Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:18]([CH2:20][C:21](Cl)=[O:22])=[CH2:19]>C(Cl)Cl>[CH:18]([CH2:20][C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:22])=[CH2:19]
Reactant: C=CCC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(=O)NCCc1ccc(O)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A 1000-mL 3-neck, round bottom flask connected with a reflux condenser and a drying tube, is charged with 250 mL of methylene chloride, 5.48 grams (0.04 mole) 4-aminoethylphenol and 4.04 grams (0.04 mole) triethylamine. The contents are chilled with an ice bath. Through a dropping funnel, 4.18 g (0.04 mole) of vinylacetyl chloride is added into the flask over a period of 30 minutes. The ice bath is then removed and the contents are continuously stirred overnight. The mixture is then filtered and then condensed using a rotavapor. High performance liquid chromatography (HPLC) analysis indicates only one major product. The product is then passed through silica gel chromatography to give a final purified product with a yield of at least 80 percent. The product is identified by NMR and Mass Spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: ClCc1ccnc(-c2ccccc2)c1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3ccccc3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (612 mg) and 4-chloromethyl-2-phenylpyridine (204 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]([O:14]CC)=[CH2:13])=[CH:7][CH:6]=2>O1CCOCC1.Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=2
Reactant: C=C(OCC)c1ccc2cnc(Cl)cc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc2cnc(Cl)cc2c1
Yield: 89 %

Procedure:
A solution of 3-chloro-6-(1-ethoxy-vinyl)-isoquinoline (934 mg, 4 mmol) in 1,4-dioxane (10 mL) and hydrochloric acid (2 M, 5 mL) was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic extracts were combined, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 4:1 to afford the title compound (732 mg, 89%) as a white solid. 1H NMR (300 MHz, CDCl3) δ2.77 (s, 3H), 7.88 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 8.15 (dd, J=8.5, 1.4 Hz, 1H), 8.37 (brs, H), 9.17 (s, 1H). LCMS (m/z) 206/208 [M+H], Tr=4.40 min.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](OC)([O:14]C)[CH:10]([O:18][CH3:19])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([O:18][CH3:19])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC1CN(Cc2ccccc2)CCC1(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COC1CN(Cc2ccccc2)CCC1=O
Yield: 90.6 %

Procedure:
1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b, 2.22g, 8.36 mmol) from Example 2 and p-toluenesulfonic acid (3.15g, 16.6 mmol) was heated to reflux in acetone (100ml) for three hours. After being cooled, the reaction solution was concentrated under vacuum, then slurried in 40ml of 10% sodium hydroxide solution. The aqueous mixture was extracted with 2×60ml of ether, the combined organic layers were dried over magnesium sulfate, then concentrated under vacuum. The crude residue was purified by chromatography (silica gel; ethyl acetate/hexane; 1:1) to provide the intermediate 1-phenylmethyl-3-methoxy-4-piperidone (5b, 1.66g, 90%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1ccc(F)cc1
Product: N#Cc1ccc(N(CCOc2ccc(F)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (El) m/z 406 (M+, 54%), 295 ([M-C6H4FO]+, 82%), 281 (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([F:27])[C:17]=1[C:18]#[N:19]>C1COCC1.O>[F:27][C:20]1[C:17]([C:18]#[N:19])=[C:16]([NH:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: Nc1cncc(F)c1
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1cncc(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of 5-Fluoropyridin-3-ylamine (1.22 g, 10.9 mmol) in THF (30 mL) at −0° C. was added potassium tert-butoxide (2.43 g, 21.7 mmol) and the reaction mixture stirred at 0° C. for 10 min. This solution was added via cannula to a solution of 2,6-difluoro-3-nitrobenzonitrile (2 g, 10.9 mmol) in THF (20 mL) at −78° C. and the dark purple reaction mixture stirred at −78° C. for 10 min. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane). The solid obtained was triturated with pentane to give the title compound as an orange solid (1.73 g, 58%). 1H NMR 400 MHz δ (CDCl3): 9.73 (1H, br s), 8.53 (1H, dd, J=9.5, 5.7 Hz), 8.47 (1H, d, J=2.5 Hz), 8.43-8.40 (1H, m), 7.33 (1H, dt, J=8.8, 2.2 Hz), 6.83 (1H, dd, J=9.5, 7.3 Hz).
Reaction SMILES: [CH3:1][C@@:2]12[C@@:11]([OH:16])([C:12]([CH2:14][OH:15])=[O:13])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:17][CH2:18][C:19]3[C@@:25]([CH3:26])([C@H:6]1[C:4](=[O:5])[CH2:3]2)[CH:24]=[CH:23][C:21](=[O:22])[CH:20]=3.[CH3:27]C(OCC([C@]1(O)[C@@]2(C)CC([C@@H]3[C@]4(C)C(=CC(C=C4)=O)CC[C@H]3[C@@H]2CC1)=O)=O)=O>>[CH3:27][C@@H:18]1[C:19]2=[CH:20][C:21]([CH:23]=[CH:24][C@:25]2([CH3:26])[C@@H:6]2[C@H:7]([C@H:8]3[C@:2]([CH3:1])([CH2:3][C@@H:4]2[OH:5])[C@@:11]([OH:16])([C:12]([CH2:14][OH:15])=[O:13])[CH2:10][CH2:9]3)[CH2:17]1)=[O:22]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@@]21C
Product: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12

Procedure:
BRAND_NAMES Ancortone, Colisone, Cortancyl, Dacortin, Decortancyl, Decortin, Delcortin, Deltacortone, Deltasone, Deltison, Di-Adreson, Encorton, Meticorten, Nurison, Orasone, Paracort, Prednilonga, Pronison, Rectodelt, Sone, Ultracorten CHEMICAL_NAME 17,21-dihydroxypregna-1,4-diene-3,11,20,trione CHEMICAL_FORMULA C21H26O5 CAS_NUMBER 53-03-2 Formulation
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][OH:15])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][O:15][S:24]([CH3:27])(=[O:26])=[O:25])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (250 mg, 0.756 mmol) and triethylamine (0.116 mL, 0.832 mmol) in CH2Cl2 (4 mL) cooled at −10° C. was added under nitrogen atmosphere mesylchloride (0.065 mL, 0.832 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched with ice and water then extracted twice with EtOAc. The combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated. The crude material (colorless oil) was used without purification in the next step. TLC, Rf (c-hexane/EtOAc 1:1): 0.46.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.CO.[C:18](#[N:21])[CH:19]=[CH2:20]>N1C=CC=CC=1>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH:15][CH2:20][CH2:19][C:18]#[N:21])=[N:12][O:13][N:14]=1
Reactant: C=CC#N
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Solvent: c1ccncc1
Solvent: CO
Product: N#CCCNc1nonc1-c1nc2ccccc2[nH]1

Procedure:
To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g, 0.497 mmol) in pyridine (5 ml) sodium in methanol (0.02 g, 0.86 mmol in 1 ml) and acrylonitrile (0.03 g, 0.39 mmol) are added sequentially at 0° C. The mixture is stirred over night. Evaporation of the solvent under reduced pressure and partitioning of the resulting residue between water and ethyl acetate followed by drying of the organic solution over sodium sulphate gives the title compound in pure form. 1H-NMR (400 MHz, d6-DMSO): 13.7 (s, 1H); 7.82 (d, 1H); 7.60 (d, 1H); 7.36 (m, 2H); 7.20 (t, 1H); 3.67 (q, 2H); 2.94 (t, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[CH:46][N:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (59 mg, 0.22 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (39 mg, 0.22 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid (55 mg, 0.19 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C., where it was stirred for 20 min. The reaction mixture was then treated with 2-aminopyridine (39 mg, 0.41 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/1 methylene chloride/methanol) to afford impure 3-cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-4-yl-phenyl)-propionamide as a yellow solid. Repurification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded pure 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide (10 mg, 14%) as a yellow solid: mp 165-167° C.; EI-HRMS m/e calcd for C24H25N3O (M+) 371.1998, found 371.1998.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:17][CH3:16])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 5.7 g. Recrystallization from ethanol-water yielded 4.9 g (85.9%) of fine white crystals, m.p. 135°-137° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH2:21]([C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)[CH2:22][CH3:23]>>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=[C:2]([S:30][C:27]3[CH:28]=[CH:29][C:24]([CH2:21][CH2:22][CH3:23])=[CH:25][CH:26]=3)[CH:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: CCCc1ccc(S)cc1
Product: CCCc1ccc(Sc2cc(N3CCN(C)CC3)nc(-c3ccccc3)n2)cc1

Procedure:
Similarly, 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine is reacted with p-propylthiophenol to afford 6-(4-methyl-1-piperazinyl)-2-phenyl-4-(4-propylphenylthio)pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[S:19])[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]([O-])([O-])=O.[Cs+].[Cs+].IC>CC#N>[CH3:20][S:19][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(=S)[nH]n(-c3ccccc3)c2c1
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CSc1nn(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 6-nitro-1-phenyl-1,2-dihydroindazole-3-thione (3.1 g, 11.44 mmol, 1.00 equiv) in CH3CN (20 mL), Cs2CO3 (21 g, 64.42 mmol, 5.63 equiv). To the resulting mixture was then added a solution of iodomethane (11.3 g, 79.58 mmol, 6.96 equiv) in CH3CN (15 mL) dropwise with stirring at 10° C. in 30 min. The resulting solution was stirred for 30 min at 10° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100) to yield 3-(methylthio)-6-nitro-1-phenyl-1H-indazole as a yellow solid. MS: 285 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C.[F:27][C:28]([F:48])([F:47])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:37]2=[O:46])=[CH:32][CH:31]=1.[OH:49][C:50]1([C:53](O)=[O:54])[CH2:52][CH2:51]1>>[OH:49][C:50]1([C:53]([N:43]2[CH2:42][CH2:41][C:38]3([C:37](=[O:46])[N:36]([C:33]4[CH:34]=[CH:35][C:30]([O:29][C:28]([F:27])([F:47])[F:48])=[CH:31][CH:32]=4)[CH2:40][CH2:39]3)[CH2:45][CH2:44]2)=[O:54])[CH2:52][CH2:51]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(O)C1(O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: O=C(N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)C1(O)CC1

Procedure:
The title compound was prepared in analogy to example 13 step A (using TBTU instead of BOP as the coupling reagent) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 1-hydroxy-cyclopropanecarboxylic acid. White solid. MS (ESI): 399.1 (MH+).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(NCc1ccc(F)cc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1

Procedure:
4-[4-(2-aminoethyl)anilino]-N-(2,4-difluorobenzyl)-1-piperidinecarboxamide formate (0.477 g, 1.1 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to give the title compound (0.25 g, 0.032 mmol).
Reaction SMILES: [CH2:1]([O:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25](OC(=O)C)(=[O:27])[CH3:26].B(F)(F)F.CCOCC>>[C:25]([C:22]1[S:21][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCOc1cccs1
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(C)=O)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
When in Example 3, 1-bromooctadecane is substituted for 1-bromohexadecane, 2-octadecyloxythiophene is obtained. A mixture of 35.3 g (0.1 mole) of 2-octadecyloxythiophene and 12.3 g (0.12 mole) of acetic anhydride is cooled in an ice bath. While rapidly stirring this mixture, 1.4 g of boron trifluoride etherate is added, and the mixture is heated to 100° C with stirring for 1 hour after which it is cooled to room temperature. Ice water is added, and the mixture is extracted with chloroform. The chloroform solution is evaporated to dryness under reduce pressure to give 2-acetyl-5-octadecyloxythiophene. In 500 ml of 10% aqueous potassium hydroxide 2-acetyl-5-octadecyloxythiophene is combined with 35.0 g (0.6 mole) of lithium hypochlorite. The mixture is stirred vigorously on a steam bath overnight, then allowed to cool to room temperature and extracted with ether. The aqueous extract is acidified with hydrochloric acid to precipitate 5-octadecyloxy-2-thiophenecarboxylic acid
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]1([CH:14]2[N:18]3[C:19](=[O:30])[N:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)C(O)[C@@H]3[CH2:16][S:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:8]1([CH:14]2[N:18]3[C:19](=[O:30])[N:20]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:6]3[CH2:16][S:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1N(Cc2ccccc2)C(O)[C@@H]2CSC(c3ccccc3)N12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1[C@@H]2CSC(c3ccccc3)N2C(=O)N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
33.69 g (0.33 mol) of acetic anhydride and 366.5 mg (3 mmol) of 4-(dimethylamino)-pyridine are added to a solution of 97.92 g (0.3 mol) of (7RS,7aR)-3-phenyl-6-benzyl-7,7a-dihydro-7-hydroxy-1H,3H-imidazo[1,5-c]thiazol-5(6H)-one in 900 ml of toluene, and the solution is stirred for 2 hours at 40° C. After cooling to room temperature the solution is washed with 180 ml of water, with 180 ml of a saturated sodium bicarbonate solution and the solvent is distilled off. 109.8 g of (7RS,7aR)-3-phenyl-6-benzyl-7,7a-dihydro-7-acetoxy-1H,3H-imidazo[1,5-c]thiazol-5(6H)-one are obtained as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4](=[O:20])[C:3]=1[C:21]#[N:22].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:3]([C:21]#[N:22])[C:4]2=[O:20])=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of Compound 8 (15 g, 48 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (12 g, 144 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solid was dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 17.17 g (98%) of yellow solids. 1H NMR (DMSO-d6): δ 2.8 (m, 2H), 3.0 (m, 2H), 3.6 (m, 2H), 3.7 (m, 2H), 5.45 (s, 2H), 7.1 (m, 2H), 7.3 (m, 3H), 7.4 (m, 1H), 7.6 (m, 1H), 7.90 (t, J=8.2 Hz, 1H); EIMS: 363 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCOCC1>CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccccc3)n2n1
Temperature: 110 °C
Yield: 25.3 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 49 mg, 0.142 mmol), phenylboronic acid (23 mg, 0.189 mmol), and [1,1′-bis[1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (9.3 mg, 13 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.76 mL of 1,4-dioxane and 0.38 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-75% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (13.9 mg, 25%). Decomposition observed at 199.8° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H), 2.40 (s, 3 H), 5.20 (br. s., 1 H), 6.40 (s, 1 H), 7.58-7.66 (m, 5 H), 7.97 (s, 1 H), 8.02 (d, J=8.59 Hz, 2 H), 8.06 (dd, J=6.57, 3.03 Hz, 2 H), 11.20 (s, 1 H); ESI-MS: m/z 387.2 (M+H)+.
Reaction SMILES: [C:1]1([P:7]([Cl:10])(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[C:1]1([P:7]([Cl:10])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: CCCCCCCCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCP(=O)(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.5 %

Procedure:
To a solution of phenylphosphonic dichloride (3.0 g, 14.2 mmol) and triethylamine (2.4 mL, 17.1 mmol) in toluene (20 mL) at 0° C. is added dropwise a solution of 1-nonanol (2.05 g, 14.2 mmol) in toluene (5 mL). The mixture is allowed to warm slowly to room temperature and stirred for 2 hours. The mixture is filtered, and the filtrate is concentrated to afford 4.5 g of the title compound as a light yellow liquid; 1H NMR (200 MHz, CDCl3)δ7.40-7.15 (m, 5 H), 4.40-4.25 (m, 2 H), 1.90-1.65 (m, 2 H), 1.45-1.20 (m, 12 H), 0.89 (t, J=7 Hz, 3 H).