Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-:10])=[O:9])[O:12][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: O=[N+]([O-])c1c(F)cc(O)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2cc(F)c([N+](=O)[O-])c(F)c2)nc1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To 3,5-difluoro-4-nitrophenol (7.44 g, 42.5 mmol), Cs2CO3 (27.7 g, 84.9 mmol), and 2-(chloromethyl)-5-methylpyridine hydrochloride (7.6 g, 42.5 mmol) was added DMF (281 mL) and the reaction was stirred at 75° Celsius for 18 hours. The reaction was allowed to cool to room temperature before being poured into sat. NaHCO3. The aqueous phase was extracted three times with EtOAc, and the combined organic layers were washed four times with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified via FCC to afford the title compound. MS (ESI): mass calcd. for C13H10F2N2O3, 280.1; m/z found, 281.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([F:25])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[C:11]([F:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:29]([Si:32](Cl)([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:24]([F:25])=[CH:23][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH:15]=2)=[C:11]([F:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Fc1cc(OCc2ccccc2)c(F)cc1Cc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(OCc3ccccc3)cc2F)c2cccnc21
Reaction time: 0.17 h

Procedure:
To 3-(4-Benzyloxy-2,5-difluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine (P-1901, 560.0 mg, 1.60 mmol, prepared as described in Example 18, Scheme 33) in tetrahydrofuran (28.0 mL) was added sodium hydride (100.0 mg, 60% in mineral oil, 2.50 mmol). After 10 minutes, triisopropylsilyl chloride (0.500 mL, 2.36 mmol) was added to the reaction. After 4 hours, the reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound (602, 0.70 g, 86.1%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=[N:38]C=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.N>ClCCl.O1CCOCC1>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:38])=[O:25])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3cccc(C(N)=O)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a stirred solution of (S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (76 mg, 0.195 mmol), HOBT (39 mg, 0.289 mmol), Et3N (39 mg, 0.786 mmol) and EDCI (55 mg, 0.289 mmol) in dichloromethane (20 mL) and dioxane (10 mL) was bubbled NH3 gas until saturation and the mixture stirred for 16 h at room temperature. The reaction mixture was filtered then the filtrate concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, MeOH:dichloromethane=1:50) to afford (S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (38 mg, 47%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.93 (s, 1H), 8.47 (s, 1H), 8.14 (d, 1H, J=8.1 Hz), 8.03-7.97 (m, 2H), 7.63-7.58 (m, 2H), 7.44 (t, 1H, J=8.1 Hz), 6.30 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.1 Hz), 4.32-4.22 (m, 1H), 3.69-3.61 (m, 1H), 3.48-3.42 (m, 1H), 2.17-2.01 (m, 3H), 1.68 (s, 1H), 1.17 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 414, tR=1.594 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=4.417 min.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][OH:8].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:4]([I:3])[CH:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(CO)cc1I
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(COCC(=O)OC(C)(C)C)cc1I
Yield: 143.6 %

Procedure:
The procedure used in Example 299: step a was followed using sodium hydride (53 mg, 2.2 mmol), 3-iodo-4-methyl-benzyl alcohol (992 mg, 4 mmol), tert-butyl bromoacetate (0.4 mL, 2.5 mmol) in DMF (10 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography yielded the title compound (1.30 g, 89%) as an oil. 1H-NMR (CDCl3): δ 7.84 (d, 1H, J=1.4 Hz), 7.27 (d, 1H, J=1.4 Hz), 7.23 (d, 1H, J=7.7 Hz), 4.55 (s, 2H), 3.99 (s, 2H), 2.44 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:29][CH3:30])(=[O:21])=[O:20])=[N:9][N:10]([C:12](=[O:18])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:11]=1.[CH3:31][S:32]SC.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[Cl:6][C:7]1[C:8]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:29][CH3:30])(=[O:21])=[O:20])=[N:9][N:10]([C:12](=[O:18])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:11]=1[S:32][CH3:31]
Reactant: CSSC
Reactant: CCc1cccc(C)c1S(=O)(=O)c1nn(C(=O)N(CC)CC)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cccc(C)c1S(=O)(=O)c1nn(C(=O)N(CC)CC)c(SC)c1Cl
Reaction time: 0.5 h
Yield: 35 %

Procedure:
0.11 ml of a 1.49M solution of butyllithium in hexane was added, at -78° C. and under an atmosphere of nitrogen, to a solution of 59 mg of 4-chloro-1-(diethylcarbamoyl)-3-(2-ethyl-6-methylphenylsulfonyl)pyrazole (prepared as described in Example 18) in 2 ml of dry tetrahydrofuran, and the resulting mixture was stirred for 30 minutes, after which 15 μl of methyl disulfide were added. The resulting reaction mixture was stirred for 30 minutes, and then mixed with an aqueous solution of ammonium chloride and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, eluted with a 10:1 by volume mixture of hexane and ethyl acetate, to afford 28 mg (yield 35%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)[C:2]#[CH:3].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C.C(OCC)(=O)C>[CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH:11]=[CH:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)[C:2]#[CH:3]
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: C#CC[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A mixture of 250 mg of 10-(2-propynyl)estr-4-ene-3,17-dione, and 460 mg of chloranil in 17 ml of tert-butyl alcohol is heated at reflux temperature for 3 hours. The mixture is diluted with ethyl acetate and filtered and the filtrate is washed with aqueous 1 N sodium hydroxide and with brine, and dried. The solvent is then evaporated and the residue is chromatographed on silica gel using ethyl acetate-hexane to give 10-(2-propynyl)estra-4,6-diene-3,17-dione. This compound has the following structural formula ##STR13##
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[NH:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1.[C:19](Cl)(Cl)=[O:20]>C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[N:4]1[C:5]2=[N:6][CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[C:10]2[NH:11][C:19]1=[O:20]
Reactant: Nc1cc([N+](=O)[O-])cnc1Nc1ccccc1F
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=c1[nH]c2cc([N+](=O)[O-])cnc2n1-c1ccccc1F
Reaction time: 2 h

Procedure:
The product from Step B (750 mg.) is dissolved in 150 ml. of benzene and treated with phosgene until reaction is complete. After standing 2 hours, the precipitate is collected and recrystallized from ethanol to give 1,3-dihydro-3-(2-fluorophenyl)-6-nitroimidazo[4,5-b]pyridin-2-one, m.p. 234°-236° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([NH:22][NH:23][C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])[C:15]=2[O:14]1>C(Cl)Cl>[CH3:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([N:22]=[N:23][C:24]([N:26]([O:28][CH3:29])[CH3:27])=[O:25])[C:15]=2[O:14]1
Reactant: CON(C)C(=O)NNc1cccc2c1OC(C)C2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CON(C)C(=O)N=Nc1cccc2c1OC(C)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4.4 g of MCPBA in 150 ml of methylene chloride was added drop-by-drop (over 15 minutes) to a stirred mixture of 5.4 g of 1E and 150 ml of methylene chloride, at 0° C. The mixture then was stirred at 0° C. for 15 minutes, washed with 10% aqueous sodium carbonate solution, then cold water, dried (MgSO4) and the solvent was evaporated, to give 1, as an orange oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34](O)=[O:35])[CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:30]5[CH2:31][CH2:32][CH2:33][O:28][CH2:29]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CCCOC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CCCOC1

Procedure:
The title compound, white solid (99 mg, 90%), MS (ISP) m/z=443.5 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-tetrahydro-pyran-3-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[CH:14][N:15](C)C)[C:11](=O)[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22]N>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH3:20])([CH3:19])[C:11]2[NH:22][N:15]=[CH:14][C:12]=2[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC(C)(C)C1=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.35 g, 22 mmol) in methanol (15 mL) was added hydrazine hydrate (1.2 mL, 1.1 equiv). The solution was stirred at room temperature overnight and concentrated to give 5.3 g (94%) which was used without purification. Mass spec.: 252.19 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]1[C:15]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:2].[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]1[C:15]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)=[O:33])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:2]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c(C)n(COCC[Si](C)(C)C)c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c9) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5]Br.[C:7]([O-:10])(=[O:9])[CH3:8].[Na+]>C(O)C>[C:7]([O:10][CH2:2][CH:3]=[CH:4][CH2:5][O:10][C:7](=[O:9])[CH3:8])(=[O:9])[CH3:8]
Reactant: CC(=O)[O-]
Reactant: BrCC=CCBr
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OCC=CCOC(C)=O
Reaction time: 1 h

Procedure:
After adding 1 g of 1,4-dibromo-2-butene (available from Sigma-Aldrich Co.) and 3 g of sodium acetate (available from Wako Pure Chemical Industries, Ltd.) into ethanol, reflux was conducted at 80° C. for 1 hour, to obtain 1,4-diacetoxy-2-butene. 1,4-diacetoxy-2-butene was dissolved in 30 ml of ethanol, and 20 ml of an aqueous sodium hydroxide solution (1 mol/l) was added, to synthesize 2-butene-1,4-diol.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:17][O:16][C:14]([CH:13]1[CH2:12][N:11]([S:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)(=[O:27])=[O:26])[CH2:10][CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CN(S(=O)(=O)c2cccc(Cl)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-1-Boc-2-piperazinecarboxylic acid methyl ester (CAS Reg. No: [129799-15-1]) (1 g) in DMF (5 mL) was added 3-chlorobenzenesulfonyl chloride (0.95 g) and triethylamine (1.71 mL). The reaction mixture was stirred at RT overnight. Water was added and the mixture was extracted with ethyl acetate (×2). The combined organic layers were washed with water (×2) and brine, were dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 3:1) yielded 4-(3-chloro-benzenesulfonyl)-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as white foam (1.66 g), MS: 436.3 ([M+NH4, 1Cl]+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
This compound was prepared by hydrolysis of 23a using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]([O:35]C)=[O:34])=[N:31][CH:32]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:39]=[CH:38][S:37][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[N:31][CH:32]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)O)nc4)C3)nc3scnc23)cc1OC
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of methyl 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)picolinate (130 mg, 0.24 mmol) in dioxane/H2O (8 mL/8 mL) was added NaOH (70 mg, 1.75 mmol), the reaction mixture was heated to 35° C. with stirring for 30 minutes, the dioxane was removed in vacuo, and the aqueous layer was adjusted to pH=4-5 with conc. HCl, the precipitate was collected by filtration and washed with methanol (5 mL) to afford 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)picolinic acid (98 mg, 76.2%) as an orange solid. 1H NMR (300 MHz, DMSO): δ 10.58 (s, 1H), 9.68 (s, 1H), 8.87 (s, 2H), 8.24 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.03 (d, 1H, J=8.7 Hz), 7.67 (d, 1H, J=2.1 Hz), 7.35 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 6.82 (brs, 1H), 4.84-4.65 (m, 2H), 3.77-3.65 (m, 6H), 3.18-3.00 (m, 2H), 2.67-2.64 (m, 1H), 2.05-1.75 (m, 4H). LC-MS: 536 [M+H]+, tR=1.50 min. HPLC: 97.47% at 214 nm, 97.48% at 254 nm, tR=4.096 min.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH3:38])[CH2:37][O:36][CH2:35]2)=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([CH:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4([CH3:38])[CH2:35][O:36][CH2:37]4)=[CH:32][CH:33]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC1(c2ccc(I)cc2)COC1
Product: CC(C)c1nc2c(c(I)c1C(O)c1ccc(C3(C)COC3)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 3-(4-iodophenyl)-3-methyloxetane.
Reaction SMILES: [S:1]1[CH2:5][CH:4]=[C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][OH:10])[CH2:2]1>C(O)C.[C].[Pd]>[S:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][OH:10])[CH2:2]1
Reactant: OCc1cccc(C2=CCSC2)c1
Agent: [Pd]
Solvent: CCO
Product: OCc1cccc(C2CCSC2)c1
Yield: 82.5 %

Procedure:
30 mg of the 3-(2,5-dihydro-3-thienyl)benzyl alcohol obtained in Referential Example 35 was dissolved in 25 ml of ethanol, and in the presence of 50 mg of 10% palladium-carbon, catalytically reduced for 8 hours under a hydrogen pressure of 3.5 kg/cm2. The catalyst was separated by filtration, and the solvent was evaporated under reduced pressure to give 25 mg (yield 82%) of the captioned compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][NH:33][CH2:32]3)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][NH:33][CH2:32]3)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc5c(c4)CNC=N5)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Nc1nc(O[C@H](c2ccc3c(c2)CNC=N3)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (a by-product from the N-CBZ deprotection of Example 55bk) using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([NH:17][C@H:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH3:19])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[N:27]([O-])=O.[Na+].O>C(O)(=O)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[N:11]=[C:12]([NH:17][C@H:18]([C:20]5[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=5)[CH3:19])[N:13]=[CH:14][C:15]=4[N:16]=[N:27]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=N[O-]
Reactant: C[C@H](Nc1ncc(N)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](Nc1ncc2nnn(-c3cc(C4CC4)[nH]n3)c2n1)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 41.2 %

Procedure:
To a solution of (S)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[1-(4-fluorophenyl)ethyl]pyrimidine-2,4,5-triamine (Method 8; 0.04 g, 0.1 mmol) in aqueous acetic acid (5%, 3 ml) was slowly added an aqueous NaNO2 solution (0.008 g, 0.1 mmol, 1 ml H2O). The reaction was allowed to stir for an additional 5 minutes, treated with water (10 ml), and extracted with DCM (3×25 ml). The combined organic layer was washed with saturated NaHCO3 solution (50 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=15:1) to give the title compound (0.015 g, 40%). NMR (400 MHz, CD3OD) 9.05 (s, 1H), 7.44-7.41 (m, 2H), 7.03-6.99 (m, 2H), 6.23 (s, 1H), 5.16-5.07 (m, 1H), 2.03-2.00 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.11-1.09 (m, 2H), 0.85-0.80 (m, 2H). MS: Calcd.: 364; Found: [M+H]+ 365.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34](O)=[O:35])=[CH:28]2>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:29]3[NH:30][C:31]4[C:27]([CH:28]=3)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=4)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cc4cc(F)ccc4[nH]3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 5-fluoro-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.91 min; [M+H]+=493.1.