Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:39])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@H:32]4[CH3:37])[N:19]=3)[CH:14]([CH3:38])[CH2:13]2)=[N:9][C:10]=1Br)=[O:4].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:39])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH:32]4[CH3:37])[N:19]=3)[C@H:14]([CH3:38])[CH2:13]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)nc1Br
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOCC4C)n3)[C@H](C)C2)c(Cl)n1

Procedure:
Stir a solution of 6′-bromo-3′-chloro-4-[6-(4-fluoro-phenyl)-2-(3-(R)-methyl-morpholin-4-yl)-pyrimidin-4-yl]-3-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (3 g) in 100 mL of THF with 5% palladium on carbon (300 mg) under 1 atmosphere of hydrogen gas for several days. Filter the mixture through celite and concentrate under reduced pressure. Partition the residue between saturated NaHCO3 solution and EtOAc. Dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify using flash column chromatography eluting with a gradient EtOAc/hexanes solvent system to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=[O:20])[NH:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.[H-].[Na+]>C1COCC1>[O:20]=[C:5]1[NH:4][CH2:3][CH2:2][N:6]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)NCCCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCNC2=O)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.5 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (50 g, 250 mmol) and Et3N (50.5 g, 500 mmol) in DCM (500 mL) was added 2-chloroethyl isocyanate (31.65 g, 300 mmol) dropwise. The resulting mixture was stirred at RT for 4 hours before being quenched with water (100 mL). The layers were separated and the organic layer was washed with brine, dried, concentrated, and subjected to silica flash column using 0 to 50% EA in to isolate (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364) (63.6 g, 81.5%) as a colorless oil. At 0° C., to a solution of (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364, 31.0 g, 102 mmol) in anhydrous THF (350 mL) was added NaH (60% in mineral oil, 4.82 g, 122 mmol) in small portions slowly. The resulting mixture was stirred at RT for 6 hours before being quenched with water (50 mL). The layers were separated and the aqueous was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (25.4 g, 93%) as a white solid. At 0° C., to a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (16.2 g, 60.2 mmol) in anhydrous THF (160 mL) was added NaH (60%, 3.6 g, 90.3 mmol) in small portions. The resulting mixture was stirred at RT for 30 min, cooled back to 0° C., and then iodomethane (12.9 g, 90.3 mmol) was added dropwise. After the addition, the mixture was stirred at RT for 3 hours. The reaction was quenched with water and extracted with DCM (50 mL×2). The combined organic layers were washed with brined, dried, concentrated, and purified by silica flash column using 0 to 3% MeOH in DCM to get (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (13.0 g, 74%) as a light yellow oil. (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (3.5 g, 12.37 mmol) was treated with 40 mL commercial 4N HCl in dioxane at RT for 2 hours. The solvent was removed in vacuo, and the residue was basified to pH 9 with ammonium hydroxide. The solvent was then removed in vacuo, and the residue was subjected to silica flash column using 0 to 10% MeOH in DCM to isolate (R)-1-methyl-3-(piperidin-3-yl)imidazolidin-2-one (367) (1.2 g, 53%) as an oil. LC-MS (ESI): m/z (M+1) 184.2. Proton NMR (CDCl3): δ 3.95-3.83 (2H, m), 3.75 (1H, s), 3.39-3.26 (5H, m), 3.08-2.97 (1H, m), 2.93-2.79 (1H, m), 2.78 (3H, s), 1.94-1.86 (2H, m), 1.82-1.56 (2H, m), 1.48-1.21 (1H, m) ppm.
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([NH:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:20])([F:21])[F:19])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[N+:22]([O-:24])=[O:23])[CH:3]=[CH2:4]
Reactant: C=CCBr
Reactant: Nc1c([N+](=O)[O-])cnn1-c1ncc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNc1c([N+](=O)[O-])cnn1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1.0 g (0.0082 mol) of 3-bromopropene was added with stirring to a mixture of 2.3 g (0.0075 mol) of 5-amino-4-nitro-1-(3-chloro-5-trifluoromethyl-2-pyridyl)pyrazole, 0.6 g (0.0041 mol) of potassium carbonate and 50 ml of dimethylformamide and it was stirred at 100° C. for 2 hours. After cooling, it was concentrated under reduced pressure and the residue was partitioned between water and methylene chloride. The organic phase was dried, filtered off with suction through silica gel and concentrated, 1.6 g (61.3% of theory) of the title compound being obtained as a viscous resin. After chromatographing on silica gel and concentrating, colorless crystals of m.p. 94-95° C. were obtained (Active Compound Example No. 9.003).
Reaction SMILES: [C@H:1]12[CH2:55][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:48])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH2:37][CH2:36][C@@H:35]([C:38]([O:40]CC6C=CC=CC=6)=[O:39])[CH2:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2.[OH-].[Li+]>C1COCC1.CO>[C@H:1]12[CH2:55][C@H:4]([N:5]([CH2:7][CH2:8][NH:9][C@:10]34[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:11]3[C@@H:12]3[C@@:25]([CH3:28])([CH2:26][CH2:27]4)[C@@:24]4([CH3:29])[C@@H:15]([C@:16]5([CH3:48])[C@@H:21]([CH2:22][CH2:23]4)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]4[CH2:37][CH2:36][C@@H:35]([C:38]([OH:40])=[O:39])[CH2:34][CH:33]=4)=[CH:18][CH2:17]5)[CH2:14][CH2:13]3)[CH2:6]1)[CH2:3][O:2]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CO4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 75 %

Procedure:
To a solution of (R)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,45)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (47.2 mg, 0.048 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added 1N lithium hydroxide (0.193 mL, 0.193 mmol). The reaction was stirred at 75° C. After 3 h the reaction mixture was concentrated and the crude material was dissolved in THF (2 mL)/H2O (150 μL), purified by reverse phase prep-HPLC using prep-HPLC method 15 and dried under vacuum to give (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (32.9 mg, 0.036 mmol, 75% yield) as a white solid. LC/MS: m/e 659.5 (M+H)+, 4.14 min (method 8). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 5.33 (br. s., 1H), 5.22-5.08 (m, 1H), 4.78 (s, 1H), 4.70 (s, 1H), 4.54 (s, 1H), 4.04 (d, J=8.8 Hz, 1H), 3.84 (br. s., 1H), 3.73 (dd, J=8.8, 1.5 Hz, 1H), 3.23-2.96 (m, 5H), 2.88-2.63 (m, 2H), 2.58-2.40 (m, 1H), 2.35-2.09 (m, 5H), 2.08-1.90 (m, 8H), 1.83-1.75 (m, 1H), 1.71 (s, 3H), 1.70-1.61 (m, 2H), 1.61-1.42 (m, 8H), 1.41-1.36 (m, 1H), 1.35 (s, 1H), 1.33-1.23 (m, 1H), 1.10 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H)
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:8]([N:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:24]2[CH:23]=[CH:22][C:21]3[O:17][CH2:18][O:19][C:20]=3[CH:25]=2)[CH2:28][CH2:29]1)=[O:16]
Reactant: O=C(Nc1ccccn1)Oc1ccccc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: O=C(Nc1ccccn1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from pyridin-2-yl-carbamic acid phenyl ester and 1-benzo[1,3]dioxol-5-ylmethyl-piperazine. 1H NMR (400 MHz, CDCl3): 8.18 (d, J=3.9 Hz, 1H), 7.67-7.64 (m, 1H), 6.66-6.64 (m, 2H), 6.54-6.51 (m, 3H), 5.94 (s, 2H), 3.80 (s, 2H), 3.53 (t, J=4.9 Hz, 4H), 2.36 (t, J=4.8 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C@:9]2([CH3:15])[OH:14])=[CH:4][CH:3]=1.[C:17]([NH:24][C@@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:29](=[O:30])[C@H:25]([NH:24][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:26]([CH3:28])[CH3:27])[CH2:10][C@@:9]2([OH:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: C[C@]1(O)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)[C@@](C)(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
To a mixture of (3S,4S)-4-(4-chlorophenyl)-3-methylpiperidine-3,4-diol (91 g, 376 mmol), Boc-D-Valine (83.1 g, 382 mmol), HOBt (69.2 g, 452 mmol), EDC (87 g, 452 mmol) in CH2Cl2 (800 mL) and DMF (80 mL) was added DIPEA (132 mL, 753 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction was concentrated and the residue partitioned between EtOAc and water. The EtOAc layer was washed with 1N HCl, sat. aq. NaHCO3, and brine to give the crude product (180 g, ˜80% purity) which was used directly in the next transformation.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.C(N(CC)CC)C>CC#N>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Fc1ccc2c(c1)CCN2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Cl)N1CCc2cc(F)ccc21
Temperature: 23 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
2-Chloronicotinoyl chloride (200 mg, 1.14 mmol) was dissolved in CH3CN (5.6 mL). 5-Fluoroindoline (171 mg, 1.25 mmol) was added followed by triethylamine (0.24 mL, 1.71 mmol) and the reaction mixture was stirred at 23° C. for 16 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 (10 mL) and sat. aq. NaHCO3 solution (10 mL). The organic phase was removed and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. Flash column chromatography (40 g SiO2, 2% CH3OH—CH2Cl2) afforded the desired product as an off-white solid (247.8 mg, 79%). 1H NMR (DMSO-d6) δ 3.14 (t, 2H, J=8.39 Hz), 3.82 (t, 2H, J=8.39 Hz), 7.09 (dt, 1H, J=9.03, 2.80 Hz,), 7.20 (dd, 1H, J=8.39, 2.80 Hz), 7.60 (dd, 1H, J=7.38, 4.83 Hz), 8.10 (dd, 1H, J=7.63, 2.03 Hz), 8.15 (dd, 1H, J=8.90, 4.83 Hz), 8.55 (dd, 1H, J=4.83, 1.78 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21]([OH:23])=O.[C:24]1([CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:34]1[CH2:33][CH2:32][C:31]([CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:37])[CH2:36][CH2:35]1)=[O:23]
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCC(O)(Cc3ccccc3)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
1,1-Carbonyl diimidazole (47 mg, 0.29 mmol) was added to a solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 31, 100 mg, 0.29 mmol) in tetrahydrofuran (4 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled and 4-(phenylmethyl)-4-piperidinol (52 mg, 0.27 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. Water (4 mL) was added and the mixture was stirred at 80° C. for 2 h. The mixture was cooled, the water was decanted and the residue was dissolved in dichloromethane. Using a Bond Elut™ cartridge to separate the layers the solution was washed with hydrochloric acid (1M), and aqueous sodium hydroxide (2M). The organic fraction was evaporated under reduced pressure to a small volume and filtered through a plug of silica on a Bond Elut™ cartridge, eluting with hexane/EtOAc (85:15 increasing to 70:30), to give the title compound as a colorless solid (101 mg, 68%). 1H NMR (360 MHz, CDCl3) δ 7.53 (1H, s), 7.40 (2H, d, J 6.5 Hz), 7.07-7.27 (9H, m), 4.29 (1H, m), 3.47 (3H, s), 3.29 (1H, m), 3.11 (1H, m), 2.90 (2H, m), 2.79 (1H, m), 2.59 (2H, s), 2.43 (2H, m), 1.52 (1H, br s), 1.40 (2H, m), 1.29 (1H, m), and 1.15 (1H, m). m/z (ES+) 521, 523 (M+1). Found: C, 69.30; H, 5.82; N, 5.36. C30H30Cl2N2O2 requires: C, 69.10; H, 5.80; N, 5.37%.
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:14][N:13]([C:15](=[O:26])[NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[C:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:15]([N:13]2[CH2:12][C:11]3([N:8]([S:34]([C:31]4[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=4)(=[O:36])=[O:35])[CH2:9][CH2:10]3)[CH2:14]2)=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCCCc1ccccc1)C2
Product: O=C(NCCCc1ccccc1)N1CC2(CCN2S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
In analogy to the experimental procedure of example 6b) 6-(3-phenyl-propylcarbamoyl)-1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate was converted using 4-chlorobenzene-1-sulfonyl chloride into the title compound which was obtained as a colorless sticky solid (25 mg, 17%). MS m/e: 434 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[O:21][CH2:20][C:19]([CH3:24])([CH3:22])[CH2:18][O:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)COC(CCc2ccc(Cl)cc2)(Cn2ccnc2)OC1
Yield: 37.1 %

Procedure:
A mixture of 1-[4-(4-chlorophenyl)butan-2-on-1-yl]imidazole (2.0 g), 2,2-dimethylpropane-1,3-diol (0.84 g) and anhydrous p-toluenesulfonic acid (1.39 g) in toluene (20 ml) were heated under reflux through a Dean-Stark trap for 2 hours. The resulting mixture was poured into aqueous potassium carbonate solution, extracted with ether (2×100 ml) and the extracts dried (MgSO4). After removal of the solvent, the crude reaction product was chromatographed on silica gel eluting with 7% methanol in methylene chloride to give 1-[[2-(2-(4-chlorophenyl)ethyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl]imidazole (1.0 g) as a colorless oil which crystallized. The oil was dissolved in ether, the solution filtered and the hydrochloride salt formed by dropwise addition of ethereal hydrogen chloride until precipitation was almost complete. The precipitate was filtered, washed with ether and dried in vacuo to give 1-[[2-(2-(4-chlorophenyl)ethyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl]imidazole hydrochloride, m.p. 190°-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([Cl:17])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A catalytic amount of N,N-dimethylformamide (DMF)(10 μL) was added to a mixture of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (1.0 g, 5.1 mmol) and oxalyl chloride (2.2 mL, 25 mmol) in methylene chloride (5 mL) at 0° C. The resulting mixture was stirred at room temperature (about 25° C.) for 2 h. The volatiles were removed under reduced pressure, and the resulting residue was co-evaporated with toluene (2×) to provide the crude product, 1-(4-chlorophenyl)cyclopropanecarbonyl chloride, which was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([S:15]([N:1]([C:2]2[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=2)[S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1onc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 25 h
Yield: 72.9 %

Procedure:
3-Amino-4-bromo-5-methylisoxazole (5.31 g, 30 mmol) was dissolved in dry pyridine (30 ml). Benzenesulfonyl chloride (5.24 ml, 42 mmol) was added dropwise with stirring at ambient temperature. N,N-(Dimethyl)aminopyridine (100 mg) was added and stirring was continued at 50° C. for 25 h. The reaction mixture was diluted with dichloromethane (200 ml), washed with 1N HCl (6×100 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product which was purified by column chromatography using 9:1, hexanes/ethyl acetate as eluent to give N-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide (7 g, 51% yield, Rf =0.27 using 3:1, hexanes/ethyl acetate as eluent) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]([F:11])=[CH:7][C:6]=1[CH3:12]
Reactant: COC(=O)Oc1ccc(F)cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
Carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (12.8 g, 69.5 mmol) was suspended in 8 ml of concentrated sulfuric acid and cooled to 0° C. A mixture of concentrated nitric acid (8 ml) in concentrated sulfuric acid (8 ml) was added slowly, maintaining a reaction temperature below 50° C. After addition the mixture was stirred for 2 hours. The reaction mixture was poured into ice-water, forming a precipitate which was filtered and dried to give carbonic acid 4-fluoro-2-methyl-5-nitro-phenyl ester methyl ester (8.0 g, 50.3%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1Oc1ccc2ccc(N)nc2n1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4OC)nc3n2)cc1
Temperature: 4 °C
Yield: 69.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (10.2 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-(2-methoxyphenoxy)-1,8-naphthyridine (13.4 g). The product produced by precipitation in water (18 g; m.p. 167° C.) is dissolved in boiling ethanol (400 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-[7-(2-methoxyphenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (14 g) is produced, m.p. 168°-170° C.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:2]=[CH2:3].[S:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOC(C)=O>[CH2:1]([N:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:32][CH2:31][CH:27]3[CH2:28][CH2:29][CH2:30][S:26]3)[C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2ccccc2)c(-c2ccccc2)c2c(Cl)ncnc21
Reactant: NCC1CCCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCn1c(-c2ccccc2)c(-c2ccccc2)c2c(NCC3CCCS3)ncnc21
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-allyl-4-chloro-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidine (Example 3, Step B; 200 mg, 0.58 mmol) and 140 mg of (tetrahydrothiophen-2-yl)methylamine (1.20 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (200 mg, 1.45 mmol). The mixture was stirred for 5 minutes at 120° C. under microwave irradiation (using powerMAX™). The reaction mixture was then cooled and diluted with EtOAc (25 mL). The mixture was extracted twice with water (10 mL) and then brine. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (C8 column, water, acetonitrile, 0.1% TFA) to give the title compound.
Reaction SMILES: C([N:8]1[C:12]2=[N:13][C:14]([F:17])=[CH:15][CH:16]=[C:11]2[C:10]([CH2:18][Br:19])=[N:9]1)(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O>[Br:19][CH2:18][C:10]1[C:11]2[C:12](=[N:13][C:14]([F:17])=[CH:15][CH:16]=2)[NH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)nc21
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(CBr)n[nH]c2n1
Yield: 100.2 %

Procedure:
A solution of 1-Boc-3-(bromomethyl)-6-fluoro-1H-pyrazolo[3,4-b]pyridine (2-1; 195 mg; 0.59 mmol) was stirred in TFA (1 mL) for approximately 30 minutes. The reaction was concentrated in vacuo to give 136 mg (99%) of the desired product as a yellow solid after pumping. The crude product was used as is in the next step.