Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19](Br)[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1>C(Cl)(Cl)(Cl)Cl>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:9]([CH3:8])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCC(Br)c1cccc(OCc2c(C)cccc2C)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC=Cc1cccc(OCc2c(C)cccc2C)c1
Reaction time: 4 h

Procedure:
Add Triethylamine to a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-bromo-butyrate (Step E) in carbon tetrachloride. After stirring approximately for 4 hours, the mixture can be filtered through a pad of silica gel few times, and concentrate to give the title compound.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH3:24]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH3:24]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CCI
Product: CCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using ethyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as a light brown amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.15 (t, 3H), 1.70–2.01 (m, 3H), 2.65–2.70 (t, J=9.6 Hz, 3H), 2.70–2.95 (m, 2H), 2,95–3.13 (m, 2H), 3.13–3.72 (m, 5H), 3.60–3.95 (m, 1H), 6.39 (d, J=8.0 Hz, 1H), 6.47 (d, J=7,4 Hz, 1H), 6,64 (t, J=7.3 Hz), 1H) ppm. MS (CI): 244 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([CH:24]3[CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[O:28]1[CH2:31][C:30](=O)[CH2:29]1.C[Si]([C:37]#[N:38])(C)C>C(OCC)(=O)C>[CH2:12]([CH:11]1[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([CH:24]3[CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH:1][C:30]1([C:37]#[N:38])[CH2:31][O:28][CH2:29]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1COC1
Reactant: NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CC1(NC2CCc3ccc(CNS(=O)(=O)C4CCC4)cc3C2Cc2ccccc2)COC1
Temperature: 200 °C
Yield: 10.8 %

Procedure:
N-((7-amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)cyclobutanesulfonamide (0.100 g, 0.260 mmol) and 3-oxetanone (0.037 g, 0.520 mmol) were sealed in a vial and heated at 200° C. for 2 minutes. Trimethylsilyl cyanide (0.69 mL, 0.520 mmol) was added, the vial was resealed and the mixture was heated again at 200° C. for 2 minutes. The mixture was diluted with ethyl acetate (40 mL) and washed with 1 N NaOH (1×20 mL) and brine (1×20 mL). The organic extract was collected, dried on MgSO4 and evaporated under reduced pressure to give a brown oil. The residue was purified by preparative HPLC. Product was obtained as a colourless oil (13.2 mg, 0.028 mmol, 11%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([C:22](O)([CH3:24])[CH3:23])=[CH:17][C:16]=2[CH3:26])[C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]>C1C=CC=CC=1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([C:22]([CH3:24])=[CH2:23])=[CH:17][C:16]=2[CH3:26])[C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)(C)O)cc2C)c1C
Solvent: c1ccccc1
Product: C=C(C)c1cc(C)c(Oc2nc(C)cc(NC(CC)CC)c2C)c(C)c1

Procedure:
The title compound was prepared by reacting of 2-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-propan-2-ol with Burgess Inner salt (Et3NS(O)2NCOOMe in benzene at reflux for 30 min. 1H NMR(CDCl3) d 7.17(s,2H), 6.08(s,1H), 5.34(s,1H), 5.02(s,1H), 3.72(d,1H), 3.32(m,1H), 2.12 and 2.15 (two sets of s, 12H), 1.4-1.6(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
This compound was prepared in a similar way as described in literature (Journal of Medicinal Chemistry (2005), 48, 2371). A mixture of 1-fluoro-4-nitro-benzene (2.06 g, 14.7 mmol), [1,4]Diazepane-1-carboxylic acid tert-butyl ester (3.52 g, 17.6 mmol) and potassium carbonate (4.85 g, 35.2 mmol) in DMF (100 mL) was heated to 100° C. and stirred for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL), brine (50 mL), dried with anhydrous sodium sulfate and the solvent was removed. The residue was purified on a flash chromatography column with EtOAc/hexanes to afford 4-(4-nitrophenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.66 g, 78% yield) as a white solid. ES-MS for C16H23N3O4 calcd. (m/e) 321, observed 322 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:21]C)[C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[OH:21])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c3ccccc3c3c(OC)cccc3c2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c3ccccc3c3c(O)cccc3c2c1
Temperature: 220 °C
Yield: 98.8 %

Procedure:
2,9-dimethoxytriphenylene (49.1 g, 0.170 mol) and pyridine hydrochloride (200 g, 1.70 mol) were placed in a 500 mL round-bottom flask equipped with a stir bar, reflux condenser, and a nitrogen inlet and heated at 220° C. for 90 minutes. The solution was cooled and water was added, resulting in the formation of a white precipitate, which was collected by vacuum filtration, washed with water, and dried in vacuo to yield 43.7 g (96%) of 2,9-dihydroxytriphenylene.
Reaction SMILES: [CH3:1][C:2]([C:11]([O:13][CH3:14])=[O:12])([CH3:10])[NH:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].C([O-])(O)=O.[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[CH3:10][C:2]([C:11]([O:13][CH3:14])=[O:12])([CH3:1])[N:3]([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:27]
Reactant: COC(=O)CCNC(C)(C)C(=O)OC
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCN(C(=O)c1ccccc1)C(C)(C)C(=O)OC
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a mixture of methyl 2-methyl-N-[3-(methyloxy)-3-oxopropyl]alaninate (11.71 g, 57.62 mmol) in 1:1 DCM-water (300 mL) was added NaHCO3 (9.68 g, 115.2 mmol) followed by benzoyl chloride (7.02 mL, 60.48 mmol). The mixture was vigorously stirred overnight, and the phases were then separated. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (35% EtOAc in hexanes) to give methyl 2-methyl-N-[3-(methyloxy)-3-oxopropyl]-N-(phenylcarbonyl)alaninate (3.6787 g, 21% yield) as a colorless oil. LCMS: (M+H)+: 308.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[S:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[C:20](Cl)=[O:21])[N:17]=1>O.CC(C)=O.O1CCOCC1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[S:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[C:20]([N:1]=[N+:2]=[N-:3])=[O:21])[N:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a cooled (0° C.) solution of NaN3 (6.2 g, 95 mmol) in water (100 mL) and acetone (100 mL) was added a solution of (E)-3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acryloyl chloride (5.7 g, 19 mmol) in dioxane (100 mL) dropwise over 15 minutes. After addition, the resulting mixture was stirred for another 1 hour at 0° C. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extract was washed brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography, eluting with EtOAc/petroleum ether (1:8) to give the desired product as a yellow solid (5.3 g, 90% yield). LCMS (ESI) m/z: 309.0 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[N:15][C:16](Cl)=[CH:17][C:12]=3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].O.[NH2:24][NH2:25]>>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[N:15][C:16]([NH:24][NH2:25])=[CH:17][C:12]=3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)N2CCc3nnc(Cl)cc3C2)cc1
Reactant: NN
Solvent: O
Product: CCOc1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1

Procedure:
11.1 g of 6-(p-ethoxybenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 60 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 1 hour and 40 minutes. The title compound has a M.P. of 171°-173° (decomp., from absolute ethanol).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]12[CH2:15][CH2:14][C:11]([C:16]([O:18]CC)=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2>C1COCC1>[N:8]12[CH2:9][CH2:10][C:11]([C:16]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:18])([CH2:12][CH2:13]1)[CH2:14][CH2:15]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A solution of phenyllithium (1.5-1.7 M in 70 cyclohexane/30 ether, 20.0 mL, 32 mmol) was chilled down to −30° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (1.51 g, 8.23 mmol) in THF (20 mL) was slowly added to the reaction mixture at −30° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with H2O and then evaporated to dryness under vacuum. H2O and EtOAc were added, causing a white solid to crash out. This solid was filtered off, to give the title compound (0.79 g). The aqueous phase was further extracted with EtOAc, the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was treated with EtOAc and hexane and filtered to yield more of the title compound (0.67 g). Total yield (1.46 g, 60.7%). EI-MS m/z 294 (M+H+) Rt (1.37 min).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)[CH3:2].[C:12](Cl)(=[O:21])[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl[Sn]Cl.Cl>C1C=CC=CC=1.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[C:7]=1[C:12](=[O:21])[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCc1cc2ccccc2o1
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: c1ccccc1
Product: CCc1oc2ccccc2c1C(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Procedure A--To an ice cooled solution of 2-ethyl benzofuran 5.0 g and 5.9 g of o-anisoyl chloride dissolved in 20 ml benzene were added 4.1 ml of SnCl2 dropwise; the reaction mixture was stirred for 3 hours at room temperature. Then it was poured into water, 30 g, containing 5 ml of conc. HCl. The benzene layer was separated and the solution was extracted with benzene again. The combined benzene layer was washed with a 5% NaHCO3 solution and then with water. After drying and removal of benzene under reduced pressure, the yellowish oil, 2-ethyl-3-(o-anisoyl)benzofuran was obtained. Pyridine-HCl was prepared by the introduction of dried HCl gas to 4.75 g of pyridine and a 50 ml of benzene solution, and then by removing benzene twice.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]3[CH2:23][CH2:22][CH2:21][C:20]([F:25])([F:24])[C@@H:19]3[NH:26][C:27]([C:29]3[S:30][C:31]([CH:43]([F:45])[F:44])=[C:32]([C:34]4[N:38]5[N:39]=[CH:40][CH:41]=[CH:42][C:37]5=[N:36][CH:35]=4)[CH:33]=3)=[O:28])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C.O>[NH2:17][C@@H:18]1[C@@H:19]([NH:26][C:27]([C:29]2[S:30][C:31]([CH:43]([F:44])[F:45])=[C:32]([C:34]3[N:38]4[N:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][CH:35]=3)[CH:33]=2)=[O:28])[C:20]([F:24])([F:25])[CH2:21][CH2:22][CH2:23]1
Reactant: O=C(N[C@H]1CCCC(F)(F)[C@@H]1NC(=O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: N[C@H]1CCCC(F)(F)[C@@H]1NC(=O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1
Reaction time: 1 h

Procedure:
To a stirred solution of 9H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (27 mg, 0.042 mmol) in DMF (0.8 mL) was added piperidine (0.08 mL, 0.83 mmol). The mixture was left to stir for 1 h, diluted with water, and extracted with EtOAc. The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.38 (s, 1H); 8.72 (d, 1H); 8.68 (dd, 1H); 8.43 (s, 1H); 8.27 (dd, 1H); 7.97 (s, 1H); 7.38 (dd, 1H); 7.35 (t, 1H); 4.05 (m, 1H); 2.82 (m, 1H); 1.30-2.10 (m, 6H). LRMS (APCI) calc'd for (C18H18F4N5OS) [M+H]+, 428.1. found 428.1.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([Si:20]([CH3:35])([CH3:34])[O:21][CH2:22][CH:23]([CH3:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([Si:20]([CH3:35])([CH3:34])[O:21][CH2:22][CH:23]([CH3:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]([OH:6])=[O:28])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)Oc1ccccc1C=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(CO[Si](C)(C)C(C)(C)C)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of sodium chlorite (1.17 g; 12.9 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.01 g; 8.44 mmol; 3.6 eq.) in water (10 mL) was added dropwise to a mixture of 2-methyl-2-butene (2 mL) and 2-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethoxy]-benzaldehyde (690 mg; 2.34 mmol; 1 eq.) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 1.5 hour. After dilution with EA, the solution was washed with 1M HCl, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (690 mg, 95%) as a white solid. UPLC/MS: (MS−) 309.1 ([M−H]−).
Reaction SMILES: Cl[C:2]1(Cl)[C:9](=[O:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([O:18][CH3:19])[CH2:16][CH3:17]>[Zn].C(O)(=O)C>[CH3:19][O:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][C:9](=[O:10])[CH2:2]2
Reactant: CCC(CCCCC1CCC2C1CC(=O)C2(Cl)Cl)OC
Agent: [Zn]
Solvent: CC(=O)O
Product: CCC(CCCCC1CCC2CC(=O)CC12)OC

Procedure:
6,6-Dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one {1,1-dichlorohexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} (45.9 g) is added to a 100 ml, round-bottomed flask fitted with a condenser. Powdered zinc metal (92 g) and glacial acetic acid (312 ml) are added to the flask and the solution allowed to reflux for an hour. The solution is filtered to remove the zinc and zinc chloride, formed in the reaction. The product is washed with an aqueous sodium bicarbonate solution and extracted three times with ether. The ether extracts are combined and dried over anhydrous sodium sulfate. The resulting yellow oil is chromatographed on silica gel and eluted with 4:1 hexane:ether. The fractions are combined, and gave 2-(5-methoxyhept-1-yl)bicyclo [3.3.0]octan-7-one {hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} as a clear, colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCCC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCC1CCCCC1
Reaction time: 3 h
Yield: 89.8 %

Procedure:
4-Cyclohexyl-1-butanol (5.00 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (9.15 g) and N-bromosuccinimide (6.21 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (6.30 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([CH:4]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]1O)[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C@H:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([CH:2]([NH2:1])[CH3:3])[CH2:13]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC(N)C1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of 43 (400 mg, 1.19 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction mixture was stirred for 2 h before being concentrated. The residue was subjected to reverse phase column chromatography (CH3CN/H2O/0.1% Formic acid=5% to 100%) to give 1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethanamine (0.31 g, 77.5%) as a mixture of two diastereomers (45 and 46).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23]C(=O)C)[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A mixture of N-{4-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (250 mg, 0.70 mmol) produced in Example 1-B (vi), 1N aqueous sodium hydroxide solution (3.5 mL), methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 3 hr. To the reaction mixture was added 1N aqueous sodium hydroxide solution (3.5 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and concentrated under reduced pressure. The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (130 mg, 58%) as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1Cl.[F:15][C:16]([F:25])([F:24])C1C=CC=CC=1O>>[ClH:2].[F:15][C:16]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](N)CCc1ccc(Cl)c(Cl)c1
Reactant: Oc1ccccc1C(F)(F)F
Agent: Cl
Product: C[C@@H](N)CCc1cccc(C(F)(F)F)c1
Yield: 88 %

Procedure:
Intermediate 5 (55 mg, 0.25 mmol, 88% yield) was prepared as a white powder following the procedure described for Intermediate 4 by replacing 2,6-dichlorophenol with 2-trifluromethylphenol. LC-MS (ESI) 218.1 (M+H), RT=1.60 min (Method B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:50]([NH:54][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[N:15][C:16]=12)=[O:24])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 20.0 mg, 0.058 mmol) and HATU (24.3 mg, 0.064 mmol) in dry DMF (0.4 mL) was added tert-butyl amine (12.7 mg, 0.174 mmol) followed by diisopropylethylamine (22.5 mg, 0.174 mmol). The mixture was stirred under an atmosphere of N2 for 18 hours and was added to H2O (3 mL) and mixed. The mixture was extracted with EtOAc and combined extracts were washed with 1M HCl, H2O, saturated NaHCO3 and dried over MgSO4. The solution was eluted through a SPE SiOH column eluting first with 50% EtOAc-hexanes then with EtOAc. The EtOAc pool was concentrated and the residual colorless glass was treated with hexanes give a white suspension. The hexanes were removed, and the solid was washed with hexanes and dried in vacuum to afford the title compound as a white solid (20 mg, 90%). MS (apci) m/z=400.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[O:20]1[C:24]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[CH:23][N:22]=[CH:21]1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([C:24]5[O:20][CH:21]=[N:22][CH:23]=5)[CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2cccc(-c3cnco3)c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 3-(1,3-oxazol-5-yl)aniline gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 20.25 min.; purity: 81%, MS (m/e): 406 (MH+).