Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].Br[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>COCCOCCOC>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[N:12]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c3[nH]c4ccnn4c(=O)c3cnc21
Reactant: CC(C)CCBr
Agent: [Na]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n3nccc3n(CCC(C)C)c12

Procedure:
7.6 g. of 3-ethyl-3,11-dihydro-6H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one (0.03 mol. ) are refluxed with stirring in 100 ml. of diethyleneglycol dimethylether together with 1.4 g. of sodium (0.06 mol.). After this time, 11.5 g. of 1-bromo-3-methylbutane (0.075 mol.) are added and the mixture is refluxed for 16 hours. The solvent is distilled off and the residue is crystallized with methanol, filtered and washed with water to obtain 3-ethyl-3,11-dihydro-11-(3-methylbutyl)-6H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one, yield 4.1 g. (42%); m.p. 167°-168° (isopropanol).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(3-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.160 g, 82%); 1H-NMR (500 MHz, DMSO-d6) 3.05 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2), 7.02 (s, 2H, NH2), 7.36 (dd, J=7.80, 4.75 Hz, 1H, pyridyl 5-H), 7.74 (dt, J=7.80, 1.70 Hz, 1H, pyridyl 4-H), 8.16 (s, 1H, 6-H), 8.47 (dd, J=4.75, 1.60 Hz, 1H, pyridyl 6-H), 8.50 (d, J=1.65 Hz, 1H, pyridyl 2-H);
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](N(OC)C)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:16][Mg]Br>C1COCC1>[N:4]1([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:10](=[O:11])[CH3:16])[CH2:8][CH2:9]1
Reactant: CON(C)C(=O)C1CCN(C(C)=O)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
1-Acetyl-N-methoxy-N-methylpiperidine-4-carboxamide (59.10 g, 276 mmol) was dissolved in THF (800 mL) and cooled to 0° C. Methylmagnesium bromide (110.3 mL, 331 mmol) (3.0M in diethyl ether) was added slowly and the resulting white slurry was agitated for 1 hour. The reaction was quenched with 300 mL of 2M HCl and the solvent was evaporated. The resulting aqueous slurry was filtered and the solids were washed with water and small amount of ether to provide the title compound (38.4 g, 82.2% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[I:15][CH3:16]>C(#N)C>[I-:15].[CH3:16][N+:3]1[C:4]2[C:9](=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1]
Reactant: CI
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Solvent: CC#N
Product: Cc1ccc2cc([N+](=O)[O-])ccc2[n+]1C
Product: [I-]
Temperature: 25 °C
Yield: 16.7 %

Procedure:
2-Methyl-6-nitroquinoline (0.5 g, 2.66 mmol) and iodomethane (1 ml, 16 mmol) were heated together in acetonitrile (10 ml) at reflux for 48 hrs. The mixture was cooled to room temperature and a grey material crystallised out of solution and was filtered off. This was shown to be starting material. The filtrate was diluted with ethyl acetate (200 ml) to give a yellow/green precipitate. The product was filtered off, washed with ethyl acetate and then dried under vacuum. The product was obtained as a yellow/green solid (147 mg, 16.8%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[O:14]C(=O)C1C=CC([N+]([O-])=O)=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1O
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of cis-2-(tert-butoxycarbonyl)amino-1-(4-nitrobenzoyloxy)cyclopentane (3.70 g) in a mixture methanol/water 1:1 (20 mL) at room temperature, potassium carbonate (2.37 g) was added and stirred overnight. Water was added and the mixture extracted with diethyl ether. The combined organic layers were separated, dried over Na2SO4 and evaporated to dryness to give cis-2-(tert-butoxycarbonyl)aminocyclopentan-1-ol (1.94 g, 91%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 6.09 (1H, d), 4.54 (1H, bb), 3.86 (1H, m), 3.53 (1H, m), 1.30-1.80 (6H, m), 1.37 (9H, s).
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCN(C(C)C)C(C)C.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>CCO>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:2]2[N:3]=[N:4][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])=[CH:35][CH:34]=1
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(Br)nn2)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1
Yield: 94.9 %

Procedure:
A mixture of 3-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridazine (example C.26 step 7) (5.76 g, 16 mmol), DIPEA (3.19 mL, 19 mmol) and 4-methoxybenzylamine (2.4 mL, 19 mmol) in EtOH (25 mL) was refluxed for 18 h under argon atmosphere. Cooled to 23 C, the mixture was poured onto water, the precipitated solid was filtered off, washed with water and dried in air at 60° C. on the heating plate to give the title compound as an off-white solid (6.49 g, 98%). MS (ISP) 428.3 [(M+H)+]; mp 101-103° C.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[NH:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:12][C:6]1([CH3:13])[NH:5][C:4]2[CH:3]=[C:2]([C:17]3[CH:18]=[N:14][NH:15][CH:16]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)cc2N1
Temperature: 120 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.125 g, 0.480 mmol), 4-pyrazoleboronic acid pinacol ester (0.279 g, 1.44 mmol), sodium carbonate (0.254 g, 2.40 mmol), 1,2-dimethoxyethane (2.4 mL) and water (1.2 mL) was purged with argon. Then, 1,1′-bis (diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.041 g, 0.050 mmol) was added to the mixture and the mixture was purged with argon again. The mixture was stirred at 120° C. for 4 h in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (50 mL). Extraction with ethyl acetate/THF (3:1, 2×50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure were carried out. The residue was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol). The fractions containing the desired product were collected. Some amount of starting material was recovered, reacted and purified with the above conditions again. The fractions containing the desired product were combined and concentrated in vacuo. This residue was further purified by column chromatography (Combiflash, 12 g silica gel, ethyl acetate to 90:10 ethyl acetate/methanol), then triturated with dichloromethane. The precipitate was collected by filtration to afford the title compound (0.0308 g, 26%) as a yellow solid:
Reaction SMILES: C([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=O)C>Cl>[NH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:6]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Agent: Cl
Product: Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Yield: 49.4 %

Procedure:
A mixture of 2-acetamido-5-fluoro-3-nitrobenzotrifluoride (1.50 g, 5.64 mmol) in concentrated HCl (10 mL) was refluxed overnight and it was extracted by ethyl acetate (2×10 mL). The extract was dried over Mg2SO4, and evaporated to give 624 mg of 2-amino-5-fluoro-3-nitrobenzotrifluoride (50%). 1H NMR (CDCl3): δ6.547 (s, 2H), 7.570 (dd, 1H, J1 =2.7 Hz, J2 =5.7 Hz), 8.114 (dd, 1 H, J1 =2.7 Hz, J2 =5.7 Hz).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@H:14]2[O:16][CH2:15]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:17][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C@H:14]2[O:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1ccc(OC[C@@H]2CO2)cc1)S(C)(=O)=O
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of compound 3-S (0.243 g, 1 mmol) and potassium carbonate (0.166 g, 1.2 mmol) in 20 ml acetone was stirred for 1 hour at room temperature, then methyl iodide (0.142 g, 0.062 ml, 1 mmol) was added dropwise at room temperature. After stirring for 8 hours, the reaction was filtered and the solvent evaporated to furnish a white solid that was used directly in the next step (0.2 g, 78% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Nc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)ccc1F
Yield: 68 %

Procedure:
The title compound is prepared from 3-amino-4-fluoro-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 68% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=311 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][O:19][CH2:20][CH3:21].CO.C(Cl)(Cl)Cl>CC(C)=O>[CH2:20]([O:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:21]
Reactant: CCOCCl
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
In a 300 milliliter, three-necked oven-dried round bottom flask equipped with a magnetic stirrer, 25 grams (0.18 mole) of 1-(4-hydroxyphenyl)ethanone and 38.6 grams (0.27 mole) of potassium carbonate (K2CO3) were suspended in 200 milliliters of acetone and the mixture was stirred at room temperature for 1 hour, forming a thick slurry. 18.6 grams (0.198 mole) of (chloromethoxy)ethane was slowly added to the reaction mixture using a dropping funnel over a period of one hour and the reaction refluxed overnight for another 12 hours until completion was ascertained by TLC analysis (1:99 methanol/chloroform). The reaction was quenched by pouring the mixture slowly into 400 milliliters of 0.01% hydrochloric acid (HCl) solution, and the product was extracted into 300 milliliters of ethyl acetate, and washed with brine then water to a neutral pH. The ethyl acetate extracts were then dried over sodium sulfate, filtered, and concentrated on a rotary evaporator affording 34.58 grams (˜99% yield) of 1-(4-(ethoxymethoxy)phenyl)ethanone as an oil. The product was used without further purification. 1H NMR (500 MHz, Acetone-d6): δ 7.94-7.91 (d, 2H, 8.5 Hz), 7.13-7.07 (d, 2H, 8 Hz), 5.31 (s, 2H), 3.702-3.67 (q, 2H), 2.49 (s, 3H), 1.16-1.11 (t, 3H).
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.C[K].[C:12](Cl)(=O)C(Cl)=O.[CH2:18]([NH2:20])[CH3:19]>>[CH2:18]([NH:20][C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][CH3:12])=[O:8])[CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CCN
Agent: C[K]
Product: CCNC(=O)C1OC1C(=O)OC
Yield: 70.4 %

Procedure:
Following the procedure of Example 34, mono methyl potassium epoxysuccinate (1.84 g) was successively treated with oxalyl chloride (0.75 g) and monoethylamine (0.9 g) to give 0.72 g of methyl N-ethyl-2,3-epoxysuccinamate (Compound No. 54) as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: COc1ccc(Cl)cc1N
Product: COc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(4-pyridinyl)-6-trifluoromethyl-pyrimidine (150 mg, 0.578 mmol) and 5-chloro-2-methoxyaniline (98 mg, 0.621 mmol) similar to Example 160 and was isolated as off-white solid (84 mg, 0.221 mmol, 38%). 1H NMR (CDCl3/MeOH-d4): 8.72 (d, J=4.2 Hz, 2H), 8.51 (s, 1H), 8.34 (d, J=4.5 Hz), 7.09 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 3.93 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:20]2[CH2:24][CH2:23][CH:22]([NH:25]C(=O)C(F)(F)F)[CH2:21]2)=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])[CH:7]=1.CO.[OH-].[Na+]>C(OCC)(=O)C>[NH2:25][CH:22]1[CH2:23][CH2:24][N:20]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=23)=[O:10])[CH2:21]1
Reactant: O=C(Nc1cc(Cl)ccc1N1CCC(NC(=O)C(F)(F)F)C1)c1cnn2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1CCN(c2ccc(Cl)cc2NC(=O)c2cnn3cccnc23)C1
Yield: 76.1 %

Procedure:
A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {5-chloro-2-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-phenyl}-amide (50 mg), methanol (2 mL) and an aqueous solution of sodium hydroxide (4 M, 1 mL) was heated at 60° C. for 1 hour. The resulting mixture was cooled, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 30 mg of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl]-amide (light yellow foam) without further purifications. MS=356 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([C@H:35]([CH3:40])[C:36]([O:38]C)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@:10]([CH:35]([CH3:40])[C:36]([OH:38])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)([C@H](C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(C(C)C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of (S)-methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate (0.041 g, 0.067 mmol) from Step B above in MeOH/THF/H2O (1 mL/1 mL/2 mL) was added lithium hydroxide (8.02 mg, 0.335 mmol). The mixture was heated to 60° C. for 14 h. The reaction mixture was acidified with 1N HCl and extracted with EtOAc (×2). The organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure to provide a colorless film. The crude material was purified by reverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compound as the first eluting peak.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[O:4][N:3]=1.[CH3:16][C:17](OC(C)=O)=[O:18]>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([N:7]([C:17](=[O:18])[CH3:16])[C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[O:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1noc(Nc2c(Cl)cccc2Cl)n1
Solvent: c1ccncc1
Product: CC(=O)N(c1nc(N)no1)c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
2.4 g (0.01 mole) 3-amino-5-(2,6-dichlorophenylamino)-1,2,4-oxadiazole in 10 ml pyridine are mixed with 5 moles acetanhydride at room temperature and stirred for 2 hours at 25°-30° C. After evaporation of the solvent, the residue is taken up at CHCl3 and shaken with sodium hydrogen carbonate solution. The CHCl3 phase contains 3 g of the N-acetyl compound, which is purified by column-chromatography on silica gel. The product has a melting point of 164°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=2)=[O:10])[C:5](F)=[N:6][CH:7]=1.N.C([N:22](C(C)C)CC)(C)C>>[NH2:22][C:5]1[C:4]([C:9]([C:11]2[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=2)=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CCn1nccc1C(=O)c1cc(Br)cnc1F
Reactant: CCN(C(C)C)C(C)C
Agent: N
Product: CCn1nccc1C(=O)c1cc(Br)cnc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
(5-Bromo-2-fluoro-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone (685 mg, 2.29 mmol) was combined with ammonia (0.5M in dioxane, 30 ml, 15.00 mmol) and di-iso-propylethylamine (4 ml, 23.43 mmol). The mixture was stirred for 18 hours at 90° C. The reaction mixture concentrated in vacuo. The crude material was combined with a saturated aqueous solution of sodium bicarbonate, and ethyl acetate and the biphasic mixture was stirred for 1 hour. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 339 mg (50%) of (2-amino-5-bromo-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone. 1H-NMR (250 MHz, d6-DMSO) δ 8.35 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.68 (s, 2H), 7.61 (d, J=1.8 Hz, 1H), 6.71 (d, J=1.8 Hz, 1H), 4.35 (quart., J=7.0 Hz, 2H), 1.37 (t, J=7.3 Hz, 3H); MS: m/z 295.1+297.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2OC(=O)[S:22][N:21]=2)=[CH:16][CH:15]=1)[CH3:13].ClC1C=CC=C(Cl)C=1>>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([C:2]([F:10])([F:11])[F:1])[S:22][N:21]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(-c2nsc(=O)o2)cc1
Reactant: CCOC(=O)C#CC(F)(F)F
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1C(F)(F)F
Temperature: 150 °C
Reaction time: 16 h

Procedure:
Into a 50-mL sealed tube, was placed ethyl 4,4,4-trifluorobut-2-ynoate (1.25 g, 7.53 mmol, 1.56 equiv), 5-(4-ethylphenyl)-2H-1,3,4-oxathiazol-2-one (1.0 g, 4.83 mmol, 1.00 equiv), 1,3-dichlorobenzene (8 mL). The resulting solution was stirred for 16 h at 150° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether (100). This resulted in 1.068 g (67%) of ethyl 3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate as yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.[CH3:20][O-:21].[Na+]>CO>[CH3:20][O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(OCCCCCCCBr)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
A solution of methyl 4-[7-bromo-n-heptyloxy)benzoate (2.3 g) in methanol (50 ml) and a solution of 28% sodium methoxide in methanol (3.5 ml) was refluxed for 12 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to the residue and adjusted to pH 1 using hydrochloric acid. The precipitates were collected by filtration, washed with water and dried in vacuo to give an oil. The oil was subjected to column chromatography on silica gel (silica gel 60 F254, Merck: 100 g) and eluted with a mixture of ethyl acetate and n-hexane (1:5). The fractions containing the objective compound were combined and concentrated under reduced pressure to give methyl 4-(7-methoxyheptyloxy)benzoate (1.6 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Cl:16])=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1[CH3:8].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1>CN(C)C=O>[ClH:16].[CH3:1][C:2]1[C:3]([N:18]2[CH2:19][CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1csc(Nc2nc(C)c(C)c(Cl)n2)n1
Solvent: CN(C)C=O
Product: Cc1csc(Nc2nc(C)c(C)c(N3CCc4ccccc4C3)n2)n1
Product: Cl
Yield: 10.8 %

Procedure:
The same procedures as in Step 4 of Example 22 were repeated using 5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-chloropyrimidine(0.85 g, 3.34 mmol), 1,2,3,4-tetrahydroisoquinoline(0.42 ml, 3.34 mmol) and dimethylformamide (5 ml) to afford 140 mg of the titled compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[CH3:8][C:9]1([CH3:18])[NH:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:11](=[O:12])[CH2:10]1>C(O)C>[CH3:16][C:14]1([CH3:17])[CH2:13][C:11](=[O:12])[CH2:10][C:9]([CH3:18])([CH3:8])[N:15]1[CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C#CC(=O)OCC
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Solvent: CCO
Product: CCOC(=O)C=CN1C(C)(C)CC(=O)CC1(C)C
Reaction time: 4 h
Yield: 63 %

Procedure:
54 g (0.55 mol) of ethyl propiolate were added dropwise to 78 g (0.50 mol) of triacetoneamine in 200 ml of ethanol at reflux, and the mixture was then stirred at this temperature for a further 4 hours. After cooling, the precipitated product was filtered off, thoroughly washed with petroleum ether and subsequently dried at 60° C. and under 0.1 mbar. 80 g (corresponding to a yield of 63%) of ethyl β-(2,2,6,6-tetramethyl-4-oxo-1-piperidinyl)acrylate were obtained in the form of a colorless solid of melting point 145° C.