Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11](=[N:13][OH:14])[NH2:12])=[C:6]2[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[Cl:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25](Cl)=O>>[Cl:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]1[O:14][N:13]=[C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([CH3:1])=[CH:3][C:4]([C:15]([F:18])([F:16])[F:17])=[N:5][C:6]=23)[N:12]=1
Reactant: Cc1cc(C(F)(F)F)nc2c(C(N)=NO)cnn12
Reactant: O=C(Cl)c1sccc1Cl
Product: Cc1cc(C(F)(F)F)nc2c(-c3noc(-c4sccc4Cl)n3)cnn12

Procedure:
The title compound was prepared from 7-methyl-5-trifluoromethyl-pyrazolo[1,5-α]pyrimidine-3-amidoxime (13.8 mg, 0.0532 mmol) and 3-chloro-thiophene-2-carbonyl chloride (9.8 mg, 0.0541 mmol) similar to Example 16, and yielded 9.8 mg (48%) of an off-white solid. 1H NMR (CDCl3): 8.89 (s, 1H), 7.62 (d, J=5.22 Hz, 1H), 7.20 (d, J=0.83 Hz, 1H), 7.14 (d, J=5.22 Hz, 1H), 2.98 (s, 3H).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1F
Product: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Yield: 42 %

Procedure:
This compound was prepared from 1,4-cyclohexanedione monoethylene ketal (15.6 g, 100 mmole) and 3,4-difluorophenyl magnesium bromide (100 mmole) in the usual mariner. The crude product was crystallized from isopropyl ether to give the product (42%, mp: 118°-120° C.).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH2:13][S:14][C:15](=N)N)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.ClC[CH2:23][C:24]#[N:25].[OH-].[Na+]>O.C(O)C>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH2:13][S:14][CH2:15][CH2:23][C:24]#[N:25])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N=C(N)SCc1cccc(CN2CCCCC2)c1
Reactant: N#CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CCCSCc1cccc(CN2CCCCC2)c1
Temperature: 20 °C

Procedure:
A stirred solution of the above isothiourea (1.2 g) and 3-chloropropionitrile (0.4 ml) in a mixture of water (7 ml) and ethanol (5 ml) was treated at 0°-5° C. with 2.5N sodium hydroxide (5.3 ml). The reaction mixture was stirred at 0°-5° C. for a further hour and then allowed to warm to 20° C. The reaction mixture was extracted with ethyl acetate and the extracts washed with water, dried and evaporated to provide 3-(3-piperidinomethylbenzylthio)propionitrile as an oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:31][CH:30]=4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:42])[N:16]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].[NH4+].[Cl-]>CO.O.[Fe]>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:33][CH:34]=4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:42])[N:16]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCN(c2ccc(Nc3ncc4c(n3)-c3c(c(C(=O)N[C@H](CN=[N+]=[N-])c5ccccc5)nn3C)CC4)cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc(Nc3ncc4c(n3)-c3c(c(C(=O)N[C@H](CN)c5ccccc5)nn3C)CC4)cc2)CC1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 129 mg (0.228 mmol) of N-[(1S)-2-azido-1-phenylethyl]-1-methyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide in 16 mL of methanol, 65 mg (1.2 mmol) of NH4Cl dissolved in 3.2 mL of water and 39 mg of iron (0.7 mmol) were added and the mixture refluxed overnight. The suspension was cooled to room temperature and filtered. After removal of methanol, solid Na2CO3 was added portionwise to the aqueous phase up to pH 10 and the product was then extracted with dichloromethane. Flash chromatography of the crude (eluant dichloromethane/methanol 95/5) yielded 94 mg of the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][O:18][C:19](=[O:21])[CH3:20])=O)C1C=CC=CC=1.[ClH:22].[H][H]>C(O)C.[C].[Pd]>[ClH:22].[C:19]([O:18][CH2:17][C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-acetoxymethyl-4-hydroxypyrrolidine (32.59 g) in ethanol (489 ml), 5% palladium-carbon (4.89 g) and 6N hydrochloric acid (18 ml) were added. The mixture was stirred at room temperature for 1 hour under an atmospheric pressure of hydrogen, followed by removal of the catalyst. Removal of the solvent gave (2S,4R)-2-acetoxymethyl-4-hydroxypyrrolidine hydrochloride.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]([CH2:10][CH3:11])([CH3:9])[CH2:7][CH3:8])=O)#[N:2].Cl.[NH2:13][OH:14].[OH-].[Na+]>O>[NH2:2][C:1]1[O:14][N:13]=[C:4]([C:6]([CH2:10][CH3:11])([CH3:9])[CH2:7][CH3:8])[CH:3]=1
Reactant: CCC(C)(CC)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(CC)c1cc(N)on1

Procedure:
A 16.5 Kg portion of methyl 2-ethylbutyrate was reacted with 60 Kg of n-butyl lithium, diisopropylamine, and 19.1 Kg of methyl iodide to provide 17.4 Kg of methyl 2-ethyl-2-methylbutyrate. A 7.5 Kg portion of the ester thus formed was reacted with 3.25 Kg of acetonitrile and 5.03 g of sodium hydride in 33 liters of tetrahydrofuran to provide 1-ethyl-1-methylpropyl cyanomethyl ketone. The ketone thus formed was reacted with 4.35 Kg of hydroxylamine hydrochloride and 2.54 Kg of sodium hydroxide in 44 liters of water to provide 5.65 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)=O.[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH2:25].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]1([C:7]2[N:6]=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]([CH2:2][CH:1]=[N:25][CH2:24][CH:23]([OH:22])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1
Reactant: NCC(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: OC(CN=CCc1cnc(-c2ccccc2)nc1-c1ccccc1)c1ccccc1
Yield: 82.1 %

Procedure:
A mixture of 61.2 g (0.223 mole) of 2,4-diphenyl-5-pyrimidyl methyl ketone, 30.6 g (0.223 mole) of β-hydroxyphenethylamine and 3.0 g p-toluenesulfonic acid monohydrate in 750 ml toluene was stirred and refluxed using a Dean-Stark apparatus for 11.0 hours, amt. H2O evolved: 4:10 ml; theoretical amt.: 4.0 ml. The toluene was removed in vacuo and the residue was dissolved in 1000 ml chloroform. The solution was washed with 300 ml H2O, dried (MgSO4), and concentrated to dryness in vacuo. Recrystallization of the residue from ethanol gave in three crops 72 g (82%) of the product, m.p. 140°-144°.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[N:29]=[C:30]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=[CH2:48])[C:42]=3[F:49])[S:31][C:32]=2[NH:33]C(=O)OC(C)(C)C)=[O:27])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[H][H].B(Br)(Br)Br.C(Cl)Cl>CO>[NH2:33][C:32]1[S:31][C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH3:48])[C:42]=2[F:49])=[N:29][C:28]=1[C:26]([NH:25][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[N:15]1[CH2:16][CH2:17][CH2:18][C@@H:12]([NH2:11])[CH2:13][CH2:14]1)=[O:27]
Reactant: C=Cc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](NC(=O)OCc4ccccc4)CC3)c(NC(=O)OC(C)(C)C)s2)c1F
Reactant: [H][H]
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c1F
Reaction time: 2 h

Procedure:
tert-butyl N-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2-fluoro-3-vinyl-phenyl)thiazol-5-yl]carbamate (51 mg, 0.086 mmol) was dissolved in methanol (50 mL) and hydrogenated on H-Cube at 60° C. and 50 bar hydrogen pressure to reduce the double bond. The solution was concentrated and the residue was dissolved in DCM (5 mL). 1.0M solution of boron tribromide in methylene chloride (0.35 ml, 0.35 mmol) was added and the mixture was stirred for 2 h. The solvent was distilled off and the residue was purified via reverse phase HPLC to afford 383. MS (ESI) m/z: 458.3 [M+H+].
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])[CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([N:15]([CH2:2][CH:3]([CH3:5])[CH3:4])[S:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:17])[CH3:14])=[CH:9][CH:8]=1
Reactant: C[C@@H](NS(=O)(=O)Cc1ccccc1)c1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CN([C@H](C)c1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
1-Bromo-2-methylpropane (10.1 g, 73 mmol) was added into a solution of (R)—N-(1-(4-bromophenyl)ethyl)(phenyl)methanesulfonamide (13 g, 36.7 mmol) and Cs2CO3 (23.8 g, 73 mmol) in DMF (150 mL) dropwise at 0° C. The mixture was then stirred at 80° C. for 20 h before it was cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo to remove the solvent. The residue was dissolved with DCM (100 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified on silica gel chromatography (petroleum ether: ethyl acetate=10:1) to provide (R)—N-(1-(4-bromophenyl)ethyl)-N-isobutyl(phenyl)methanesulfonamide (10.8 g, 72% yield) as colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71 (d, 3H), 0.77 (d, 3H), 1.48 (d, 3H), 1.60-1.66 (m, 1H), 2.77-2.83 (m, 2H), 4.11-4.22 (m, 2H), 4.94-4.96 (m, 2H), 7.24-7.48 (m, 9H); >99% ee value (Chiral-HPLC, 214 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][CH2:17]Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][CH2:17][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: ClCCOC(c1ccccc1)c1ccc(Cl)cc1
Reactant: C1CNCCN1
Product: Clc1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 73 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 2-[α-(4-chlorophenyl)benzyloxy]ethyl chloride and anhydrous piperazine, the title compound was obtained in a yield of 73%.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)N1CCCCC1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing piperidine (170 mg, 2.0 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (31 mg, 0.082, 82%). ESI-MS m/z calc. 377.1. found 378.2 (M+1)+ Retention time 2.21 minutes.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[O:3][CH2:2]1.C1(=O)O[CH2:14][CH2:13][O:12]1.C([O-])([O-])=O.[K+].[K+].C(=O)=O>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:14][CH2:13][OH:12])[C:4]=2[O:3][CH2:2]1
Reactant: Oc1cccc2c1OCO2
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc2c1OCO2
Temperature: 150 °C
Yield: 65 %

Procedure:
A mixture of 1,3-benzodioxol-4-ol*(0.74 g, 5.36 mmol), ethylene carbonate (0.47 g, 5.3 mmol) and K2CO3 (0.67 g, 4.8 mmol) in DMF (30 mL) was heated at 150° C. After the evolution of carbon dioxide had ceased (1 h), the reaction mixture was filtered and concentrated. The crude product was purified by chromatography on silica gel using petroleum ether/EtOAc (70:30) as eluent to give 0.64 g (65%) of the title product as an oil which spontaneously crystallized to a white solid: mp 56-57° C. Anal. (C9H10O4) C, H.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[N:15]=[C:14]([N:16]([CH2:23][CH2:24][O:25][CH3:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=[C:12]([C:27]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][C:35]([CH2:38]OS(C)(=O)=O)=[N:36][CH:37]=3)[O:29][N:28]=2)[N:11]=1>C1COCC1>[CH3:26][O:25][CH2:24][CH2:23][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]1[N:15]=[C:10]([NH2:9])[N:11]=[C:12]([C:27]2[N:31]=[C:30]([C:32]3[CH:37]=[N:36][C:35]([CH2:38][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:34][CH:33]=3)[O:29][N:28]=2)[N:13]=1
Reactant: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COS(C)(=O)=O)nc3)n2)n1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COCC(F)(F)F)nc3)n2)n1
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
To a solution of [5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-methanol (Intermediate 130, 185 mg, 0.44 mmol) in DCM (40 mL) was added methanesulfonyl chloride (48 μL, 0.61 mmol) drop-wise, followed by triethylamine (92 μL, 0.66 mmol). The resulting solution was stirred for 3 h under an inert atmosphere. Incomplete reaction was observed so additional methanesulfonyl chloride (9 μL, 0.10 mmol) and triethylamine (16 μL, 0.11 mmol) were added and stirring was continued for 1 h. The reaction mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate and evaporated to dryness to afford the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate. In a separate flask 2,2,2-trifluoro-ethanol (190 μL, 2.64 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.42 mmol) in anhydrous THF (30 mL) at 0 C under nitrogen. The resulting solution was stirred at 0 C for 30 min and then transferred via cannula to a solution of the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate (220 mg, 0.44 mmol) in anhydrous THF (30 mL) at 0 C drop wise. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a saturated ammonium chloride aq. solution (5 mL) and extracted with EtOAc (3×50 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method C) to afford the title compound as an off-white solid (21 mg, 10%).
Reaction SMILES: C[Si](C)(C)[O-].[K+].[CH:7]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:38][C@@H:37]([C:39]4[CH:50]=[CH:49][C:42]5[O:43][C:44]([CH3:48])([CH3:47])[O:45][CH2:46][C:41]=5[CH:40]=4)[O:36]C3=O)[CH:18]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.P([O-])([O-])([O-])=O>C1COCC1>[CH:7]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:38][C@@H:37]([C:39]3[CH:50]=[CH:49][C:42]4[O:43][C:44]([CH3:47])([CH3:48])[O:45][CH2:46][C:41]=4[CH:40]=3)[OH:36])[CH:18]=2)=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)NC5CCCCC5)c4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)NC4CCCCC4)c3)ccc2O1
Temperature: 65 °C
Yield: 69.6 %

Procedure:
Potassium trimethylsilanolate (0.177 g) was added to a solution of N-cyclohexyl-N′-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy]methyl}phenyl)urea (0.207 g) in deoxygenated anhydrous THF (6 ml) whilst stirring under nitrogen. The reaction mixture was heated to 65° C. for 4.5 h, at which point the reaction mixture was cooled to room temperature. Phosphate buffer (25 ml, pH6.5) was added and the mixture left to stir for 10 min before extracting with EtOAc (3×25 ml). The combined organic layers were separated and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with 150:8:1 dichloromethane:EtOH:ammonia followed by solvent evaporation in vacuo gave the title compound (0.138 g). LCMS RT=2.87min, ES+ve 598 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][NH:40]2)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][N:40]2[CH2:18][C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (122 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 520 mg) in DCE (10 mL) was stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 85:15) to give (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a white solid. TFA (3 mL) was added to a solution of (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: MeOH; gradient from 100:0 to 85:15) to afford 395 as a white solid (153 mg, 63%). LCMS (Method G): RT=5.78 min, M+H+=474. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.26 (m, 2 H); 4.34 (m, 4 H); 4.00 (d, J=13.6 Hz, 1 H); 3.92-3.83 (m, 8 H); 3.70 (s, 1 H); 3.45 (s, 1 H); 3.35 (q, J=7.5 Hz, 2 H); 3.25 (d, J=10.2 Hz, 1 H); 2.97-2.91 (m, 2 H); 2.70 (d, J=10.2 Hz, 1 H); 1.85 (d, J=10.1 Hz, 1 H); 1.70 (d, J=10.1 Hz, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([S:19][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:13][CH:12]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])=[CH:21][C:22]=2[CH3:28])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(SC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 358 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 530.2 [M−H]−.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:19])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][C:28]([N:30]([CH3:41])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36](=[O:39])(=[O:38])[NH2:37])=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C3C(=CC(C([N:59]4[CH:63]=[CH:62][N:61]=[CH:60]4)=O)=CC=3)N(C)C=2C2C=CC=CC=2OCC(N(C)CCOCCN(C)S(=O)(=O)N)=O)CCCCC1>>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([N:59]4[CH:63]=[CH:62][N:61]=[CH:60]4)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:19])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][C:28]([N:30]([CH3:41])[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:40])[S:36](=[O:39])(=[O:38])[NH2:37])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(CCCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Reactant: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)n3ccnc3)cc2n1C
Product: CN(CCCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)n3ccnc3)cc2n1C
Yield: 92 %

Procedure:
2-{2-[3-cyclohexyl-6-(1H-imidazol-1-ylcarbonyl)-1-methyl-1H-indol-2-yl]phenoxy}-N-methyl-N-{4-[methyl(sulfamoyl)amino]butyl}acetamide 14 was synthesized in 92% yield from intermediate 13 following the procedure reported for the synthesis of intermediate 9: m/z=635 (M+H)+.