Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21](=[O:23])[C:20]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:19]=2)=[CH:14][CH:13]=1>CN1CCOCC1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:19][C:20]2([C:21]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:23])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Reactant: CSCC[C@H](N)C(=O)O
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)NC2(C(=O)N[C@@H](CCSC)C(=O)O)CCCCC2)cc1
Yield: 12.7 %

Procedure:
10 ml of N-methylmorpholine was added to 298 mg (2 mmol) of L-methionine and 259 mg (1 mmol) of 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium hydrogensulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 52 mg (13%) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:12]3[S:16][C:15](=[S:17])[NH:14][C:13]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.IC.[CH:21](N(C(C)C)CC)(C)C.O>C(O)C>[CH3:21][S:17][C:15]1[S:16][C:12](=[CH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][N:3]=[CH:4]3)[C:13](=[O:18])[N:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1NC(=S)SC1=Cc1ccc2ncncc2c1
Solvent: CI
Solvent: CCO
Solvent: O
Product: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
The suspension of 5-quinazolin-6-ylmethylene-2-thioxo-thiazolidin-4-one (example 1b, 2.6 g, 9.52 mmol), iodomethane (1.2 mL, 19.0 mmol) and diisopropylethylamine (DIEA) (2.4 mL, 14.3 mmol) in anhydrous ethanol (100 mL) was stirred at room temperature for 12 h. After adding water (200 mL), the solid was collected by filtration, washed with water and dried to obtain 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one (2.5 g, 92%) as a black solid. LC-MS m/e 288 (MH+).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:15])=[CH:8][CH:7]=1.CO.[B-][N+](C)(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]3)[C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: O=C1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [B-][N+](C)(C)C
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Reaction time: 8 h

Procedure:
6′-(3-Fluoropropoxy)spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 63, 3.14 g, 10.8 mmol) were dissolved in tetrahydrofuran (50 mL) and MeOH (4.38 mL, 108 mmol). Borane-trimethylamine complex (1.74 g, 23.8 mmol) was added and the resulting mixture was stirred overnight. Citric acid monohydrate (31.8 g, 151 mmol) was added all at once and was followed by dropwise addition of water (3.90 mL, 216 mmol). The mixture was stirred for 3 h before being diluted with water and extracted with EtOAc (×2). The combined organic phases was dried over MgSO4 and concentrated in vacuo. The product was purified using silica gel flash chromatography using a gradient of MeOH (0-10%) in DCM to give 1.94 (61% yield) of the title compound which was used in the next step without further purification: MS (ES+) m/z 307 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C@@H:13]([NH:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([C@H:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:31][CH2:32][CH2:33][NH:34][C:35](=[O:38])[O:36][CH3:37])[CH2:25]1)=[O:23])[CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)C(OCC[Si](C)(C)C)=O.CCN(CC)CC.C(O)=O>CC#N>[CH3:1][NH:2][CH2:12][C@@H:13]([NH:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([C@H:30]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:31][CH2:32][CH2:33][NH:34][C:35](=[O:38])[O:36][CH3:37])[CH2:25]1)=[O:23])[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: COC(=O)NCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCOCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CNC[C@H](CC1CCOCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2ccccc2)C1
Yield: 42.4 %

Procedure:
In a round bottom flask methyl 2-((R)—((R)-1-((S)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate (20 mg, 0.03 mmol) and TEAF (15 mg, 0.07 mmol) was dissolved in a 15 mL of in MeCN. The solution was allowed to stir at reflux for 1 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give methyl 2-((R)—((R)-1-((S)-1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate (6.24 mg, 42%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].[CH2:15]=O>CO>[CH2:6]([N:10]([CH2:15][N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]
Reactant: C=O
Reactant: CCCCNCCCC
Reactant: c1c[nH]nn1
Solvent: CO
Product: CCCCN(CCCC)Cn1ccnn1
Yield: 97 %

Procedure:
7 parts of triazole and 12.9 parts of di-n-butylamine and 8.1 parts of 37% aqueous formaldehyde mixed with 100 parts of methanol, are reacted as in Example 1 to provide 20.4 parts (97% yield) 1-di-n-butylaminomethyltriazole. Boiling point 105° C./0.075 m bar.
Reaction SMILES: C(O[C:4](=[O:31])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:23][C:20]3([CH2:22][CH2:21]3)[N:19](CC3C=CC=CC=3)[CH2:18][CH2:17]2)[CH:7]=1)C.C(N1CCN(C2[CH:48]=[C:49]([CH2:57][C:58]([NH2:60])=[O:59])[C:50]3[C:55](C=2)=[CH:54][CH:53]=[CH:52][CH:51]=3)CC21CC2)C1C=CC=CC=1.[CH:61]([NH2:63])=O.C[O-].[Na+]>CN(C=O)C.CO>[CH2:21]1[C:20]2([CH2:23][N:16]([C:8]3[CH:7]=[C:6]([C:5]4[C:4](=[O:31])[NH:60][C:58](=[O:59])[C:57]=4[C:49]4[C:50]5[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=5)[N:63]([CH3:61])[CH:48]=4)[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:17][CH2:18][NH:19]2)[CH2:22]1
Reactant: CCOC(=O)Cc1cc(N2CCN(Cc3ccccc3)C3(CC3)C2)cc2ccccc12
Reactant: NC(=O)Cc1cc(N2CCN(Cc3ccccc3)C3(CC3)C2)cc2ccccc12
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cc(C2=C(c3cc(N4CCNC5(CC5)C4)cc4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
2-[3-(4-Benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-naphthalen-1-yl]-acetamide [3-(4-Benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-naphthalen-1-yl]-acetic acid ethyl ester (347 mg, 0.84 mmol) and formamide (126 mg, 2.80 mmol) are dissolved under an atmosphere of argon in DMF (1 ml). The solution is heated to 105° C., and NaOMe (155 μL of a 5.4 M solution in MeOH, 45 mg, 0.84 mmol) is added dropwise during 15 minutes. After 30 minutes at 105° C., TLC analysis indicates complete consumption of starting material. The reaction mixture is cooled to RT, diluted with water, and extracted with EtOAc. The EtOAc layers are washed twice with water. Removal of solvent and purification by FCC (EtOAc/MeOH 98:2 to 96:4 to 90:10) yielded the title compound. 1H NMR (CDCl3, 400 MHz) δ 0.7-1 (ddd, 2H), 0.89 (ddd, 2H), 3.10 (ddd, 2H), 3.16 (s, 2H), 3.31 (ddd, 2H), 3.93 (s, 2H), 3.99 (s, 2H), 5.33 (br, 1H), 5.42 (br, 1H), 7.11 (s, 1H), 7.23 (d, J=2.0, 1H), 7.32 (m, 5H), 7.37 (dd, J=6.7 Hz, 1H), 7.45 (dd, J=6.7 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H); ES-MS: 386 [M+H]+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:21]1([C:27]2[NH:31][N:30]=[C:29]([C:32]([OH:34])=O)[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:32]([C:29]1[CH:28]=[C:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:31][N:30]=1)=[O:34]
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
HOBt (45 mg, 0.33 mmol) and DIPEA (137.5 mg, 1.06 mmol) were added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid hydrochloride (50 mg, 0.22 mmol) in DMF (1.0 mL). The reaction mass was cooled to 10° C. and EDCI.HCl (64 mg, 0.33 mmol) was added, followed by the addition of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (as TFA salt) (125 mg, 0.29 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and the resulting precipitate was filtered and dried in vacuo to afford 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide as a solid product in 62% yield, LC-MS purity: 99.127%, 1H NMR (DMSO): δ 13.6 (s, 1H), 8.1 (s, 1H), 7.7 (m, 5H), 7.4 (m, 4H), 7.1 (s, 1H), 4.1 (m, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[H-].[Na+].[H][H].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>O1CCCC1>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:7][CH:3]([CH2:4][CH:5]=[CH2:6])[CH:2]=[CH2:1]
Reactant: BrCCCCCCCCCCBr
Reactant: [H][H]
Reactant: C=CCC(O)C=C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C=C)OCCCCCCCCCCBr
Reaction time: 8 h
Yield: 35 %

Procedure:
10 g of 1,5-hexadien-3-ol was dissolved in 100 ml of tetrahydrofuran (THF), and the atmosphere was replaced with argon. 4.1 g of 60% sodium hydride was added little by little. After hydrogen gas had ceased to generate, a THF solution of 75 g of 1,10-dibromodecane was added, and reflux was carried out for 8 hours. The insoluble matter generated was filtered off, and the solvent was evaporated. The residue was purified by column chromatography, to obtain 11.3 g of the objective compound (1). (Yield: 35%).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]2[N:9]([CH2:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)[N:10]=[N:11][C:6]2=[N:5][CH:4]=1)=C.CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=[O:32].[Na+]>O.O1CCOCC1.[Os](=O)(=O)(=O)=O>[N:19]1[C:20]2[C:15](=[CH:14][C:13]([CH2:12][N:9]3[C:7]4=[N:8][C:3]([CH:1]=[O:32])=[CH:4][N:5]=[C:6]4[N:11]=[N:10]3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 2233.8 %

Procedure:
To a mixture of 6-((6-vinyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (100 mg, 0.347 mmol) and 2,6-dimethylpyridine (74.3 mg, 0.694 mmol) was added a solution of osmium(VIII) oxide (297 mg, 1.387 mmol) in water (1.333 mL), followed by addition of a solution of sodium periodate (88 mg, 6.94 μmol) in 1,4-dioxane (4 mL). The reaction mixture was stirred at rt for 10 h. The solvent was removed in vacuo and DCM was added to dilute the residue. The resulting solution was washed with saturated NaHCO3 solution, NH4Cl and brine. The organic layer was separated, dried over Na2SO4, and concentrated to give the crude product which was purified with Analogix system on silica gel (hexanes:EtOAc) to afford 45 mg (43%) of the title compound. LCMS (method B): [MH]+=291, tR=1.00 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(2-hydroxyethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH. A second crop was obtained by filtration from the filtrate, dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.90 (s, 3 H), 3.19-3.30 (m, 2 H), 3.46-3.61 (m, 8 H), 4.14 (s, 2 H), 4.34 (t, J=6.53 Hz, 2 H), 4.60-4.64 (m, 1 H), 7.09-7.16 (m, 2 H), 7.23-7.29 (m, 1 H), 7.37-7.44 (m, 2 H), 8.11 (d, J=0.84 Hz, 1 H), 8.55 (d, J=1.54 Hz, 1 H), 10.35 (t, J=5.48 Hz, 1 H), 17.12 (s, 1 H); ES+ MS: 523 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:37])[C:24]([S:26]SC4C=CC=CC=4[N+]([O-])=O)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[BH4-].[Na+]>CCO.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:37])[C:24]([SH:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SSc4ccccc4[N+](=O)[O-])c(Cl)cc3n2COCCOC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(-c2nc3cc(S)c(Cl)cc3n2COCCOC)c1
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a stirred cooled (0° C.) solution of 1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-(2-nitro-phenyldisulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (2.99 g, 5.29 mmol) and EtOH (24 mL) was added dropwise a solution of NaBH4 (0.729 g, 19.3 mmol), EtOH (24 mL), and water (10 mL) over 10 minutes. The reaction mixture was stirred for 15 min and additional NaBH4 (0.486 g, 12.8 mmol) in EtOH (16 mL) and water (6.7 mL) was added. The reaction mixture was stirred for an additional 30 min and then partitioned between DCM (200 mL) and water (200 mL). The aqueous layer was acidified to pH 5 with 1M HCl and the product was extracted with DCM (3×300 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-80% EtOAc/hexanes) to yield the titled compound (1.27 g, 48%) as a 2:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C17H19ClN4O4S, 410.1; m/z found, 411.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.85-8.84 (m, 2H), 8.17 (s, 2H), 7.75 (s, 0.67H), 7.72 (s, 1.33H), 7.68 (s, 1.33H), 7.64 (s, 0.67H), 6.10-6.09 (m, 4H), 4.36 (q, J=7.1 Hz, 4H), 4.02 (s, 0.67H), 3.93 (s, 1.33H), 3.66-3.62 (m, 4H), 3.47-3.44 (m, 4H), 3.31-3.30 (m, 6H), 1.38 (t, J=7.1 Hz, 6H). Large-scale synthesis of the titled compound also provided a dimer by-product, where the dimer linkage is thru the sulfur bond forming a disulfide intermediate of 1-[6-chloro-5-mercapto-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester, this by-product was isolated but not tested: MS (ESI/CI): mass calcd. for C34H36Cl2N8O8S2, 818.1; m/z found, 819.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]([C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1)[NH2:6])C.[OH-].[Na+].Cl.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO.C(N(CC)CC)C.O>[C:17]([O:21][C:22]([NH:6][CH:5]([C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1)[C:4]([OH:3])=[O:13])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CCOC(=O)C(N)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 2-(2-aminothiazol-4-yl)glycine ethyl ester (24.2 g) and 2N aqueous solution of sodium hydroxide (7.2 g) in methanol (240 ml) was stirred at ambient temperature for an hour. After adjusting to pH 7 with conc. hydrochloric acid, water (250 ml), and then 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (29.5 g) and triethylamine (18.2 g) were added thereto. After stirring at ambient temperature for an hour, the reaction mixture was evaporated. The resultant aqueous solution was washed twice with ethyl acetate, followed by adding ethyl acetate and adjusting to pH 7 with 10% hydrochloric acid. After removal of the insoluble substance by filtration, the aqueous layer was separated out, adjusted to pH 4 with 10% hydrochloric acid and treated with activated charcoal. To the filtrate was added sodium chloride, followed by stirring under ice-cooling. The precipitated solid was collected by filtration and dried to give N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycine (10.2 g).
Reaction SMILES: [C:1]([N:5]1[CH2:37][CH2:36][CH2:35][CH2:34][C:8]2[C:9]([C:28]3[CH2:29][CH2:30]O[CH2:32][CH:33]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:38])([CH3:4])([CH3:3])[CH3:2].C(N1CCCCC2C(Br)=C3C4C=C(C5C=NC=CC=5)C(OC)=CC=4CCN3C=2C1=O)(C)(C)C.[S:72]1CC=C(B2OC(C)(C)C(C)(C)O2)CC1>>[C:1]([N:5]1[CH2:37][CH2:36][CH2:35][CH2:34][C:8]2[C:9]([C:28]3[CH2:29][CH2:30][S:72][CH2:32][CH:33]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(C3=CCOCC3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Agent: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Product: COc1cc2c(cc1-c1cccnc1)-c1c(C3=CCSCC3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3

Procedure:
Compound 25d was synthesized in a similar way as 25c, starting from 40 mg 25b and 21.4 mg 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane to give 1.4 mg of compound 25d.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:41]=[CH:40][CH:39]=[CH:38][C:13]=1[C:14]([NH:16][CH2:17][C:18]1[C:19]([NH:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:20]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]2=[N:22][C:23]=1[CH2:24][CH3:25])=[O:15])=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]3[CH:38]=[CH:39][CH:40]=[CH:41][C:12]=3[NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])[C:19]([NH:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CNCCO
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)CCCCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)CCCCCCCN(C)CCO
Temperature: 60 °C

Procedure:
A solution of 2-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (68 mg, 0.11 mmol, e.g. which can be as prepared in Intermediate 46) in N,N-dimethylformamide (5 ml) was treated with 2-(methylamino)ethanol (0.0175 ml, 0.22 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.038 ml, 0.22 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (5 mg). LCMS showed MH+=622; TRET=2.15 min.
Reaction SMILES: [Na].[C:2]([C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[CH:14][N:15]=2)[CH:12]=1)(OCC)=O.[CH:16]1([N:21]2[C:25]([NH2:26])=[C:24]([C:27]([NH2:29])=[O:28])[C:23]([CH2:30][CH3:31])=[N:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH:16]1([N:21]2[C:25]3=[N:26][C:2]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([CH:13]=[CH:14][N:15]=5)[CH:12]=4)=[N:29][C:27](=[O:28])[C:24]3=[C:23]([CH2:30][CH3:31])[NH:22]2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)c1ccc2nccn2c1
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4nccn4c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 60 h
Yield: 61.1 %

Procedure:
Sodium metal (0.21 g, 9.2 mmol) was dissolved in ethanol (25 ml) and 6-carboethoxyimidazo[1,2-a]pyridine (1.75 g, 9.2 mmol) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.02 g, 4.6 mmol) were added. The reaction mixture was heated to reflux for 24 hours, cooled to room temperature and stirred for 60 hours. The solvent was removed in vacuo, the residue was dissolved in water (100 ml) and the solution was neutralized by the addition of concentrated HCl. A precipitate was obtained which was collected by filtration through a glass frit. The solid was recrystallized from ethanol and washed with ether to afford 0.98 g (62%) of 1-cyclopentyl-3-ethyl-6-(6-imidazo[1,2-a]-pyridinyl)-pyrazolo[3,4-d]pyrimidin-4-one as white crystals, m.p. >300° C. when dried for 18 hours at 120° C. in high vacuum.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[C@H:14]([C:15]([F:18])([F:17])[F:16])[CH2:13][N:12]([C:19]2[C:28]([F:29])=[C:27]3[C:22]([C:23](=[O:36])[C:24]([C:33]([OH:35])=[O:34])=[CH:25][N:26]3[CH:30]3[CH2:32][CH2:31]3)=[CH:21][C:20]=2[F:37])[CH2:11]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].C(OCC)C>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:8][CH2:9][C@H:10]1[C@H:14]([C:15]([F:17])([F:18])[F:16])[CH2:13][N:12]([C:19]2[C:28]([F:29])=[C:27]3[C:22]([C:23](=[O:36])[C:24]([C:33]([OH:35])=[O:34])=[CH:25][N:26]3[CH:30]3[CH2:31][CH2:32]3)=[CH:21][C:20]=2[F:37])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NC[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In 2 ml of dichloromethane, is suspended 330 mg (0.606 mmol) of 7-(trans-3-(tertbutoxycarbonylaminomethyl)-4-trifluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid obtained in Example 10a. To the suspension, is added 2 ml of trifluoroacetic acid on cooling with ice. The mixture is stirred at 0° C. for 1 hour. Diethyl ether was added to the reaction mixture to give a precipitate. The resulting precipitate was obtained by filtration to give 340 mg of the objective substance as a colorless powder (yield 100%).