Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])=[C:12]([F:26])[CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]([CH3:28])[C:15]3=[O:25])=[C:12]([F:26])[CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
A stirred solution of 0.85 gram (2.1 mmole) of 3-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, 0.48 gram (3.5 mmole) of potassium carbonate, 0.91 gram (6.4 mmole) of iodomethane, and 35 mL of acetone was heated at 40° C. for 2 hours, then stirred at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was extracted with two 50 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a yellow oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 8:1 hexane:ethyl acetate. The product-containing fractions were combined and concentrated under reduce pressure, yielding 0.60 gram of 3-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 68°-70° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.[H][H]>[Pt]>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to isopropyl acetate (1 ml). 10% Platinum on carbon (10 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). Spectroscopic data as in Example 42, Method 1.
Reaction SMILES: OC1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[O:12]1[CH2:16][CH2:15][O:14][C:13]1=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:12][CH2:16][CH2:15][O:14][C:13]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=C1OCCO1
Reactant: COc1cc(O)cc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OCCO)c1
Temperature: 110 °C

Procedure:
3-Hydroxy-5-methoxy-benzaldehyde (12.0 g, 78.9 mmol) and [1,3]dioxolan-2-one (13.9 g, 157.0 mmol) in anhydrous DMF (50 mL) was added potassium carbonate (21.6 g, 157.0 mmol). The mixture was then heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature. Solid potassium carbonate was filtered and washed with ethyl acetate. The organic phase was collected and solvent was removed. The residue was purified by column chromatography (silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate 7:1), to give 3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde as a brown liquid. Yield: 10.0 g (65%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][N:9]=[C:10]2[CH2:17][CH:16]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I.O>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[N:9]=[C:10]2[CH2:17][CH:16]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CC(=NNc1cccc(Br)n1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(N=C1CC2CCCC(C1)N2C(=O)OC(C)(C)C)c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 103.8 %

Procedure:
tert-Butyl 3-(2-(6-bromopyridin-2-yl)hydrazono)-9-azabicyclo[3.3.1]nonane-9-carboxylate (609 mg, 1.49 mmol) was dissolved in DMF, and NaH (60%, 65 mg, 1.63 mmol) was added. After 30 min, MeI (232 mg, 1.63 mmol, 102 μL) was added, and stirring continued for 30 min. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was concentrated to provide the crude product (655 mg, >100%) as a red oil: ESI MS m/z 423 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH3:9])(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[C:14]([O:13][C:11](=[O:12])[NH:10][C@@H:7]([CH2:8][CH3:9])[CH2:6][N:18]=[N+:19]=[N-:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)butyl methanesulfonate (13.4 g, 50 mmol) in DMF (100 mL) was added sodium azide (6.5 g, 100 mmol). The reaction mixture was heated at 70° C. for 18 h. After cooling to rt, water was added, and the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (SiO2; 0-50% EtOAc/hexanes) provided the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.87 (d, J=8.6 Hz, 1H), 3.54-3.37 (m, 1H), 3.27-3.20 (m, 2H), 1.45-1.25 (m, 2H), 1.39 (s, 9H), 0.82 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[S:6].[CH:7]1([CH:10]([NH2:14])[CH:11]2[CH2:13][CH2:12]2)[CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([CH:10]([NH:14][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[S:6])[CH:11]2[CH2:13][CH2:12]2)[CH2:9][CH2:8]1
Reactant: NC(C1CC1)C1CC1
Reactant: S=C=NCCCl
Solvent: C1CCOC1
Product: S=C(NCCCl)NC(C1CC1)C1CC1
Temperature: 25 °C

Procedure:
9.2 g of β-chloroethyl isothiocyanate dissolved in 20 ml tetrahydrofuran are added dropwise to a solution of 9 g of dicyclopropylmethylamine in 70 ml tetrahydrofuran. The reaction mixture is kept at a temperature of from 0° to +5° C. during the addition, then maintained at room temperature for 2 hours. The solvent is evaporated to dryness and the residue, consisting essentially of N-(1,1-dicyclopropylmethyl) N'-(β-chloroethyl) thiourea, is recovered and used without any further purification for the next step of the synthesis.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][C@H:14]2[CH3:30])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(O)(C(F)(F)F)=[O:32].OS(O)(=O)=O.[OH-].[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[C:26]([F:27])([F:29])[F:28])[CH2:15][C@H:14]2[CH3:30])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(F)c(C#N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(F)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 58.4 %

Procedure:
To a flask containing 2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)benzonitrile (399 mg, 0.90 mmol) was added a mixture of TFA/H2SO4 (4 mL, 2/2 v/v). The reaction mixture was stirred at room temperature for 5 days. Reaction was complete as determined by TLC. Slowly poured the reaction mixture to the ice, then neutralized the reaction mixture with 3N NaOH until pH=7-8, extracted with EtOAc (2×150 mL). The combined organic layer washed with sat. brine and dried over Na2SO4, and concentrated under reduced pressure. Purification by prep HPLC under neutral condition to yield 2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)benzamide as a white solid (243.7 mg, 58.4%). HRMS: calcd for C19H18F5N3O3S+H+, 464.10618. found (ESI-FTMS, [M+H]1+), 464.10639.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:15]([Cl:27])[CH:14]=1)=[O:11].[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[OH:35].CN(C=O)C>ClCCl>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:15]([Cl:27])[CH:14]=1)=[O:11]
Reactant: CCN(CC)CCOc1ccc(NC(=O)CBr)cc1Cl
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(-c3ccccc3)cc2Cl)cc1Cl

Procedure:
65 mg (0.47 mmol) of potassium carbonate was added to a solution of 70 mg (0.159 mmol) of 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide (intermediate product Z1c) and 64 mg (0.314 mmol) of 3-chloro-biphenyl-4-ol in 1 mL of abs. DMF and the mixture was stirred for 1 hour at 40° C. and for 15 hours at RT. The reaction mixture was diluted with dichloromethane, the org. phase was washed with sat. aqueous sodium bicarbonate solution and water and dried over magnesium sulphate. Column chromatography (silica gel, dichloromethane/MeOH 9:1) yielded the product.
Reaction SMILES: [C:1]1([C:7]2([OH:26])[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[C:15]3=[O:25])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[N+](=[CH2:31])=[N-]>O>[C:1]1([C:7]2([OH:26])[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:31])[CH:20]=4)[C:15]3=[O:25])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=[N+]=[N-]
Reactant: O=C1c2ccc(O)cc2CCC1CN1CCC(O)(c2ccccc2)CC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCC(CN1CCC(O)(c3ccccc3)CC1)C2=O

Procedure:
3.51 g. of 2-(4-phenyl-4-hydroxypiperidinomethyl)-6-hydroxy-1-tetralone are dissolved in a mixture of 45 ml. of methanol and 5 ml. of water. An ethereal solution of diazomethane is added at 20° until a faint yellow coloration remains. The mixture is evaporated to give 2-(4-phenyl-4-hydroxypiperidino-methyl)-6-methoxy-1-tetralone, m.p. 163°-165°.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:22][C:18]1[NH:10][N:9]([CH2:8][C:7]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[C:16](=[O:15])[CH:17]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: CC(C)c1ccc(CNN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)c1ccc(Cn2[nH]c(N)cc2=O)cc1
Reaction time: 2 h

Procedure:
32 g of p-isopropylbenzylhydrazine were added, under nitrogen, to a solution of 31.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 150 ml of ethanol. After stirring for a further two hours, the mixture was left to stand overnight. The compound identified above, which separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 105°, 18.3 g (40%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)C(C(O)=O)=[N:20][CH:19]=[CH:18]3)[CH:9]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:1]([C:2]([Cl:4])=[O:3])=[N:20][CH:19]=[CH:18]3)[CH:9]=1
Reactant: O=C(O)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 870 μl (10.2 mMol) oxalyl chloride in 10 ml CH2Cl2 is added to an ice-cooled solution of 1.54 g (5.1 mMol) 6-(6-chloro-pyrimidin-4-yloxy)-isoquinoline-1-carboxylic acid and 10 μl DMF in 75 ml CH2Cl2. The reaction mixture is stirred at room temperature for 1 h. The solvent is then evaporated off under reduced pressure to afford the title compound as a brown solid, which is used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[C@@H:5]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1.C(Cl)Cl.Cl[C:31]([O:33][CH3:34])=[O:32]>CN(C)C1C=CN=CC=1>[CH3:1][O:2][C@@H:3]1[CH2:8][N:7]([C:31]([O:33][CH3:34])=[O:32])[C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[C@@H:5]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl(2S,3S,5S)-5-methoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-3-carboxylate (0.0233 g, 0.0000645 mol) and 4-dimethylaminopyridine (0.0118 g, 0.0000967 mol) in methylene chloride (1.00 mL, 0.0156 mol) was added methyl chloroformate (0.00648 mL, 0.0000838 mol). The reaction was stirred at rt overnight. After quenched with aq. sodium bicaronate, the reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, concentrated to dry. The resulting residue was used directly in next step. MS (ESI): (M+H)+=420.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.8 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (47 mg, 35%).
Reaction SMILES: [CH2:1]([C:3]([N:8]=[C:9]=[N:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C([N:21]=[C:22]=[N:23]C1C=NC=CC=1)(C)(C)C>>[C:22]([N:23]=[C:9]([NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:3]([CH2:4][CH3:5])([CH2:6][CH3:7])[CH2:1][CH3:2])#[N:21]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CCC(CC)(CC)N=C=Nc1cccnc1
Product: CCC(CC)(CC)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure in Example 1, but substituting N-(1,1-diethylpropyl)-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-(1,1-diethylpropyl)-N'-3-pyridylguanidine was obtained with a melting point of 192.5°-193.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].CN1CCCC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:30][CH2:29][CH2:27][OH:28])[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: NCCO
Agent: CN1CCCC1
Solvent: c1ccncc1
Product: Cc1c(NCCO)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 90 °C
Reaction time: 71 h
Yield: 11.1 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (500 mg), monoethanolamine (410 mg) and N-methylpyrrolidine (170 mg) were added to pyridine (1,500 mg), and the mixture was stirred at 90° C. for 71 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (1.5 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. The resultant residue was subjected to column chromatography (silica gel: 15 g, eluent; chloroform:methanol=50:1→10:1). Ethanol (0.5 ml) was added to a concentrate of a fraction containing a main product, and the mixture was stirred at room temperature. Deposits formed were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (62 mg) as a brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[C:6]=12.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:6]=12
Reactant: Cn1cc(-c2cc(OCC3CCCN(C(=O)OC(C)(C)C)C3)c3c(Br)cnn3c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cc(OCC3CCCNC3)c3c(Br)cnn3c2)cn1
Reaction time: 0.5 h

Procedure:
tert-butyl 3-({[3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy}methyl)piperidine-1-carboxylate (55.0 mg, 0.112 mmol) was dissolved in dichloromethane (3 ml) at 0° C. Trifluoroacetic acid (1.0 ml) was added and the solution was allowed to stir for 30 minutes. The solution was concentrated to a colorless oil, which was dissolved in 2 ml of methanol and eluted through a bicarbonate resin cartridge (StratoSpheres SPE, PL-HCO3 MP SPE), flushing with 10 mL of methanol. The solution was concentrated and eluted through a second bicarbonate resin cartridge to afford 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)-4-(piperidin-3-ylmethoxy)pyrazolo[1,5-a]pyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H); 8.28 (s, 1H); 8.01 (s, 1H); 7.96 (s, 1H); 6.89 (s, 1H); 3.98-4.06 (m, 2H); 3.85 (s, 3H), 3.12-3.16 (m, 1H); 2.84-2.89 (m, 1H); 1.92-2.01 (m, 1H); 1.84-1.90 (m, 1H); 1.58-1.64 (m, 1H); 1.20-1.45 (m, 4H). LRMS (ESI) calculated for C17H2179BrN5O [M+H]+, 390.1; found 390.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[NH:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:15]([C:24](O)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C@@H:15]([NH:14][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:24](=[O:25])[N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccn2)CC1

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-oxo-2-[4-(2-pyridylmethyl)piperazinyl]ethyl}(tert-butoxy) carboxamide was prepared according to the procedure for Preparation XIX using (2-pyridylmethyl)piperazine (650 mg. 3.7 mmol) (Array), Boc-p-Cl-D-Phe-OH (1.1 g, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (2.2 g, 7.2 mmol), HOAT (560 mg, 4.10 mmol) and DMF (15 mL) (730 mg). MS (ESI, pos. ion) m/z: 459 (M+H), (ESI, neg. ion) m/z: 457 (M−H). Calc'd for C24H31ClN4O3: 458.98.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].O>CN(C=O)C>[CH3:1][C:2]1([CH3:23])[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of 4,4-dimethyl-17β-hydroxyandrost-5-en-3-one (3.34 g) in DMF (30 ml), imidazole (1.40 g) and tert-butyldimethylsilyl chloride (3.15 g) were added. After stirring the mixture overnight at RT, water was added, and stirring was continued for 30 min at 0° C. The formed solid was filtered and, after drying, 4,4-dimethyl-17β-tert-butyldimethylsilyloxyandrost-5-en-3-one was obtained (4.0 g, 93% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[N:33]1([CH2:39][CH2:40][C:41](O)=[O:42])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:41](=[O:42])[CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=C(O)CCN1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)CCN3CCCCC3)CC2)nc1N

Procedure:
The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and 1-piperidine propionic acid (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-3-piperidin-1-yl-propan-1-one. MS (M+H)+: 485.