Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:25]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=O)[CH:21]=[C:22]([F:24])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:25](/[C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:27]1[O:28][CH:29]=[CH:30][N:31]=1)[CH3:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1cc(F)cc(Br)c1)c1ncco1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C(/c1cc(F)cc(Br)c1)c1ncco1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of NaH (60%, 1.6 g, 40 mmol) in dry THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (9.15 g, 40 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (3-Bromo-5-fluoro-phenyl)-oxazol-2-yl-methanone (10.8 g, 40 mmol) in 20 ml THF was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature followed by stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5 N) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a petroleum ether/EtOAc mixture to afford 9.5 g of the desired product (Yield: 61%)
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[CH2:42][NH2:43].Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[CH2:42][NH:43][C:14](=[O:16])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: NCc1ccc(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1Cl)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
5-Oxo-1-(phenylmethyl)-proline (0.176 g, 0.80 mmol, prepared as described below) was dissolved in dichloromethane (3 ml) and to this was added 1-hydroxybenzotriazole (0.119 g, 0.88 mmol), triethylamine (0.113 ml, 0.81 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.134 g, 0.84 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.169 g, 0.88 mmol) under an atmosphere of argon. The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-5-oxo-1-(phenylmethyl)-prolinamide (0.112 g) as a white solid.
Reaction SMILES: N.C(=O)([O-])[O-].[Na+].[Na+].[Cl:8][C:9]1[C:10](=S)[NH:11][C:12](=[O:16])[NH:13][C:14]=1[CH3:15]>O.[Ni]>[CH3:15][C:14]1[C:9]([Cl:8])=[CH:10][NH:11][C:12](=[O:16])[N:13]=1
Reactant: Cc1[nH]c(=O)[nH]c(=S)c1Cl
Agent: [Ni]
Agent: N
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1nc(=O)[nH]cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Conc. aqueous ammonia (200 ml) and sodium carbonate (0.012 mol) were added to Raney-Ni (20 g) in water (200 ml) followed by the addition of 5-chloro-6-methyl-4-thiouracil (0.023 mol). The reaction mixture was stirred at room temperature for 1 hr and then heated under reflux for 3 hr. The catalyst was removed from the cold reaction mixture and the filtrate evaporated. The residual material was stirred in 5 N NaOH (20 ml) and the sodium salt filtered off from the ice-cold mixture and washed with abs. ethanol and acetone. The product was recrystallised from aqueous ethanol; yield 53%, m.p. 300° C. (decomp.); For elemental analysis the sodium salt in aqueous solution was neutralised with HCl. Found: C, 41.40; H, 3.60. Calc. for C5H5ClN2O: C, 41.54; H, 3.48.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:35])[C:14]2[O:20][C:19]3[C:21]([Cl:31])=[CH:22][C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:33])(=[O:32])[C:15]=2[CH:34]=1)=[O:10].C([BH3-])#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:35])[C:14]2[O:20][C:19]3[C:21]([Cl:31])=[CH:22][C:23]([N:25]4[CH2:26][CH2:27][N:28]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:29][CH2:30]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:33])[C:15]=2[CH:34]=1)=[O:10]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: CCCCC=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CCCCCN1CCN(c2cc(Cl)c3c(c2)CS(=O)(=O)c2cc(C(=O)OC)cc(C)c2O3)CC1
Temperature: 10 °C

Procedure:
Pentanaldehyde (0.042 gm, 0.5 mmol) was added with stirring to a solution of Example 104k (0.180 g, 0.4 mmol) in dry methanol (10 mL). Titanium isopropoxide (0.117 g, 0.4 mmol) was added and the reaction mixture was cooled to 10° C. Sodium cyanoborohydride (51 mg, 0.8 mmol) was added and the reaction mixture was heated at 60° C. overnight. It was concentrated, treated with water and extracted with n-butanol. The organic layer was washed with water, brine, concentrated and purified using flash chromatography (silica gel, 1-3% MeOH/CHCl3) to obtain the title compound. Yield: 0.2 g (99%), 1H NMR (CDCl3): δ 0.90 (s, 3H, CH3), 1.3 (t, 4H, 2CH2), 1.7 (t, 2H, CH2), 2.40 (t, 2H, CH2), 2.8 (t, 4H, 2CH2), 2.90 (s, 3H, CH3), 3.20 (t, 4H, 2CH2), 3.90 (s, 3H, CH3), 4.8 (s, 2H, CH2), 6.70 (s, 1H, Ar), 6.90 (s, 1H, Ar). 8.1 (s 1H Ar), 8.4 (s 1H Ar); MS: m/e (EI+) 507 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:7](=[O:25])[NH:6][CH2:5]2.[CH:26]1([NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:28][CH2:27]1.CCO.COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[Cl-]>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>[CH:26]1([NH:29][C:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:7](=[O:25])[NH:6][CH2:5]4)[CH:32]=2)=[O:47])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)NCc3cc(Br)ccc32)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: [Cl-]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(c1)CNC(=O)N2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
Into a 100-ml RBF under argon were charged with tert-butyl 4-(6-bromo-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)piperidine-1-carboxylate (0.50 g, 1 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.6 g, 2 mmol), tetrakis(triphenylphosphine)palladium (0.07 g, 0.06 mmol), EtOH (1.00 ml, 17 mmol), and ethylene-glycol dimethyl ether (5.00 ml, 48 mmol), followed by sodium carbonate (2 ml, 4 mmol). The reaction was stirred at 90° C. for 20 h. LC-MS indicated mainly the desired product and none of the starting chloride. The reaction was cooled, diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4). Flash chromatography with 25:10:65, 40:10:50, 50:10:40, 60:10:30, 70:10:20, and 80:10:10 EtOAc-CH2Cl2-Hexane of the concentrated organic layers gave tert-butyl 4-(6-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)piperidine-1-carboxylate as a white amorphous solid. MS m/e 527.2 (M+H+Na)+.
Reaction SMILES: Br[C:2]1[CH:32]=[C:31]([F:33])[C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:19]([O:29][CH3:30])=[CH:18][N:17]=3)=[N:8]2)=[C:4]([F:34])[CH:3]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:35]1([C:2]2[CH:32]=[C:31]([F:33])[C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([C:16]4[N:21]=[C:20]([NH:22][C:23]5[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=5)[C:19]([O:29][CH3:30])=[CH:18][N:17]=4)=[N:8]3)=[C:4]([F:34])[CH:3]=2)[CH2:37][CH2:36]1
Reactant: OB(O)C1CC1
Reactant: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3F)c3ccccc23)nc1Nc1ccncc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cnc(-c2nn(Cc3c(F)cc(C4CC4)cc3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-12-1, 0.191 mmol, 1. eq.) were suspended in 3 ml of dry toluene. 21.3 mg of cyclopropylboronic acid (0.248 mmol, 1.3 eq.) 5.36 mg of tricyclohexylphosphane (0.019 mmol, 0.1 eq.), 142 mg of potassium phosphate (0.669 mmol, 3.5 eq.) and 50 μl of water were added. Then 2.15 mg of palladium (II) acetate (0.01 mmol, 0.05 eq.) were added under a nitrogen atmosphere. The mixture was stirred at 100° C. bath temperature for 5 hours. Upon the mixture was cooled to room temperature it was partitioned between water and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Preparative HPLC purification provided 28.7 mg (0.06 mmol, 31%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]1[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(Cl)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
To a solution of 3-(trifluoromethyl)benzhydrol (5 mL, 20 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (3 mL, 41 mmol) at rt. The reaction was stirred at 50° C. for 18 h, concentrated under vacuum, azeotroped with toluene and dried under vacuum to give the title compound (4.9 g, 89% yield) as oil, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 235.0 (M-HCl).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc2oc(Cl)nc2c1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2oc(Nc3ccc(Br)cc3)nc2c1

Procedure:
The mixture containing 2-chloro-5-methoxybenzoxazole (1 eq), 4-bromoaniline (2 eq) and diisopropylethylamine was refluxed in dimethylformamide. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave (4-bromo-phenyl)(5-methoxybenzoxazol-2-yl)amine. MS: MH+=318
Reaction SMILES: C(N(CC)CC)C.C1(C)C=CC=CC=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@H:23]1[C:35](=[O:41])[CH2:36][C:37](=[O:40])[NH:38][CH3:39])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1CC=CCCC=C1.Cl[Ru]Cl.C(O)C>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][Si:28]([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:29])[CH3:30])[CH2:24][C@H:23]1[CH:35]([OH:41])[CH2:36][C:37](=[O:40])[NH:38][CH3:39])=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: CNC(=O)CC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: Cl[Ru]Cl
Agent: C1=C\CC/C=C\CC/1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)CC(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 22 h
Yield: 79 %

Procedure:
Under an argon atmosphere, (1,5-cyclooctadiene)ruthenium(II) chloride polymer (10 mg, 3.6×10-2 mmol), (S)-(-)-bis(diphenylphosphino)-1,1'-binaphthyl (24 mg, 3.6×10-2 mmol), triethylamine (0.1 ml, 6.5×10-1 mmol) and toluene (5 ml) were stirred in a sealed tube at 140° C. for 6 h. The solvent was removed in vacuo from the obtained red solution. To the residue was added a tetrahydrofuran (5 ml)--ethanol (10 ml) solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[2-(N-methylcarbamoyl)-1-oxoethyl]pyrrolidine (1.5 g, 3.9 mmol). The mixture was stirred under a hydrogen pressure of 4 kg/cm2 at 80° C. for 22 h. Then, the reaction solution was concentrated. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=3:1→1:3) to give the title compound [1.19 g, yield: 79%; by high performance liquid column chromatography YMC PACKED COLUMN, AQ-32 S-5 120A ODS, developer:acetonitrile--water 70:30, detection at 210 nm (R)-isomer (polar compound):(S)-isomer (less polar compound)=1.89:1].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH3:45])[C:23]2[O:27][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:30]=3)=[N:25][C:24]=2[CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:3]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:26]4[O:27][C:23]5[C:22]([CH3:45])=[CH:21][C:20]([CH3:19])=[CH:44][C:24]=5[N:25]=4)=[CH:34][CH:33]=3)[C:10]=12
Reactant: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C)CC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 60.7 %

Procedure:
A mixture of 3-iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.2 g, 0.00056 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.2 g, 0.00056 mol), tetrakis(triphenylphosphine)-palladium (0.032 g, 0.000028 mol) and sodium carbonate (0.15 g, 0.0014 mol) in ethylene glycol dimethyl ether (20 mL) and water (5 mL) was heated at 80° C. for 3 hours under an atmosphere of nitrogen. Additional N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.2 g, 0.00056 mol) and tetrakis(triphenylphosphine)palladium (0.032 g, 0.000028 mol) were added, and the mixture was stirred at 80° C. for 16 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 5%-25% methanol/dichloromethane as a mobile phase to give N2-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine (0.16 g, 0.00034 mol).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[C:21]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([CH3:33])=[CH:27][C:26]=1[S:34]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:24])([CH3:23])[CH3:22].CCN(CC)CC>C(#N)C>[C:21]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([CH3:33])=[CH:27][C:26]=1[S:34][C:3]1[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=1[OH:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccsc2CO)CC(O)=CC(=O)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3CO)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16b using 4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-24; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.05 mmol), NEt3 (2.2 mmol) in acetonitrile (5 mL). The product was chromatographed over silica gel using 97.5:2.5 CH2Cl2:MeOH, mp 87-90° C. MS (APCI): 503 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.CN(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].[CH2:34](I)[CH3:35]>C1C=CC=CC=1>[CH2:34]([N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:9]([C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])[C:10]([OH:12])=[O:11])[CH3:35]
Reactant: CCI
Reactant: O=C(O)C(Nc1cccc(Cl)c1)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Product: CCN(c1cccc(Cl)c1)C(C(=O)O)c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of 13.2 parts of N-(m-chlorophenyl)-2-(2,6-dichlorophenyl)glycine in 80 parts of hexamethylphosphoramide are added portionwise 2.1 parts of sodium hydride 50% and the whole is stirred for 30 minutes. Then there are added dropwise 6.9 parts of ethyl iodide and stirring is continued for 20 hours at room temperature. The reaction mixture is poured onto 320 parts of benzene. The organic layer is washed successively twice with 50 parts of water, twice with 50 parts of a sodium hydroxide solution 5% and again twice with 50 parts of water, dried, filtered and evaporated. The oily residue solidifies on standing at room temperature. The solid product is filtered off and crystallized from 2-propanol, yielding 8.9 parts of ethyl N-(m-chlorophenyl)-2-(2,6-dichlorophenyl)glycine; mp. 120.5° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:23])=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C(O)c1ccc(C(=O)c2ccco2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(C(=O)N2CCc3ccoc3C2)cc1)c1ccco1
Reaction time: 8 h

Procedure:
To a solution of 0.165 g (1.034 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.25 g (1.1 mmol) of 4-(2-furoyl)benzoic acid and 0.58 ml (4.1 mmol) of triethylamine in 30 ml of dichloromethane, 0.19 ml (1.2 mmol) of diethyl cyanophosphonate was added dropwise at room temperature, followed by overnight stirring. This mixture was poured into aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C:13]3=[O:27])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[CH:29]1[CH:30]=CC2N(O)N=NC=2[CH:34]=1.CCN=C=NCCCN(C)C.C(CN1C2C(=CC=CC=2)CC(NC(C2NC3SC(Cl)=CC=3C=2)=O)C1=O)(O)=O>CN(C=O)C>[CH3:34][C:29]1([CH3:30])[O:26][CH:23]([CH2:22][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH:12]([NH:11][C:9]([C:7]3[NH:6][C:5]4[S:28][C:2]([Cl:1])=[CH:3][C:4]=4[CH:8]=3)=[O:10])[C:13]2=[O:27])[CH2:24][O:25]1
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)O1
Reaction time: 18 h
Yield: 69.2 %

Procedure:
5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9; 243 mg, 1.20 mmol), HOBT (178 mg, 1.32 mmol), anhydrous DMF (10 mL) and finally EDCI (252 mg, 1.32 mmol) were added to 3-amino-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3,4-dihydroquinolin-2(1H)-one (Method 2, 330 mg, 1.20 mmol) and the reaction was stirred for 18 h. The reaction was evaporated and the residue was dissolved in EtOAc (100 mL) and washed with 1M aqueous HCl (50 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (30 mL) and brine (30 mL). The organic layer was then separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (EtOAc:hexanes 1:2) to afford the title compound (382 mg, 69%) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.[BH4-].[Na+].O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.[Co](Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][NH2:14])[N:9]=[C:8]([C:19]([F:21])([F:20])[F:22])[CH:7]=1
Reactant: N#Cc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Agent: Cl[Co]Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.2 %

Procedure:
Cobalt chloride (1.76 g, 13.6 mmol) was added to 2-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile (4.12 g, 13.6 mmol) and sodium borohydride (1.03 g, 27.2 mmol) in DMF (40 mL). The reaction turned black and became warm. An ice bath was added and the reaction was stirred at 0° C. for 45 min, then at room temperature for 23 h. Additional sodium borohydride (0.25 g, 6.6 mmol) was added and the resulting mixture was stirred at room temperature for 6 h. A room temperature water bath was added, and the reaction was quenched with water (10 mL) over 10 min, then MeOH (20 mL), then 6M HCl (20 mL) over 15 min. The quenched reaction was stirred at room temperature for 16 h, diluted with EtOAc, and extracted with water and 0.1M HCl. The resulting emulsion was filtered through celite, and the organic layer was removed, dried over Na2SO4, filtered, and evaporated to yield crude product (857 mg). The aqueous layers were combined and neutralized (pH 8) with solid Na2CO3 (6.9 g). Addition of EtOAc yielded another emulsion, which was filtered through celite. The organic layer was removed, and the aqueous layer was extracted again with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and evaporated to yield a second batch of crude product (3.55 g). The two batches of crude product were combined and chromatographed on silica gel (0-10% MeOH/CHCl3) to yield the desired product (3.77 g, 90%). 1H NMR (CDCl3) δ7.59 (m, 2H), 7.38 (m, 2H), 7.33 (d, 1H, J=7.3), 6.96 (s, 1H), 6.27 (m, 1H), 5.59 (d, 1H, J=3.6), 3.51 (s, 2H).