Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:14][CH2:15]N(C(C)C)C(C)C.CN(C(ON1N=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:37]12[CH2:36][CH2:35][CH:34]([CH2:14][CH2:15]1)[C@@H:33]([NH:38][C:11]([C:9]1[CH:8]=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=1)=[O:13])[CH2:32]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1noc2cc(C(=O)O)ccc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1noc2cc(C(=O)N[C@H]3CN4CCC3CC4)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
3-Methyl-1,2-benzisoxazole-6-carboxylic acid (139 mg, 0.78 mmole) is combined with (3R)-aminoquinuclidine dihydrochloride (156 mg, 0.78 mmole) and DIEA (272 μL, 1.56 mmole) in 3 ml DMF under nitrogen. The mixture is treated with HATU (296 mg, 0.78 mmole), and the reaction is stirred overnight at rt. The volatiles are removed in vacuo and the residue is partitioned between 1×10 ml 10% MeOH/CHCl3 and 1×10 ml 1:1 saturated sodium chloride/conc. NH4OH. The aqueous layer is washed with 1×10 ml CHCl3 and the combined organic layer is dried over K2CO3. The dried organic layer is concentrated in vacuo to give an amber residue. The crude material is chromatographed over 15 g silica gel (230-400 mesh) eluting with 7% MeOH/CHCl3+1% conc. NH4OH. The appropriate fractions are combined and concentrated to give a pale foam. The foam is crystallized from Et2O to provide 163 mg (72%) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide as an off-white solid. MS (EI) m/z: 285 (M+).
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][C:5]=1[Br:17].C[O-].[Na+].Cl.CO.[N+](C1C=CC=C(O)C=1)([O-])=[O:27]>CCCCCCC.C(Cl)Cl>[Br:17][C:5]1[CH:6]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[OH:27]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)(C)c1cc(Br)c(COC(=O)[O-])cc1[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCCC
Product: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(2-Bromo-4-tert-butyl-5-nitro-phenyl)methyl carbonate (72.9 g, 219.5 mmol) was charged to a reactor and DCM (291.6 mL) was added. The yellow reaction solution was cooled using an ice bath. Sodium methoxide (67.04 g, 69.11 mL of 5.4 M, 373.2 mmol) was added portion-wise at 2.2-6.9° C. After complete addition, the reaction was slowly warmed to ambient temperature. When complete, the reaction was cooled to 0° C. and quenched with 1M HCl (373.2 mL, 373.2 mmol). The biphasic mixture was stirred for 20 min and transferred to a separatory funnel. The organic layer was separated and washed with water (300 mL) followed by brine (300 ml). The organic layer was concentrated and the crude product dried under high vacuum. The product was further purified using Supercritical Fluid Chromatography (SFC) separation on a Berger MultiGram III (Mettler Toledo AutoChem, Newark Del.). The method conditions were 20% methanol at 250 mL/min on a PPU column (30*150) from Princeton Chromatography, 100 bar, 35 C, 220 nm. An injection of 3.5 mL of a 55-70 mg/mL solution was injected. The data was collected using SFC ProNTo software. The purified product received from SFC purification was a methanol solvate. To remove the methanol, an azeotropic distillation was performed. The dark yellow solid, 2-bromo, 4-tertbuyl, 5-nitro phenol methanol solvate, (111.3 g, 59.9 mmol) was charged to a 1 L round bottom flask, followed by heptane (500 mL). The slurry is heated to 64° C. to obtain a clear solution. The solvent was distilled under reduced pressure (649 mbar) for 30 minutes and then stripped to dryness. This procedure was repeated three times until no MeOH was detected by 1H-NMR. The product was dried under high vacuum for 16 hours to give the product as a dark yellow semi solid. 1H-NMR (400 MHZ, DMSO-d6) δ 11.2 (bs, OH), 7.69 (s, 1H); 7.03 (s, 1H); 1.30 (s, 9H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@H:12]([CH3:31])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:17][CH2:16]1)=[O:14])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.Cl[C:40]([O:42][CH3:43])=[O:41].C(#N)C>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@H:12]([CH3:31])[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:40](=[O:41])[O:42][CH3:43])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH2:19][CH2:20]1)=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: C[C@H](C(=O)N1CCN(c2ccc(S(N)(=O)=O)cc2)CC1)N1CCCc2cc(F)ccc21
Reactant: COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NS(=O)(=O)c1ccc(N2CCN(C(=O)[C@@H](C)N3CCCc4cc(F)ccc43)CC2)cc1

Procedure:
Synthesized according to General Procedure 1. The reaction was set-up with 0.07 mmol of (R)-4-(4-(2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene sulfonamide, 0.18 mmol of triethyl amine, 0.11 mmol of methyl chloroformate and 0.75 mL of acetonitrile. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=505.3; tR=2.28 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:12]3[CH2:13][N:14]([C:34]([NH:33][C:27]4[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=4[F:25])=[O:35])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cc1ccc(C2(c3ccc(C)cc3)OC(=O)N3CCNCC32)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2(c3ccc(C)cc3)OC(=O)N3CCN(C(=O)Nc4ccc(F)cc4F)CC32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of 1,1-bis(4-methylphenyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.62 mmol) in tetrahydrofuran (6 mL) was added 2,4-difluorophenyl isocyanate (0.090 mL, 0.76 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=98:2 to hexane:ethyl acetate=1:1), and then recrystallized from diisopropyl ether to obtain the title compound (0.20 g, yield 68%).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[N:9]=[C:8]2[N:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:17]([F:29])[CH:16]=3)[C:7]2=[N:6][CH:5]=1>>[F:29][C:17]1[CH:16]=[C:15]([O:14][C:13]2[C:7]3[C:8](=[N:9][C:4]([NH:2][CH3:1])=[CH:5][N:6]=3)[N:10]=[CH:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3nc(Cl)cnc23)cc1F
Reactant: CN
Product: CNc1cnc2c(Oc3ccc(NC(=O)OC(C)(C)C)c(F)c3)ccnc2n1

Procedure:
Method D6 was used with methylamine and Tert-butyl 4-(3-chloropyrido[2,3-b]pyrazin-8-yloxy)-2-fluorophenylcarbamate to give the title compound as a white solid. Yield: 80 mg (90%).
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].F[C:22](F)(F)[C:23](O)=[O:24].C(Cl)(=O)C.[Cl-].[Cl-].[Cl-].[Al+3]>ClC(Cl)C.O>[NH2:13][C:10]1[N:9]=[C:8]([NH2:14])[C:7]([O:6][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:18][C:17]([O:19][CH3:20])=[C:16]([C:23](=[O:24])[CH3:22])[CH:15]=2)=[CH:12][N:11]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Oc2cnc(N)nc2N)c(C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)Cl
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 31 %

Procedure:
5-(2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine in anhydrous dichloroethane (20 mL) was added to trifluoroacetic acid (0.06 mL, 0.77 mmol), acetyl chloride (0.31 mL, 4.37 mmol), and aluminum trichloride (583 mg, 4.37 mmol). After stirring for 22 hours at room temperature, water (1.2 mL) was added to the reaction at 0° C. The mixture was dried using anhydrous sodium sulfate and concentrated in vacuo. Aqueous sodium hydroxide (0.2M, 10 mL) was added to the residue and the mixture was heated at 100° C. for 1 hour. After cooling, the reaction was extracted with dichloromethane. The dichloromethane layer was dried using anhydrous magnesium sulfate, concentrated, and purified with silica gel column chromatography eluting with 96/4/0.1 dichloromethane/methanol/ammonium hydroxide to yield 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone (72 mg, 31%) as off-white solid, MS (M+H)=317. Also recovered was 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-2-hydroxy-4-isopropyl-phenyl]-ethanone (43 mg, 20%) as pale yellow solid, MS (M+H)=303.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C1COCC1.N1C=CC=CC=1>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:22][CH2:21]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 107 mg (0.24 mmol) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in a mixture of 20 mL of THF and 20 mL of pyridine was cooled to 0° C. and 41 mg (0.36 mmol) of methanesulfonyl chloride was added. The mixture was allowed to warm to room temperature, and after 1 hr, water was added. The precipitate was collected, washed with water, and dried to give 95 mg (75% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (MeOH) 311-314° C.; 1H NMR (CDCl3) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 4.03 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.33 (m, 4H), 2.81 (s, 3H); Anal. Calcd. for C21H26F2N8O4S: C, 48.1; H, 5.0; N, 21.4. Found: C, 48.0; H, 4.9; N, 21.2%.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](Cl)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH:12]1[CH2:15][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][NH:2][C:3]([C:5]1[C:10]([N:12]2[CH2:15][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH2:13]2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1nccnc1Cl
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1nccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A mixture of 3-chloro-pyrazine-2-carboxylic acid methylamide (100 mg, 0.41 mmol) and 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared by Preparation 5) (71 mg, 0.41 mmol) and K2CO3 (113 mg, 0.82 mmol) was dissolved in DMF (20 mL) and heated for 2 h at 100° C. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give the pure product (70 mg, yield 44%). [M+1] 343. IC50 (uM) 3.882.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]>C(O)CCC.CN(C=O)C.C1CCN2C(=NCCC2)CC1>[NH2:17][C:14]1[N:13]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:12]2[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][NH:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:28]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=3[F:26])[C:16]=2[N:15]=1
Reactant: NCCCCNc1ccc(F)cc1F
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CCCCO
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc2c(ccn2CCNCCCCNc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 110 °C

Procedure:
The title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (20 mg, 0.06 mmol) and the title A compound, N′-(2,4-difluorophenyl)butane-1,4-diamine (22 mg, 0.12 mmol) are dissolved in 1 mL of n-butanol/DMF (1:1), to which solution is added 8 drops of DBU. The solution is heated at 110° C. for 1 h. The reaction is complete as indicated by TLC. The solvent is removed under vacuum and the residue is purified by flash chromatography to obtain N1-(2-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)-N4-(2,4-difluorophenyl)butane-1,4-diamine as an off-white solid: 1H NMR (CDCl3) 51.51-1.68 (m, 4H), 2.7 (t, 2H, J=6.81 Hz), 3.04-3.10 (m, 4H), 4.29 (t, 2H, J=6.05 Hz), 6.50-6.57 (m, 1H), 6.58 (dd, 1H, J=3.44, 1.73 Hz), 6.66-6.78 (m, 2H), 6.80 (d, 1H, J=3.47 Hz), 6.91 (s, 1H), 7.24 (dd, 1H, J=3.44, 0.76 Hz), 7.61 (dd, 1H, J=1.73, 0.76 Hz).
Reaction SMILES: O.[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:7]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=2)[NH:6][N:5]=1)[CH3:3].[OH:31]OS([O-])=O.[K+]>ClCCl>[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:7]([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:30])=[O:31])=[CH:27][CH:28]=2)[NH:6][N:5]=1)[CH3:3]
Reactant: O=S([O-])OO
Reactant: CCc1n[nH]c(CCOc2ccc(SC)cc2)c1Oc1cc(C#N)cc(C#N)c1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1n[nH]c(CCOc2ccc(S(C)=O)cc2)c1Oc1cc(C#N)cc(C#N)c1
Yield: 37.2 %

Procedure:
Wet alumina was prepared by adding water (1 ml) to Brockman grade I alumina (5 g). A sample of this material (160 mg) was added to a stirred solution of the sulfide from Example 1 (106 mg, 0.16 mmol) in dichloromethane (1 ml), followed by oxone (98 mg, 0.16 mmol). The reaction mixture was heated at reflux for 45 minutes, before being filtered. The solids were washed with dichloromethane (10 ml) and the combined organics were concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (100:0, 98:2 and 96:4, by volume) to give the title compound as a colourless oil (25 mg).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)[CH2:3][CH2:4][OH:5].[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.C(Cl)Cl>CN(C1C=CN=CC=1)C.O>[Si:18]([O:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)[NH2:1])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: NC(CCO)c1ccc(F)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC(N)c1ccc(F)c(F)c1
Yield: 69.8 %

Procedure:
A solution of 304 (0.400 g, 2.14 mmol), TBDMS-Cl (0.386 g, 2.56 mmol), DIPEA (0.744 mL, 4.27 mmol), DMAP (0.0261 g, 0.214 mmol) and DCM (10 mL) was stirred at RT for 1 h and then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:7) to afford 0.45 g (69.9%) of 3-(tert-butyldimethylsilyloxy)-1-(3,4-difluorophenyl)propan-1-amine (306).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=2)[CH2:26][CH2:25]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:37][CH:35]([C:32]1[N:31]=[C:30]([N:27]2[CH2:26][CH2:25][CH:24]([CH2:23][O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH2:29][CH2:28]2)[O:34][N:33]=1)[CH3:36]
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(COc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (0.15 g, 0.60 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, except that on small scale no heptane wash was performed, 0.25 g, 0.81 mmol) and K2CO3 (0.17 g, 1.20 mmol) in DMF (6 mL) was stirred at ambient temperature overnight, then heated at 100° C. for 5 h. The mixture was cooled to ambient temperature, water was added, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown solid. The crude material was purified by chromatography on a silica gel column eluted with 1:20 acetone/CH2Cl2 to 1:15 acetone/CH2Cl2 to give 0.14 g (51%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (d, 1H, J=0.9 Hz), 8.31 (s, 1H), 8.11 (d, 2H, J=8.6 Hz), 8.02 (d, 2H, J=8.6 Hz), 4.30-4.20 (m, 4H), 3.10-3.05 (m, 5H), 2.91 (septet, 1H, J=7.0 Hz), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.27 (d, 6H, J=6.6 Hz); LRMS (ESI), m/z 458 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C([Li])CCC.CCCCCC.[CH3:34][C:35](=[O:38])[CH2:36][CH3:37]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:35]([OH:38])([CH2:36][CH3:37])[CH3:34])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CCC(C)=O
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (5.0 g, 15 mmol) in THF (100 mL) was cooled to −42° C. and treated with a solution of 2.5M n-Butyllithium (n-BuLi) in hexane (12.35 mL, 31 mmol) dropwise over 5 minutes. After 15 min at −42° C., 2-butanone (3.1 mL, 34 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 2 hr. The mixture was quenched with water, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)butan-2-ol as a yellow-orange foam (quant). LC/MS (ESI+): m/z 396 (M+H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>CN1CCCC1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: CN1CCCC1
Product: Cc1cc([N+](=O)[O-])c(C)cc1N1CCc2ccccc2C1
Temperature: 140 °C
Reaction time: 15 h

Procedure:
A mixture of 1-chloro-2,5-dimethyl-4-nitrobenzene (1.65 g) and 1,2,3,4-tetrahydroisoquinoline (5 ml) in N-methylpyrrolidine (5 ml) is stirred at 140° C. for 15 h. Dilution in water followed by extraction with diethyl ether and chromatography on silica (eluent: 1/1 petroleum ether/diethyl ether) of the dried and evaporated organic phase gives 2-(2,5-dimethyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([N:32]2[CH2:37][CH2:36]S[CH2:34][CH2:33]2)=[O:31])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1.O[O:39][S:40]([O-:42])=O.[K+]>C1COCC1.CO.O>[O:39]=[S:40]1(=[O:42])[CH2:36][CH2:37][N:32]([C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH:10]=3)[N:4]=2)=[O:31])[CH2:33][CH2:34]1
Reactant: O=S([O-])OO
Reactant: O=C(c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F)N1CCSCC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-fluoro-N2-{3-[2-(4-morpholinyl)ethyl]phenyl}-N4-[2-(4-thiomorpholinylcarbonyl)phenyl]-2,4-pyrimidinediamine (100 mg, 0.19 mmoles) was dissolved in 5 mL of THF and 5 mL of methanol, and treated with a solution of OXONE® reagent (15 equivalents) in 5 mL water. The system was stirred for 48 h at room temperature, and then filtered and concentrated to dryness. The residue was immobilized onto silica gel and purified by flash chromatography on silica gel, using a gradient of 100% A to 90% A-10% B, where “A” is chloroform and “B” is 10:90:1 methanol-chloroform-concentrated aqueous ammonium hydroxide). The title compound was isolated and characterized. MS: M(C27H31FN6O4S)=554.2, (M+H)+=555.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C@@H:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[C:17]([OH:19])=O)[CH:10]=2)[NH:5][CH:4]=1)#[N:2].Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]=[C:3]2[C:1]#[N:2])=[O:19]
Reactant: CNOC
Reactant: N#Cc1c[nH]c2ccc([C@@H]3CCC[C@H]3C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H]1CCC[C@H]1c1ccc2[nH]cc(C#N)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of trans-2-(3-Cyano-1H-indol-5-yl)-cyclopentanecarboxylic acid (0.66 g, 2.60 mMol), N,O-dimethylhydroxylamine hydrochloride (0.51 g, 5.20 mMol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g, 2.86 mMol), and dichloromethane (20 mL) was treated with triethylamine (1.05 g, 10.4 mMol) and stirred at ambient temperature for 18 h. The resulting solution was diluted with 30 mL dichloromethane, washed with 1M hydrochloric acid, 1M sodium hydroxide, and brine, dried over sodium sulfate and concentrated in vacuo to give the crude product as a clear oil which was used without further purification (0.51 g, 66%). LC-MS: 1.38 min (2 min gradient); 298.11 (MH)+.