Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][NH:16][CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:25](C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH3:25])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCNC3)c1=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of 205a (2.75 g, 7.5 mmol), formaldehyde (37 percent in water, 30 ml, 375 mmol), NaBH(OAc)3 (4.75 g, 22.5 mmol) and acetic acid (25 ml, 150 mmol) in methanol (125 ml) was stirred for 4 hours at room temperature. The mixture was then brought to basic condition with saturated NaOH solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 4:1 ethyle acetate/methanol to give 205b (2.0 g, 77%). LC/MS: m/z 349 (M+H)+
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28].C(=O)([O-])[O-].[Cs+].[Cs+]>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>[NH2:20][C:4]1[N:3]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]([Cl:21])=[C:27]([Cl:28])[CH:26]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1nc(-c2ccc(Cl)c(Cl)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 11.6 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 3,4-dichlorophenylboronic acid (116 mg, 0.61 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 30 s) for 110 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (30 mL) and washed with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 20 g, 18-32%, gradient 2.5-20% ethanol in DCM, residue dry loaded) and twice by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 48% acetonitrile) and (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 50% acetonitrile) afforded (2R,3R,4S,5R)-2-{6-amino-2-(3,4-dichlorophenyl)-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 9 as a white solid (24.4 mg, 11%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:4].[Na+].[I-].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]([S:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:10])[C:27](=[O:28])[N:26]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])=[O:4]
Reactant: COC(=O)C1CN1S(=O)(=O)c1ccccc1
Reactant: O=C=Nc1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Product: COC(=O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl

Procedure:
In analogy to example 1,1-benzenesulfonyl-aziridine-2-carboxylic acid methyl ester (example 39, step 2) was reacted with NaI and 2-chlorophenylisocyanate to give 1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:28][CH3:29])[C:21]([O:23]C(C)(C)C)=[O:22])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18]>C(O)=O.C(OCC)C>[CH2:1]([O:19][CH:20]([CH2:28][CH3:29])[C:21]([OH:23])=[O:22])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCOC(CC)C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: O=CO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCOC(CC)C(=O)O
Temperature: 40 °C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
A mixture of tert-butyl 2-((3Z,6Z,9Z,12Z,15Z)-octadeca-3,6,9,12,15-pentaen-1-yloxy)butanoate (2.09 g, 4.58 mmol) in HCOOH (9 mL) was stirred at 40° C. under N2-atmosphere for 6 hrs. The reaction mixture was diluted with diethyl ether (100 mL), washed with water (30 mL), dried (MgSO4), filtered and evaporated under reduced pressure. Dry-flash on silica gel (50 g) eluting with toluene-toluene/EtOAc (85:15) yielded 1.44 g of the crude title compound. Flash chromatography on silica gel (30 g) eluting with heptane-heptane/(EtOAc w/5% HCCOH) 98:2-95:5-80:20 yielded 1.07 g (58% yield) of the title compound as a liquid. 1H NMR (200 MHz, CDCl3) δ 0.97 (t, 3H), 0.99 (t, 3H), 1.75-1.91 (m, 2H), 2.00-2.15 (m, 2H), 2.35-2.48 (m, 2H), 2.78-2.87 (m, 8H), 3.47-3.62 (m, 2H), 3.86 (dd, 1H), 5.25-5.55 (m, 10H). MS (electrospray) (neg): 345 (M−H)−.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:16]C(=O)OC(C)(C)C)[C:9]([NH:11][CH2:12][CH2:13][C:14]#[N:15])=O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Si]([N:67]=[N+:68]=[N-:69])(C)(C)C>C1COCC1>[NH2:16][C@H:8]([C:9]1[N:11]([CH2:12][CH2:13][C:14]#[N:15])[N:69]=[N:68][N:67]=1)[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:2][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCCn1nnnc1[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of (S)-tert-butyl 3-(biphenyl-4-yl)-1-(2-cyanoethylamino)-1-oxopropan-2-ylcarbamate (563 mg, 1.431 mmol) and triphenylphosphine (450 mg, 1.717 mmol) in THF (10 mL) were added DIAD (0.334 mL, 1.717 mmol) and TMSN3 (0.228 mL, 1.717 mmol) at room temperature. After 2 hours, additional triphenylphosphine (180 mg, 0.687 mmol), DIAD (0.134 mL, 0.687 mmol) and TMSN3 (0.0912 mL, 0.687 mmol) were added. After being stirred overnight, additional triphenylphosphine (180 mg, 0.687 mmol), DIAD (0.134 mL, 0.687 mmol) and TMSN3 (0.0912 mL, 0.687 mmol) were added. After being additional 3 hours, the reaction mixture was concentrated and purified by silica gel flash column chromatography (eluent; EtOAc/heptane). The obtained product was treated with 4M HCl in dioxane (10 mL) at room temperature. After being stirred for 1 hour, the reaction mixture was concentrated. The residue was diluted with EtOAc, washed with saturated NaHCO3aq and brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel flash column chromatography (eluent; MeOH/DCM) to give (S)-3-(5-(1-amino-2-(biphenyl-4-yl)ethyl)-1H-tetrazol-1-yl)propanenitrile (334 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.83 (dt, J=6.82, 16.9 Hz, 1H), 2.96 (dt, J=6.82, 13.89 Hz, 1H), 3.21 (dd, J=8.08, 13.64 Hz, 1H), 3.42 (dd, J=6.06, 13.64 Hz, 1H), 4.47-4.59 (m, 2H), 4.60-4.68 (m, 1H), 7.21 (d, J=8.08 Hz, 2H), 7.33-7.39 (m, 1H), 7.42-7.48 (bt, 2H), 7.54-7.60 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH3:8][C:9]([CH3:11])=O>C1COCC1>[C:9](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([CH3:11])[CH3:8]
Reactant: CC(C)=O
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: CC(C)=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
To a solution of 2-Methyl-2-propanesulfinamide (1.47 g) and acetone (0.98 ml) in THF (24 ml) chilled to 0° C. was added Ti(OEt)4 (5.36 ml) dropwise over the course of 15 minutes. After being stirred at room temperature for 3 days, the reaction mixture was quenched by the rapid addition into ice cooled saturated sodium bicarbonate solution. The suspension was filtered through glass fiber filter paper, washing with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate solution and brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-60% ethyl acetate in hexanes) gave the product (0.923 g, 47%). 400 M Hz 1H-NMR (CDCl3) δ: 2.34 (s, 3H), 2.18 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][C@@H:8]([CH3:10])[CH2:7][N:6](CC2C=CC=CC=2)[CH2:5]1)[CH:2]=[CH2:3].[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>[Pd]>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:10][C@H:8]1[O:9][C@@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][NH:6][CH2:7]1
Reactant: C=CC[C@@H]1CN(Cc2ccccc2)C[C@H](C)O1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H]1CNC[C@@H](C)O1
Reaction time: 17 h

Procedure:
A mixture of cis-2-allyl-4-benzyl-6-methylmorpholine (520 m, 2.25 mmol), trifluoroacetic acid (0.5 mL, Aldrich) and 5% palladium on carbon (54 mg, 10% w/w, Aldrich) is sealed in a Parr bottle under 40 PSI of H2, and is shaken for 17 hours. The mixture is filtered and the solvent removed by rotary evaporation yielding cis-2-methyl-6-propylmorpholine trifluoroacetate as a light golden oil. The oil is taken up in CH3CN (8 mL) and treated with N,N-diisopropylethylamine (1.2 mL, 6.9 mmol, Aldrich). 2-Fluoro-5-nitrobenzaldehyde (419 mg, 2.48 mmol, Oakwood) is added and the mixture is shaken at 60° C. for 21 hours. N,N,N′-trimethylethylenediamine (1.0 mL) is added and the reaction is shaken for an additional 30 minutes @ 60° C. after which the solvent is removed by rotary evaporation. The residue is taken up in EtOAc (100 mL) and washed with 1.0 M HCl, saturated NaHCO3 and brine (100 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 40M+ using 20% EtOAc in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum at 60° C. yielding a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:23]2[C:18](=[C:19]([O:24]C)[N:20]=[CH:21][CH:22]=2)[N:17]([CH3:26])[CH:16]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:23]2[CH:22]=[CH:21][NH:20][C:19](=[O:24])[C:18]=2[N:17]([CH3:26])[CH:16]=1
Reactant: COc1nccc2c(-c3cc(S(N)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(N)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc[nH]c(=O)c21
Temperature: 70 °C
Yield: 45.5 %

Procedure:
The product from Example 51D (0.116 g, 0.26 mmol) and 4 M hydrogen chloride (5 mL, 20.0 mmol) in dioxane were combined and heated at 70° C. for 24 hours, cooled and concentrated. Purification by reverse phase chromatography (C18, CH3CN/water (0.1% TFA), 10-100%) afforded the title compound (0.051 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.99 (d, J=5.09 Hz, 1H) 7.96 (d, J=2.37 Hz, 1H) 7.66 (dd, J=8.82, 2.37 Hz, 1H) 7.64 (s, 1H) 7.46-7.57 (m, 1H) 7.35-7.43 (m, 1H) 7.33 (s, 2H) 7.12-7.21 (m, 1H) 6.94 (d, J=6.78 Hz, 1H) 6.90 (d, J=8.48 Hz, 1H) 6.55 (d, J=6.10 Hz, 1H) 4.12 (s, 3H). MS (ESI+) m/z 432 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Oc2ccccc2)cc1
Yield: 39.8 %

Procedure:
The title compound was prepared in a similar manner to Preparation 18 from (±) N-tert-butoxycarbonyl-1,2-iminoindane (3 g, 13 mmol), 4-phenoxyphenol (2.42 g, 13 mmol), pyridinium p-toluenesulfonate (50 mg) and chloroform (100 ml). After a reaction time of 3 h, the reaction was diluted with chloroform (100 ml) then washed sequentially with saturated aq. sodium bicarbonate, water and brine. After drying over Na2 SO4, volatiles were removed in vacuo and the residue subjected to column chromatography on neutral alumina eluting with 10% diethyl ether in hexanes to afford the title compound (2.16 g) as a foam.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1>C1COCC1>[CH3:12][O:13]/[CH:14]=[CH:44]/[C:43]1[CH:46]=[CH:47][C:40]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][N:34]=2)=[CH:41][CH:42]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO/C=C/c1ccc(-c2cnccn2)cc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
Sodium hexamethyldisilazide (10.80 mL, 10.80 mmol, 1.0M in THF) was added to a suspension of methoxymethyltriphenylphosphonium chloride (3.72 g, 10.80 mmol) in THF (20 mL) at −10° C., and the red-orange mixture was stirred for 15 min at −10° C. A solution of 4-pyrazinylbenzaldehyde (1.00 g, 5.43 mmol) prepared as described in reference example 17) in THF (3 mL) was added dropwise, and stirring was continued at −10° C. for 1 h. The reaction mixture was quenched with sat. aq. NH4Cl, extracted with ethyl acetate, the organic layer dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 3:1 hexane/ethyl acetate) yielded 820 mg (71%) of the title compound (E:Z=1:1). MS 213 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([CH:29]([CH2:33][CH2:34][CH3:35])[C:30](Cl)=[O:31])[CH2:27][CH3:28]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:30](=[O:31])[CH:29]([CH2:33][CH2:34][CH3:35])[CH2:26][CH2:27][CH3:28])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: CCCC(CCC)C(=O)Cl
Product: CCCC(CCC)C(=O)N[C@@H](CC(C)C)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Yield: 60 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (20 mg) with di-n-propylacetyl chloride(14 uL) provided 16 mg (60%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[Cl:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=2)[NH:22][N:21]=1.N=C=N>CN(C=O)C>[Cl:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:16]([C:9]3[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][C:12](=[O:14])[NH:11][C:10]=3[CH3:15])=[O:18])[CH:27]=2)[NH:22][N:21]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)cc2)CC(=O)N1
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(F)cc2)CC(=O)N1
Yield: 16.6 %

Procedure:
The product from Example 2, Step 2 (170 mg, 0.68 mmol, 1.0 equiv) was combined with 3-chloro-1H-indazol-5-amine (172 mg, 1.02 mmol, 1.5 equiv) and PS-carbodiimide resin (0.994 mmol/g loading, 1.085 g, 1.02 mmol, 1.5 equiv) in 10 mL of DMF and reacted overnight at room temperature. The reaction mixture was filtered and washed alternately with MeOH and CH2Cl2 (twice), then with diethyl ether. The filtrate was concentrated en vacuo and redissolved in ethyl acetate. The solution was washed with 0.5 N HCl, 0.5 N NaOH, and satd. NaCl. The organic layer was concentrated en vacuo. Purification by flash chromatography (0-50% EtOAc in CH2Cl2) followed by trituration with CH2Cl2 provided 45 mg (16.5%) of the title compound as light pink crystals. MS (ES+) m/e 399 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCC[C@@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine, 12a, (0.018 g, 0.050 mmol) and pyridine (0.7 mL) in CH2Cl2 (0.7 mL) was added methanesulfonyl chloride (0.004 mL, 0.050 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[CH:9](Br)[CH3:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>C(#N)C.C(OCC)(=O)C>[OH:12][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[NH:13][CH:9]1[CH3:10]
Reactant: CC(C)(N)CO
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1NC(C)(C)COC1(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 3′-chloro-2-bromo-propiophenone (61.2 g, 247 mmol) in acetonitrile (752 mL) was added 2-amino-2-methyl-1-propanol (56.5 g, 630 mmol). The reaction mixture was allowed to reflux for 8 hours, then slowly cooled to room temperature. The solution was concentrated in vacuo to provide a yellow solid. The crude material was dissolved in 600 mL of ethyl acetate and washed with water (300 mL×2). The ethyl acetate layer was dried (MgSO4), filtered, and concentrated in vacuo to give the product in 90% yield. 1H NMR (CDCl3) δ0.82 (d, J=6.6 Hz, 3H), 1.07 (s, 3H), 1.39 (s, 3H), 3.19 (q, J=6.5 Hz, 1H), 3.42 (d, J=11.2 Hz, 1H), 3.83 (d, J=11.2 Hz, 2H), 7.2-7.65 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][N:9]=1.Cl.[CH3:20][NH2:21]>O.CC(C)=O>[Cl:7][C:8]1[N:13]=[C:12]([NH:21][CH3:20])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][N:9]=1
Reactant: CN
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CNc1nc(Cl)ncc1C(=O)OC
Reaction time: 1 h

Procedure:
19.1 g of potassium carbonate in 50 ml water are added dropwise to 13 g of 2,4-dichloro-5-methoxycarbonyl-pyrimidine and 4.7 g of methylamine-hydrochloride in 500 ml acetone at 0 to 5° C. within one hour. Then the mixture is stirred for one hour in an ice bath. The acetone is largely removed in vacuo and the residue is distributed between water and ethyl acetate. Then the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are dried and evaporated down. The residue is separated by chromatography through a silica gel column with cyclohexane/ethyl acetate (2:1).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O.O>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (1.56 g, 6.2 mmol) is treated with 248 mg (6.2 mmol) of 60% NaH/mineral oil in dimethylformamide and the mixture stirred for 0.67 hours. 0.6 mL(6.2 mmol) of methyl bromoacetate is added and the mixture stirred for 17 hours. The reaction mixture is diluted with water and then extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried, and concentrated at reduced pressure. The product is purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 1.37 g (69% yield) of [[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 89-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:22])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].I[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:22])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)([O:15][CH3:26])[C:11]([F:12])([F:13])[F:14]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccncc1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccncc1)(C(C)c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-pyridin-4-yl-butan-2-ol (Example 11) by 0-methylation: 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-pyridin-4-yl-butan-2-ol (45 mg) was dissolved in dry DMF (4 mL) under argon at room temperature. To the mixture was added sodium hydride (8.4 mg, 50% in mineral oil) and the mixture was allowed to stir for 30 minutes. Iodomethane (22 mg, 0.01 mL) was added and stirring was continued for 1 hour at room temperature. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (20 g silica gel, gradient of ethyl acetate in heptane (10 to 40%) to give the desired material as light yellow oil (28 mg). MS (m/e)=364.1 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[C:17]([CH:16]=[CH:15][CH:14]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-hydroxybenzoate (0.400 g; 2.63 mmol), 3-fluorobenzene boronic acid (0.735 g; 5.26 mmol), copper acetate (0.955 g; 5.26 mmol) and pyridine (0.425 mL; 5.26 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure.