Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:21][CH2:22][CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)=[O:3]>[Pd].CO>[CH2:25]([O:24][CH:23]([O:27][CH2:28][CH3:29])[CH2:22][CH2:21][N:4]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[C:2]([NH2:1])=[O:3])[CH3:26]
Reactant: CCOC(CCN(C(N)=O)C1CCN(C(=O)OCc2ccccc2)CC1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(CCN(C(N)=O)C1CCNCC1)OCC

Procedure:
A solution of benzyl 4-oxopiperidin-1-carboxylate (11.2 g), 3,3-diethoxypropane-1-amine (7.0 g), acetic acid (3 mL) and sodium triacetoxyborohydride (12.7 g) in dichloroethane (300 mL) was stirred at room temperature overnight. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution of the resulting residue and potassium isocyanate (3.4 g) in a mixture of methanol/acetic acid (190 mL/10 mL) was refluxed for 3 hours. Potassium isocyanate (3.4 g) was further added thereto and the mixture was refluxed for additional 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and an aqueous saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (from ethyl acetate/hexane=4/1 to ethyl acetate) to obtain benzyl 4-[(aminocarbonyl)(3,3-diethoxypropyl)amino]piperidin-1-carboxylate (12.1 g, 62%) as a white powder. A solution of the resulting benzyl 4-[(aminocarbonyl)(3,3-diethoxypropyl)amino]piperidin-1-carboxylate (12.1 g) and 20% palladium on carbon (containing 50% water, 0.24 g) in methanol (300 mL) was stirred at room temperature overnight under a hydrogen atmosphere, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound as a white powder.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[NH2:13][C:11]([C@H:10]([NH:9][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCBr
Reactant: CC[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCN[C@H](CC)C(N)=O
Temperature: 80 °C

Procedure:
143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (R)-2-amino-butanamide hydrochloride ([alpha]D25 : -26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° C. and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH3:16])=[N:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[C:17]([OH:21])(=O)[CH2:18]O>>[OH:21][CH2:17][C:18]1[N:15]([CH3:16])[C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:4]=2
Reactant: O=C(O)CO
Reactant: CNc1nc(Sc2ccccc2)ccc1N
Product: Cn1c(CO)nc2ccc(Sc3ccccc3)nc21
Yield: 58.6 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 2.62 g of 3-amino-2-methylamino-6-phenylthiopyridine (prepared as described in Preparation 89) and 2.58 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 50:1 to 10:1 by volume as the eluent, to give 1.80 g of the title compound, melting at 119°-120° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]([CH3:40])[C:32]1=[O:41]>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]([CH3:40])[C:32]1=[O:41]
Reactant: Cn1c(=O)n(CCC(C)(C)N)c2ccccc21
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Product: Cn1c(=O)n(CCC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c2ccccc21

Procedure:
Prepared according to General Method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-3-methyl-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][O:13][N:35]1[C:39](=[O:40])[C:38]2[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NCCO)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Benzyl(2-hydroxyethyl)carbamate (5.857 g, 30.0 mmol) was stirred under an argon atmosphere at room temperature with dehydrated tetrahydrofuran (150 mL). Then, triphenylphosphine (7.90 g) and N-hydroxyphthalimide (Pht-OH, 4.89 g) were added. After the reaction mixture was under ice cooling, 2.2M diethyl azodicarboxylate toluene solution (13.7 mL) was added dropwise gradually, followed by stirring overnight at room temperature. After completion of the reaction, the residue resulting from distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=1/1) to afford 9.36 g of the title compound (yield 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C2CO2)C1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H]([C@H]2CO2)C1
Reaction time: 6 h

Procedure:
(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (30 g, 140.6 mmol, 1.0 eq.) was combined with (S,S)-Salen Co(II) (418 mg, 0.7 mmol). Water (⅓ mL) was added and the resulting mixture was stirred vigorously for 6 hours. Hexanes (200 mL) was added. The resulting solids were crushed and stirred in hexanes to yield a yellow precipitate. The precipitate was purified by column chromatography (200-300 mesh, hexanes:EtOAc=1:3, 3 L) to yield (R)—(S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(-c2ccc(C(F)(F)F)nc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2ccc(C(F)(F)F)nc2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 116) was reacted with pyridine-3-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 485.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH2:23])=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O>[NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:37]([C:36]2[CH:35]=[CH:34][C:33]([CH2:32][NH:31][C:29](=[O:30])[O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:41][CH:40]=2)=[O:38])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carbohydrazide (100 mg, 0.2833 mmol) and 4-[(tert-butoxycarbonylamino)methyl]benzoic acid (71.19 mg, 0.2833 mmol) in dmf (1.000 mL) was treated with triethylamine (28.67 mg, 39.49 μL, 0.2833 mmol) followed by TBTU (109.2 mg, 0.3400 mmol) and the resulting solution stirred at room temperature overnight. The solution was poured dropwise onto rapidly stirred water (15 ml), stirred at room temperature for 1 h and then filtered to give the product as a pale yellow solid which was dried under high vacuum at 83° C. and then used directly in the next step without further purification (136 mg, 84%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH3:34])=[C:16]([CH:22]4[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[ClH:35].O1CCOCC1>C(Cl)Cl>[ClH:20].[ClH:35].[NH:24]1[CH2:23][CH:22]([C:16]2[C:15]([O:33][CH3:34])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[CH3:21])[CH2:25]1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate (318 mg, 0.653 mmol) (peak 1 from above) in methylene chloride (3.2 mL) was added 4.0 M hydrogen chloride in 1,4-dioxane (1.6 mL, 6.5 mmol). The resulting mixture was stirred at room temperature for 75 minutes. The solvents were evaporated and the residue dried in vacuo to give 0.30 g of the desired product as the bis-HCl salt. LCMS calculated for C19H24ClN6O (M+H)+: m/z=387.2; Found: 387.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[C:9]2=[O:18])=[CH:5][CH:4]=1.[CH2:21]=O.C[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[NH2:15][C:10]1[C:9](=[O:18])[N:8]([CH2:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:21]
Reactant: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Reactant: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1ccn(Cc2ccc(OC)cc2)c(=O)c1N
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (1.38 g, 5.0 mmol) and paraformaldehyde (0.152 g) in dimethylsulfoxide (8 mL) was added sodium methoxide (0.018 g). After 2 hours, the mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was dried, filtered and evaporated. The residual solid was triturated with chloroform/ethyl acetate (10 mL, 1/1) and 1-(4-methoxybenzyl)-4-hydroxyethyl-3-nitro-2-pyridone was collected by filtration (0.496 g). Fractionation of the supernatant over silica gel (chloroform/ethyl acetate to ethyl acetate/methanol 99/1) gave additional product (0.404 g) (total yield, 2.96 mmol, 59%).
Reaction SMILES: OC1C=C([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)C=C(S(C)(=O)=O)C=1OCCC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:32][O:31][C:23]1[CH:22]=[C:21]([CH:18]2[O:17][CH2:16][CH2:20][CH2:19]2)[CH:26]=[C:25]([O:27][CH3:28])[C:24]=1[O:29][CH3:30]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C2CCCO2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans-2-(3-hydroxy-5-methylsulfonyl-4-propyloxyphenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (242), 130 mg, 0.28 mmol) was dissolved in dry DMF (1.5 mL) and K2CO3 (58 Mg, 0.42 mmol) was added to it. Stirred, at room temperature under argon, for 30 min and a solution of 241, made above, in 1.0 mL of dry DMF was added. The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with methylene chloride (25 mL) and washed with water (25 mL). The water layer was extracted once with 25 mL of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and concentrated in vacuo to obtain trans-2-13-methylsulfonyl-5-(4-phthalimido-but-2-ynyloxy)-4-propyloxyphenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran, 244, which was used without further purification. 1H-NMR (CDCl3) (5 7.85 (2H, dd, J=5.3, 3.2 Hz), 7.73 (2H, dd, J=5.3, 3.2 Hz), 7.55 (1 H, d, J=2.0 Hz), 7.32 (1 H, d, J=2.0 Hz), 6.62 (2H, s), 5.16-5.21 (2H, m), 4.77 (2H, s), 4.49 (2H, s), 4.11 (2H, t, J=6.8 Hz), 3.89 (6H, s), 3.84 (3H, s), 3.24 (3H, s), 2.41-2.46 (2H, m), 1.80-2.01 4H, m), 1.04 (3H, t, J=6.8 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[N:18]=[C:19]([CH2:34][CH3:35])[C:20]([NH:25][C@H:26]2[C@@H:30]([O:31][CH2:32][CH3:33])[CH2:29][NH:28][CH2:27]2)=[N:21][C:22]=1[CH2:23][CH3:24]>>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[N:18]=[C:19]([CH2:34][CH3:35])[C:20]([NH:25][C@H:26]2[C@@H:30]([O:31][CH2:32][CH3:33])[CH2:29][N:28]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:27]2)=[N:21][C:22]=1[CH2:23][CH3:24]
Reactant: Brc1cccnc1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2cccnc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrzin-2-amine but substituting 3-bromopyridine and starting with 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.17, 1.26–1.33, 2.51, 2.73, 3.39, 3.57, 3.76, 3.78, 3.86, 3.93, 4.31, 4.91, 5.26, 6.89, 7.04, 7.25, 8.00; IR (diffuse reflectance) 2970, 2430 (w), 2054 (w), 1914 (w), 1603, 1584, 1566 (s), 1481 (s), 1434, 1396, 1372, 1287, 1228, 1122, 1044 cm−1 HRMS (ESI) calcd for C26H32N5O2Cl+H1 482.2322. found 482.2311.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[O:7][N:6]=[C:5]([NH:8]C(=O)C2C=CC=CC=2C(OC)=O)[CH:4]=1.O.NN.O>CO>[F:1][C:2]([F:22])([F:21])[C:3]1[O:7][N:6]=[C:5]([NH2:8])[CH:4]=1
Reactant: COC(=O)c1ccccc1C(=O)Nc1cc(C(F)(F)F)on1
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
In methanol (15 ml) was dissolved 5-trifluoromethyl-3-(2-(methoxycarbonyl)benzoyl)aminoisoxazole (1.57 g, 0.0050 mole) and 90% hydrazine hydrate (0.42 g, 0.0075 mole) was added to the solution. It was allowed to stand to room temperature for 46 hours. Water (30 ml) was added to it and the mixture was stirred at room temperature for 15 minutes. Crystals were filtered off. The filtered off crystals were washed repeatedly with methylene chloride (45 ml) and the filtrate was extracted with these washings. The filtrate was further extracted with methylene chloride (45 ml×2) and the solvent was distilled off from the combined extract at atmospheric pressure by using a distillation apparatus equipped with a fractionating column packed with glass raschig rings (15 mm in diameter, 200 mm in length). The residue was purified by column chromatography on silica gel to give the title compound. Yield: 0.714 g (93.9%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:51])[NH:10][CH:11]([C:25](=[O:50])[NH:26][CH:27]([C:36](=[O:49])[N:37]([CH2:41][CH:42](OCC)OCC)[CH:38]([CH3:40])[CH3:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([O:8][C:9](=[O:51])[NH:10][CH:11]1[C:25](=[O:50])[N:26]2[CH:27]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[C:36](=[O:49])[N:37]([CH:38]([CH3:40])[CH3:39])[CH2:41][CH:42]2[N:13]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])(=[O:16])=[O:15])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1)C(C)C)OCC
Solvent: O=CO
Product: CC(C)N1CC2N(C(=O)C(NC(=O)OCc3ccccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Yield: 92.9 %

Procedure:
A solution of 2.74 g (3.49 mmol) of benzyl[1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)-isopropylcarbamoyl]ethylcarbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]-carbamate in 45 ml of formic acid was heated at 60° C. for 6 h. The reaction mixture was then concentrated in vacuo, and the residue was purified by chromatography on 40 g of SiO2 (eluent DCM followed by 20% EtOAc/DCM). 2.25 g of the cyclized compound are obtained as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].[O:46]1[CH:50]=[CH:49][CH:48]=[C:47]1[C:51](Cl)=[O:52]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:51]([C:47]2[O:46][CH:50]=[CH:49][CH:48]=2)=[O:52])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Cl)c1ccco1
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccco1
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (162 mg, 0.26 mmol), 4-dimethylaminopyridine (63 mg, 0.52 mmol), and 2-furoyl chloride (62 mg, 0.47 mmol) in 6.0 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[C:33]2[CH:40]=[N:39][N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[CH3:48])[C:34]=2[N:35]=[CH:36][N:37]=1)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Sodium hydride (60% in mineral oil) (0.191 g, 4.77 mmol) was added in one portion to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1.6 g, 3.97 mmol) in THF (15 mL) cooled to 0° C. under nitrogen. Slow gas evolution. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AE5) (1.109 g, 3.97 mmol) in THF (10 mL) was added dropwise over 2 minutes. The resulting suspension was stirred at 0° C. for 10 minutes, allowed to warm to ambient temperature and stirred for 72 hours to give an orange solution. Cooled to ˜5° C., 1M citric acid (30 mL) added, the mixture stirred for 10 minutes, diluted with EtOAc (50 mL), the organic phase separated and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (2.1 g, 82%). 1H NMR (400 MHz, DMSO) δ 0.95 (9H, s), 2.03 (3H, s), 3.68 (3H, s), 3.67-3.74 (2H, m), 3.78-3.82 (2H, m), 4.04-4.07 (1H, m), 5.87-5.91 (1H, m), 7.37-7.45 (8H, m), 7.61-7.65 (4H, m), 7.67-7.69 (1H, m), 8.48 (1H, s), 8.57 (1H, s); m/z (ESI+) (M+H)+=645; HPLC tR=3.65 min.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:21]([C:22](=O)[C:23]#[CH:24])=[C:15]2[CH:14]=1.C(OCC)(=O)C>C(O)C>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:20]2[C:21]([C:22]3[CH:23]=[CH:24][N:4]=[C:3]([S:2][CH3:1])[N:5]=3)=[C:15]3[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][N:16]3[N:19]=2)=[CH:31][CH:30]=1
Reactant: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
The suspension of 2-methyl-2-thiopseudourea (358 mg, 1.29 mmol) and potassium carbonate (178 mg, 1.29 mmol) in ethanol was stirred at room temperature for 10 minutes. 1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (200 mg, 0.64 mmol) was added. The suspension was stirred at room temperature for 12 hours. Ethyl acetate was added. The ethyl acetate phase was washed with water and brine and dried over magnesium sulfate. Filtration and concentration, followed by chrornatography (3:2 hexanes/ethyl acetate), gave 4-{5-chloro-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl methyl ether (77 mg, 31%) as a white solid. 1H NMR (CDCl3) δ 8.49 (d, 1H), 8.37 (d, 1H), 8.20 (d, 1H), 7.48 (d, 2H), 6.98 (d, 2H), 6.85 (dd, 1H), 6.70 (d, 1H), 3.85 (s, 3H), 2.62 (s, 3H). MS m/z 383 (M+1).