Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH3:21]I>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]=[C:9]1[N:13]([CH3:21])[CH:12]=[CH:11][S:10]1
Reactant: CCOC(=O)C(C)c1ccc(Nc2nccs2)c(Cl)c1
Reactant: CI
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N=c2sccn2C)c(Cl)c1
Temperature: 100 °C
Yield: 62 %

Procedure:
A mixture of ethyl 2-[3-chloro-4-(N-thiazol-2-ylamino)phenyl]propionate (3.8 g), methyl iodide (11.4 ml) and ethanol (11.4 ml) is heated at 100° C for 6 hours in a sealed tube. The ethanol and methyl iodide are evaporated. The residue is washed with benzene and dissolved in methylene chloride. The solution is washed with 20 % aqueous potassium carbonate solution and evaporated to remove methylene chloride. The residue is treated in the same manner as in Example 1 to give ethyl 2-[3-chloro-4-(3-methyl-4-thiazolin-2-ylideneamino)phenyl]propionate (2.45 g). (Yield 62 %).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1F

Procedure:
The title compound is prepared in analogy to Example 20a) from 3-fluoro-4-nitrophenol and 3-fluoro benzyl bromide. Yield: 100% of a colorless solid. MS: m/e=265.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][C@H:26]1[CH2:31][CH2:30][CH2:29][NH:28][C@H:27]1[CH2:32][OH:33]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:28]2[CH2:29][CH2:30][CH2:31][C@H:26]([CH3:25])[C@@H:27]2[CH2:32][OH:33])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H]1CCCN[C@H]1CO
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H]1CCCN(C(=O)Cc2ccc(Cl)c(Cl)c2)[C@H]1CO
Reaction time: 16 h
Yield: 60.2 %

Procedure:
A solution of 3,4-dichlorophenylacetic acid (1.82 g) and 1,1'-carbonyldiimidazole (1.70 g) in dry tetrahydrofuran (30 ml) was stirred at room temperature under nitrogen for 20 min. A solution of cis-3-methyl-2-piperidinemethanol (1.15 g) in dry tetrahydrofuran (10 ml) was then added and stirring was continued for 16 h. before concentrating the reaction mixture in vacuo. The residue was dissolved in dichloromethane (50 ml), and this solution was washed with 2M hydrochloric acid (50 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), dried and concentrated in vacuo to give a solid. This crude product was crystallised from ethyl acetate:methanol to give the isomerically pure title compound as needles (1.69 g) m.p. 161°-162°.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][C@H:7]([NH2:9])[CH3:8])[NH:3][CH:2]=1.[CH2:10]=O.[OH-].[Na+]>P([O-])([O-])([O-])=O.C(O)C>[CH3:8][C@H:7]1[NH:9][CH2:10][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH2:6]1
Reactant: C[C@@H](N)Cc1cnc[nH]1
Reactant: C=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1Cc2[nH]cnc2CN1
Temperature: 37 °C
Reaction time: 12 h

Procedure:
0.5 g (R)-2-(3H-imidazol-4-yl)-1-methyl-ethylamine are dissolved in 50 mL phosphate buffer (pH 7) and combined with 1.35 mL formaldehyde. The pH is adjusted to 8 by the addition of 1 N NaOH and the reaction solution is stirred for 12 h at 37° C. Then by the further addition of 1 N NaOH the pH is adjusted to 12, the solvent is eliminated in vacuo, the residue is suspended in ethanol and filtered to remove any undissolved constituents. After elimination of the ethanol in vacuo a crude product is left which is further used directly for the following reactions.
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:19]1([CH:15]2[CH2:16][CH2:17][N:12]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:13][CH2:14]2)[CH2:22][CH2:21][CH2:20]1
Reactant: C1CNC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(N3CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.0 mL (17.5 mmol) glacial acetic acid were added to the stirred mixture of 3.0 mL (16.5 mmol) 1-benzyl-4-piperidone, 1.0 g (17.5 mmol) azetidine and 100 mL DCM. Then 6.0 g (39.5 mmol) sodium triacetoxy-borohydride was added batchwise within one hour while cooling with an ice bath and the mixture was stirred for a further 12 h at RT. The reaction mixture was extracted with 200 mL EtOAc, the organic phase was dried, evaporated down under reduced pressure and the residue was purified by chromatography.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Reactant: ClCCN1CCOCC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCOCC1)CC2c1ccccc1

Procedure:
The title compound, MS: m/e=584.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and 4-(2-chloroethyl)-morpholine.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22]C=C)[CH2:6][C:5]=2[CH:4]=1.[F:25][C:26]([F:49])([C:45]([F:48])([F:47])[F:46])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[C:33]([O:35]CC)=[O:34]>>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([F:25])([F:49])[C:45]([F:46])([F:47])[F:48])[C:33]([OH:35])=[O:34])[CH2:6][C:5]=2[CH:4]=1
Reactant: C=CCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O)[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol prepared in Example 13 and ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[C-:10]#[N:11].[Na+].[I-].[Na+].O>CN(C=O)C>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][CH2:2][C:10]#[N:11]
Reactant: ClCCCC1OCCO1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCC1OCCO1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
A mixture of 2-(3-chloropropyl)-1,3-dioxolane (15.88 g; 0.1054 moles), sodium cyanide (6.46 g; 0.132 moles) and sodium iodide (1.57 g; 0.0105 moles) in DMF (100 mL) was heated at 80° C., with magnetic stirring, under a nitrogen atmosphere for 15 hours. The mixture was allowed to cool, added to water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with water (200 mL) and saturated aqueous sodium chloride solution (100 mL) and then dried over sodium sulfate. Filtration and evaporation of solvent gave a crude yellow oil which was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (5:2). Removal of solvent under vacuum gave the product 4-(1,3-dioxolan-2-yl)-butanenitrile (11.28 g; 76%) as a colorless oil. 1H NMR (CDCl3) δ 4.89–4.91 (1H, m), 3.92–4.01 (2H, m), 3.82–3.90 (2H, m), 2.40–2.46 (2H, m), 1.77–1.85 (4H, m).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH:12]=[N:13][CH:14]=[CH:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CC(C)=O.O1CCOCC1.[Pd]>[CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH2:12][N:13]([C:31](=[O:33])[CH3:32])[CH2:14][CH2:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(=O)N1CCc2nc(N3CCN(Cc4ccc(F)cc4F)CC3)c(NC3CCC3)nc2C1
Temperature: 45 °C
Reaction time: 50 h
Yield: 51.1 %

Procedure:
To N-cyclobutyl-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazin-3-amine (0.500 g, 1.218 mmol) in acetone (25 mL) and dioxane (25 mL) was added palladium, 10 wt % on activated carbon (0.052 g, 0.487 mmol) as a slurry in dioxane (3 mL) under nitrogen. Next, acetic anhydride (1.144 mL, 12.18 mmol) was added at 23° C. The mixture was stirred under hydrogen at 310 kPa for 50 hr at 45° C. The crude mixture was filtered through Celite™, rinsed with dioxane, and concentrated via rotary evaporation. The crude material was purified via medium pressure chromatography using a 10% to 100% gradient eluant of EtOAc in heptanes on an NH 60 μM size 60 column (Shoko Scientific Purif-Pack™) to give the title compound 1-(3-(cyclobutylamino)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone (284 mg, 51.1%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.56-1.72 (m, 2H), 1.97-2.06 (m, 2H), 2.07 (s, 1.3H), 2.08 (s, 1.7H), 2.18-2.27 (m, 2H), 2.52-2.66 (m, 4.9H), 2.69 (t, J=5.9 Hz, 1.1H), 2.99 (br s, 4H), 3.59 (s, 2H), 3.69 (dt, J=11.5, 6.0 Hz, 2H), 4.27-4.46 (m, 3H), 5.89 (d, J=7.3 Hz, 0.4H), 5.93 (d, J=7.8 Hz, 0.6H), 7.02-7.13 (m, 1H), 7.17-7.27 (m, 1H), 7.41-7.55 (m, 1H); ESI-MS m/z [M+H]+ 457.0.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.C(=O)([O-])N.[C:26]([N:43]=[C:44]=[O:45])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[C:26]([NH:43][C:44](=[O:45])[O:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=1)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCC(=O)N=C=O
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCCCCCCCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1CC
Yield: 57 %

Procedure:
The compound 19 (250 mg, 0.725 mmol) was converted to the carbamate with palmitoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 85 (259 mg, 57%). Mp. 95-97° C. Rf 0.33 (1:2 EtOAc - hexane).
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2C=C[CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C.C(N(C)CCN)(OC(C)(C)C)=O>CN(C=O)C>[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([NH:16][CH2:11][CH2:10][NH:15][CH3:14])=[O:50]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(CCN)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNCCNC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
HATU (0.157 g, 0.41 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.145 g, 0.38 mmol) and Hünig's base (65 μL, 0.38 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N-Boc-N-methylethylenediamine (335 μL, 1.88 mmol) was added, the coolant removed and the reaction mixture stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the crude product dissolved in DCM. The organic layer was washed with water, concentrated in vacuo (10 mL) and trifluoroacetic acid added (3.0 mL). The mixture was stirred at ambient temperature overnight, concentrated in vacuo and purified by ion-exchange chromatography (SCX-2 eluting with hydrochloric acid/MeOH→ammonia/MeOH). Further purification by flash-column chromatography (100% DCM→10% ammonia/MeOH/DCM) yielded the title compound as pale yellow solid (0.043 g, 25%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10]C)[CH:5]=1.C(Cl)(Cl)Cl.B(Br)(Br)Br.[NH4+].[OH-]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(CCBr)c1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1cccc(CCBr)c1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-bromoethyl)-3-methoxybenzene (1.00 g, 4.7 mmol) in CHCl3 (50 mL, 0.6 mol) was cooled to at 0° C. 1.0 M of BBr3 in DCM (27.9 mL) was cooled to 0° C. and added to the solution. The solution was allowed to warm to 30° C. over 30 minutes, then was poured into a solution of ice and 30% NH4OH, which was stirred at 0° C. for 30 minutes. The organic layer was taken and concentrated with no reduced pressure.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[OH-].[K+].O>CN1CCCC1=O>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([NH:37][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:23][CH:22]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cnc2[nH]cc(Cc3cnc(NC4CCCCC4)nc3)c2c1
Temperature: 155 °C
Yield: 25.7 %

Procedure:
In a microwave vial, to 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (37, 60 mg, 0.13 mmol) in 1.0 mL of N-methylpyrrolidinone, cyclohexanamine (62, 0.20 g, 2.0 mmol) is added. The reaction is heated at 155° C. for 25 minutes in a microwave, then potassium hydroxide (1.0 mL, 1.00 M in water, 1.0 mmol) is added and the reaction heated at 95° C. for 15 minutes in a microwave. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are collected and concentrated under vacuum to provide the desired compound (P-3001, 11.4 mg). MS (ESI) [M+H+]+=341.9.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:14]([CH3:15])=[CH:13][C@H:12]2[C@@:7]([OH:20])([C@@H:8]([CH3:19])[CH2:9][CH2:10][C@H:11]2[C:16]([CH3:18])=[CH2:17])[C@H:6]1[OH:21])(=[O:3])[CH3:2].[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=C[CH:23]=1>COC(OC)(C)C>[C:1]([O:4][C@H:5]1[C@@H:6]2[O:21][C:22]([CH3:27])([CH3:23])[O:20][C@:7]32[C@@H:12]([C@H:11]([C:16]([CH3:18])=[CH2:17])[CH2:10][CH2:9][C@@H:8]3[CH3:19])[CH:13]=[C:14]1[CH3:15])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(C)[C@@H]1CC[C@H](C)[C@]2(O)[C@@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2O
Solvent: COC(C)(C)OC
Product: C=C(C)[C@@H]1CC[C@H](C)[C@@]23OC(C)(C)O[C@H]2[C@H](OC(C)=O)C(C)=C[C@H]13
Reaction time: 72 h
Yield: 776 %

Procedure:
A stirred solution of (1S,2R,4aR,5R,8S,8aS)-1,8a-dihydroxy-5-isopropenyl-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydro-2-naphthalenyl acetate (Preparation 126, 10 g) in 2,2-dimethoxypropane (200 ml) was treated with para-toluenesulfonic acid (700 mg). After 3 days, the solution was concentrated in vacuo and the residue purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (5:95) to give the product (10.55 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH:26]([C:28]1[C:36]2[C:31](=[C:32]([CH2:37][N:38]([CH3:46])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O>CO.N1CCCCC1>[C:41]([O:40][C:39]([N:38]([CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[NH:30][CH:29]=[C:28]2/[CH:26]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9])[CH3:46])=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: CN(Cc1cccc2c(C=O)c[nH]c12)C(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCNCC1
Product: CN(Cc1cccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c12)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.029 g, 0.10 mmol) obtained in Example A16, Step 1 in methanol (3.0 mL) was added with tert-butyl (3-formyl-1H-indole-7-yl)methyl(methyl)carbamate (0.038 g, 0.11 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→95:5)) to obtain tert-butyl (Z)-4-({2-[(7-{[tert-butoxycarbonyl(methyl)amino]methyl}-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.044 g, 71%).
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].N1C=CN=C1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].O>CN(C)C=O>[C:1]([C:3]1([O:11][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2]
Reactant: C[Si](C)(C)Cl
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CC1(O[Si](C)(C)C)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
3-Ethynyl-3-hydroxyquinuclidine (1.5 g) and imidazole (1.7 g) were stirred in dimethyl formamide (25 ml). Trimethylsilylchloride (1.35 g) was added slowly to the solution and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (150 ml) and the aqueous phase extracted with ethyl acetate (2×100 ml). The ethyl acetate extracts were combined, washed with water (2×100 ml), brine (100 ml), dried (MgSO4) and evaporated to give 3-ethynyl-3-trimethylsilyloxyquinuclidine as an oil (1.8 g), NMR: 0.15 (9H, s), 1.2-1.38 (1H, m), 1.42-1.6 (1H, m), 1.65-1.9 (3H, m), 2.55-2.7 (4H, m), 2.76 (1H, d), 3.02 (1H, d), 3.55 (1H, s), m/z 224 (M+H).
Reaction SMILES: [CH:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[CH2:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([N:6]1[CH2:5][CH2:4][C:3]([CH:1]=[CH2:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7]1)(=[O:17])=[O:16]
Reactant: C=CC1(C(=O)OCC)CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C=CC1(C(=O)OCC)CCN(S(C)(=O)=O)CC1
Yield: 98 %

Procedure:
Following the procedure reported in Example 84, the N-Boc group of 1-tert-butyl 4-ethyl 4-vinylpiperidine-1,4-dicarboxylate 84a (450 mg) was removed via treatment with 4N HCl in dioxane/DCM at RT for 1 h to give ethyl 4-vinylpiperidine-4-carboxylate. Ethyl 4-vinylpiperidine-4-carboxylate reacted with MsCl with TEA in DCM at RT for 18 h to give ethyl 1-(methylsulfonyl)-4-vinylpiperidine-4-carboxylate 85a (409 mg, 98% yield). LCMS [M+H]+=249.90 (-Boc); Tr=1.96 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][C:10]([C:21]#[N:22])=[C:9]2Cl)[CH2:2][CH2:3][CH3:4].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH2:27].Cl.N1C=CC=CC=1>C(OCCO)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][C:10]([C:21]#[N:22])=[C:9]2[NH:27][C:26]1[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:25]=1[Cl:24])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: CCCCOc1cc2c(Cl)c(C#N)cnc2cc1OCCOC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: CCCCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1OCCOC
Temperature: 120 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
A mixture of 6-butoxy-4-chloro-7-(2-methoxyethoxy)-3-quinolinecarbonitrile (184 mg, 0.55 mmol), 2,4-dichloro-5-methoxyaniline (127 mg, 0.66 mmol) and pyridine hydrochloride (76 mg, 0.66 mmol) in 5 mL of 2-ethoxyethanol is heated at 120° C. for 7 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. Diethyl ether is added to the residue and the solids are collected and suspended in saturated aqueous sodium bicarbonate. After stirring for 1 hour the solids are collected by filtration and washed with water. Purification by preparatory thin layer chromatography, eluting with 7% methanol in dichloromethane provides 93 mg of 6-butoxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 166-167° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:35]1[CH:36]=[N:37][CH:38]=[N:39][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:37]1[CH:36]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[O:14][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:11][N:12]=3)=[CH:16][CH:17]=2)[CH:40]=[N:39][CH:38]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Reactant: Brc1cncnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (149.6 mg, 0.75 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (119.2 mg, 0.75 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (87.0 mg). Yield 43.5%.