Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:17])[C:8]([CH3:13])=[N:7]2
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccc(F)c(Br)c2nc1Cl
Temperature: 90 °C
Yield: 49.1 %

Procedure:
In a 500-mL round-bottomed flask, a mixture of 8-bromo-7-fluoro-3-methylquinoxalin-2(1H)-one (600) (3.57 g, 13.89 mmol) and POCl3 (20.0 mL, 215 mmol) was heated at 90° C. for 1.5 h with a reflux condenser. The reaction mixture was cooled to RT and most of the excess POCl3 was removed under reduced pressure (rotary evaporator). The mixture was treated with EtOAc (100 mL), cooled in an ice bath, treated with ice chips and 1 N NaOH slowly. After phase separation, the organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated to afford the crude product as a brown solid. The crude residue was purified by chromatography on the ISCO Combiflash Rf (80 g Redisep column, using a gradient of 0-100% DCM in hexanes (eluted with ca. 35-60% DCM)) affording 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (1.88 g, 6.82 mmol, 49% yield) as a light orange crystalline solid. m/z (ESI, +ve ion) 275.0/277.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.01 (1H, dd, J=9.3, 5.4 Hz), 7.58 (1H, dd, J=9.1, 8.1 Hz), 2.86 (3H, s). 19F NMR (376 MHz, CDCl3) δ ppm −99.07 (1F, s).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:29])=O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2cc(OC3CCCCC3)ccc2c1O
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2cc(OC3CCCCC3)ccc2c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
A mixture of 7-cyclohexyloxy-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (Compound A-74 c1) (1.3 g) and phosphorus oxybromide (1.35 g) in anhydrous toluene (25 ml) was heated in a microwave reactor (sealed tube) at 130° C. for 15 min. After cooling, reaction mixture was concentrated. The residue was treated with saturated sodium bicarbonate aqueous solution (100 ml) and stirred at room temperature for 20 min. Extracted with ethyl acetate. Organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound (1.2 g). MS-(+)-ion M+1=422.12, 424.12.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([OH:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+](C1C=C(S(O[CH2:34][C@@H:35]2[CH2:37][O:36]2)(=O)=O)C=CC=1)([O-])=O>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:12][CH2:34][C@@H:35]2[CH2:37][O:36]2)=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COc1cc(O)c(NC(C)=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cc(OC[C@@H]2CO2)c(NC(C)=O)cc1Cl
Temperature: 25 °C
Yield: 98.1 %

Procedure:
N-(5-chloro-2-hydroxy-4-methoxyphenyl)acetamide (227 mg, 1.05 mmol) and caesium carbonate (376 mg, 1.25 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added (2S)-oxirane-2-ylmethyl 3-nitrobenzenesulfonate (301 mg, 1.16 mmol) dissolved 2-methyl-2-pyrrolidine (2 mL) drop wise. The resulting brown slurry was stirred over night, at room temperature. The mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and concentrated to yield crude 280 mg (98%) of the titled compound.
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.[CH2:30](I)[CH3:31]>>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:30][CH3:31])[CH:20]=2)[O:17][CH:18]=1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Reactant: CCI
Product: CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 272 and ethyl iodide, white powdery 1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>ClC(Cl)C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: c1ccccc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)C(Cl)Cl
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 8 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
A solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (26.7 g, 0.112 mol) and benzene (12.0 mL, 0.134 mol) in 1,1,2,2-tetrachloroethane is cooled to 0° C. to 5° C., treated with aluminum chloride (18.1 g, 0.136 mol), stirred for 15 minutes at about 8° C., heated to and stirred at 50° C. for one hour, cooled to room temperature, and diluted sequentially with an ice-water mixture and concentrated hydrochloric acid. The organic phase is separated, washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and methylene chloride gives the title product as an orange solid (30.8 g) which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:13][CH2:14][CH3:15])([CH2:11]I)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[K].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][Si:4]([O:13][CH2:14][CH3:15])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CCO[Si](CI)(OCC)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O
Product: CCO[Si](Cn1cncn1)(OCC)c1ccccc1
Yield: 78.1 %

Procedure:
A mixture of 4.0 g (0.012 mol) of diethoxy(iodomethyl)phenylsilane, 1.5 g (0.014 mol) of 1,2,4-triazole potassium salt, and 0.5 g (0.14 mmol) of tetrabutylammonium hydrogen sulfate in 10 ml of toluene was stirred and warmed to 100°-110° C. for 5 hours, cooled, diluted with water, and extracted with methylene chloride. The methylene chloride solution was washed with brine, dried over magnesium sulfate, and evaporated to leave 2.6 g (79%) of the title compound as a pale brown oil: nD19 1.5543; ir (neat) 2980, 1590, 1505, 1430, 1270 cm-1 ; nmr (CDCl3) 1.2 (6H, t, J=7), 3.8 (4H, q, J=7), 3.9 (2H, s), 7.2-7.7 (5H, m), 7.8 (s, 1H) and 8.0 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>>[CH3:44][N:45]([CH3:49])[C:46]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[O:47]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: CN(C)C(=O)Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)N(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and dimethylcarbamoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[N:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[C:8]([F:33])[CH:7]=1)=O)C.O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[F:33][C:8]1[CH:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][C:9]=1[CH2:12][CH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CCc3ccc(CO)cc3F)nc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of tert-butyl 4-(6-{2-[4-(ethoxycarbonyl)-2-fluorophenyl]ethyl}pyridin-3-yl)piperazine-1-carboxylate (1.414 g, 3.091 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise at −78° C. 1M diisobutylaluminum hydride tetrahydrofuran solution (12 ml, 12 mmol) over 10 mins. After stirring at −78° C. for 30 mins, the mixture was heated to room temperature and stirred for 1 hr 40 mins. After cooling to −78° C., 1M diisobutylaluminum hydride tetrahydrofuran solution (6 ml, 6 mmol) was added dropwise over 5 mins. The mixture was heated to room temperature and stirred for 40 mins. Saturated aqueous potassium sodium tartrate solution (150 ml) was added and the mixture was stirred and extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1→ethyl acetate) to give tert-butyl 4-(6-{2-[2-fluoro-4-(hydroxymethyl)phenyl]ethyl}pyridin-3-yl)piperazine-1-carboxylate (1.046 g, yield 81.4%) as a slightly yellow solid.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[C-:20]#[N:21].[K+]>Cl.O>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([C:20]#[N:21])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: [C-]#N
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCCCC1OC(=O)c2cc(C#N)ccc21
Reaction time: 2 h

Procedure:
A suspension of 7.2 g (32.12 mmol) of the compound obtained in Example 4 in 100 ml of 18% hydrochloric acid is diazotized by a solution of 6 g of sodium nitrite in 30 ml of water at 3-5° C. To this solution there is added, with vigorous stirring, a solution of cuprous cyanide, prepared from 21.0 g of CuSO4.5H2O in 87 ml of H2O and 24.7 g of potassium cyanide in 133 ml of H2O at 50-60° C. The mixture is stirred at the same temperature for 2 hours. The separated solid is extracted with methylene chloride, the organic phase is washed with sodium carbonate solution and water. After removing the solvent, the residue is crystallised from ethanol to give the title compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:6][CH2:7][C@H:8]([C:10]1[O:11][C:12](=O)[C:13]2[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)[OH:9])([CH3:4])[CH3:3].C1COCC1.[CH3:46][NH2:47]>>[Si:5]([O:6][CH2:7][C@H:8]([C:10]1[N:47]([CH3:46])[C:12](=[O:11])[C:13]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)=[CH:24][CH:25]=[CH:26][CH:27]=2)[OH:9])([C:2]([CH3:3])([CH3:1])[CH3:4])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN
Reactant: Cc1ccc(-c2c([C@H](O)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)oc(=O)c3ccccc23)cc1C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c([C@H](O)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C)c(=O)c3ccccc23)cc1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
A solution of 3-((1R)-2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-1-hydroxyethyl)-4-(3,4-dimethylphenyl)-1H-2-benzopyran-1-one (92 mg, 0.168 mmol) was dissolved in 2M methyl amine in THF (1.3 mL, 2.51 mmol) was heated to 80° C. After 18 h, the reaction mixture was concentrated in vacuo and treated with 4M HCl in dixoane (2 mL). The reaction stirred for 20 min and poured into 1M aqueous NaOH and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-50%) to afford the title compound (13 mg, 0.023 mmol, 14% yield) as a colorless film: Rt=1.28, ES+ MS: 562 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[BH4-].[Na+]>C(O)C>[OH:1][C:2]1[C:11]2[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnc2c(c1O)CC(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c1O)CC(O)CC2

Procedure:
To a suspension of 6 g of ethyl 4-hydroxy-6-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate in 200 mL of ethanol, 1.92 g of NaBH4 is added in small portions under ice-cooling and stirring. The reaction mixture is then stirred at room temperature for 6 hours and evaporated to dryness. The residue is taken up in CHCl3, washed successively with 6N NH4OH, and sat. aq. NaCl, dried (MgSO4) and evaporated dryness obtaining ethyl 4,6-dihydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([Cl:31])[CH:3]=1.[NH:32]1CCC[C@H:33]1C(O)=O.[Cu]C#N.O>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:29]1[CH:28]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])[C:4]([Cl:31])=[CH:3][C:2]=1[C:33]#[N:32]
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: O=C(O)[C@@H]1CCCN1
Agent: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 120 °C
Reaction time: 17 h
Yield: 25.4 %

Procedure:
To a suspension of 0.20 g (0.43 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 26) in 0.2 mL N,N-dimethylformamide was added 0.044 g (0.38 mmol) L-proline (commercially available, CAS RN 147-85-3) followed by the addition of 0.068 g (0.76 mmol) copper(I) cyanide. The resulting dark brown suspension was stirred at 120° C. for 17 hours. Then another 0.2 mL N,N-dimethylformamide were added and stirring was continued for another 7 hours at 120° C. The reaction was allowed to cool to room temperature, stirred for another 64 hours and then partioned between water and ethyl acetate. The resulting turbid mixture was filtered and washed with ethyl acetate. The layers of the filtrate were separated and the water layer extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The remaining light brown oil was dissolved in dichloromethane, treated with silica gel and then evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to afford 0.045 g (25%) of the title compound as a brown solid. MS (ESI): m/z=465.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:14]([F:15])=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([OH:16])[CH:5]=1.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([Cl:28])[CH:22]=1)(=[O:20])=[O:19]>CN(C=O)C>[Cl:28][C:23]1[CH:22]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:26]=[CH:25][C:24]=1[O:16][C:6]1[CH:5]=[C:4]([F:3])[C:14]([F:15])=[CH:13][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)COc1cc(F)c(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(F)c(F)cc2OCC(=O)O)c(Cl)c1
Temperature: 85 °C

Procedure:
A mixture of sodium hydride (60% wt. disp. in oil, 0.275 g) and the product from step (iii) (0.7 g) in DMF (10 ml) was stirred at RT for 15 min. The product from example 7 step (ii) (0.715 g) was added and the mixture heated at 85° C. for 15 h. The mixture was partitioned between 2M sodium hydroxide solution and diethylether, the aqueous layer was acidified with 2M hydrochloric acid and extracted with ethylacetate. The ethylacetate layer was dried, evaporated under reduced pressure and the residue purified by RPHPLC. Yield 0.076 g.
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1([F:34])[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:8][CH2:7]1.O[N:36]1C(=O)CCC1=O.N>CN(C=O)C>[F:5][C:6]1([F:34])[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([NH2:36])=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Temperature: 25 °C

Procedure:
0.029 g EDC was added to a mixture of 0.050 g 4-[2-(4,4-difluoro-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 33.2) and 0.020 g 1-hydroxy-pyrrolidine-2,5-dione in 1 ml DMF and stirred at rt over the weekend. After the addition of 0.327 ml ammonia (7M) the reaction mixture was stirred at rt for further 1.5 hours. The mixture was concentrated and the residue was recrystallized from hot MeOH.
Reaction SMILES: C([C@H]([NH:11][C@@:12]([CH3:25])([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([NH2:15])=[O:14])C1C=CC=CC=1)(=O)N.C([O-])=O.[NH4+].C1(CC(N)=O)C=CC=CC=1>CC(O)C.[Pd]>[NH2:11][C@@:12]([CH3:25])([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C:13]([NH2:15])=[O:14]
Reactant: COc1ccc(C[C@](C)(N[C@@H](C(N)=O)c2ccccc2)C(N)=O)cc1
Agent: [Pd]
Agent: NC(=O)Cc1ccccc1
Agent: O=C[O-]
Solvent: CC(C)O
Product: COc1ccc(C[C@](C)(N)C(N)=O)cc1
Yield: 95.7 %

Procedure:
Method B, Transfer hydrogenolysis: Amine 3 (500 mg, 1.47 mmol, 1 eq) was dissolved in i-PrOH (5 mL) under Argon. 10% Pd/C (200 mg, 56% moisture content, 18 wt %) and ammonium formate (601 mg, 9.56 mmol, 6.5 eq.) were added. The mixture was stirred at reflux temperature for 1 h. The mixture was filtered through Celite, the filter pad was washed with EtOH (10 mL) and the filtrates were concentrated to provide 480 mg of a 1:1 mixture of desired compound (293 mg, 96%) and phenylacetamide as a white solid. 1H NMR (DMSO, 400 MHz) 1.14 (s, 3H); 2.10 (bs, 2H); 2.50 (d, J=13.1 Hz, 1H); 2.95 (d, J=13.1 Hz, 1H); 3.69 (s, 3H); 6.80 (d, J=8.5 Hz, 2H); 6.81 (bs, 1H); 6.90 (bs, 1H); 7.09 (d, J=8.5 Hz, 2H). (Phenylacetamide 3.34 (s, 2H); 7.15-7.28 (m, 6H); 7.42 (bs, 1H).). HPLC/MS 4 tR=1.96 min. MS (ESI (+)) m/z=164.2 (M-CONH2). (Phenylacetamide tR=1.76 min. MS (ESI (+)) m/z=136.2 (M+1)).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:21]=[C:22]([C:24]2[NH:25][C:26]([C:29]3[O:30][C@@H:31]([CH2:34][O:35][Si](C(C)C)(C(C)C)C(C)C)[CH2:32][N:33]=3)=[CH:27][CH:28]=2)[CH:23]=1)[O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:15][CH:16]=1)[CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:5])[O:6][C:7]1[CH:23]=[C:22]([C:24]2[NH:25][C:26]([C:29]3[O:30][C@@H:31]([CH2:34][OH:35])[CH2:32][N:33]=3)=[CH:27][CH:28]=2)[CH:21]=[C:9]([O:10][C:11]2[CH:16]=[N:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[CH:8]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=NC[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(5R)-5-{[(tripropan-2-ylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine (1.18 g, 1.79 mmol) synthesized in Example (82a) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 2.00 mL, 2.00 mmol) was added at room temperature, followed by stirring at room temperature for 30 minutes under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (680 mg, yield 76%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][NH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH:27][CH3:26])=[O:25])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12
Reactant: CN
Product: CNC(=O)c1cnn2ccc(N3C[C@@H](O)C[C@@H]3c3cccc(F)c3)nc12

Procedure:
Prepared according to the method of Example 212, Step F, using 5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 216, Step B) and methyl amine. The title compound was obtained as a white solid (6.1 mg, 29% yield). MS (apci) m/z=356.1 (M+H).
Reaction SMILES: C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:6].[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CS(C)=O>[CH:37]1([NH:36][C:35](=[O:6])[NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.0 g (2.5 mmol) diethylenetriamine pentaacetic acid in 50 ml dimethyl sulfoxide (DMSO) was added 1.28 g (6.25 mmol) dicyclohexyl carbodiimide (DCC) and this was stirred for 24 hr at room temperature. During this time the granular solid of DTPA was consumed and the white fluffy solid of dicyclohexyl urea formed. The reaction mixture was filtered and washed with DMSO. The filtrate was split into two equal volumes. The first fraction was concentrated to a thick oil under reduced pressure and heat. A solid precipitated from the oil upon the addition of 30 ml acetonitrile. The solid was collected by filtration, washed with cold acetonitrile and dried under vacuum to give 0.32 g (68%) of a brown solid mp 110°-130° C. NMR analysis revealed an average of one anhydride/DTPA.