Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:36]([NH:35][CH2:33][CH3:34])=[O:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCN=C=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCNC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.44 g, 2.91 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxoisoindolin-2-yl]piperidine-2,6-dione hydrochloride (0.6 g, 1.94 mmol) in acetonitrile (50 mL). After stirring for 30 min, ethyl isocyanate (0.21 g, 2.91 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed and the residue was stirred with methylene chloride (70 mL) to give N-{[2-(2,6-dioxo(3-piperidyl))-1-oxoisoindolin-4-yl]methyl}(ethylamino)carboxamide (0.28 g, 42%) as a white solid: mp 341–343° C.; 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 7.62–7.47 (m, 3H), 6.40 (t, J=5.9 Hz, 1H), 5.95 (t, J=5.6 Hz, 1H), 5.18–5.10 (dd, J=5.3 and 13.3 Hz, 1H), 4.52–4.30 (dd, J=17.3 and 37.7 Hz, 2H), 4.28 (d, J=5.9 Hz, 2H), 3.04 (q, J=7.2 Hz, 2H), 3.01–2.86 (m, 1H), 2.65–2.34 (m, 2H0, 2.04–1.99 (m, 1H), 0.98 (t, J=7.2 Ha, 3H); 13C NMR (DMSO-6) δ 172.82, 170.97, 168.10, 157.86, 139.78, 136.24, 131.55, 130.25, 128.16, 121.32, 51.51, 46.13, 34.14, 31.16, 22.59, 15.67; Anal. Calcd for C17H20N4O4: C, 59.29; H, 5.85; N, 16.27. Found: C, 58.98; H, 5.85; N, 16.89.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:35][CH2:34][N:33]([C:29]3[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][N:30]=3)[CH2:38][CH2:37]2)=[O:48])[C:44]=1[CH3:45]
Reactant: COc1ccnc(N2CCNCC2)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccnc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Methoxy-pyridin-2-yl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.92 (d, 1H), 6.67 (s 1H), 6.63 (d, 1H), 5.42 (s, 2H), 3.96 (s, 3H), 3.88 (m, 2H), 3.73 (m, 4H), 3.62 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=418.1, found=418.0.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[NH:4][N:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].[C:25]([C:29]1[CH:46]=[CH:45][C:32]([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40](=O)[CH2:41]CCl)[CH2:36][CH2:35]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[N:4]([C:19](=[O:22])[CH2:41][CH2:40][N:37]2[CH2:36][CH2:35][N:34]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:46][CH:45]=3)[CH2:39][CH2:38]2)[N:3]=1
Reactant: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(CN2CCN(C(=O)CCCl)CC2)cc1
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(Cc5ccc(C(C)(C)C)cc5)CC4)c3C2=O)cc1

Procedure:
A target compound (109.8 mg, 0.207 mmol, 50.4%) was yielded as yellow solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(p-tolyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (100 mg, 0.412 mmol) with potassium carbonate (85.4 mg, 0.618 mmol) and 1-{4-(4-t-butylbenzyl)piperazin-1-yl}-3-chloropropan-1-one (146.2 mg, 0.453 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:14]([CH3:30])[C:15]([C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1C(OC(C)(C)C)=O)=[O:16])[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]>C(Cl)Cl>[CH2:8]([N:14]([CH3:30])[C:15]([C@@H:17]1[CH2:21][C@@H:20]([OH:22])[CH2:19][NH:18]1)=[O:16])[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid was added dropwise to a solution of compound 48 (1 g, 1 eq.) in DCM (10 mL). The reaction mixture was stirred for 3 hrs at room temperature, and then trifluoroacetic acid was removed under reduced pressure. The residue was co-evaporated with toluene to yield compound 49 as pale yellow oil in quantitative yield.
Reaction SMILES: C([O:5][C:6](=[O:56])[CH:7]([NH:18][C:19](=[O:55])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[O:54])[NH:35][CH:36]([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:8][CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[CH:31]1[CH:30]=[C:29]([C:34]([NH:35][C@H:36]([C:47]([OH:49])=[O:48])[CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:54])[C:28]([S:27][S:26][C:21]2[C:20]([C:19]([NH:18][C@H:7]([C:6]([OH:56])=[O:5])[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:55])=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CCCC(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(CCCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC[C@H](NC(=O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CCCC(=O)O)C(=O)O)C(=O)O
Yield: 72.3 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-{2-[2-(1,4-bis-tert-butoxycarbonyl-butylcarbamoyl)-phenyldisulfanyl]-benzoylamino}-hexanedioic acid di-tert-butyl ester (1.1 g, 1.4 mmol) from Example 37, 10 mL dichloromethane, 10 mL trifluoroacetic acid, and 1 mL anisole. The crude product was recrystallized from methanol/dimethylformamide/water to afford 0.6 g of the title compound, mp 259°-260° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:8]=[C:7]([CH3:17])[N:6]=1>CO.COCCOC.C(OCC)C>[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([O:2][CH3:1])[N:8]=[C:7]([CH3:17])[N:6]=1
Reactant: C[O-]
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)Cc1c(Cl)nc(C)nc1OC
Reaction time: 0.5 h

Procedure:
Sodium methylate in methanol (33 ml of a 5.4 molar solution) is added at room temperature to a solution of methyl 4,6-dichloro-2-methyl-pyrimidin-5-yl-acetate (35.5 g, 0.15 mol) in 1,2-dimethoxyethane (60 ml). After stirring for 30 minutes the mixture is diluted with diethyl ether and washed with water. Drying and distillation gives the methyl 4-chloro-6-methoxy-2-methyl-pyrimidin-5-yl-acetate as a colorless oil (30 g), b.p. 108°-110° C./0.5 torr.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH3:10]O>O>[O:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:6][CH3:10])=[O:9])[CH2:8][CH2:7]1
Reactant: CO
Reactant: O=C1OCCC1CCO
Solvent: O
Product: COC(=O)C1CCOCC1
Reaction time: 60 h

Procedure:
A solution consisting of 45 wt % of 3-(2'-hydroxyethyl)-dihydro-2(3H)furanone, 45 wt % of methanol, and 10 wt % of water, was evaporated at a rate of 25 g per hour and the vapors were passed over 90 g of aluminum oxide catalyst (diameter 1.5 ram) in a tubular reactor at a temperature of 250° C. The gaseous effluent was condensed in cold traps and analyzed by gas chromatography. The experiment was carried out for a period of 60 h and the total amount of starting material used was 1500 g. 57 mol % of methyl tetrahydropyran-4-carboxylate was formed, plus 32 mol % of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone and 4 mol % of 5-oxaspiro-[2.4 ]heptan-2-one, the conversion of 3-(2'-hydroxyethyl)-dihydro-2(3H)furanone being better than 97%.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:8]2[C:5]3[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][C:4]=3[C:32]3[CH2:31][N:30]([CH3:29])[CH2:35][CH2:34][C:33]2=3)=[CH:14][CH:13]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Reactant: Fc1ccc(CCBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(F)cc2)CCN(C)C1
Yield: 1.6 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (312 mg, 1.9 mmol), 4-fluorophenyl ethyl bromide (400 mg, 1.9 mmol), triethyl amine (0.264 ml, 1.9 mmol) and N-methyl-4-piperidone hydrochloride (424 mg, 2.8 mmol) were combined in ethanol (3 ml) to obtain 10 mg of 5-(4-fluorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole after purification by silica gel chromatography (100-200 mesh or 230-400 mesh) using ethyl acetate-hexane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [ClH:1].C([O:9][C:10](=[O:40])[CH:11]([N:15]([CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[CH2:33][CH2:32]1)=[O:30])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:1].[OH:39][CH2:38][CH2:37][N:34]1[CH2:35][CH2:36][N:31]([C:29](=[O:30])[CH2:28][CH2:27][N:15]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]([CH:12]([CH3:14])[CH3:13])[C:10]([OH:40])=[O:9])[CH2:32][CH2:33]1
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)OCc2ccccc2)C(C)C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)O)C(C)C)cc1
Yield: 126.5 %

Procedure:
To a solution of 2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester hydrochloride (1.49 grams, 2.49 mmol) in ethanol (80 mL) was added 10% palladium on activated carbon (0.11 grams). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 16 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving 2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxo-propyl}(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid hydrochloride as a white solid (1.6 grams, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=[O:14])C(C)(C)C)=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])CCC.CCCCCC.[F:34][C:35]([F:42])([F:41])[C:36](OCC)=[O:37].Cl>COC(C)(C)C>[OH2:14].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[C:6]([C:36](=[O:37])[C:35]([F:42])([F:41])[F:34])[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Product: O
Temperature: -20 °C
Reaction time: 2 h
Yield: 175 %

Procedure:
N-(4-Chlorophenyl)-2,2-dimethyl propanamide (36.7 kg, 173 mol) was charged to a solution of TMEDA (20.2 kg, 174 mol) in anhydrous t-butyl methyl ether (271.5 kg) and cooled to -20° C. To the cold slurry was added 2.7 N n-butyllithium in hexane (101.9 kg, 393 mol) while keeping the temperature below 5° C. After aging 2 hr at 0 to 5° C., the solution was cooled below -15° C. then rapidly reacted with ethyl trifluoroacetate (34.5 kg, 243 mol). After 30 min, the resulting solution was quenched into 3N HCl (196 L, 589 mol) keeping the temperature below 25° C. After removal of the aqueous phase, the organic solution was concentrated by distilling approximately 200 L of solvent. Acetic acid (352 kg) was added while distilling 325 kg solvent under 100 mm vacuum. After cooling the solution to 30° C., 12 N HCl (43.4 kg, 434 mol) was added and the mixture heated to 65 to 70° C. and held 4 hours. The resulting slurry was cooled to 5° C and the product was collected by filtration, washed with ethyl acetate (50.5 kg) and dried in vacuo to give 42.1 kg (87%) of the title compound as a white crystalline solid: mp 159-162 dec; 1H NMR (300 MHz, DMSO-d6) d 7.65-7.5 (complex, 2H), 7.1 (d, J=8 Hz, 1H), 7.0 (brs, 3H); 19F NMR (282 MHz, DMSO-d6) δ -69.5.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:21][C:22]1[C:23]([F:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:31])=[CH:25]2)C1C=CC=CC=1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[F:32][C:23]1[C:22]([O:21][C:12]2[C:11]3[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[CH:10]=3)[N:15]=[CH:14][N:13]=2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:31])[NH:27]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A solution of 6-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (1.32 g, 3 mmol), ammonium formate (1.94 g, 30 mmol) and 10% palladium on carbon (0.2 g) in DMF (15 ml) containing water (2 ml) was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether, filtered, washed with diethyl ether followed by water and dried under vacuum over P2O5 overnight to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (1 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.O>[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[NH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cn1cc(Br)cc(Nc2cc(C(C)(C)C)[nH]n2)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2cc(C(C)(C)C)[nH]n2)c(=O)n(C)c1
Temperature: 135 °C
Yield: 105.4 %

Procedure:
A mixture of 5-Bromo-3-(5-tert-butyl-1H-pyrazol-3-ylamino)-1-methyl-1H-pyridin-2-one (125 mg; 0.38 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (180 mg; 0.46 mmol), tetrakis-(triphenylphosphine)palladium (24 mg; 0.02 mmol), sodium carbonate (400 mg; 1.2 mmol), and 1,2-dimethoxyethane (4 mL) and water (4 mL) were heated in a sealed microwave reactor for 5 min (135° C., 300 W). The mixture diluted with ethyl acetate, adsorbed onto silica gel, and flash chromatographed (9:1 CH2Cl2:MeOH) to give 4-tert-Butyl-N-{3-[5-(5-tert-butyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-methyl-phenyl}-benzamide as a tan solid (205 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[NH2:18][OH:19]>C(O)C>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[N:18][OH:19])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(=NO)CC1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
4-Dimethylamino-4-phenylcyclohexanone (10 g) and hydroxylamine hydrochloride (4.8 g) were dissolved in absolute ethanol (120 ml), basic ion exchanger Amberlyst A 21 (30.7 g) was added to the solution, and stirring was carried out overnight at RT. The ion exchanger was filtered off and washed with ethanol (3×50 ml) on the frit. The ethanol was removed in vacuo and the residue was adjusted to pH 11 with 5M NaOH, diluted with water and extracted with ethyl acetate (4×30 ml). The combined extracts were dried with Na2SO4 and concentrated. 11 g of 4-dimethylamino-4-phenyl-cyclohexanone oxime were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:29]C(OC(C)(C)C)=O)([C:14](=[O:28])[NH:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[NH2:29][C:11]1([C:14]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19][OH:20])=[O:28])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1(C(=O)NC(CCCO)c2ccc(Cl)cc2)CCNCC1
Yield: 84.9 %

Procedure:
Tert-butyl-4-(tert-butoxycarbonylamino)-4-(1-(4-chlorophenyl)-4-hydroxybutylcarbamoyl)piperidine-1-carboxylate (Intermediate 71) (1.98 g, 3.76 mmol) was stirred in THF (18.82 mL) and 4M hydrogen chloride (14.11 mL, 56.46 mmol) in dioxane was added with stirring. The resulting solution was stirred at ambient temperature overnight. The crude mixture was purified by SCX chromatography (eluent 20% 7N ammonia/MeOH in DCM). Pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-4-hydroxybutyl)piperidine-4-carboxamide (1.04 g, 85%), as a colourless, transparent gum.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH:5]([N+:11]([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C.[H][H]>>[NH2:11][CH:5]([CH:4]([O:14][CH2:15][CH3:16])[O:3][CH2:1][CH3:2])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C(OCC)OCC)[N+](=O)[O-]
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)C(N)C(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethyl 3,3-diethoxy-2-nitropropanoate (2.45 g, 10.42 mmol) was dissolved in Ethanol (70 mL, 1240 mmol). Nitrogen gas was bubbled through the mixture for 5 minutes. Raney® nickel was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 13 psi of hydrogen gas. Reaction shook at room temperature for 1 hour. Mixture was removed from the apparatus and filtered over celite. Filter cake was washed with 150 mL ethanol followed by 250 mL hot ethanol. Filtrate was concentrated to dryness. Title compound was obtained as red oil in 92% yield. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 4.59 (d, J=4.39 Hz, 1 H) 4.05-4.30 (m, 2 H) 3.65-3.81 (m, 2 H) 3.38-3.63 (m, 3 H) 1.87 (s, 2 H) 1.20-1.29 (m, 3 H) 1.12-1.20 (m, 6 H).
Reaction SMILES: [CH3:1][C@H:2]1[O:4][C@@H:3]1[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.C([S:14][C@@H:15]1[CH2:20][O:19][C@@H:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[O:17][CH2:16]1)(=O)C>>[N:6]1([CH2:5][C@@:3]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)([OH:4])[C@H:2]([S:14][C@@H:15]2[CH2:16][O:17][C@@H:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=3)[O:19][CH2:20]2)[CH3:1])[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: CC(=O)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)OC1
Reactant: C[C@H]1O[C@@H]1Cn1cncn1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1
Yield: 71 %

Procedure:
Reaction was carried out in the same manner as in Example 1 using (2R*,3R*)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and trans-5-(acetylthio)-2-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]-1,3-dioxane to obtain the title compound as an oil in a yield of 71%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[N:14][CH:15]=1
Reactant: O=C1CCc2c(O)cccc21
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2c(Oc3ccc(C(F)(F)F)cn3)cccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 4-hydroxyindan-1-one (2.94 g, 19.8 mmol), 2-chloro-5-(trifluoromethyl)pyridine (3.00 g, 16.5 mmol), potassium-carbonate (6.84 g, 49.5 mmol) and N,N-dimethylformamide (40 mL) was stirred under a nitrogen atmosphere at 100° C. for 8 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-hexane/ethyl acetate=60/40) to give the title compound (2.74 g, yield 69%) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:26]([CH2:28][C:29]1([N:40]2[CH:44]=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:42]=[N:41]2)[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([CH2:28][C:29]1([N:40]2[CH:44]=[C:43]([C:2]3[CH:7]=[N:6][N:5]4[C:8]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:12]=5)=[CH:9][N:10]=[C:4]4[CH:3]=3)[CH:42]=[N:41]2)[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1
Temperature: 100 °C

Procedure:
A mixture of N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (600 mg, 2 mmol), tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (760 mg, 1.9 mmol), tetrakis(triphenylphosphine)palladium(0) (94.9 mg, 0.0822 mmol) and potassium carbonate (570 mg, 4.1 mmol) in 1,4-dioxane (9.0 mL) and water (4 mL) was heated at 100° C. under an atmosphere of nitrogen for 4 h. After cooling, the reaction mixture was extracted with ethyl acetate (3×20 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-10%) to afford the desired product. LCMS (M+H)+: m/z=596.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O-:12])=[O:11])=[CH:8][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].[I-].[Na+].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:15])=[O:11])=[CH:8][CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C([O-])c1ccc(OCCCCl)cc1
Reactant: C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCN2CCCCC2)cc1
Yield: 92 %

Procedure:
A mixture of 4-(3-chloropropoxy)benzoate ax13 (2.01 g, 8.79 mmol, 1 eq), potassium carbonate (2.43 g, 17.6 mmol, 2 eq), sodium iodide (catalytic amount) and piperidine (1 ml, 9.67 mmol, 1.1 eq) in acetonitrile (100 ml) is stirred at reflux for 56 h. The solvent is removed under vacuum and the solid is triturated in hexane and filtered. The resulting solution is concentrated to give methyl 4-(3-piperidin-1-ylpropoxy)benzoate ax15 as a yellow oil (2.2 g).