Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([F:26])[C:7]([O:23]CC)=[C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[O:13])[CH:9]=2)[NH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:10]2[C:5](=[C:6]([F:26])[C:7]([OH:23])=[C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[O:13])[CH:9]=2)[NH:4][N:3]=1
Reactant: CCOc1c(NC(=O)NCc2cccc(F)c2)cc2c(N)n[nH]c2c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1n[nH]c2c(F)c(O)c(NC(=O)NCc3cccc(F)c3)cc12
Reaction time: 24 h
Yield: 23.2 %

Procedure:
70 mg of 1-(3-amino-6-ethoxy-7-fluoro-1H-indazol-5-yl)-3-(3-fluorobenzyl)urea are suspended in 2 ml of dichloromethane, and 105 μl of BBr3 are added. After 24 hours at RT, the mixture is carefully quenched using 1 ml of methanol and evaporated to dryness. Purification by chromatography on RP-18 silica gel (eluent:acetonitrile/water) gives 15 mg of 1-(3-amino-7-fluoro-6-hydroxy-1H-indazol-5-yl)-3-(3-fluorobenzyl)urea (“A 15”) as a virtually colourless solid (22%), MS-FAB (M+H+)=334;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1

Procedure:
Tetrakis(triphenylphosphine)palladium (1 g) was added to a mixture of 5 g of 2-methoxyphenylboronic acid, 6.6 g of 5-bromo-2-fluoronitrobenzene and 30 mL of 2 M sodium carbonate solution in 50 mL of toluene and 50 mL of ethanol. The mixture was refluxed for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried, and concentrated to give a dark green oil which solidified on standing to give crude 4-fluoro-2′-methoxy-3-nitrobiphenyl.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][CH3:30])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CN.O1CC[CH2:38][CH2:37]1>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][CH2:30][CH2:37][CH3:38])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1CCOC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC)cc4)cc23)CC1
Agent: CN
Product: CCCNCCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Yield: 27.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-indole-7-carboxamide, substituting 2 M propylamine in tetrahydrofuran (0.4 mL) for methylamine to afford 15 mg of the title compound (27.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(OCC)C>N1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([F:1])[CH:18]=[C:17]([F:19])[CH:16]=3)=[CH:15][CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Oc3cc(F)cc(F)c3)cc2)cc1
Temperature: -20 °C
Yield: 92.8 %

Procedure:
To a solution of 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (2.66 g, 10.0 mmol) in pyridine (2.8 g), p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was gradually added with stirring while cooling at -20° C., and the resultant mixture was allowed to stand in a refrigerator overnight. Diethyl ether was added to the reaction mixture, which was washed with dilute hydrochloric acid until the aqueous layer became acidic, followed by washing with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The obtained ether layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give 2-[4-(3,5-difluorophenoxy)phenoxy]ethyl p-toluenesulfonate (3.90 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:49]#[N:50].[K+]>C(O)C.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:11]2)=[CH:32][C:33]=1[CH2:38][C:49]#[N:50]
Reactant: Clc1ccc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of the (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)-tetrahydro-2H-pyran in ethanol (260 mL) and water (130 mL) was added potassium cyanide (31.8 g, 488 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. Purification was accomplished by chromatography to provide the titled compound 39 (105 g, 80%, ca. 2:1 mixture of anomers β:α).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:55])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:46][C:47]=3[CH3:48])=[CH:37][CH:36]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:48][C:47]1[O:46][C:45]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[N:44][C:43]=1[CH2:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([NH:33][C:23]2[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:24]=2)=[O:55])=[CH:36][CH:37]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C(=O)Nc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a solution (5 mL) of tetraethyl methylenediphosphonate (265 mg) in N,N-dimethylformamide was added sodium hydride (60% in oil, 40 mg) and the mixture was stirred at room temperature for 20 min. A solution (5 mL) of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzamide (400 mg) in N,N-dimethylformamide was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v) to give diethyl (E)-2-[3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless amorphous form (195 mg, yield 37%).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12](=[S:14])[NH:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[CH2:24]1COCC1.CI>C(N(CC)CC)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12]([S:14][CH3:24])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: Fc1cc2[nH]c(=S)[nH]c2cc1-c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CI
Product: CSc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Temperature: 40 °C

Procedure:
To a solution of 5 (2.23 g, 6.9 mmol) in 40 ML of THF was added triethylamine (2.2 mL) followed by the dropwise addition of methyliodide (0.43 mL, 6.9 mmol). The reaction mixture was heated to 40° C. for 2 h. The solvent was then removed in vacuo and the residue was taken up in EtOAc and washed two times with 100 mL portions of saturated aqueous ammonium chloride and one 100 mL portion of brine. The combined organic layers were dried over MgSO4 filtered and concentrated to dryness in vacuo. Then 150 mL of CH2Cl2 were added and the resulting precipitate was collected by vacuum filtration to give title compound 6.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:26][CH2:25]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of crude 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (13.33 mmol, 75% pure) in DCM (10 mL) was added Et3N (1.4 mL, 10 mmol) and 1-methylpiperazine (1.1 mL, 10 mmol). After stirring for 3 h at rt, aq. NaHCO3 was added, and the mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 10% MeOH/DCM) to provide 2.21 g of product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccccn1
Product: O=C(Nc1ccccn1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 2-pyridinamine (CAN 504-29-0) as starting materials, MS (D) m/e: 310.0 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]2[O:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:9]=2[CH:8]=[C:7](N)[CH:6]=1)(=[O:3])[CH3:2].N(OC(C)(C)C)=O.[I:24]I.Cl>C(#N)C>[C:1]([O:4][C:5]1[C:10]2[O:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:9]=2[CH:8]=[C:7]([I:24])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)Oc1cc(N)cc2c1OC(C)(C)C2
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: CC(=O)Oc1cc(I)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A stirred solution of 1.0 gram (0.0045 mole) of 5-amino-2,2-dimethyl-2,3-dihydrobenzo[2,3-b]furan-7-yl acetate in 40 mL of acetonitrile was cooled in an ice-bath and 0.55 mL (0.0045 mole) of tert-butyl nitrite was added. Upon completion of addition, the reaction mixture was stirred for an additional 15 minutes with continued cooling. After this time 1.2 grams (0.0045 mole) of iodine was added in two portions during a five-minute period. Upon completion of addition, the reaction mixture was stirred for an additional one hour with continued cooling, allowed to warm to ambient temperature where it stirred for three hours, and then it was warmed to reflux where it stirred for 30 minutes. After this time the reaction mixture was cooled and poured into 50 mL of aqueous 10% hydrochloric acid and the mixture was extracted with two 25 mL portions of methylene chloride. The combined extracts were washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.78 gram of the subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional intermediate.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[C:3]#[C:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C@@H:13]2[OH:18])[CH3:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[OH:1][C:2]([CH3:20])([CH3:21])[C:3]#[C:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH3:7]
Reactant: C[C@H](CC#CC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H](CC#CC(C)(C)O)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Yield: 71 %

Procedure:
1.22 g (4.17 mmol) of (1S,4aR,5R,8aR)-5-((R)-5-hydroxy-1,5-dimethyl-hex-3-ynyl)-4a-methyl-decahydro-naphthalen-1-ol was dissolved in 36 ml of abs. CH2Cl2 and oxidized with 4.72 g (12.51 mmol) of pyridinium dichromate during 2 h at ambient temperature. Filtration overCelite, evaporation to dryness, and flash chromatography (SiO2, Hexane/AcOEt=7/3) produced 860 mg of the title compound as colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl>[Pd].CO>[NH2:15][CH2:14][C:13]1[C:12]([NH:19][C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH3:21])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a MeOH solution (5 ml) was added (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Example 1; 0.15 g, 0.4 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.12 g). The mixture was then flushed with N2, evacuated, and then placed under 40 psi of H2 for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml), and a saturated aqueous solution of Na2CO3 (100 ml) was added, and the mixture was shaken vigorously for 30 min. The layers were then allowed to separate, and the aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were dried, filtered and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=9:1) to give the title compound (0.09 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.38 (m, 2H), 7.15 (d, J=11. Hz, 1H), 7.02-6.97 (m, 2H), 5.15-5.08 (m, 1H), 3.74 (s, 2H), 1.88-1.81 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.93-0.92 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 384. Found: [M+H]+ 385.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([NH:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:3]=1[C:21]1[C:26]([F:27])=[CH:25][C:24](F)=[CH:23][C:22]=1[F:29].[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][OH:35].[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([NH:14][C@@H:15]([CH3:20])[C:16]([F:18])([F:19])[F:17])[C:3]=1[C:21]1[C:26]([F:27])=[CH:25][C:24]([O:35][CH2:34][CH2:33][CH2:32][NH:31][CH3:30])=[CH:23][C:22]=1[F:29]
Reactant: C[C@H](Nc1nc(-c2cnccn2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: CNCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2N[C@@H](C)C(F)(F)F)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine (251 mg, 0.58 mmol) and 3-(methylamino)propan-1-ol (267 mg, 3.0 mmol) in 3 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol). The mixture is stirred at 60° C. for 2 h, cooled to room temperature, and partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 50% methyl alcohol in ethyl acetate. Concentration provides 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine as a light tan solid (181 mg, mp 48-50° C.). MS: m/z 503.1 (M+H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1

Procedure:
A solution of 5 g (16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one in 50 ml of methanol is hydrogenated in the presence of 0.5 g of Nishimura catalyst under normal pressure for 2 hours at room temperature. Removal of the catalyst by filtration is followed by concentration in a rotary evaporator and drying under a high vacuum. TLC Rf (D)=0.5; FAB-MS (M+H+)=312.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:16]=2)[NH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][NH:55][CH3:56]>CN(C=O)C.CS(C)=O>[CH3:51][N:52]([CH3:57])[CH2:53][CH2:54][N:55]([CH3:56])[C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)[CH:19]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Reactant: CNCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)CCN(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (21 mg, 0.06 mmol) in anhydrous DMF (1 mL) was added HATU (23 mg, 0.06 mmol) and N,N,N′-trimethylethylenediamine (7.9 μL, 0.06 mmol). The reaction solution was stirred 16 hours at ambient temperature then diluted with DMSO (1 mL), filtered through a 0.45 um syringe filter, and purified by reverse phase chromatography in a mobile phase of H2O and acetonitrile (with 0.1% formic acid as the modifier). Clean fractions were combined and lyophilized, affording the title compound as a white powder (14.0 mg, 54% yield). 1H NMR (500 MHz, CD3OD) δ8.51 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.83 (br s, 1H), 7.81 (bs, 1H), 7.69 (s, 1H), 7.60 (m, 2H), 7.49 (m, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.13 (d, 8.5 Hz, 1H), 7.07 (t, J=6.5 Hz, 1H), 3.90 (t J=6.0 Hz, 2H), 3.86 (s, 3H), 3.33 (s, 3H), 3.17 (s, 3H), 2.91 (s, 3H), 2.80 (br s, 2H). MS: m/e 429.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:29])[CH2:27][CH3:28])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:29][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH2:27][CH3:28])=[CH:22][CH:21]=1
Reactant: CC[C@H](N)c1ccc(OC)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC)cc1
Yield: 53 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-methoxy-phenyl)-propylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 53% of theory; LC (method 5): tR=1.02 min; Mass spectrum (ESI+): m/z=392 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52](=[O:68])[C@H:53]([OH:67])[C@H:54]([NH2:66])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]([F:65])([F:64])[F:63])[CH3:50]>C(Cl)Cl>[CH2:49]([O:51][C:52]([C@H:53]([OH:67])[C@H:54]([NH:66][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]([F:65])([F:63])[F:64])=[O:68])[CH3:50]
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1C(F)(F)F)NC(=O)CCCc1ccccc1C(=O)O
Reaction time: 1 h
Yield: 34.6 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (50 mg, 240 μmol, 1.0 eq.) was combined with DIPEA (134 μL, 3.2 eq.) and HATU (91.3 mg, 240 μmol, 1.0 eq.) in DCM (5 mL). (2R,3R)-3-Amino-2-hydroxy-4-(2-trifluoromethyl-phenyl)-butyric acid ethyl ester (69.9 mg, 240 μmol, 1.0 eq.) was added and the resulting mixture was stirred for 1 hour. The reaction was quenched by adding saturated NH4Cl and the product was extracted with DCM, dried, evaporated, and purified by preparative HPLC to yield the title compound (40 mg, 100% purity). MS m/z [M+H]+ calc'd for C24H26F3NO6, 482.17. found 482.