Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[N:16]([CH3:17])[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N:30]4[CH:34]=[N:33][N:32]=[CH:31]4)[CH:28]=3)[NH:23][CH:22]=2)[CH2:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([NH:8][CH2:9][CH:11]1[N:16]([CH3:17])[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N:30]4[CH:31]=[N:32][N:33]=[CH:34]4)[CH:28]=3)[NH:23][CH:22]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1C(=O)NCc1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1CNCc1ccccc1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
To a solution of 3-(N-benzylaminocarbonyl)-4-methyl-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperazine (29 mg, 0.06 mmol) in THF (5 mL) at room temperature, under nitrogen, was added borane-THF (1.0 mL of a 1.0M solution in THF, 1.0 mmol). The mixture was heated at reflux for 18 h, then cooled to room temperature. MeOH (2 mL) was added and the solvents evaporated. The residue was dissolved in EtOH (10 mL), and K2CO3 (17 mg, 0.13 mmol) was added. The mixture was heated at 75° C. for 20 h, before the solvent was evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (95:5:1), to afford the amine (12 mg, 45%) as a gum. The title compound was characterised as its hydrogen oxalate salt. 1H nmr (360 MHz, d6 -DMSO) δ 1.80-1.96 (2H, m), 2.31 (3H, s), 2.37-2.62 (4H, m), 2.66-2.79 (3H, m), 2.80-3.06 (6H, m), 3.98 (1H, d, J=13.4 Hz), 4.03 (1H, d, J=13.4 Hz), 7.28-7.50 (8H, m), 7.78 (1H, s), 9.02 (2H, s), 11.12 (1H, br s). MS (ES+) 444 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1)#[N:2].C(N[C:33](=[O:47])[CH:34]([C:41]1C=CC=C[CH:42]=1)[CH:35]1CCNC[CH2:36]1)C.FC1C=CC([N+]([O-])=O)=CC=1C#N.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[C:7]([NH:9][C:33](=[O:47])[CH:34]([CH2:41][CH3:42])[CH2:35][CH3:36])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:19](=[O:20])[NH:21][CH2:22][CH3:23])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13]1)#[N:2]
Reactant: CCNC(=O)C(c1ccccc1)C1CCNCC1
Reactant: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Agent: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2C#N)CC1
Temperature: 80 °C
Yield: 86 %

Procedure:
2-[1-(2-Cyano-4-nitro-phenyl)-piperidin-4-yl]-N-ethyl-2-phenyl-acetamide. To a solution of N-ethyl-2-phenyl-2-piperidin-4-yl-acetamide (500 mg, 2 mmol) and 2-fluoro-5-nitro-benzonitrile (337 mg, 2.03 mmol) in DMF was added K2CO3 (840 mg, 6.1 mmol). The solution was heated to 80° C. for 16 h. After cooling to rt, H2O and 3:1 EtOAc/hexanes were added. The organic portion was washed three times with H2O and once with brine, dried (Na2SO4) and concentrated to provide the title compound (yellow powder, 686 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([CH2:19][CH3:20])(O)[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1.B(F)(F)F.O(CC)CC>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([CH2:19][CH3:20])([C:23]3[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:22]=3)[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CCC(O)(CC)c1ccc2ccc(C(=O)OC)cc2c1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2ccc(C(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Cool a CH2CL2 (20 mL) solution of 7-(1-ethyl-1-hydroxypropyl)naphthalene-2-carboxylic acid methyl ester (0.73 g, 2.68 mmol) and o-cresol (1.54 mL, 15.0 mmol) to −78° C.; then dropwise add BF3-OEt2 (0.76 mL, 6.0 mmol). Allow the reaction mixture to warm to RT and stir for 1 h. Quench the reaction with ice water. Dilute the resulting mixture with EtOAc (200 mL). Wash the mixture with brine, dry the organic layer over Na2SO4, filter and concentrate the filtrate. Purify by silica gel radial chromatography (5:95 to 35:65 EtOAc:hex) to give the title compound as a yellow oil (0.93 g, 86%). MS (ES) m/e 363 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O(C(C)(C)C)[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:18]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1ccncn1)c1ccc(N2CCNCC2)cc1

Procedure:
Synthesized according to general procedure 4. The reaction was set up with 1.6 mmol 4-bromo-N-(pyrimidin-4-yl)benzenesulfonamide, 16.0 mmol piperazine, 0.12 mmol Pd2(dba)3, 0.15 mmol of 2-(di-t-butylphosphino)biphenyl, 10 mmol of NaO-tBu and 12 mL toluene. For the purification, 10% MeOH in CH2Cl2 without the addition of triethylamine was used as a solvent system. Yield: 430 mg (84%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=320.2; tR=0.42 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=2)[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:59][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([NH:64][C:63]3[CH:65]=[CH:66][C:60]([F:59])=[CH:61][CH:62]=3)=[O:25])=[CH:21][N:22]=2)[CH:19]=1
Reactant: O=C(O)c1cnc2ccc(N3CCCC3c3cc(F)ccc3F)cn12
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1cnc2ccc(N3CCCC3c3cc(F)ccc3F)cn12
Reaction time: 0.17 h
Yield: 9.4 %

Procedure:
To a stirred solution of 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int-15) (0.15 g, 0.44 mmol) in dry DMF (1.5 ml) was added HATU (0.215 g, 0.57 mmol), DIPEA (0.084 g, 0.65 mmol) under N2 atm at RT and stirred for 10 min, then added 4-fluoroaniline (0.053 g, 0.48 mmol) and stirred for 16 h at RT. After completion of reaction, quenched with ice water and solid was filter. Solid thus obtained was dried under high vacuum to afford 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (0.018 g, 9.7% Yield) MS (ESI): m/z 437.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.07 (1H, s), 8.72-8.71 (1H, d J=3 Hz), 8.41 (1H, s), 7.74-7.71 (2H, m), 7.59-7.57 (1H, d J=6 Hz), 7.35-7.28 (1H, m), 7.23-7.12 (3H, m), 7.00-6.94 (2H, m), 5.02-5.00 (1H, d), 3.80-3.77 (1H, t), 2.05-1.89 (3H, m).
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCc1ccccc1
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 84.9 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.0.740 mmol), benzylamine (0.5 mL, 4.6 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 207 mg of the product 189. 1H NMR (CDCl3) δ 8.56 (s, 1H), 7.50-7.20 (m, 5H), 5.15-4.95 (m, 2H), 4.35-4.05 (m, 2H), 2.85-2.55 (m, 1H), 2.25-2.05 (m, 1H), 1.90-1.05 (m, 15H); MS: m/z 330 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](O)=[O:13])=[CH:7]2.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][OH:13])=[CH:7]2
Reactant: O=C(O)c1ccc2c(Cl)cccc2c1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(Cl)cccc2c1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
To a cooled (0° C.), stirred suspension of 5-chloro-2-naphthoic acid (1.10 g, 5.32 mmol) in THF (10 mL) was added BH3.THF (1M in THF, 7.50 mL, 7.50 mmol) over 10 minutes. The resulting mixture was then heated under reflux for 1 hour 30 minutes, recooled to 0° C., and saturated aqueous K2CO3 (4 mL) was added. H2O (20 mL) was added and the mixture was extracted with ether. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give a pale yellow solid (0.94 g, 97%), m.p. 72°-75° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:47]=[CH:46][C:36]([O:37][C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[CH:40]=[O:41])=[CH:35][CH:34]=2)O1.O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>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.CCOCC.COCCOC>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:34]3[CH:35]=[C:36]([CH:46]=[CH:47][CH:33]=3)[O:37][C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[CH:40]=[O:41])[C:10]=12
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3C=O)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: O=C([O-])[O-]
Solvent: CCOCC
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(Oc5ccccc5C=O)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 73.6 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.970 g, 2.20 mmol, 1 equiv), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzaldehyde (0.842 g, 2.60 mmol, 1.2 equiv), tetrakis(triphenylphosphine)palladium (0.186 g, 0.180 mmol, 0.08 equiv), DME (9 mL), and sodium carbonate monohydrate (0.655 g, 5.30 mmol, 2.4 equiv) in water (7 mL) was heated at 85° C. for 7 h then allowed to cool to ambient temperature. Saturated aqueous sodium bicarbonate solution (50 mL) was added, and the solution was extracted with EtOAc (25 mL). The organic extract was dried over MgSO4, filtered, and concentrated to afford a light brown solid. Trituration from Et2O (35 mL) afforded cis-2-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzaldehyde as an off-white solid (0.830 g, 1.62 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 10.42 (1H, s), 8.24 (1H, s), 7.89 (1H, d, J=7.7 Hz), 7.69-7.71 (3H, m), 7.30-7.36 (1H, m), 7.29 (2H, d, J=6.3 Hz), 7.16 (1H, d, J=8.2 Hz), 4.79-4.81 (1H, m), 2.18-2.55 (11H, m), 2.17 (3H, s), 2.05-2.09 (2H, m), 1.56-1.71 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.56 min. MS: MH+ 512.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1.[H-].[Na+].I[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2CO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2COC)cc1
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Ethyl 2'-hydroxymethyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylate (D54) (0.51 g, 1.5 mmol) was stirred in dry DMF (8 ml) under argon. Sodium hydride (80% dispersion, 0.07 g, 2.3 mmol) was added, and the resulting suspension was stirred for 10 min. Iodomethane (0.19 ml, 3.0 mmol) was added; the mixture was stirred for 30 min, diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to a yellow gum. Chromatography on silica gel, eluting with 0-50% ethyl acetate/dichloromethane, gave the title compound (0.34 g, 64%) as a colourless gum, solidifying on standing. A little methyl ester was also present.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:13]([O:15]CC3C=CC(OC)=CC=3)=[O:14])=[C:8]([CH:11]=[CH2:12])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C(=O)(O)[O-].[Na+:31]>C1(OC)C=CC=CC=1.ClCCl.P([O-])([O-])([O-])=O>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:13]([O-:15])=[O:14])=[C:8]([CH:11]=[CH2:12])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+:31]
Reactant: C=CC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
to -60° C. To this mixture was added a solution of 33.7 mg (0.0944 mmol) of the compound prepared in Example 5 in 1.4 ml of anisole and 0.2 ml of dichloromethane, and the mixture was stirred for 30 minutes at the same temperature. And then, to the mixture was added a solution of 143 mg (1.7 mmol) of sodium bicarbonate in 4 ml of 0.1 M phosphate buffer (pH 7.0), and the mixture was stirred for 30 minutes under ice-cooling. After the reaction mixture was filtered, the filtration was washed twice with dichloromethane. The aqueous layer was separated, and purified by reverse phase silica gel column chromatography (elution with 10% methanol-water) to give 5.74 mg (yield: 23.5% of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])=[N:14][C:15]=2[CH2:17][S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:10](COCC[Si](C)(C)C)[N:9]=1.FC(F)(F)C(O)=O.[BH4-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])=[N:14][C:15]=2[CH2:17][S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[NH:10][N:9]=1
Reactant: CN(C)S(=O)(=O)Cc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2COCC[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)Cc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.9 %

Procedure:
C-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-methanesulfonamide (273 mg, 0.447 mmol) was dissolved in 5 mL chloroform, and 2.5 mL of trifluoroacetic acid was added. The reaction mixture was stirred for 22 hours at room temperature, and was then concentrated to dryness under reduced pressure. The residue was dissolved in 7 mL of MeOH, and sodium borohydride (109 mg, 4.47 mmol) was added. The reaction mixture was stirred for 15 minutes, then concentrated under reduced pressure. The residue was partitioned between 100 mL EtOAc and 100 mL brine, and the organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0% to 40% EtOAc in hexanes) to yield 167 mg of C-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-methanesulfonamide. Mass Spec. M+H=481.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:14])[CH3:13].Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:32])=[CH:29][C:28]=2[O:43][CH3:44])[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1>[C:12]([NH:11][C@@H:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C@H:2]1[O:1][C:20]1[C:21]([C:22]([F:23])([F:25])[F:24])=[CH:16][N:17]=[C:18]([NH:26][C:27]2[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[O:32])=[CH:29][C:28]=2[O:43][CH3:44])[N:19]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)N[C@@H]1c2ccccc2C[C@H]1O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(O[C@@H]2Cc3ccccc3[C@H]2NC(C)=O)n1
Temperature: 25 °C

Procedure:
N-((1R,2R)-2-hydroxy-indan-1-yl)-acetamide (43 mg) and 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (50 mg) are suspended in 0.70 mL dioxane, mixed with Cs2CO3 (184 mg) and some MgSO4 and stirred overnight at 85° C. The reaction mixture is allowed to cool to RT and the solvent is eliminated using the rotary evaporator. The residue is taken up in MeOH and purified by preparative HPLC. The product-containing fractions are freeze-dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.[CH2:32]([OH:35])[C:33]#[CH:34].C(N(CC)CC)C>C1COCC1.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>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[N:6]=[C:5]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21]2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:34]#[C:33][CH2:32][OH:35])[CH:3]=2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(Br)cc23)C1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Yield: 42.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.030 g, 0.026 mmol) was added to a solution of (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (prepared as described in Synthesis 32-A, 0.250 g, 0.515 mmol), propargyl alcohol (0.043 g, 0.773 mmol) and triethylamine (0.108 mL, 0.773 mmol) in THF (2.5 mL) and the solution heated to reflux for 16 hours. The mixture was cooled then purified by ion exchange chromatography on SCX-2 Isolute acidic resin (5 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by column chromatography, eluting with 5% methanol in dichloromethane, gave the title compound as a solid (0.100 g, 42%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10]O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:7][C:4]([O:3][C:1]([NH:8][C@@H:9]1[C:12](=[O:13])[O:14][CH2:10]1)=[O:2])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1COC1=O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
Methyl azodicarboxylate-derivatized resin (6.55 g, 4.0 meq) was swollen briefly (15 min) in dry THF (100 mL). The stirred suspension of beads was cooled to -45° C. and BOC-L-serine (473.5 mg, 2.30 mmol) was added. To this mixture at -45° C. was added a solution of triphenylphosphine (1.06 g, 4.0 mmol) in THF (5 mL) dropwise over 10 min. The suspension was stirred 30 min at -45° C., allowed to warm slowly to 0° C. over 1 h, and stirred 2 h further. H2O (36μL) was added as a precautionary quench and the resin was filtered and washed with THF (2 ×100 mL) and CH3CN (100 mL). The filtrate and washings were pooled and concentrated in vacuo at 35° C. The residue was flash chromatographed (35% EtOAc/hexane) to yield 242.7 mg (56%) of BOC-L-serine β-lactone: mp 119.5-120.5° C (dec); [α]25 -26.7 (±0.2)°(c 1.0, CH3CN); IR [Fluorolube (trademark) mull](CH2Cl2 cast) 3358 (s), 1836 (s), 1678 (vs), 1532 (s), 1291 (m), 1104 (s) cm-1 ; ε1847 cm-1 (0.1 mm KBr, THF or CH3CN) 0.34 mL mg-1 mm-1, 64 M-1 ; mm-1 ; 1H NMR (200 MHz, CD2Cl2) δ5.53 (br s, 1H, NH), 5.05 (dd, 1H, 8, 6 Hz, CH), 4.47 (~d, 2H, 6 Hz, CH2O), 1.47 (s, 9H, tert-Bu); 13C NMR (50.32 MHz, CD2Cl2) ≃170.0 (s), 155.1 (s), 81.5 (s), 66.6 (t), 59.9 (d), 28.2 (q); Anal. Calc. for C8H13NO4 : C, 51.33; H, 7.00; N, 7.48. Found: C, 51.04; H, 6.97; N, 7.42; EI--MS: 188.0929 (MH+, 188.0923 calcd.); CI--MS (NH3) 205 (M+NH+), 392 (2M+NH4+).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.[NH2:40][C@H:41]1[CH2:45][CH2:44][C@@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]1>>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21]([NH:40][C@H:41]3[CH2:45][CH2:44][C@@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42]3)=[O:22])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Agent: Cl
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N[C@H]2CC[C@@H](C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 5 from 2-{3-[4-(1,1′-biphenyl-4-yl-methoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and methyl (1R,3S)-3-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(C(C)C)CC)(C)C.[CH2:20]([O:22][CH2:23]OCl)[CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:20]([O:22][CH2:23][O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:21]
Reactant: CCOCOCl
Reactant: Cc1cccc(C=O)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOc1c(C)cccc1C=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
To a stirred solution of 2-hydroxyl-3-methylbenzaldehyde (1.46 g, 10.7 mol), diisopropyl ethylamine (3.3 mL, 20.0 mmol) and 4-(dimethylamino)pyridine (122 mg, 1.0 mmol) in dichloromethane (35 mL) was added ethoxymethoxyl chloride (1.85 mL, 20.0 mmol) at RT. The mixture was stirred at RT for 17 h. The reaction was quenched with water (30 mL). The product was extracted with CH2Cl2 (3×40 mL). The combined organic extracts were washed with water (50 mL), and brine (50 mL), dried over anhydride Na2SO4. The residue was purified by flash column chromatography (hexanes/ethyl acetate=5:1, v/v) to provide the title compound (2.02 g, 97%) as a colorless oil.