Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]([N:26]([CH3:28])[CH3:27])[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[C:11]([O:13][C:14]([CH3:19])([CH3:18])[CH2:15][O:16][CH3:17])=[O:12])=[O:4].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C:30]1=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:27][N:26]([CH3:28])[C:8]1[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]([C:11]([O:13][C:14]([CH3:19])([CH3:18])[CH2:15][O:16][CH3:17])=[O:12])=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][C:30]2=[O:38])[N:7]=1
Reactant: COCC(C)(C)OC(=O)c1c(NC(=O)CBr)nc(N(C)C)n1-c1ccccc1
Reactant: O=C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(C)(C)OC(=O)c1c(NC(=O)CN2C(=O)Cc3ccccc32)nc(N(C)C)n1-c1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
2-Methoxy-1,1-dimethylethyl 4-[(bromoacetyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate (35 mg, 1 eq, synthesized in an analogous manner/method as described for example 90), 2-indolinone (26 mg, 2.5 eq) and K2CO3 (22 mg, 2 eq) were dissolved in DMF (5 mL). The reaction was stirred for 1 h at 75° C. The solvent was evaporated off and to the residue was added K2CO3(aq) (1 M, 50 mL) and extracted with ether. The organic phases were pooled, dried (MgSO4.H2O), filtered and evaporated. Eventually the crude material was purified by preparatory HPLC, which gave pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](O)([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.CS(OS(C)(=O)=O)(=O)=O.FC(F)(F)C(O)=O.[OH:51][C@H:52]1[CH2:56][NH:55][C@H:54]([C:57]([N:59]([CH3:61])[CH3:60])=[O:58])[CH2:53]1.[NH4+].[Cl-]>C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([N:55]3[CH2:56][C@H:52]([OH:51])[CH2:53][C@H:54]3[C:57]([N:59]([CH3:61])[CH3:60])=[O:58])([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:9](=[O:21])[N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])(=[O:23])=[O:24])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3cc(C)ccc3OC)c3cc(Cl)cnc32)c(OC)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)cnc32)c(OC)c1
Reaction time: 0.33 h

Procedure:
To a solution of 500 mg of the compound obtained in Step 119-1 and 200 mg of Et3N in CHCl3 (5 ml) was added 207 mg of methane sulfonic acid anhydride under ice cooling. The solution was stirred at the same temperature for 20 minutes, then, 1.90 g of Et3N was added. Thereafter, a solution of (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (4.95 mmol) in CHCl3 (5 ml) was added dropwise at the same temperature. The solution was stirred at the same temperature for one hour, then, was gradually warmed and stirred for 30 minutes under room temperature conditions, then, was poured into a saturated aqueous solution of NH4Cl and extracted with CHCl3. The combined organic layer was washed with saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by column chromatography (first time: silicagel 60N; mobile phase: CHCl3/MeOH=10/0 to 9/1; v/v, first time: silicagel 60N; mobile phase: EtOAc/MeOH=10/0 to 9/1; v/v) to obtain respectively 7.6 mg (Isomer A: brown amorphous) and 18.9 mg (Isomer B: brown amorphous) of two species of diastereoisomers of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[NH:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[H-].[Na+]>CN(C)C=O>[C:24]([O:23][C:21]([N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[CH3:1])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 2-methyl-3-nitrobenzyl chloride (1.07 g) in dimethylformamide (30 ml) was added dropwise to a solution of di-t-butyl iminodicarboxylate (1.38 g) and sodium hydride (content, 60%; 0.30 g) in dimethylformamide (30 ml) at 0° C. Following 1-h stirring at room temperature, the temperature of the mixture was raised to 80° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to give 1.49 g of the titled compound (yield, 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C:11](=[N:13][OH:14])[NH2:12].[CH2:16](OC(OCC)OCC)C.B(F)(F)F.CCOCC>>[CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C:11]1[N:12]=[CH:16][O:14][N:13]=1
Reactant: CN(C)c1ccccc1SCC(N)=NO
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Product: CN(C)c1ccccc1SCc1ncon1
Reaction time: 5 h

Procedure:
A mixture of 2-(2-dimethylaminophenylthio)acetamidoxime (1.0 g), triethylorthoformate (1.5 ml) and boron trifluoride etherate (0.015 ml) was warmed at 70° whence a solution soon formed. Heating at 70° was continued for 5 hours, the reaction mixture cooled and solvent removed by evaporation under reduced pressure. The residual oil was taken up in diethyl ether, washed with 5% aqueous sodium carbonate solution and water, dried and evaporated to dryness under reduced pressure. The residue was distilled under reduced pressure to give 3-(2-dimethylaminophenylthiomethyl)-1,2,4-oxadiazole as a colourless oil, b.p. 119° (0.07 mm Hg).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:15][S:16](Cl)(=[O:18])=[O:17].[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[CH3:15][S:16]([O:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12])(=[O:18])=[O:17]
Reactant: CN(CCO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(CCOS(C)(=O)=O)Cc1ccccc1

Procedure:
N-Benzyl-N-methyl-ethanolamine (20.73 g), 61.94 g of toluene and 83.41 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 300-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.8° C. Then, 31.68 g of methanesulfonyl chloride was added dropwise over 3 hours and 17 minutes at a flask inside temperature of 5 to 10° C. Water (33 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of N-benzyl-N-methyl-ethanolamine methanesulfonate was thus obtained in a yield of 68.8 mole percent.
Reaction SMILES: C(OP([CH2:9][S:10]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=[O:12])=[O:11])(OCC)=O)C.[H-].[Na+].[N:29]1[CH:30]=[C:31]2[N:40]3[C:35](=[CH:36][CH:37]=[CH:38][C:39]=13)[S:34][C:33]([CH:41]=O)=[CH:32]2>C1(C)C=CC=CC=1.CN(C)C=O.O>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([CH2:13][S:10](/[CH:9]=[CH:41]/[C:33]2[S:34][C:35]3[N:40]4[C:31](=[CH:30][N:29]=[C:39]4[CH:38]=[CH:37][CH:36]=3)[CH:32]=2)(=[O:11])=[O:12])[CH2:19][CH2:18]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: O=CC1=Cc2cnc3cccc(n23)S1
Reactant: CCOP(=O)(CS(=O)(=O)CC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CS(=O)(=O)/C=C/C2=Cc3cnc4cccc(n34)S2)CC1
Reaction time: 1 h

Procedure:
To a solution of 2.01 g (4.87 mM) of tert-butyl 4-(diethoxyphosphorylmethanesulfonylmethyl)piperidine-1-carboxylate in 30 ml of toluene was added 0.18 g (4.43 mM) of a 60% suspension of sodium hydride in liquid paraffin at room temperature, and the mixture was stirred at the prevailing temperature for 1 hour. This reaction mixture was added to a solution of the above crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde in N,N-dimethylformamide (10 ml)-toluene (30 ml) at room temperature and the mixture was stirred at the prevailing temperature for 0.5 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol=9/1) to provide crude (E)-4-[2-[1-(tert-butoxycarbonyl)piperidin-4-ylmethane-sulfonyl]viny]-5-thia-1,8b-diazaacenaphthylene. This crude product was not purified but used as it was in the next reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[O:10]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccsc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccsc2)=CC1=O
Temperature: 60 °C
Yield: 80.2 %

Procedure:
To a solution of 3-thiophenecarboxaldehyde (1.5 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 12 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM). The reaction solution was heated to 60° C. for 4 hours. After the reaction solution cooled, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow crystalline solid. The residue was purified by chromatography (silica gel, hexane/ethyl acetate) to yield yellow crystals (2.1 g, 72% yield), m.p. 79°-80° C.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].C1COCC1.CCCCCCC.[CH:29]1(/[C:32](=[N:34]/[S:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])/[CH3:33])[CH2:31][CH2:30]1>C1COCC1>[C:37]([S:35]([NH:34][C:32]([CH:29]1[CH2:31][CH2:30]1)([CH3:33])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(=O)OC(C)(C)C
Reactant: C/C(=N\S(=O)C(C)(C)C)C1CC1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C)(NS(=O)C(C)(C)C)C1CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 74.5 %

Procedure:
To a solution of tert-butyl acetate (1.29 g, 1.48 ml, 11.1 mmol) in THF (20 ml) cooled to −78° C. was added a 2M solution of lithium diisopropylamine in THF/n-heptane (5.55 ml, 11.1 mmol) over 10 minutes. The reaction mixture was stirred for 40 minutes at −78° C. followed by addition of a solution of (E)-N-(1-cyclopropylethylidene)-2-methylpropane-2-sulfinamide (CAN 1426425-10-6, 1.6 g, 8.54 mmol) in THF (5 ml) to the reaction cooled at −78° C. The reaction was stirred at −78° C. for 90 minutes and then let to warm up to 0° C. After stirring 1 hour at 0° C. the reaction was quenched by addition of water. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.93 g, 75%). MS (ESI, m/z): 304.5 (M+H+).
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:18].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>CO>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([CH2:20][N:15]2[CH2:14][CH2:13][CH:12]([N:4]3[CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:2][C:3]3=[O:18])[CH2:17][CH2:16]2)=[O:22])=[CH:24][CH:25]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(=O)CN2CCC(N3Cc4ccccc4NC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
In this example, 4.00 g 4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine mono-hydrochloride, 3.44 g of α-bromo-p-methoxyacetophenone, 4.2 ml of triethylamine and 60 ml of methanol are mixed and stirred at room temperature overnight. Then, the white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 4.71 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 3.79 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][S:38](Cl)(=[O:40])=[O:39])=[CH:33][CH:32]=1.C(N(CC)CC)C>ClCCl>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][S:38]([CH2:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)(=[O:39])=[O:40])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: O=S(=O)(Cl)Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C#N)C(c2ccc3c(c2)c(NS(=O)(=O)Cc2ccc(F)cc2)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1

Procedure:
To 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 160 mg (0.77 mmol) (4-fluorophenyl)methanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine. The mixture was stirred at reflux for 12 h. Then, further batches of 160 mg (0.77 mmol) (4-fluorophenyl)-methanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine were added, and the mixture was again stirred at reflux for 1 h. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed with brine. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 28 mg (19% of th.) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[CH:6]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1.F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:3][O:4][C:5](=[O:25])[CH:6]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:22][CH:23]=1)[CH2:7][C:8]1[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.25 g, 6.3 mmol) in DMF (2 mL) under argon, 15 (2.0 g, 6.3 mmol) in dry DMF (3 mL) was added. To the resulting yellow solution, 4-fluorobenzaldehyde (0.68 mL, 6.3 mmol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and solvent was evaporated. An ethyl acetate solution of crude product was filtered through a small bed of silica gel to yield 16 (1.83 g, 69%) as oil: 1HNMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.04 (d, J=5.4 Hz, 2H), 7.01 (d, J=5.4 Hz, 2H), 6.30 (t, J=2.1 Hz, 1H), 6.25 (d, J=2.1 Hz, 2H), 3.86 (t, J=7.8 Hz, 1 Hz), 3.76 (s, 6H), 3.66 (s, 3H), 3.36 (dd, J=12.6 and 8.1 Hz, 1H), 2.97 (dd, J=13.5 and 7.5 Hz, 1H); MS (EI) m/z 421 [M]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,4-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.37-7.48 (m, J=9.3, 9.3, 7.1, 2.4 Hz, 1H), 7.64 (ddd, J=7.9, 5.0, 1.0 Hz, 1H), 8.08-8.18 (m, 1H), 8.56 (dt, J=8.0, 1.9 Hz, 1H), 8.75 (dd, J=5.0, 1.8 Hz, 1H), 9.30 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 278 (M+H)+.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:16][CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[S:21][CH:22]=1.Cl.[CH2:33]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1)[CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1.C(Cl)Cl>[Cl:16][CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:43][CH2:42][C:41]3[CH:44]=[CH:45][C:38]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=3)=[O:29])=[CH:30][CH:31]=2)[S:21][CH:22]=1
Reactant: CCCCCc1ccc(CN)cc1
Reactant: O=C(O)c1ccc(-c2nc(CCl)cs2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCc1ccc(CNC(=O)c2ccc(-c3nc(CCl)cs3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
N-methylmorpholine (1.7 mL, 15.3 mmol) and isobutyl chloroformate (1.0 mL, 7.65 mmol) were added to a solution of 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoic acid (1.85 g, 7.29 mmol) in anhydrous THF (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then (4-pentylbenzyl)amine hydrochloride (1.64 g, 7.65 mmol) was added neat. The reaction mixture was stirred for 15 min at 0° C., then 2 hours at RT. The reaction mixture was diluted with DCM (100 mL) and washed with 1M aqueous HCl (50 mL), then saturated aqueous NaHCO3 (50 mL). The aqueous layers were extracted with DCM (100 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give a brown solid. Recrystallization from a mixture MeOH/water gave 2.30 g (75%) of the title compound as beige solid. HPLC, Rt: 5.2 min (purity: 98.0%). 1H NMR (CDCl3) δ: 8.01 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.37 (s, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.47 (m, 1H), 4.76 (s, 2H), 4.63 (d, J=5.5 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.63 (m, 2H), 1.34 (m, 4H), 0.90 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][N:24](CC5C=CC(OC)=CC=5)[C:17]=34)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.FC1C(C2C=C(NC3C4C(=CN(CC5C=CC(OC)=CC=5)N=4)N=CC=3)C=CN=2)=NC(C)=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2ncc3nccc(Nc4ccnc(-c5nc(C)ccc5F)c4)c32)cc1
Agent: COc1ccc(Cn2cc3nccc(Nc4ccnc(-c5nc(C)ccc5F)c4)c3n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)ccn2)n1
Temperature: 70 °C

Procedure:
N-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine and N-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and trifluoroacetic acid (20 mL) were combined and heated at 70° C. for 3 hours. The reaction mixture was then cooled, concentrated give a residue which was suspended in dichloromethane (50 mL) and added to a saturated solution of sodium bicarbonate (50 mL) with stirring. The mixture was sonicated and filtered. The solid was dried under vacuum and suspended in ethyl acetate. The solid again collected by filtration to give N-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine. MS [M+H] found 321.3.
Reaction SMILES: C[O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]#N.C(OC(=O)C)(=[O:22])C>I.C(O)(=O)C>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][C:8]1[C:3]2[O:2][C:18](=[O:22])[CH2:17][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(CC#N)cccc1Sc1ccccc1C
Reactant: CC(=O)OC(C)=O
Agent: I
Solvent: CC(=O)O
Product: Cc1ccccc1Sc1cccc2c1OC(=O)C2

Procedure:
A solution of 2-[2-methoxy-3-(o-tolylthio)phenyl]acetonitrile (5.9 g) in hydriodic acid (58%, 15 ml) and acetic acid (30 ml) was refluxed under heating for 17 hours. After concentration, water and aqueous sodium hydrogen sulfite were added to the residue and extracted with diethyl ether. The extract was washed with dil. aqueous sodium hydrogen sulfite and water in turn and evaporated. To the residue was added a solution of potassium hydroxide (2 g) in methanol (50 ml), and the mixture was refluxed under heating for 2 hours. Methanol was distilled off under reduced pressure, and the residue was dissolved in water, washed with diethyl ether, acidified with conc. hydrochloric acid and then extracted with diethyl ether. The extract was washed with water, dried and exaporated under reduced pressure to give crude 2-[2-hydroxy-3-(o-tolylthio)phenyl]acetic acid (4.2 g). To this product was added acetic anhydride (5 ml), and the mixture was refluxed under heating. The reaction mixture was evaporated, and the resultant oily residue was crystallized with ethanol to give pale yellow needles of 7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one (1.58 g), mp. 108°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[O:8][CH2:9][C:10]2[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(OCC)(=O)C.C(=O)([O-])O.[Na+].O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[O:8][CH2:9][C:10]2[CH:16]=[C:15]([NH:17][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: COc1ccccc1CNC1=Nc2ccc(N)cc2CO1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)C3CC3)cc2CO1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 60.1 %

Procedure:
To a vigorously stirred solution of N2-(2-methoxy-benzyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 4) (128 mg, 0.45 mmol; HPLC 0.41 min) in ethyl acetate (2 ml) and sat. sodium hydrogen carbonate-sol. (1.2 ml) at 23° C. was dropwise added cyclopropanecarbonyl chloride (50 ul, 0.54 mmol) and the mixture was stirred at 23° C. for 20 min. Diluted with ethyl acetate and water, separated phases, washed organic layer with brine and dried over sodium sulfate. Removal of the solvent in vacuum left an off-white solid which was purified by silica gel column chromatography with heptane/ethyl acetate 1:1 to 0:1 followed by trituration with diethyl ether to give the title compound as a white solid (95 mg, 55%, HPLC 0.998 min 100%), MS (ISP) m/e=352.3 [(M+H)+].