Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH3:2].Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>CO>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:8]([C:1]3[CH:2]=[CH:15][CH:16]=[CH:17][N:20]=3)=[CH:7][CH:6]=[N:21]2)=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: c1ccc(COc2ccc(-n3nccc3-c3ccccn3)cc2)cc1
Temperature: 60 °C

Procedure:
To a solution of 3-Dimethylamino-1-pyridin-4-yl-propenone (590 mg) in methanol (10 ml) was added acetic acid (0.5 ml) and (4-Benzyloxy-phenyl)-hydrazine hydrogen chloride (836 mg) and the reaction mixture heated to 60° C. for 6 h. The reaction mixture was poured into saturated sodium bicarbonate, extracted with ethyl acetate, dried magnesium sulfate, filtered and concentrated. Purification via combiflash MPLC provided the title compound (795 mg). MS: (M+H m/z=328.1).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.[CH:33]1([C:36]2[O:40][N:39]=[C:38]([C:41](O)=[O:42])[CH:37]=2)[CH2:35][CH2:34]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[CH:33]1([C:36]2[O:40][N:39]=[C:38]([C:41]([N:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[CH2:20][O:21][C:22]3[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:42])[CH:37]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)c1cc(C2CC2)on1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cc(C2CC2)on1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroacetic acid) salt (EXAMPLE 34 Step 1) and 5-cyclopropylisoxazole-3-carboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m ethoxy)picolinic acid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6](OCC)(OCC)([O:8][CH2:9]C)[CH3:7]>C(O)C>[CH3:9][O:8][C:6](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH3:7]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC#N
Solvent: CCO
Product: COC(C)=C(C#N)C#N
Temperature: 45 °C
Yield: 65.9 %

Procedure:
To a 100 mL flask equipped with air stirrer and thermometer and distillation condensor were added malononitrile (9.1 g, 0.138 mol, triethyl orthoacetate (26.8 g, 0.165 mol) and glacial acidic acid (0.4 mL) sequentially, and the mixture was stirred and gently heated (90° C.) until the ethanol formed in the reaction began to distill off. When all the ethanol had distilled off, the reaction temperature was raised slowly from 90° C. to 140° C. for 30 min to ensure completion of the reaction. The reaction mixture was allowed to cool to 45° C. to solidify. The resulting solid mass was broken up under hexane (20 mL) and hexane was decanted off. The solid was washed with ethanol (50 mL) to afford a colorless crystal. The ethanol solution was concentrated and allowed to cool to room temperature. Then the crystal was filtered, washed with ethanol dried under vacuum (12.3 g, 65.9% yield).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11](COCC[Si](C)(C)C)[N:12]=[CH:13][C:8]2=[C:7]([NH:22][CH2:23][C@H:24]([OH:26])[CH3:25])[N:6]=1.Cl>CO>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[CH:13][C:8]2=[C:7]([NH:22][CH2:23][C@H:24]([OH:26])[CH3:25])[N:6]=1
Reactant: C[C@@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2c1cnn2COCC[Si](C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]ncc12
Temperature: 80 °C
Yield: 63.2 %

Procedure:
(R)-1-[6-(2,4-Difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (258 mg) was dissolved in 8 mL MeOH, and 0.6 nL of 6M HCl was added. The reaction mixture was heated to 80° C. for 3.5 hours, then cooled. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (10% MeOH in methylene chloride) to give 116 mg of (R)-1-[6-(2,4-Difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=322.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]([CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)=[O:4].O>CCCCCC>[C:3]([CH2:5][CH2:6][N:7]([CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]1)([OH:4])=[O:2]
Reactant: COC(=O)CCN(CCCCCCN(CCC(=O)OC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Solvent: O
Solvent: CCCCCC
Product: CC1(C)CC(N(CCCCCCN(CCC(=O)O)C2CC(C)(C)NC(C)(C)C2)CCC(=O)O)CC(C)(C)N1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a four-necked flask equipped with a stirrer and a reflux condenser were added 26.3 g (46 mmoles) of N,N'-bis(2-methoxycarbonylethyl)-N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,6-hexanediamine (Compound A) obtained in Example 1 and 100 g of water. The resulting mixture was stirred at room temperature. After dissolution of Compound A was confirmed, 100 ml of hexane was added to separate the reaction mixture into two layers. The aqueous layer of the two layers was isolated and concentrated to obtain 23 g (43 mmoles) of Compound C in a yield of 92%.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([OH:15])[C:9]([C:16]([O:18]C)=[O:17])=[C:8]2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>[OH-].[Na+]>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([OH:15])[C:9]([C:16]([OH:18])=[O:17])=[C:8]2[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1c(O)c(C)c(=O)n(C2CCCCC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(O)c(C(=O)O)c(C)n(C2CCCCC2)c1=O
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A solution of methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate (0.35 g, 1.25 mmol) in 2 N NaOH (5 mL) was heated at reflux for 3.5 h. The reaction mixture was cooled room temperature, acidified to pH 1-2 with 1 N HCl, and washed with EtOAc. The organic solution was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid as a white solid (0.31 g, 94%): 1H NMR (300 MHz, MeOD) δ 4.30-4.00 (br s, 1H), 2.76 (br s, 5H), 1.90 (s, 3H), 1.90-1.80 (m, 2H), 1.75-1.60 (m, 3H), 1.50-1.15 (m, 3H).
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:18][CH:14]([N:15]([CH3:17])[CH2:16]2)[CH2:13][CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1.Br>>[OH:3][C:4]1[CH:5]=[C:6]([C:10]23[CH2:18][CH:14]([N:15]([CH3:17])[CH2:16]2)[CH2:13][CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C23CCCC(C2)N(C)C3)c1
Agent: Br
Product: CN1CC2(c3cccc(O)c3)CCCC1C2
Yield: 88 %

Procedure:
A mixture of 0.4 g of 1-(3-methoxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane hydrobromide and 4 ml of aqueous 48% hydrobromic acid is refluxed for 1.5 hours. After the reaction, the mixture is concentrated under reduced pressure. Aqueous ammonia is added to the residue, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from ethylacetate. 0.245 g of 1-(3-hydroxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane is obtained. M.p. 144.5°-145.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH2:20])[N:17]([CH3:19])[N:18]=[C:11]12.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH:20][C:28](=[O:31])[CH2:29][CH3:30])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Reactant: CCC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (0.51 g) and triethylamine (0.27 mL) in dichloromethane (40 mL) at 0° C. was added propionyl chloride (0.17 mL) in dichloromethane (10 mL) dropwise over 25 minutes. The resulting mixture was stirred for an additional 1 hour at 0° C., followed by 14 hours at room temperature. The reaction mixture was then stirred with an aqueous 5% citric acid solution (40 mL) for 10 minutes. The layers were separated, and the aqueous layer was further extracted with dichloromethane (50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, then decanted from the desiccating agent and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a dichloromethane/methanol gradient to afford N-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide (0.49 g) as an off white solid, ms m/z 347 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][CH:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][OH:10].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][C:3]([O:10][CH2:9][CH2:8][CH:7]([CH3:6])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(CCO)CCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(CCOC(=O)CCl)CCc1ccccc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A 127.05 g (1.125 mol) of chloroacetyl chloride and 200 ml of dichloromethane were out into a flask and, while stirring under ice-cooling, a mixture consisting of 199.6 g (1.12 mol) of 3-methyl-5-phenylpentanol and 88.59 g (1.12mol) of pyridine was added dropwise thereto spending 2 hours (reaction temperature 5 to 15° C.). After completion of the dropwise addition, this was further stirred at room temperature for 3 hours, and white crystals of the thus precipitated pyridine hydrochloride were removed by filtration. The reaction mixture was washed with water (3×300 ml), the organic phase was dehydrated with anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. By distilling the remained yellow oil under a reduced pressure, the title compound was obtained as a light yellow transparent oil. Yield 242.25 g (0.849 mol; yield 84.9%, boiling point 148-151° C./0.2 kPa).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.CN(C)C1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([O:29][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Product: CN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-(4-methyl-3-oxopiperazin-1-yl)fluorobenzene (2.94 g) was dissolved in dry DMF (40 ml) under argon, and the solution cooled to -20° C. N,N-Dimethylaniline (2.1 ml) was added, followed by benzyl chloroformate (2.07 ml), and the mixture stirred for 10 minutes at -20° C. The temperature was allowed to rise to ambient over 16 hours. The mixture was diluted with ethyl acetate, and washed twice with water, and then brine. After drying (MgSO4) and evaporation of solvent, the residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 5-benzyloxycarbonylamino-2-(4-methyl-3-oxopiperazin-1-yl)fluorobenzene (4.6 g).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][C:12]=2[CH:15]=1
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
13.8 g (100 mmol) Na2CO3 are added to a solution of 4.02 g (20.0 mmol) 5-bromo-salicylaldehyde and 2.26 mL (20.0 mmol, 98%) ethyl bromoacetate in 50 mL DMF. The reaction mixture is heated to 80° C. and stirred for 2 h at this temperature. It is diluted with 200 mL water, the aqueous phase is extracted three times with 100 mL tert-butylmethylether and the combined organic extracts are washed twice with 50 mL water. The organic phase is dried over MgSO4, filtered through activated charcoal and the solvent is eliminated i.vac.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][C:64]([O:92][CH3:93])=[C:65]([O:87][CH2:88][CH2:89][O:90][CH3:91])[CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH3:93][O:92][C:64]1[CH:63]=[C:62]2[C:67]([C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)=[N:69][C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([NH:53][C:8](=[O:10])[CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:55]=3)=[N:61]2)=[CH:66][C:65]=1[O:87][CH2:88][CH2:89][O:90][CH3:91]
Reactant: O=C(O)CN1CCOCC1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(N)c3)nc2cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-morpholinoacetic acid (0.034 g, 0.24 mmol), DIEA (0.165 mL, 0.94 mmol) and PyBOP® (0.125 g, 0.24 mmol) in CH2Cl2 (1 mL) was stirred at RT for 10 minutes, upon which it was added to a solution of tert-Butyl 5-(2-(3-aminophenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.260 g, 0.47 mmol) in CH2Cl2 (10 mL), the subsequent was stirred at RT for 1 hr upon which further aliquots of 2-morpholinoacetic acid (0.034 g, 0.24 mmol) and PyBOP® (0.125 g, 0.24 mmol) were added. The resulting mixture was stirred at RT overnight upon which the mixture was concentrated in vacuo and taken directly to the next step. HPLC retention time 5.35 mins.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9].C([O-])(=O)C.[NH4+:16]>C1(C)C=CC=CC=1>[NH2:16][C:8]([CH3:9])=[CH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:11].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9]
Reactant: [NH4+]
Agent: CC(=O)CC(=O)c1cccs1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(N)=CC(=O)c1cccs1

Procedure:
The intermediate 3-amino-1-(2-thienyl)-2-buten-1-one was prepared as follows: A mixture containing 153 g of 1-(2-thienyl)-1,3-butanedione, 176.7 g of ammonium acetate and 1 liter of toluene was azeotroped for five hours and then allowed to cool. The solid that separated from the reaction mixture was collected, washed successively with toluene and ether, and dried in a vacuum oven at 90° C. to yield 122 g of 1-(2-thienyl)-1,3-butanedione, m.p. 167°-171° C. A 10 g sample of this material was dissolved in 300 ml of boiling toluene, the solution treated with decolorizing charcoal and filtered, and the filtrate allowed to cool. The solid that separated was collected and dried in a vacuum oven at 90° C. to yield 5.8 g of 3-amino-1-(2-thienyl)-2-buten-1-one, as off-white needles, m.p. 170°-172° C. The main portion of the product was then dissolved in boiling isopropyl alcohol, the hot solution treated with decolorizing charcoal and filtered, and the filtrate allowed to cool. The solid that crystallized was collected, washed with isopropyl alcohol, dried in a vacuum oven at 80° C. to yield 74.1 g of product melting at 169°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ncccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(3-Chloro-phenylethynyl)-2-methyl-1H-imidazole (200 mg, 0.92 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (255 mg, 1.85 mmol) and 2-chloro-pyrimidine (159 mg, 1.38 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from diisopropyl ether and the desired compound was obtained as an off-white solid (212 mg, 78%), MS:m/e=295.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]2([CH3:32])[CH3:31])[C:14]1=[O:33].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][C:19]1([CH3:32])[CH:18]([N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=3[F:1])[C:14]2=[O:33])[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Nc3ccc(S(C)(=O)=O)cc3F)C2=O)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCCC1N1CC[C@H](Nc2ccc(S(C)(=O)=O)cc2F)C1=O
Reaction time: 1 h
Yield: 24.8 %

Procedure:
tert-Butyl 4-((S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.10 g, 0.21 mmol) was dissolved in DCM (5 mL). TFA (5 mL) was added and the reaction was stirred for 1 hour. The solution was concentrated, neutralized with saturated NaHCO3 solution, and extracted with dichloromethane (3 times). The organic layers were combined, dried, filtered and concentrated to give (3S)-1-(3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.020 g, 0.052 mmol, 25% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20].O>C(Cl)Cl>[CH2:19]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5])=[O:24])[CH3:20]
Reactant: CCOCC(=O)Cl
Reactant: CCNc1cccc(N)c1C#N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNc1cccc(NC(=O)COCC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzonitrile (4 g) in methylene chloride (100 ml) is added pyridine (2.8 ml), and thereto is added dropwise ethoxyacetyl chloride (3.9 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (4.1 g) having the following physical properties.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:15]([C:26]([F:29])([F:28])[F:27])=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(O[N:47]1[N:55]=[N:54][C:49]2[CH:50]=[CH:51]C=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC(N)=CN=1>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:15]([C:26]([F:27])([F:29])[F:28])=[CH:14][C:10]=2[C:11]([NH:54][C:49]2[CH:50]=[CH:51][N:55]=[N:47][CH:48]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccnnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Reaction time: 0.08 h

Procedure:
2-[(Phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 58; 70 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (4 ml). Diisopropylethylamine (0.06 ml, 0.34 mmol) and HATU (131 mg, 0.34 mmol) were added. The mixture was stirred for 5 minutes then 4-pyridazinamine (32.7 mg, 0.34 mmol) was added. The solution was stirred for 90 minutes. The solvent was removed in vacuo and the residue purified by MDAP to give the title compound as a white solid. 30 mg.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:16])[CH3:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.Br>>[OH:2][C:3]1[CH:4]=[C:5]([C:14](=[O:16])[CH3:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(C(C)=O)cc([N+](=O)[O-])c1OC
Agent: Br
Product: CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2 g of 3',4'-dimethoxy-5'-nitroacetophenone are treated with 30 ml of constant-boiling hydrobromic acid and stirred at 140° for 2.5 hours. After cooling the mixture is poured into 200 ml of ice-water and extracted three times with 100 ml of ethyl acetate each time. The organic phase is washed twice with 25 ml of sodium chloride solution each time, dried over sodium sulfate and evaporated. The product obtained is filtered with ethyl acetate over a 20-fold amount of silica gel. By recrystallization of the material obtained from water there is obtained 3',4'-dihydroxy-5'-nitroacetophenone in the form of yellow crystals of m.p. 159°-160°.