Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C1N=[CH:36][N:35](C(N2C=NC=C2)=O)[CH:34]=1.CNC>C1COCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([N:35]([CH3:36])[CH3:34])=[O:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 47.8 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide was prepared by the procedure of example 13 from 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.1 g, 0.22 mmol), CDI (0.05 g, 0.33 mmol) and dimethylamine (0.33 ml, 0.66 mmol) in THF (10 ml) to give as 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide white solid (0.05 g, 50% yield): mp 141-143° C.; 1H NMR (CDCl3): δ 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 15 Hz, 1H, CH2), 3.10 (s, 3H, NCH3), 3.60 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 4.33 (d, J=18 Hz, 1H, CH2N), 4.44 (d, J=18 Hz, 1H, CH2N), 5.59 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.04 (m, 4H, Ar), 7.45 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=7.5 Hz, 1H, Ar), 10.35 (s, 1H, NHCO). 13C NMR (DMSO-d6): δ 14.5, 24.8, 35.5, 35.9, 37.2, 49.0, 53.8, 64.7, 111.9, 113.4, 113.5, 116.0, 116.8, 117.5, 117.8, 119.1, 119.1, 120.1, 122.6, 133.0, 137.7, 138.2, 139.7, 138.2, 139.6, 139.7, 141.5, 150.6, 168.9, 169.2, 169.5; Anal. Calcd. for C24H27F2N3O5: C, 60.62; H, 5.72; N, 8.84; Found: C, 59.90; H, 5.46; N, 8.66.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH2:15][CH3:14])[CH3:21]
Reactant: CCOC(=O)CCCBr
Reactant: O=c1ccc2ccc(O)cc2o1
Product: CCOC(=O)C(CC)Oc1ccc2ccc(=O)oc2c1

Procedure:
Coumarin-7-oxybutyric acid N-hydroxysuccinimide ester was prepared by reacting 7-hydroxycoumarin with ethyl 4-bromobutyrate to form coumarin-7-oxybutyric acid ethyl ester. Next, the ethyl ester was reacted with acid to form coumarin-7-oxybutyric acid which was reacted with N-hydroxysuccinimide to form the N-hydroxysuccinimide ester in accordance with the Scheme 1 above.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC(=O)N(C)C)cc(Cl)c21
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (60 mg, 0.22 mmol) in DMF (3 mL) was slowly added NaH (27 mg, 0.66 mmol) at 0° C. The mixture was stirred for 20 min and N,N-dimethylcarbamic chloride (29 mg, 0.27 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature and quenched with ice water. The resulting mixture was extracted with EtOAc (2×15 mL) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step reaction without further purification. MS (ESI) m/z=342 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(S(C)(=O)=O)C2)ncc1Cl
Reaction time: 0.08 h
Yield: 88.2 %

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (30 mg, 0.0667 mmol) was placed in dichloromethane (3 mL) and triethylamine (20.3 mg, 0.201 mmol, 28.2 μL, 3.0 eq) was added followed by methanesulfonyl chloride (8.4 mg, 0.0734 mmol, 5.7 μL, 1.1 eq). The reaction was stirred for 5 minutes and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-8% MeOH/CH2Cl2 as the eluting solvent to obtain 2-[5-chloro-2-(10-methanesulfonyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a yellow foam (31 mg, 88%). LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.99 (s, 1H), 8.60 (d, 1H, J=7.8 Hz), 8.10 (s, 1H), 7.55-7.40 (m, 3H), 7.30-7.20 (m, 1H), 7.15-7.02 (m, 2H), 6.92 (s, 1H), 6.23 (bs, 1H), 3.87-3.77 (m, 2H), 3.20-3.05 (m, 4H), 3.03 (d, 3H, J=4.9 Hz), 2.47 (s, 3H), 2.20 (d, 2H, J=8.8 Hz), 1.81-1.70 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:27]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH2:25][CH3:26])[CH:18]=2)[CH2:12][CH2:11]1)=[O:8].[C:28](Cl)(=[O:30])[CH3:29]>>[C:28]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:27]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH2:25][CH3:26])[CH:18]=2)[CH2:12][CH2:11]1)=[O:8])(=[O:30])[CH3:29]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cncc(N)c3)CC2)ccc1Cl
Reactant: CC(=O)Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(NC(C)=O)c3)CC2)ccc1Cl
Yield: 26 %

Procedure:
The title compound (12 mg, 26%) was prepared analogously to example 7 by coupling of 5-amino-N-[1-(4-chloro-3-ethoxy-benzyl)piperidin-4-yl]-nicotinamide with acetyl chloride. MS: 431.4 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:4])=[O:3]
Reactant: O=C(OCc1ccccc1)c1ccc(-c2ccc(OCCO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCOc1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.086 mL) was added to an ice-cooled mixture of benzyl 4′-(2-hydroxyethoxy)biphenyl-4-carboxylate (0.30 g) and triethylamine (0.182 mL) in methylene chloride (20 mL) with stirring, and the mixture was stirred at room temperature for 1 hr. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford benzyl 4′-(2-methanesulfonyloxyethoxy)biphenyl-4-carboxylate (0.37 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([C:33]2[N:41]3[C:36]([CH:37]=[N:38][C:39](O)=[N:40]3)=[CH:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH:21][C:39]2[N:38]=[CH:37][C:36]3=[CH:35][CH:34]=[C:33]([C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=4)[N:41]3[N:40]=2)[CH:18]=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(N)ccc1Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Nc2ncc3ccc(-c4cccc(S(C)(=O)=O)c4)n3n2)ccc1Cl

Procedure:
This example was prepared by using (R)-2-(5-Amino-2-chloro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Med. Chem. 2007, 50, 4353) and 7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c. 1H-NMR (CDCl3) δ 8.7 (brs, 1H), 8.6 (m, 1H), 8.4 (d, J=8.0 Hz, 1H), 8.0 (d, J=8.0 Hz, 1H), 7.7 (t, 1H), 7.5-7.0 (m, 5H), 4.1-3.9 (m, 3H), 3.5-3.2 (m, 2H), 3.0 (s, 3H), 2.2 (m, 3H), 1.9 (m, 1H); LC/MS (ESI+): 598 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl.O>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of (S)-1-Boc-2-hydroxymethyl-piperazine (500 mg) in DCM (15 mL) were added NaHCO3 (369 mg), water (3 mL) and benzyl chloroformate (0.464 mL) at RT. The resulting emulsion was vigorously stirred at RT overnight. The mixture was diluted with water and extracted with DCM. The combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 50 for 6CV, 50 to 70 over 3CV, 70 for 2CV) to afford 714 mg of colourless oil. LC-MS (B): tR=0.82 min; [M+H]+: 350.94.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:34]=[CH:33][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=5)[N:17]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:34]=[CH:33][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc([N+](=O)[O-])cc45)nc3c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CC1
Yield: 80.3 %

Procedure:
3-(5-(4-Methylpiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (100 mg, 0.217 mmol) was added to 10% Pd/C (2.302 mg, 0.022 mmol) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for 8 h at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (75 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 7.66 (d, 1H, J=2.0 Hz), 7.51 (m, 2H), 7.17 (bs, 1H), 7.05-7.00 (m, 2H), 5.78 (dd, 1H, J=2.4 & 9.2 Hz), 3.98 (m, 1H), 3.78 (m, 1H), 3.56 (m, 2H), 2.67 (m, 3H), 2.14-2.03 (m, 2H), 1.76 (m, 3H), 1.65 (m, 2H), 1.40 (m, 3H), 0.98 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 431.3.
Reaction SMILES: C(OC1C=CC(C=O)=CC=1)CCC.Br[C:15]1[CH2:19][CH2:18][O:17][N:16]=1.[OH:20][C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>>[N:23]1[CH:22]=[C:21]([O:20][C:15]2[CH2:19][CH2:18][O:17][N:16]=2)[CH:26]=[N:25][CH:24]=1
Reactant: Oc1cncnc1
Reactant: BrC1=NOCC1
Agent: CCCCOc1ccc(C=O)cc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-139a and I-139b was prepared in 3 steps from 4-butoxybenzaldehyde using Method 8 followed by cycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=314.9 m/z. Activity: A
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)CCC.[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19]>C1COCC1.C(Cl)Cl>[Br:14][C:15]1[C:16]([F:23])=[C:17]([CH:18]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[OH:19])[CH:20]=[CH:21][CH:22]=1
Reactant: Ic1cnccn1
Reactant: O=Cc1cccc(Br)c1F
Agent: CCCC[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(c1cnccn1)c1cccc(Br)c1F
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a stirring solution of 2-iodopyrazine (0.195 mL, 1.970 mmol) in THF (3.28 mL) at 0° C. was slowly added butyl magnesium chloride (0.985 mL, 1.970 mmol). The mixture was allowed to stir for 30 min, then 3-bromo-2-fluorobenzaldehyde (0.400 g, 1.970 mmol) was added. After 2 hr, the reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 30-70% EtOAc in hexanes over 19 min, tr=12 min) gave the title compound (347 mg, 1.226 mmol, 62.2% yield) as a yellow residue.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21]CC3C=CC=CC=3)=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[C:1]1([CH2:7][N:8]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Yield: 33.6 %

Procedure:
A solution of {5-{(1R)-2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-[(phenylmethyl)oxy]phenyl}formamide (1.40 g) in EtOAc (15 ml) and EtOH (15 ml) was hydrogenated over 10% palladium on carbon (140 mg). When hydrogen uptake had ceased the mixture was filtered through celite, the solvent evaporated in vacuo and the residue purified on a silica SPE bond elut cartridge (70 g) using a gradient of 0% to 5% MeOH in DCM (Gradmaster™). The appropriate fractions were evaporated in vacuo to give the title compound (380 mg). LCMS RT=2.17 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[C@@H:14]([CH3:28])[CH2:13]3)[N:11]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:10](=[O:36])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][NH:15][C@@H:14]([CH3:28])[CH2:13]3)[N:11]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[C:10](=[O:36])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H]1C[C@]2(CCN1C(=O)OCc1ccccc1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H]1C[C@]2(CCN1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzyl (5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-2-oxo-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (27.9 g, 0.057 moles) was suspended in MeOH (˜200 mL) and methanolic HCl was added until the solids all went into solution. Pd(OH)2 (4 g, moisture content 60%) was added and the reaction was flushed with hydrogen and kept under a hydrogen balloon. The reaction was stirred at room temperature for 30 min. The reaction was evacuated and recharged with H2 once to remove CO2. The reaction was filtered through celite and concentrated, then the free base was obtained by portioning between CHCL3 and 1 N NaOH. The organic was dried over MgSO4, filtered and evaporated to give the product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(Cl)n1)c1ccccc1
Yield: 93 %

Procedure:
6-Chloropyridin-2-amine (0.3 g, 2 mmol) was dissolved in DCM (20 mL) and then pyridine (0.57 mL, 7.0 mmol) was added to the mixture with stirring. Then, benzenesulfonyl chloride (0.36 mL, 2.8 mmol) was added into the mixture. The mixture was allowed to stir under inert atmosphere for 2 hours. The mixture was diluted with DCM and saturated NaHCO3, and then the aqueous layer was extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (10-100% EtOAc/hexanes) to provide N-(6-chloropyridin-2-yl)benzenesulfonamide (0.5 g, 80% yield) as a colorless oil. MS (ESI pos. ion) m/z: 254 (MH+). Calculated exact mass for C11H8ClNO2S: 253.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorobenzyl chloroformate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]4[NH:34][C:33]5[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=5[N:31]=4)[CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C>C(O)(C)C>[NH:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[C:25]1[CH:24]=[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][N:16]([C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[O:15])[CH2:17][CH2:18]2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)C1
Solvent: CC(=O)Cl
Solvent: CC(C)O
Product: O=C(C1CCCNC1)N1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Temperature: 40 °C
Yield: 111.2 %

Procedure:
3-{4-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-[1,4]diazepane-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester (0.21 g, 0.39 mmol) was dissolved in isopropanol (4 mL) and acetyl chloride (0.17 mL, 2.4 mmol) was added. Reaction was heated at 40° C. for 16 h then cooled to room temperature and concentrated under reduced pressure and dried at 60° C. to afford 0.19 g of the title compound as dichlorhydrate salt. (94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[CH3:39][N:40]([CH3:47])[CH2:41][CH2:42][CH2:43][C:44](O)=[O:45].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:40]([CH3:47])[CH3:39])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: CN(C)CCCC(=O)O
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)CCCN(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to which Et3N (3 equiv.) and 4-(dimethylamino)butanoic acid (2 equiv.) was added. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stifling was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired product.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:12]1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[N:25][C:16]=1[NH:15][C@H:13]1[CH2:14][C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[C:33]2[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=2)[CH2:12]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ncnc2c1ncn2[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
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: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ncnc3c2ncn3[C@H]2C[C@H](Nc3ncc4ccccc4n3)C2)cc1
Temperature: 120 °C

Procedure:
N-(Trans-3-(6-chloro-9H-purin-9-yl)cyclobutyl)quinazolin-2-amine (example 21, 0.110 g, 0.313 mmol), tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), (4-methoxycarbonylphenyl)boronic acid (0.073 g, 0.406 mmol), and cesium carbonate (0.357 g, 1.094 mmol) were suspended in a mixture of dioxane (1.25 mL) and water (0.15 mL) and heated in the microwave to 120° C. for 25 minutes. The crude was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-3% methanol in dichloromethane gradient) gave the desired methyl 4-(9-(trans-3-(quinazolin-2-ylamino)cyclobutyl)-9H-purin-6-yl)benzoate (0.0531 g, 0.118 mmol, 37.6% yield). M+1: 452.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.89 (ddd, J=13.60, 8.51, 4.89 Hz, 2 H) 3.15-3.33 (m, 2 H) 3.98 (s, 3 H) 4.89-5.00 (m, 1 H) 5.44 (quin, J=7.34 Hz, 1 H) 7.30-7.35 (m, 1 H) 7.65 (d, J=8.41 Hz, 1 H) 7.69-7.81 (m, 2 H) 8.24 (d, J=8.41 Hz, 2 H) 8.45 (s, 1 H) 8.84 (d, J=8.41 Hz, 2 H) 9.01-9.14 (m, 2 H).