Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][OH:18])=[C:12]2[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:5].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37])=[C:12]2[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:5]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(Nc1cccc2c(-n3ccnc3)c(CO)cnc12)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-4-(imidazol-1-yl)quinoline (800 mg) in dichloromethane (10 ml) were dropwise added pyridine (230 mg) and phenyl chloroformate (333 mg) at ambient temperature, and the mixture was stirred for 1 hour at ambient temperature. The mixture was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)-3-(phenoxycarbonyloxymethyl)quinoline (100 mg).
Reaction SMILES: [NH2:1][C:2](=[S:14])[C:3]([NH:6]C(=O)OC(C)(C)C)([CH3:5])[CH3:4].Br[CH2:16][CH:17](OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH3:5][C:3]([CH3:4])([C:2]1[S:14][CH:16]=[CH:17][N:1]=1)[NH2:6]
Reactant: COC(CBr)OC
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CC(C)(N)c1nccs1
Temperature: 120 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
A mixture of tert-butyl 1-amino-2-methyl-1-thioxopropan-2-ylcarbamate (5.31 g, 24 mmol), 2-bromo-1,1-dimethoxyethane (CAN:7252-83-7, 5.11 g, 30 mmol) and TsOH (0.49 g, 3 mmol) in acetic acid (50 mL) was stirred at 120° C. for 4 h. After evaporation of solvents, the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The water phase was washed with ethyl acetate (3×50 mL). Then water phase was lyophilized to give the title compound as brown solid (2.1 g, 65%); MS (LC/MS): 143.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH2:17][CH3:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.Cl.O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH2:17][CH3:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(CC)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 91.6 %

Procedure:
Employing ethyl 1-cyclopropyl-6,7,8-trifluoro-5-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (5 g), conc. hydrochloric acid (11 ml), water (4.4 ml) and acetic acid (44 ml), the procedure of Reference Example 23 is repeated to give 1-cyclopropyl-6,7,8-trifluoro-5-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.2 g), as white powder, m.p. 197°-198° C.
Reaction SMILES: Br[CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:13][C:14]1([CH3:26])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)[O:15]1.[H-].[Na+]>CN(C)C=O>[CH3:13][C:14]1([CH3:26])[C:18]([CH3:19])([CH3:20])[O:17][B:16]([C:21]2[CH:25]=[N:24][N:23]([CH2:2][C:3]34[CH2:12][CH:7]5[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]5)[CH2:4]3)[CH2:10]4)[CH:22]=2)[O:15]1
Reactant: BrCC12CC3CC(CC(C3)C1)C2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC34CC5CC(CC(C5)C3)C4)c2)OC1(C)C
Temperature: 0 °C

Procedure:
A mixture of 1-(bromomethyl)adamantane (0.458 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.377 g) in N,N-dimethylformamide (5 mL) was cooled to 0° C. To this solution was added 60% sodium hydride (0.096 g). The solution was heated at 70° C. overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 25% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4][N:5]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7](=[O:9])[NH2:8].CN(C)[CH:21]=[O:22]>>[CH2:13]([O:12][CH2:11][CH2:10][N:5]1[C:6]2[C:7](=[O:9])[NH:8][C:21](=[O:22])[NH:1][C:2]=2[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4]1)[CH3:14]
Reactant: CCOCCn1nc(C(=O)OC)c(N)c1C(N)=O
Reactant: CN(C)C=O
Product: CCOCCn1nc(C(=O)OC)c2[nH]c(=O)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the amide of Step 4 (570 mg, 3.38 mmol) in N,N-dimethylformamide (30 mL) was treated with N,N′-carbonyldiimidazole (658 mg, 4.06 mmol) and the reaction mixture stirred at room temperature for 1 hour and then at 90° C. for 18 hours. The reaction mixture was concentrated in vacuo and the crude product suspended in acetone and sonicated for 30 minutes. The solid product was filtered off and dried in vacuo to yield the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]4[C:25]5=[N:26][CH:27]=[CH:28][CH:29]=[C:24]5[C:23]([C:30]#[N:31])=[N:22]4)[C:17]3=[O:32])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:33](N)[CH2:34][NH2:35]>CC(O)=O.CCO>[NH:31]1[CH2:33][CH2:34][N:35]=[C:30]1[C:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]([CH:18]2[CH2:19][CH2:20][N:16]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[CH:13]([CH3:14])[CH3:15])[C:17]2=[O:32])[N:22]=1
Reactant: NCCN
Reactant: CC(C)c1c(N2CCC(n3nc(C#N)c4cccnc43)C2=O)cnn1-c1ccc(F)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1c(N2CCC(n3nc(C4=NCCN4)c4cccnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 1-[1-[1-(4-fluorophenyl)-5-isopropyl-pyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]pyrazolo[3,4-b]pyridine-3-carbonitrile (0.082 g, 0.19 mmol) in ethane-1,2-diamine (1 mL), HOAc (0.1 mL) and EtOH (2.5 mL) was stirred at 100° C. for 1 hr. The mixture was then cooled to room temperature, quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-[3-(4,5-dihydro-1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.085 g, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:28]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(NC(C)=O)cc3)ccnc2cc1OCc1ccccc1
Temperature: 150 °C
Yield: 1328.7 %

Procedure:
Twelve carousel tubes were charged with 7-benzyloxy-4-chloro-6-methoxy-quinoline (12×2.00 g, 12×6.67 mmol) and N-(4-hydroxy-phenyl)-acetamide (12×3.03 g, 12×20.00 mmol, 3.0 eq) in NMP (12×2.00 ml) and heated under to nitrogen to 150° C. for 2.5 hours. The reaction mixtures were allowed to cool to room temperature, diluted with DCM (12×20 ml). The combined organic solutions were washed with 2N NaOH (3×200 ml), water (200 ml), brine (200 ml), dried (MgSO4), filtered and concentrated under reduced pressure to leave a brown oil. Purification by column chromatography (4% methanol in DCM) afforded the title compound as a beige solid (36.73 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[OH:22]S(O)(=O)=O.[OH-].[Na+]>O>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:18])=[O:22])[N:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A mixture of 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyronitrile (0.14 g.) and concentrated H2SO4 was left at room temperature for 3 hours and then diluted with crushed ice and water. The solution was basified with 10 N aqueous NaOH and the mixture extracted three times with EtOAc. The combined extracts were dried and evaporated to dryness to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyramide (0.13 g.) which was characterised as the hydrogen maleate, m.p. 202°-203° on recrystallisation from aqueous EtOH.
Reaction SMILES: [C:1]([S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[C:11](O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:45])([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C@@H:37]([NH2:42])[CH2:38][CH:39]([CH3:41])[CH3:40])[C:31](=[O:34])[NH:32][CH3:33]>C(OCC)(=O)C.O>[CH3:45][C:29]([CH3:28])([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C@@H:37]([NH:42][CH2:11][C@@H:10]([S:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH2:38][CH:39]([CH3:41])[CH3:40])[C:31](=[O:34])[NH:32][CH3:33]
Reactant: O=C(S[C@@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)O)c1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC[C@H](CCCN1C(=O)c2ccccc2C1=O)SC(=O)c1ccccc1)C(C)(C)C
Reaction time: 0.17 h

Procedure:
(S)-2-Benzoylsulfanyl-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (62.6 g, 0.163 mol) and (S)-2-amino-4-methylpentanoic acid (2,2-dimethyl-1-(S)-methylcarbamoylpropyl)amide (40 g, 0.155 mol) were dissolved in a biphasic mixture of ethyl acetate (480 mL) and water (240 mL) at 45° C. and stirred to equilibrate for 10 min. An HPLC reference sample was removed for t=0. The PeptiCLEC-TR enzyme (40 mL) is added to the reaction and the reaction is stirred at 45° C. Samples are removed at regular intervals for HPLC analysis which shows that the reaction is complete in 2 hours. Filtration of tile enzyme followed by acidic then basic aqueous washes gives a solution of (S)-2-[(S)-2-benzoylsulfanyl-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanylamino]-4-methylpentanoic acid (2,2-dimethyl-1(S)-methylcarbamoylpropyl)amide which is then evaporated to dryness to give the product as a glass foam 80 g, 83%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:25]=1)#[N:2].Cl[C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28].N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:10]1([CH3:13])[CH2:9][CH:8]([N:14]2[CH2:15][CH2:16][N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:27]2=[O:28])[C:7]2[CH:25]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CC(NCCNCc2ccccc2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(N2CCN(Cc3ccccc3)C2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-N'-benzylethylenediamine (0.91 g, 2.71 mmole, from Example 22, part A) and 4-nitrophenyl chloroformate (0.57 g, 2.85 mmole) in methylene chloride (22.5 ml) cooled to 0° C. was added pyridine (0.27 g, 3.39 mmole ). The reaction mixture was stirred at room temperature for 24 hours, diluted with methylene chloride and washed with 5% aqueous HCl solution, 2N NaOH solution and saturated NaCl solution. The extract was dried over MgSO4 and evaporated in vacuo to obtain 1.32 g of an orange gum. The crude product was chromatographed on silica eluting with hexane/ethyl acetate (3:2) to obtain 0.65 g (66%) of the title compound as a colorless amorphous solid, m.p.=45°-48° C. 1H NMR (CDCl3) δ7.51-7.39 (m, 7H), 6.9 3 (d, J=9.38 Hz, 1H), 5.43 (dd, J=7.03 and 11.14 Hz, 1H), 4.55 (m, 2H), 3.36-3.20 (m, 3H), 3.05 (m, 1H), 1.99 (m, 2H), 1.59 (s, 3H), 1.45 (s, 3H); 13C (CDCl3) δ160.77, 158.29, 136.70, 132.49, 1 31.66, 128.60, 128.03, 127.48, 121.38, 119.16, 1 18.61, 103.29, 76.94, 48.17, 45.15, 41.90, 37.26, 34. 96, 34.67, 29.75, 24.01; MS: (M+H)+ 169 362.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Yield: 81.2 %

Procedure:
5-(4-Nitrophenyl)-2-(1H)-pyrazinone (0.1 g) was hydrogenated over 10% Palladium on Charcoal (0.01 g) at atmospheric pressure in 50% aqueous dimethylformamide containing 2N sodium hydroxide (0.46 ml). Once the theoretical quantity of hydrogen uptake had been observed, the reaction mixture was filtered and the filtrate treated with HCl to pH6 and evaporated. Trituration of the residue with water afforded the title compound 0.07 g, m.p. 269°-271.5° C. (with decomposition).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:9]1
Reactant: COCCOC(=O)NC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOC(=O)NC[C@@H]1CCCNC1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To 2-methoxyethyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (496 mg, 1.6 mmol) dissolved in 10 mL CH2Cl2 was added 5 mL TFA, and the reaction was stirred for 1 hour. After neutralizing the mixture with a 1 N NaOH solution it was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give 2-methoxyethyl ((R)-piperidin-3-yl)methylcarbamate (300 mg, 87%) which was used without further purification. LC/MS: m/z 217.5 (M+H)+ at 0.49 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH2:17]([NH:21][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 81 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 23 mg of butan-1-amine and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-Butyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)[CH2:10]1.C([O-])([O-])=O.[Na+].[Na+].[CH:28](I)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH:28]([N:19]1[CH:20]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10]2)[CH:16]=[CH:17][C:18]1=[O:21])([CH3:30])[CH3:29]
Reactant: CC(C)I
Reactant: COc1ccccc1C1CCN(Cc2ccc(=O)[nH]c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccccc1C1CCN(Cc2ccc(=O)n(C(C)C)c2)C1
Reaction time: 8 h

Procedure:
9.75 g of (+)-5-[3-(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-pyridin-2-one (example 2) are dissolved in 170 ml of toluene. 14.2 g of Na2CO3, followed by 6.9 ml of isopropyl-iodide are added to the solution which is stirred at 100° overnight. Subsequently, another 3.4 g of isopropyliodide are added and stirring continued for additional 17 hours. The reaction solution is extracted with water and the combined organic phases dried and evaporated resulting in an oily residue which is purified by flash chromatography on silica gel using CH2Cl2/MeOH/conc. aqueous NH4OH 95/4.5/0.5 as solvent system which provides (+)-1-Isopropyl-5-[3-(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-pyridin-2-one {[αD25]=+19.7° (c=1.0, EtOH); MS (Cl): MH+=327; NMR (DMSO, 120°): 1.3 (6H, d), 1.95 (1H, m), 2.3 (1H, m), 2.7-3.4 (4H, m), 3.6-3.8 (3H, m), 3.8 (3H, s), 5.0 (1H, q), 6.35 (1H, d) 6.9-7.0 (2H, m), 7.2 (1H, t), 7.3 (1H, m), 7.4 (1H, m), 7.6 (1H, m)} and (+)-2-Isopropoxy-5-[3-2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-pyridine {[αD25]=+22.8° (c=1.0, EtOH); MS (EI): M+=326; NMR (DMSO): 1.3 (6H, d), 1.75 (1H, m), 2.15 (1H, m), 2.4 (1H, t), 2.65 (2H, m), 2.8 (1H, t), 3.5-3.65 (3H, m), 3.75 (3H, s), 5.2 (1H, m), 6.7 (1H, d), 6.85-6.95 (2H, m), 7.15 (1H, t), 7.3 (1H, d), 7.6 (1H, m), 8.05 (1H, s)}
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>>[CH:1]([CH:11]=[CH:10][C:9]#[N:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC#N
Product: N#CC=CC=Cc1ccccc1
Yield: 684.5 %

Procedure:
Polymerization reaction was carried out in the same way as in Example 6 by employing 520 g of ethylene-propylene block copolymer (PEP), 430 g of styrene and 50 g of acrylonitrile to obtain 1001 g of styrene-acrylonitrile-modified ethylene-propylene block copolymer particles.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:31])=O.CN(C=O)C>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:31])=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Cl)CC1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-(tert-butyl)-2-(1-Boc-piperidin-4-yloxy)benzoic acid (4.0 g, 10.6 mmol) in dichloromethane (20 mL) at 0° C., was added oxalyl chloride (13 mmol), followed by a small amount of DMF. After 30 min, the solvents were removed in vacuo and the residue was dissolved in dichloromethane to make a solution of the title compound, approximately 0.1 g/mL.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].[CH3:24][NH2:25]>C1C=CC=CC=1>[CH3:24][NH:25][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Reactant: CN
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNC)C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.2 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 2 g. of methylamine in 30 ml. of benzene is allowed to stir at room temperature overnight. The reaction mixture is concentrated to a foam which is subsequently crystallized twice from ethyl acetate-hexane, 1.95 g., m.p. 154°-156°C. A small sample is again recrystallized from the same solvent system for analysis, m.p. 155°-156°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C1CCCCO1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31]2)[CH:27]=[N:26][CH:25]=1.Cl>CCOCC.O.C([O-])([O-])=O.[K+].[K+]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]2)[CH:27]=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: NC1CCCN(c2cncc(-c3n[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 1-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-3-ylcarbamate (350 mg, 0.592 mmol) in Et2O (6 mL) was added HCl in Et2O (6 mL). The reaction mixture was heated at 80° C. overnight and cooled to RT. The resulting mixture was diluted with water and neutralized with K2CO3. The resulting precipitate was collected by filtration, washed with water and a mixture of EtOH/EtOA (1:10), and dried overnight to give 1-(6-(5-(2,6-difluorophenyl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-3-amine MS (ESI, pos. ion) m/z: 407 (M+1).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[S:30]1[C:34]2[CH2:35][CH2:36][CH2:37][C:33]=2[N:32]=[C:31]1[NH2:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][O:23][C:5]1[C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:10]=[CH:11]/[C:12]1[N:13]=[C:14]2[N:18]([C:19]=1[C:20]([NH:38][C:31]1[S:30][C:34]3[CH2:35][CH2:36][CH2:37][C:33]=3[N:32]=1)=[O:22])[CH:17]=[CH:16][S:15]2
Reactant: Nc1nc2c(s1)CCC2
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc3c(s2)CCC3)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine (37 mg, 0.260 mmol) in the presence of EDCI hydrochloride (91 mg, 0.472 mmol) and DMAP (26 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 20 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 2.42-2.52 (m, 2H), 2.75-2.81 (m, 4H), 3.58 (s, 2H), 7.18 (t, J=76.2 Hz, 1H), 7.20-7.28 (m, 2H), 7.38-7.45 (m, 1H), 7.71 (d, J=6.9 Hz, 1H), 7.84 (d, J=15.9 Hz, 1H), 8.05-8.12 (m, 1H), 8.46-8.53 (m, 1H), 13.03 (br s, 1H); APCI-MS (m/z) 545.53 (MH)+.