Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][C:28]=1[F:35].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[CH:29][C:28]=1[F:35]
Reactant: OCc1ccc(Cl)c(F)c1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (4-chloro-3-fluorophenyl)methanol (0.073 ml), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. overnight. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-EtOAc to give the title compound (59.7 mg) as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:22]([NH:24][C@H:25]([C:33](OC)=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:32])[NH2:31])=[O:23])[CH2:20][OH:21])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[NH3:37]>CO>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:22]([NH:24][C@H:25]([C:33]([NH2:37])=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:32])[NH2:31])=[O:23])[CH2:20][OH:21])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[O:8])[CH2:3][C:4](=[O:6])[OH:5]
Reactant: N
Reactant: COC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(=O)O
Solvent: CO
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(=O)O)C(N)=O

Procedure:
Asp-Lys-Ser-Arg-OMe is treated with a saturated solution of ammonia in methanol at room temperature for 2 days. The solvent is removed in vacuo to afford Asp-Lys-Ser-Arg-NH2.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].CCC(N)C(O)=O.[CH3:37][O:38][CH2:39][CH2:40][OH:41]>>[CH3:37][O:38][CH2:39][CH2:40][O:41][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]
Reactant: COCCO
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Agent: CCC(N)C(=O)O
Product: COCCOc1ccc(C(=O)NC2C(C)(C)[C@@H]3CC[C@@]2(C)C3)cc1S(=O)(=O)N1CCOCC1

Procedure:
Compound 2L was prepared from 4-bromo-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide 2.4.AaBa and 2-methoxyethanol 3.3 following the procedure described in Example 2I.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@H:13]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[C:14]([NH2:16])=[O:15].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:12][C@H:13]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:14]([NH2:16])=[O:15])[CH:9]=1
Reactant: NC(=O)[C@H](N)CC1CC1
Reactant: N#Cc1cc(F)c(F)cc1Br
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Br
Yield: 99.9 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (218 mg, 1.00 mmol), (R)-2-amino-3-cyclopropylpropanamide (188 mg, 1.14 mmol) and DIEA (0.600 mL, 3.45 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-cyclopropylpropanamide (326 mg).
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])=[CH:16][CH:15]=1)#[N:18]
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Yield: 16.3 %

Procedure:
A mixture of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (257 mg, 1.0 mmol) and methyl urea (148 mg, 2.0 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.0 mL, 1.40 mmol) was heated to reflux for 48 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 ethyl acetate/hexanes) afforded 1-[2-(4-cyano-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (48.8 mg, 16.3%) as a white solid: mp 61-65° C.; FAB-HRMS m/e calcd for C17H21N3O2 (M+H)+300.1712 found 300.1722.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:7]2=[O:19].[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:23][CH:20]([CH3:22])[CH3:21])[N:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:7]2=[O:19]
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1-c1cccnc1
Reactant: CC(C)N
Product: CC(C)Nc1nc2c(Br)cccc2c(=O)n1-c1cccnc1
Temperature: 80 °C
Yield: 103 %

Procedure:
A slurry of 8-bromo-2-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one (403b, 0.20 g, 0.594 mmol) and isopropylamine (2.04 mL, 23.77 mmol) was sealed and heated in an 80° C. oil bath for 1 h. The reaction was partitioned between sat'd aq. NaHCO3 and DCM. The aqueous layer was extracted with DCM 2 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-(isopropylamino)-3-(pyridin-3-yl)quinazolin-4(3H)-one (0.22 g, 0.612 mmol, 103% yield) as a light yellow foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (1H, d, J=3.5 Hz), 8.60 (1H, br. s.), 8.08 (1H, dd, J=7.8, 1.6 Hz), 7.94 (1H, dd, J=7.7, 1.5 Hz), 7.66-7.75 (1H, m), 7.60 (1H, dd, J=8.0, 4.9 Hz), 7.04 (1H, t, J=7.8 Hz), 4.32-4.49 (1H, m), 3.80 (1H, d, J=6.3 Hz), 1.23 (6H, m). m/z (ESI, +ve) 359.0/361.0 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:46][C:47]1[C:48]([N:57]2[CH2:62][CH2:61][CH2:60][C@H:59]([NH:63][C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])[CH2:58]2)=[C:49]2[CH2:55][CH2:54][CH:53]([OH:56])[C:50]2=[N:51][CH:52]=1)=[O:45])=[O:29])([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>C(Cl)Cl.CO>[C:23]([O:27][C:28]([NH:30][C:31]1[S:35][C:34]([C:36]2[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=2[F:42])=[N:33][C:32]=1[C:44]([NH:46][C:47]1[C:48]([N:57]2[CH2:62][CH2:61][CH2:60][C@H:59]([NH:63][C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])[CH2:58]2)=[C:49]2[CH2:55][CH2:54][C:53](=[O:56])[C:50]2=[N:51][CH:52]=1)=[O:45])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
Dess-Martin periodinane (12 mg, 0.028 mmol) was added to a solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (15 mg, 0.022 mmol) in DCM (0.098 mL). The reaction mixture was stirred at room temperature for 1 h. The solution was neutralized with 1 M NaOH, diluted with MeOH and filtered. The mixture was then concentrated under reduced pressure and the crude product was purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give sub-title compound as off-white powder (7.5 mg, 50%). LCMS calc. for C33H39F2N6O6S (M+H)+: m/z=685.3. Found: 685.1.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:36][CH3:37])[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[N:20][S:21][C:17]=2[CH:16]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:36]([N:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]2[C:19]([C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:26][CH:27]=3)=[N:20][S:21][C:17]=2[CH:16]=1)[CH2:8][CH2:7][OH:6])[CH3:37]
Reactant: CCN(CCCCOc1ccc2c(-c3ccc(N4CCCCC4)cc3)nsc2c1)CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(N4CCCCC4)cc3)nsc2c1
Yield: 82.5 %

Procedure:
220 mg (0.39 mmol) [2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-{4-[3-(4-piperidin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine in 5 ml THF were treated with 0.6 ml 1M TBAF in THF for 1 h at RT. The solution was concentrated and the crude product subjected to column chromatography on silica gel with CH2Cl2:MeOH 9:1 to give 146 mg (83%) 2-(Ethyl-{4-[3-(4-piperidin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol as yellow oil, MS: 454 (MH+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[CH:19][C:18]=3[O:30][CH3:31])=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]([Cl:47])([Cl:46])[C:43](Cl)=[O:44]>ClCCl>[Cl:41][C:42]([Cl:47])([Cl:46])[C:43]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[CH:19][C:18]=3[O:30][CH3:31])=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:44]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanone of Step D (1.36 g, 3.33 mmol) in dichloromethane (15 mL) was added N,N-diisopropylethyl amine (1.2 mL, 6.89 mmol) followed by slow addition of trichloroacetyl chloride (1.1 mL, 9.85 mmol). The reaction mixture was stirred overnight at room temperature then was quenched with water. The organic phase was washed with 0.1 N hydrochloric acid followed by water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a green oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane gave 1.7 g of title product as a yellow foam.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[S:13]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[S:13]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([OH:24])=[O:23])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(F)cc1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(F)cc1C1CCCC1
Temperature: 80 °C
Yield: 102.9 %

Procedure:
To a solution of 136 (78.0 mg; 0.2 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added aqueous sodium hydroxide (7.5 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether (20 mL). The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×15 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as a brown solid (76 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([Cl:14])([Cl:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([Cl:14])([Cl:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(Cl)(Cl)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of 0.60 g (0.0018 mole) of 2-chloro-9-cyclopentyl-7,7-dichloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-298) in 12 mL of dimethylformamide was added 0.88 g (0.0027 mole) of cesium carbonate, followed by 0.34 mL (0.0054 mole) of iodomethane. After stirring four hours, the mixture was filtered and then concentrated under reduced pressure. Ice water was added to the residue and the resulting solid was collected by filtration, washed with water and dried under vacuum to give 0.47 g of 2-chloro-9-cyclopentyl-7,7-dichloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-298) as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=1)[NH:26][CH:25]=[CH:24]2>ClCCl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[C:24]2[C:23]3[C:27](=[C:28]([CH2:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH:29]=[C:21]([F:20])[CH:22]=3)[NH:26][CH:25]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
64 mg (0.35 mmol) of the compound from Example 153A and 0.03 ml (0.42 mmol) of trifluoroacetic acid were added to 80 mg (0.35 mmol) of the compound from Example 87A in 2.5 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 110 mg (80% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[C:15]([CH3:22])[CH:14]=1)(=[O:12])=[O:11].[CH3:27][C:28]1([NH2:32])[CH2:31][O:30][CH2:29]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:20])[CH2:21][NH:32][C:28]2([CH3:27])[CH2:31][O:30][CH2:29]2)=[C:15]([CH3:22])[CH:14]=1)(=[O:12])=[O:11]
Reactant: CC1(N)COC1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)c(C)c2)c(C)c1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CNC3(C)COC3)c(C)c2)c(C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-N-isobutyl-3-methyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.054 mmol) in ethanol at 25° C. was added 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50° C. for 18 hours. Another portion of 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50° C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 9.3 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 461 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(=O)O[CH2:23][CH3:24]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][CH:24]3[CH2:23][CH2:15][CH2:16][NH:8][CH2:6]3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)n1ncc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2cc(NC3CCCNC3)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 5-nitro-indazole-1-carboxylic acid tert-butyl ester (300 g, 1.1 mol, 1.0 eq) in THF (3 L), and the mixture was hydrogenated at 40° C. with Pd/C (30 g) as catalyst in the presence of H2 (50 psi). The reaction mixture was stirred at 40° C. for 16 hrs. TLC (PE:EA=4:1) showed the reaction was complete. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated to afford the crude 5-amino-indazole-1-carboxylic acid tert-butyl ester (252 g, 95%) which was used directly for next step without purification.
Reaction SMILES: [CH2:1]([N:3]([C:20]1[C:21]2[CH:28]=[CH:27][N:26]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:22]=2[N:23]=[CH:24][N:25]=1)[C@H:4]1[CH2:9][CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([N:3]([C@H:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)[C:20]1[C:21]2[CH:28]=[CH:27][N:26]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[C:22]=2[N:23]=[CH:24][N:25]=1)[CH3:2]
Reactant: CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCNC1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A mixture of (S)-benzyl 3-(ethyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (130 mg, 0.243 mmol), 10% Pd/C (130 mg) in ethanol (4 mL) was placed under an atmosphere of hydrogen (1 atm) for 1 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to yield the title intermediate (60 mg, 61%). LC-MS: m/z [M+1]=400.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)#[N:2].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][N:19]2[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]2=[O:26])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][N:19]2[C:20](=[O:26])[CH:21]=[CH:22][C:23]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=3)=[CH:24]2)=[CH:16][CH:15]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Reactant: N#CCc1ccc(B(O)O)cc1
Product: N#CCc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Yield: 100 %

Procedure:
According to Scheme 3 Method A: The title compound was synthesized as described in Example 2 Step 2 using 4-(cyanomethyl)phenyl boronic acid (1.5 eq, 0.50 mmol, 80.9 mg) and 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 0.33 mmol, 0.10 g, Example 2 Step 1) as substrates. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt to afford 2-(4-(1-(4-chlorobenzyl)-1,6-dihydro-6-oxopyridin-3-yl)phenyl)acetonitrile as a yellow solid (0.33 mmol, 110 mg, 98%).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@H](O)Cc1ccccc1
Yield: 407 %

Procedure:
Following the procedure of Cohen (J. Am. Chem. Soc., 1964, 86, 5326), the resultant compound from Example 89 (8.6 g, 52 mmol) was dissolved in dry methanol (250 ml). p-Toluenesulfonic acid (2 g, 10.5 mmol) was added and the solution was refluxed for 2 h. The cooled solution was concentrated in vacuo and the residue was dissolved in ether (400 ml). The ether solution was washed with saturated aqueous NaHCO3 (3×50 ml), water (2×50 ml), 0.1N H2SO4 (1×50 ml), water (1×50 ml), dried over Na2SO4, and concentrated in vacuo to afford a colorless solid. The solid was recrystallized from hexane to provide the title compound as colorless needles (7.7 g, 83%); mp=46°-47° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17][C@H:18]1[O:23][C@@H:22]([CH3:24])[CH2:21][NH:20][CH2:19]1.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[CH3:24][C@@H:22]1[O:23][C@H:18]([CH3:17])[CH2:19][N:20]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:3]=2)[CH2:21]1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc[nH]c3n2)C[C@H](C)O1
Temperature: 130 °C
Reaction time: 40 h
Yield: 98.3 %

Procedure:
To the solution of 2-chloro-6-morpholin-4-yl-9H-purine (1.5 g, 6.26 mmol) in DMA (5 mL) was added cis-2,6 dimethylmorpholine (1.42 g, 12.52 mmol), followed by DIPEA (2.1 mL, 12.02 mmol). The mixture was stirred at 130° C. for 40 hours. Upon completion of the reaction, the solution was poured into water. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to provide 2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purine (1.96 g, 98%) as a yellow solid. LC/MS analysis method 7, mass (ES+) m/z 319.2 1HNMR (DMSO-d6): 12.37 (1H, s), 7.76 (1H, s), 4.38 (2H, d), 4.12 (4H, brs), 3.69 (4H, m), 3.54 (2H, m), 2.40 (2H, m), 1.14 (6H, d).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:19][CH2:20][CH:21]1[O:25][C:22]1([CH3:24])[CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH:21]([CH2:20][O:19][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:22]([CH3:24])([OH:25])[CH3:23]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCOCC1OC1(C)C
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(NCCO)C(C)(C)O
Temperature: 80 °C
Yield: 57.8 %

Procedure:
A 100-ml two-necked flask equipped with a stirrer and a dropping funnel was charged with 15.3 g (16.7 mmol) of ethanolamine and 5.0 g of ethanol. While heating and stirring the mixture at 80° C. in a nitrogen atmosphere, an ethanol solution of 5.00 g (16.7 mmol) of 1-tetradecyloxy-3-methyl-2-butene oxide was added dropwise over 3 hours. After heating and stirring the mixture further for 16 hours, the resultant reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 3.47 g (yield: 58%) of the title compound (IIc-4).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[O:10])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)COc2ccc(Cl)cc2)CC1
Yield: 63.7 %

Procedure:
Prepared following the method of Example 94 using (4-chlorophenoxy)acetic acid (0.50 g), 1,1-carbonyldiimidazole (0.50 g) and tert-butyl 4-amino-1-piperidinecarboxylate (0.46 g) to give the subtitle compound (0.54 g).