112][Cl:113])[C:104]=1[O:105][C:106](=[O:109])[CH2:107][Cl:108])[C:99](Cl)=[O:100])=[O:94]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:61][CH:62]=2)=[N:56]\[O:57][C:99](=[O:100])[C:98]2[CH:97]=[C:96]([O:95][C:93](=[O:94])[CH2:92][Cl:91])[C:104]([O:105][C:106](=[O:109])[CH2:107][Cl:108])=[C:103]([O:110][C:111](=[O:114])[CH2:112][Cl:113])[CH:102]=2)[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: O=C(CCl)Oc1cc(C(=O)Cl)cc(OC(=O)CCl)c1OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(=O)c4cc(OC(=O)CCl)c(OC(=O)CCl)c(OC(=O)CCl)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To an ice-cooled solution of (6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (0.7 g) in dry dichloromethane (17 ml) was added potassium carbonate (0.1 g) all at once, followed by dropwise addition of a solution of 3,4,5-tris(chloroacetoxy)benzoyl chloride (0.376 g) in dry dichloromethane (10 ml) over a period of five minutes, and the yellow mixture was stirred at 0° C. for 30 minutes. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the yellow residue was crystallized with ether (50 ml), giving 0.92 g of the objective compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@@:9]([F:16])([CH:14]=[CH2:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:36])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH:17]1([N:7]2[CH2:8][C@:9]([F:16])([CH:14]=[CH2:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:33]([O:34][CH3:35])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:36])[CH:25]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)OC)cc3OC)ncc2N(C)C1=O
Temperature: 95 °C
Reaction time: 36 h
Yield: 26.6 %

Procedure:
A mixture of (R)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.0 g, 3.086 mmol), and methyl 4-amino-2-fluoro-5-methoxybenzoate (3.07 g, 15.43 mmol) was dissolved in dioxane (20 ml), and p-toluenesulfonic acid, monohydrate (2.99 g, 15.74 mmol) was added. The mixture was stirred at 95° C. for 24-48 h. The final compound was purified by reverse phase HPLC to give 400 mg product as white solid (40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.82 (m, 4H) 1.93-1.98 (m, 4H) 3.29 (s, 3H) 3.51 (br. s., 2H) 3.61 (m, 3H), 3.86 (m, 3H) 3.94 (s, 3H) 4.88 (t, J=8.08 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1H) 7.41-7.57 (m, 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'd for C24H27F2N5O4, 488. found 488.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:17][C:2]([F:1])([F:16])[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:21][CH2:20][CH2:19][Br:18])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12

Procedure:
A solution of 3-trifluoromethyl-7-propyl-6-hydroxybenzisoxazole (2.5 grams) in 2-butanone (30 mL) was treated with 1,3-dibromopropane (4.8 mL) and potassium carbonate (5.0 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was flitered through a silica gel plug using methylene chloride and hexane (1:2) to give 3-trifluoromethyl-7-propyl-6-(3-bromopropyloxy)-benzisoxazole. A solution of 3-chloro-4-dimethylcarbamoylthio-phenylacetic acid methyl ester (0.33 grams) in dry methanol (3.5 mL) was treated with a solution of sodium methoxide in methanol (25 wt %; 0.341 mL). The solution was refluxed for 2 hours. HPLC analysis showed the disappearance of the carbamate. The solution was allowed to cool to 50° C. 3-trifluoromethyl-7-propyl-6-(3-bromopropyloxy)-benzisoxazole (0.31 grams) was added and the solution stirred for 1 hour. The reaction was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once more with pH 4 buffer, then water. The organic was dried over magnesium sulfate, filtered and concentrated to an oil. The oil was applied to a silica gel column packed with hexane/methylene chloride (2:1). The column was eluted with this mobile phase until the product began to appear in the eluant. The mobile phase was switched to 100% methylene chloride and elution continued until all the product was recovered.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:29][C:30]([O:32]CC)=[O:31])[C:4]([CH3:28])=[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:22])=[O:21])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1[N:3]([CH2:29][C:30]([OH:32])=[O:31])[C:4]([CH3:28])=[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:21])=[O:22])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c(C)n1CC(=O)O
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirring solution of ethyl 2-(2,5-dimethyl-3-phenyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (0.029 g, 0.060 mmol) in tetrahydrofuran (1 ml) and water (1 ml) was added 1N sodium hydroxide (0.121 ml, 0.121 mmol). Upon addition, the reaction changed color from pink to yellow. The mixture was stirred overnight, after which LCMS analysis indicated reaction completion. The reaction was quenched with 0.050 ml of 3N HCl and stirred to afford a pink color. The crude mixture was concentrated and taken up in acetonitrile and purified by reverse phase HPLC chromatography. Acetonitrile and water spiked with 0.1% TFA were used as eluents. The desired fractions were collected and quenched with aqueous saturated sodium bicarbonate solution and washed with ether. The aqueous layer was then acidified with 3N HCl to pH=1 and this aqueous layer was extracted 3 times with ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford a purple solid (0.0203 g, 0.045 mmol, 74.3% yield). 1H NMR (CDCl3/400 MHz)ppm) 7.91 (d, 1H), 7.37-7.33 (m, 1H), 7.23-7.17 (m, 1H), 7.15-7.11 (m, 3H), 7.08-7.05 (m, 1H), 6.99-6.97 (m, 2H), 4.63 (s, 2H), 4.07 (s, 2H), 3.08-3.04 (m, 4H), 2.14 (s, 3H), 1.98 (s, 3H), 1.61-1.58 (m, 4H). LCMS (M+1): 453.3.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1.C(N(C(C)C)CC)(C)C>C(O)C>[F:28][C:26]([F:27])([F:29])[C:23]1[N:21]2[N:22]=[C:17]([N:7]3[CH2:6][CH:5]4[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]4[CH2:8]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3.15 g, 14.83 mmol) was added to a mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3 g, 13.48 mmol) and diisopropyethylamine (4.66 mL, 26.96 mmol) and ethanol (50 mL). The mixture was warmed to 70° C. over a period of 10 minutes, stirred at 70° C. for 1 hour, and then allowed to cool to ambient temperature to give a precipitate. The precipitate was collected by filtration, washed with ethanol (50 mL), and dried under vacuum to afford tert-butyl 5-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3.00 g, 55.9%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:11][OH:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:11][O:12][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(=O)Cl
Product: C[C@H](COC(=O)c1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Following the procedure of example 47A, but replacing N-(tert-butoxycarbonyl)-L-alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with benzoyl chloride, provided N-(tert-butoxycarbonyl)-O-benzoyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:6].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1.O>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:13]2[C:10]3=[N:11][CH:12]=[C:7]([C:5]([OH:4])=[O:6])[CH:8]=[C:9]3[CH:15]=[CH:14]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(C(=O)O)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.1 %

Procedure:
To a stirred cooled 0° C. suspension of NaH (272 mg, 6.81 mmol) in DMF (23 mL) was added 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (400 mg, 2.27 mmol). After 5 min, PMBBr (548 mg, 2.72 mmol) and KI (377 mg, 2.27 mmol) were added and the reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The following day, water was added to quench the remaining Nail and the aqueous mixture was washed with EtOAc, which was discarded. The aqueous phase was collected and carefully acidified (pH ˜3) before extraction with EtOAc. The combined organics were dried and evaporated to afford 1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (160 mg, 0.57 mmol, 25% yield). ES MS (M+H+)=283.
Reaction SMILES: [CH2:1]([C@@:4]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].C1COCC1>CCOC(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>[CH2:1]([C@@:4]1([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:36]3[S:37][CH:38]=[CH:39][N:40]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3nccs3)cc2)C(=O)O1
Temperature: 140 °C
Yield: 33 %

Procedure:
(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.043 mmol), 2-bromothiazole (14 mg, 2 equiv), 2M aq Na2SO4 solution (0.5 mL) and Pd(PPh3)2Cl2 were mixed with THF (0.6 mL) and heated in a microwave oven for 2 h at 140° C. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with water (2 mL), 1% aq HCl (2 mL) and brine (1.5 mL). After concentration, the residue was purified by preparative HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(thiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (6.0 mg, 33%). LC-MS (3 min) tR=1.86 min, m/z=423 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH3:11])[N:7]=2)[CH:23]=[CH:22][C:21]=1[OH:35]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CC[C@H](Nc1cncc(Cl)n1)c1ccccc1
Product: CC[C@H](Nc1cncc(-c2ccc(O)c(OC)c2)n1)c1ccccc1
Yield: 45.5 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(1S)-1-phenylpropyl]pyrazin-2-amine (135 mg, 0.57 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (158 mg, 0.63 mmol) furnished the product (87 mg, 45%).
Reaction SMILES: [OH-].[Na+].ClC1C=CC(C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[C:16]([F:18])[F:17])=O)=CC=1>O.C(O)C>[F:17][C:16]([F:18])=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][OH:10]
Reactant: O=C(OCCCCC=C(F)F)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a stirred solution of 0.84 gram (0.0121 mole) of sodium hydroxide in 1.5 ml of water was added a solution of 3.3 grams (0.0121 mole) of 6,6-difluoro-5-hexenyl 4-chlorobenzoate (prepared in Example 19) in 20 ml of ethanol. Upon completion of addition, the reaction mixture was warmed to reflux where it was stirred for 18 hours. After this time the reaction mixture was cooled to ambient temperature, and it was concentrated under reduced pressure to a residual semi-solid. The semi-solid was taken up in water and diethyl ether. The aqueous layer was separated, and it was washed with two 100 ml portions of diethyl ether. The ether washes were combined with the organic layer, and the combination was washed in turn with one 50 ml portion of water and one 100 ml portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 1.6 grams of 6,6-difluoro-5-hexen-1-ol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl[C:13]1[CH:18]=CC=C[CH:14]=1.C(Cl)Cl>CO>[N:3]1[C:2]2[C:7](=[CH:14][CH:13]=[CH:18][N:1]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ccccc1
Reactant: Nc1ccccn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: c1cnc2ncccc2c1
Temperature: 120 °C

Procedure:
To a mixture of aminopyridine (1.12 g, 5.833 mmol) and AlCl3 (3.11 g, 0.023 mol) was added chlorobenzene (10.0 mL) in a sealed vessel under Ar. The reaction was sealed and heated to 120° C. for 12 h. The reaction mixture was cooled to RT and the mixture was poured over ice/HCl mixture and extracted with EtOAc (3×50.0 mL). The aqueous layer was neutralized via addition of solid NaHCO3 and extracted with EtOAc (5×50 mL). Combined organic layers were dried over Na2SO4 and evaporated to dryness to yield crude compound. Chromatography (Silica gel, CH2Cl2:MeOH, 99:1) yielded pure naphthyridin.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=1[CH2:29][CH2:30][CH3:31].N1C=CC=CC=1>ClCCl>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:13][S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)(=[O:11])=[O:10])[CH:34]=[CH:33][CH:32]=2)=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 106.3 %

Procedure:
Add 3-cyano-benzenesulfonyl chloride (673 mg, 3.34 mmol) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.34 mmol) and pyridine (0.98 mL) in dichloromethane (20 mL) at 0° C. Warm to room temperature. Partition the mixture between dichloromethane and 2N hydrochloric acid (60 mL). Wash the organic layer with saturated sodium bicarbonate and brine. Dry and concentrate to afford the title compound as an orange solid (1.65 g): 1H NMR (DMSO-d6) δ 0.85 (t, 3H), 1.47 (sextet, 2H), 2.55 (t, 2H), 2.57 (s, 3H), 5.19 (s, 2H), 6.62 (d, 1H), 7.05 (d, 1H), 7.14 (d, 1H), 7.23 (s, 1H), 7.29 (t, 1H), 7.73 (t, 1H), 7.77 (d, 1H), 7.98 (d, 1H), 8.07 (d, 1H) 8.12 (s, 1H), 10.55 (s, 1H), 12.86 (s, 1H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH3:14].[Si:24]([N:31]1[C@H:34]([CH2:35][CH:36]=[O:37])[C@@H:33]([C@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:39])[C:32]1=[O:48])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O1CCCC1>[Si:24]([N:31]1[C@H:34]([CH2:35][CH:36]([OH:37])[CH2:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@@H:33]([C@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[CH3:39])[C:32]1=[O:48])([C:27]([CH3:30])([CH3:28])[CH3:29])([CH3:26])[CH3:25]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC=O
Reactant: CC(=O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(O)CC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.81 mmol) is added by syringe to a solution of diisopropylamine (1.81 mmol) in 9 ml of freshly distilled tetrahydrofuran at -78° C. The resulting solution is stirred for 15 min at -78° C. Benzyl acetate (1.81 mmol) is then added dropwise by syringe and the resulting solution is stirred at -78° C. for 20 min. A solution of (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one (1.64 mmol) in 3 ml of anhydrous tetrahydrofuran is added slowly by syringe. The reaction mixture is stirred at -78° C. an additional 15 min and then quenched by addition of saturated aqueous ammonium chloride solution. Ethyl acetate (50 ml) is added and the organic phase is separated, washed with water (2×10 ml) and brine and dried over magnesium sulfate. Removal of solvents in vacuo gives a white solid which is chromatographed on a short silica gel column (40 % ether in petroleum ether) to yield (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one. n.m.r. (CDCl3) δ7.32 (s,5), δ5.1 (s,2), δ4.0 (m,3), δ2.4-3.8 (m,4), δ2.0 (m,2), δ1.25 (overlapping d, 3), δ0.95 (s,9), δ0.9 (s,9), δ0.3 (s,6), δ0.18 (s,6).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.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>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C@@H:10]1[CH2:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(-c3ccc(C#N)cc3)cc2)C1
Temperature: 25 °C
Yield: 33.5 %

Procedure:
A solution of the product from Example 2A (100 mg, 0.34 mmol), 4-cyanophenyl boronic acid (65 mg, 0.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (12 mg, 17 μmol) and potassium carbonate (120 mg, 0.85 mmol) under an atmosphere of nitrogen in isopropyl alcohol (8 mL) was heated at reflux for 5 hrs. Then, the reaction mixture was cooled to ambient temperature. The mixture was partitioned between ethyl acetate (25 mL) and H2O (10 mL). The organic layer was washed with brine, dried with magnesium sulfate, filtered, concentrated, and chromatographed on silica gel, eluting with 3% (9:1 MeOH:conc NH4OH) in dichloromethane to provide 36 mg of the title compound. 1H NMR (300 MHz, CD3OD) δ 1.21 (d, J=6 Hz, 3 H), 1.54 (m, 1 H), 1.84 (m, 2 H), 2.07 (m, 1 H), 2.18 (m, 2 H), 2.57 (m, 2 H), 2.71 (m, 2 H), 3.11 (m, 1 H), 3.27 (m, 2 H), 7.39 (d, J=9 Hz, 2 H), 7.64 (d, J=9 Hz, 2 H), 7.79 (s, 4 H); (DCl/NH3) m/z 317 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([NH2:22])[CH:16]=2)[N:7]=1
Reactant: Clc1nccc(Sc2ccccn2)n1
Reactant: Nc1cccc(N)c1
Product: Nc1cccc(Nc2nccc(Sc3ccccn3)n2)c1
Yield: 30.1 %

Procedure:
In a procedure analogous to Example 6, reaction of 2-chloro-4-(pyridin-2-ylthio)pyrimidine (100 mg, 0.45 mmol) and 1,3-phenylenediamine (193 mg, 1.78 mmol) furnished the product (40 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:23]=[C:24]([C:25]3[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=3)[C:18]=2[N:17]=1>>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:16]3[NH:17][C:18]4[C:24]([C:25]5[CH:26]=[C:27]([F:33])[C:28]([F:32])=[C:29]([F:31])[CH:30]=5)=[CH:23][C:22]([C:34]([F:37])([F:35])[F:36])=[CH:21][C:19]=4[N:20]=3)[C@H:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
The piperazine from step (a) above (84 mg. 0.4 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (105 mg, 0.3 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 526 (M+1).