Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.CN1C(=O)C[CH2:16][CH2:15]1.CC[Mg+].[Br-]>C1COCC1.CCOCC.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:15]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)[CH3:16]
Reactant: COC(=O)c1ccc(Cl)cc1C
Reactant: CN1CCCC1=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC[Mg+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)OC)c(C)c1
Yield: 83 %

Procedure:
4-Chloro-2-methylbenzoic acid (3 g, 17.6 mmol) was suspended in 12 ml of MeOH with 1 ml of concentrated H2SO4. The mixture was refluxed overnight, MeOH was evaporated and the residue was extracted with EtOAc, dried over MgSO4 filtered and evaporated to give methyl 4-chloro-2-methylbenzoate as a colorless viscous liquid (2.96 g, 92%) that was used in the next step without further purification. The ester (2.96 g, 16 mmol) was, under inert atmosphere, dissolved in THF (100 mL) and NMP (9 mL) and Iron(III) acetylacetonate (318 mg, 0.9 mmol) was added giving a red solution. Then EtMgBr (7 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 10 ml). The crude product was extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (30% EtOAc/hexanes) to give methyl 4-ethyl-2-methylbenzoate as an oil (2.37 g, 83%). (1H NMR (500 MHz, CDCl3): δ 1.26 (t, 3H), 2.63 (dd, 2H), 3.9 (s, 3H), 7.1 (b, 2H), 7.85 (d, 1H)).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[C:9]1[NH:12][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([C:15]([NH2:17])=[O:16])[C:8]1=[CH:7][CH:6]=2.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[C:9]1[N:12]([CH3:24])[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]([C:15]([NH2:17])=[O:16])[C:8]1=[CH:7][CH:6]=2
Reactant: NC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnc(N)nc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2ccccc2)c(C(N)=O)c2ccc3cnc(N)nc3c21
Temperature: 70 °C
Yield: 78 %

Procedure:
To a solution of 8-amino-2-phenyl-1H-1,7,9-triaza-cyclopenta[a]naphthalene-3-carboxylic acid amide N9 (0.16 mmol) in dry DMF (5 mL), caesium carbonate (0.7 mmol) and methyl iodide (0.7 mmol) were added. The reaction mixture was heated at 70° C. in a sealed tube for 1 h then the solvent was evaporated. The solid residue was washed with water and dried, giving the title compound (78% yield). ESI (+) MS: m/z 391 (MH+). 1H NMR: 4.21 (s, 3H), 6.15 (bs, 1H), 6.76 (bs, 2H), 7.08 (bs, 1H), 7.42 (d, J=8.50, 1H), 7.52-7.65 (m, 5H), 7.83 (d, J=8.50, 1H), 9.03 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[C:4]([O:20][CH3:21])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:46][CH:47]1[CH2:54][CH:53]2[N:55]([CH3:56])[CH:49]([CH2:50][CH2:51][CH2:52]2)[CH2:48]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:56][N:55]1[CH:49]2[CH2:50][CH2:51][CH2:52][CH:53]1[CH2:54][CH:47]([NH:46][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[O:20][CH3:21])=[N:12][C:11]=13)=[O:18])[CH2:48]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: COc1cc(Cl)ccc1-c1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
A mixture of 2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxylic acid (95 mg, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol), 1-hydroxybenzotriazole (76 mg, 0.62 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (89 mg, 0.39 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.18 mL, 1.25 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (3×50 mL), brine (3×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methoxyphenyl)benzoxazole-4-carboxamide (102 mg, 67%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.17 (br s, 1H), 8.20 (dd, J=7.7, 0.8 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.69 (dd, J=7.3, 0.9 Hz, 1H), 7.45 (t, J=4.0 Hz, 1H), 7.16-7.10 (m, 2H), 4.67-4.56 (m, 1H), 4.04 (s, 3H), 3.10-3.02 (m, 2H), 2.70-2.60 (m, 5H), 2.57 (s, 3H), 2.20-2.00 (m, 3H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 440 (M+H); HPLC 98.7% (AUC), tR=14.10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)C.O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][OH:19])=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nccnc1-c1ccc(CO)cc1)c1ccccc1Cl
Temperature: 110 °C
Yield: 91 %

Procedure:
2-chloro-N-(3-chloropyrazin-2-yl)benzenesulfonamide (2.2 g; 7.23 mmol; 1.00 eq.) and 4-hydroxymethyl benzene boronic acid (1.21 g; 7.96 mmol; 1.10 eq.) were dissolved in 48 mL of a 1:1 mixture of Dioxane:MeOH that was previously degassed. Potassium carbonate (2.75 g; 19.89 mmol; 2.75 eq.) and triphenylphosphine (284.58 mg; 1.08 mmol; 0.15 eq.) were added to the reaction mixture under nitrogen, followed by palladium II (81.19 mg; 0.36 mmol; 0.05 eq.). The reaction mixture was then heated at 110° C. under N2 for 30 minutes. The reaction mixture was cooled down to room temperature, diluted with diethyl ether (50 mL) and water (25 mL) and filtered through celite. The aqueous layer was separated and the organic layer washed with water (50 mL). The combined aqueous solutions were washed with diethyl ether (50 mL), then acidified aqueous layer with HCl 5N and extracted with AcOEt. The organic extracts were combined, washed with brine (10 ml), dried over MgSO4 and evaporated down to give the pure 2-chloro-N-{3-[4-(hydroxymethyl)phenyl]pyrazin-2-yl}benzene sulfonamide as a yellowish solid (2.5 g, 91% yield, 98% HPLC purity). This compound was used as such for the next reaction.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN(C)[CH:22]=[O:23]>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:22]=[O:23]
Reactant: Clc1ccncc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cnccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of diisopropylamine (18.2 mL, 0.13 mol) in THF (200 mL, 0.5 M) at −78° C. was added n-butyl lithium (2.5 M in hexane, 52 mL, 0.13 mol) dropwise. After 30 min, 4-chloropyridine from Step A in THF (10 mL) was added and the reaction mixture was stirred at −78° C. for 1 h. To the resulting reddish-brown solution at −78° C. was added N,N-dimethylformamide (12.4 mL, 0.16 mol). The reaction mixture was allowed to warm slowly to room temperature over a 15 h period, and then the reaction was quenched with water (150 mL). The THF was removed in vacuo and the aqueous layer was extracted with isopropyl acetate (3×150 mL). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the crude product as a brown oil. This residue was purified by silica gel chromatography (using 5% EtOH in EtOAc) to afford 3.97 g of the title intermediate as a yellow solid (Rf=0.6, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:23]([NH:22][S:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[CH2:10][CH2:11][CH2:12]3)(=[O:21])=[O:20])=[O:24])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C=NS(=O)(=O)c1ccc2c(c1)CCC2
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1ccc2c(c1)CCC2
Reaction time: 7 h
Yield: 84.7 %

Procedure:
A solution of 2.67 g of 3,4-dichloroaniline in 10 ml of toluene was added to 3.87 g of 2,3-dihydro5-indenylsulfonylisocyanate in 20 ml of toluene. After stirring 7 hours, the resulting precipitate was recovered by filtration, washed with toluene and dried providing 5.38 g of the title product, m.p. 155.5°-158° C.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][S:2]1(=[O:11])=[O:10].[Br:12]Br>[Fe].C(Cl)(Cl)(Cl)Cl>[Br:12][C:9]1[C:4]2[CH2:3][S:2](=[O:10])(=[O:11])[CH2:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=S1(=O)Cc2ccccc2C1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: O=S1(=O)Cc2cccc(Br)c2C1

Procedure:
1,3-Dihydrobenzo[c]thiophene 2,2-dioxide [Chem. & Ind., 1024 (1965)] is brominated according to the method described in Khim. Tadzh., 107 (1973), [C.A., 84, 89,930 (1976)], using bromine (1.1 equivalents) in refluxing carbon tetrachloride which contains iron until the bromine color is dissipated. Removal of the carbon tetrachloride and recrystallization from ethanol gives 4-bromo-1,3-dihydrobenzo[c]thiophene 2,2-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:29]#[N:30])[C:11]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[NH2:30][C:29]1[C:10]2[C:11](=[N:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[O:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)COc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from Step B (0.130 g; 0.282 mmol) in THF (3 mL) cooled to 0° C. was treated with 1 M solution of lithium bis(trimethylsilyl)amide in THF (0.85 mL; 0.85 mmol) and stirred at 0° C. under nitrogen for 30 minutes. The reaction mixture was quenched at 0° C. with 10% aqueous NaHSO4 solution. The reaction mixture was partitioned between ethyl acetate and 10% NaHSO4 aqueous solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 460.9 (M+1), 462.9 (M+3); Rt=4.35 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([OH:13])[CH2:11]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([O-:17])(=[S:16])[CH3:15].[K+]>CC(C)=O>[C:14]([S:16][CH2:11][CH:10]([OH:13])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(O)CI
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCC(O)CNC(=O)OC(C)(C)C
Yield: 27 %

Procedure:
1-(tert-butyloxycarbonylamino)-3-iodopropan-2-ol (example 22a) (2 g, 6.64 mmol) and potassium thioacetate (0.948 g, 8.30 mmol) were dissolved in acetone (30 ml) and the medium was refluxed for 16 hours. The solvent was vacuum evaporated and the residue was taken up in diethyl ether, then filtered on Celite®. The filtrate was evaporated. The residue obtained (1.69 g) was purified by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 98:2) then repurified by flash chromatography (eluent: dichloromethane) to give the desired compound in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22](OCC)=[O:23])[C@@H:18]([C:27](OCC)=[O:28])[C@@H:17]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[BH4-]>C1COCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([CH2:27][OH:28])[C@@H:17]2[C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:8]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 68 °C
Yield: 95.4 %

Procedure:
To a solution of 9.2 g (15.9 mmol) diethyl (1S,2S,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-dicarboxylate (step F) in 100 mL THF under nitrogen atmosphere at RT was added 2 g (112.4 mmol, excess) LiBH4 powder. The resulting mixture was heated at 68° C. for 2 hr then cooled to RT. The reaction mixture was carefully quenched by the addition of 30 mL water, then extracted with EtOAc. The combined organic extracts were dried over drying agent, filtered and the solvent evaporated under vacuum to give 7.5 g of the crude title compound as an oil which was used without further purification. 1H-NMR (CDCl3): δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.87 (2H, t, J=8.2 Hz), 4.20 (1H, q, J=6.0 Hz), 3.78 (1H, m), 3.67 (1H, m), 3.52 (1H, m), 3.30-3.20 (2H, m), 2.58 (1H, t, J=11.9 Hz), 2.32 (1H, m), 1.87 (1H, m), 1.65 (1H, m), 1.58-1.35 (3H, m), 1.30 (3H, t, J=6.0 Hz).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[Br:15][C:16]1[CH:17]=[C:18]2[CH2:27][CH2:26][N:25]3[C:19]2=[C:20]([CH:32]=1)[CH:21]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=13.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[Br:15][C:16]1[CH:17]=[C:18]2[CH:27]=[CH:26][N:25]3[C:19]2=[C:20]([CH:32]=1)[CH:21]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=13
Reactant: Brc1cc2c3c(c1)CCN3c1ccccc1N=C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Brc1cc2c3c(ccn3-c3ccccc3N=C2)c1

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 22 g) in toluene (200 ml) was added dropwise to a refluxing solution of 4-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (10 g) in toluene (750 ml) under nitrogen. The mixture was refluxed for 1 hour, cooled, stirred with triethylamine (3 g) for 10 minutes, and fed to a flash chromatography column (slurry packed with silica, 300 g in dichloromethane). The adsorbed material was eluted with dichloromethane (4 L); 1% methanol/dichloromethane (2 L); and 1% methanol/0.5% ammonium hydroxide/dichloromethane (2 L), whereby the desired product was separated from the remaining quinone. The crude product (10 g) was purified further on a second flash chromatography column (silica gel, 180 g; eluted with 20:80 hexane/dichloromethane, 6 L). The desired product was isolated as a solid (5.4 g). Recrystallization from ethanol (70 ml) at 0° C. gave 3.2 g of crystals which turned to powder after vacuum drying at 110° C., m.p. 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24].ClC1C(C)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1cccc(O)c1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O)c2)[C@@H](C)O)ccc(C#N)c1Cl

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (663 mg, 2.5 mmol) (intermediate 3a) and 3-hydroxy-benzohydrazide (376 mg, 2.5 mmol) were coupled similarly to the procedure used for intermediate 1b. After column chromatography (5% methanol/EtOAc) the title compound was isolated as a white solid (615 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.79 (br s, 1H), 8.81 (br s, 1H), 7.45 (ad, J=8.7 Hz, 1H), 7.38 (m, 2H), 7.27 (t, J=7.87 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.61 (m, 1H), 4.23 (m, 1H), 4.14 (m, 1H), 2.29 (s, 3H), 1.37 (d, J=6.5 Hz, 3H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OS(O)(=O)=O.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([CH3:42])([CH3:41])[C:28]([CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([O:33]CC)=O)=[O:29]>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:22]=1[C:27]([CH3:42])([CH3:41])[C:28](=[O:29])[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:31]2[OH:33]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cccc(Cl)c2C(C)(C)C1=O
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
P2O5 (19.0 g, 134 mmol) was treated with concentrated H2SO4 (17.1 mL, 308 mmol) at 0° C., and the resulting mixture was stirred for 30 minutes. Diethyl 2-(2-(2-chlorophenyl)-2-methylpropanoyl)malonate (1.500 g, 3.83 mmol) was added, and the mixture was stirred at 25° C. for 1 hour. The solution was quenched with ice, and, on melting, was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, and concentrated and dried in vacuo to give ethyl 8-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.320 g). MS m/e=295 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:15][CH2:16][CH2:17][O:18][CH3:19]>>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: COCCCBr
Product: COCCCn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 1-bromo-3-methoxypropane according to the procedure for the preparation of Example 35, part A. [M+H] Calc'd for C13H14N4O, 243. Found, 243.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:21][CH:22]=3)[N:17](COCC[Si](C)(C)C)[N:16]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F>ClCCl>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:21][CH:22]=3)[NH:17][N:16]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3)n2)c2cnc(NCCN3CCCCC3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCCCC5)ncc34)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of [3-(6-benzylamino-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine (133 mg, 0.24 mmol) in dichloromethane (2 mL) was added CF3CO2H (3 mL). This mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding saturated aqueous NaHCO3 to pH about 9, and then extracted with dichloromethane (3×20 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was washed with EtOAc (4 mL) and dried to give [3-(6-benzylamino-pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine as a white solid. (Yield 78 mg, 76%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:19]=[P:20](Cl)([Cl:22])[Cl:21]>C1(C)C=CC=CC=1>[P:20]([Cl:22])([Cl:21])([O:8][CH:6]1[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7]1)=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OP(=O)(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99 %

Procedure:
A solution of 7.5 g (48 mmol) of (1S, 2R, 5S)-(+)-menthol (Aldrich) and 4.86 g (48 mmol) of triethylamine in 20 ml of toluene was dropped into 7.36 g (48 mmol) of POCl3 at 0° C. The entire solution was stirred for 23 hours at room temperature. The insoluble triethylamine hydrochloride was filtered and the solvent was evaporated. Yield 99%, 31P NMR δ 6.76 (CDCl3). (lit. T. Milobedzki, W. Janczak, Roczniki Chemji 11, 840 (1931)).
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.Cl>[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reaction time: 2 h
Yield: 30.5 %

Procedure:
Cyclopentyl bromide (1.2 g, 8.1 mmol) was added to a solution of N-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.0 g, 6.76 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in acetonitrile (50 ml), followed by stirring for 2 hours under refluxing. After completion of the reaction, IN hydrochloric acid (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (5 ml) was added to the resulting pale yellow oily substance, and the precipitated N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (0.75 g, 2.06 mmol, 30.5% yield) was isolated by filtration. Spectral data and the like are as shown in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]([NH:53][NH2:54])(=[O:52])[CH2:42][NH:43][C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45]>>[C:44]([NH:43][CH2:42][C:41]([NH:53][NH:54][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:52])(=[O:45])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: NNC(=O)CNC(=O)c1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NNC(=O)CNC(=O)c1ccccc1
Yield: 18.9 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and hippuric acid hydrazide (42 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (24 mg). IR (KBr) 3274, 1652, 1616 cm−1; HRMS m/z 705.2640 (calc. of monoisotopic mass for C35H39N5O11 gives 705.2646).