Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][NH2:32])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18]([NH:32][CH2:31][CH2:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=4)=[N:17][C:16]3=[O:22])[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: NCCc1cccc(F)c1
Reactant: CCOc1ccnc2ccc(C=C3SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccnc2ccc(C=C3SC(NCCc4cccc(F)c4)=NC3=O)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
The suspension of 5-(4-ethoxy-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one (example 40b) (100 mg, 0.3 mmol), m-fluorophenylethylamine (80 ul, 0.6 mmol) and DIEA (0.10 mL, 0.6 mmol) in acetoniltile (2 mL) was stirred under at 80° C. for 3 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 5-(4-ethoxy-quinolin-6-ylmethylene)-2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (90 mg, 70%) as a light yellow solid: LC-MS m/e 422 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N+:21]([C:10]1[CH:9]=[C:8]([C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O-:23])=[O:22]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 81.8 %

Procedure:
1.67 g of bis(triphenylphosphine)palladium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of tert-butyl 4-bromo-2-nitrobenzoate (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxyethane and 100 mL of water. The reaction medium is heated at 100° C. for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CH2Cl2/AcOEt: 100:0 to 70:30, 30 min). The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].C([N:36]1[C:44]2[C:39](=[N:40][C:41]([C:46]3[CH:51]=[CH:50][C:49]([N:52]4[CH:56]=[C:55]5[CH2:57][N:58]([CH2:60][C:61]([F:64])([F:63])[F:62])[CH2:59][C:54]5=[N:53]4)=[CH:48][CH:47]=3)=[C:42]([Cl:45])[CH:43]=2)[N:38]=[C:37]1[O:65][C@H:66]1[C@H:70]2[O:71][CH2:72][C@@H:73]([OH:74])[C@H:69]2[O:68][CH2:67]1)C=C>C(O)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:45][C:42]1[CH:43]=[C:44]2[NH:36][C:37]([O:65][C@H:66]3[C@H:70]4[O:71][CH2:72][C@@H:73]([OH:74])[C@H:69]4[O:68][CH2:67]3)=[N:38][C:39]2=[N:40][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH:56]=[C:55]3[CH2:57][N:58]([CH2:60][C:61]([F:62])([F:63])[F:64])[CH2:59][C:54]3=[N:53]2)=[CH:48][CH:47]=1
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CN(CC(F)(F)F)C5)cc3)c(Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-n4cc5c(n4)CN(CC(F)(F)F)C5)cc3)c(Cl)cc2[nH]1
Reaction time: 0.25 h

Procedure:
A 4 mL vial was charged with palladium(II) acetate (2.6 mg, 0.012 mmol), 1,4-bis(diphenylphosphino)butane (3.0 mg, 7.03 μmol), and ethanol (0.1 ml). This catalyst mixture was degassed (3×) and stirred under nitrogen for 15 min. Sodium borohydride (3.5 mg, 0.093 mmol) was added to a stirred solution of (3R,3aR,6R,6aR)-6-[1-allyl-6-chloro-5-[4-[5-(2,2,2-trifluoroethyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-2-yl]phenyl]imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (9.5 mg, 0.016 mmol) in ethanol (0.15 ml) and DCM (0.05 ml). The sodium borohydride mixture was degassed (3×) and placed under nitrogen. The catalyst mixture was transferred via syringe to the sodium borohydride reaction mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:82]1[CH2:87][CH2:86][CH2:85][CH2:84][CH2:83]1>O1CCOCC1.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:82]3[CH2:87][CH2:86][CH2:85][CH2:84][CH2:83]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH:14]=1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g (3.96 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.12 g (0.198 mmol), piperidine 0.28 g (3.3 mmol) and Pd (dba)3 60 mg (0.066 mmol) in 6 ml dioxane. The crude reaction mixture was purified using HPLC to yield the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:40][C:36]3[CH:35]=[C:34]4[C:39](=[CH:38][CH:37]=3)[N:31]([CH3:30])[CH:32]=[CH:33]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cn1ccc2cc(N)ccc21
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc4c(ccn4C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 89.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 1-methyl-5-aminoindole (0.072 g, 0.49 mmol), the title compound (0.169 g, 90%) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+].C(O)(=O)C>CO>[O:15]1[C:14]2([CH2:19][CH2:20][N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:21])=[O:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)[O:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzoic acid ethyl ester (14 g, 48.1 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) in methanol/tetrahydronfuran (1:1, 100 mL) and sodium hydroxide (2 N, 150 mL) was refluxed for 2 hours. After cooling to room temperature the solution was acidified by acetic acid and the solid which was formed was collected and dried to give the title compound as a white solid (12.5 g, 99%); 1H NMR (300 MHz, CDCl3) δ 1.67 (t, J=5.6 Hz, 4 H), 3.43 (t, J=5.6 Hz, 4 H), 3.92 (s, 4 H), 6.96 (d, J=9.0 Hz, 2 H), 7.75 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 264.4 (MH+); HRMS Calcd. for C14H17NO4(M+): 263.1158. Found: 263.1160.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10].[OH-].[Na+]>O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1c(O)cccc1O

Procedure:
A resorcinol-formaldehyde was prepared by the addition of resorcinol (16.6 parts weight), formaldehyde (5.4 parts weight dry; 14.7 parts weight wet), sodium hydroxide (1.3 parts weight), and soft water (366 parts weight). The total solids content of the resin was approximately 6.0 wt %, and the pH was approximately 9.0.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:18])[C:10]([CH2:15][C:16]#[N:17])=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[OH-:19].[Na+]>C(O)C.O>[CH2:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:18])[C:10]([CH2:15][C:16](=[O:19])[NH2:17])=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [OH-]
Reactant: CC(=O)N1CCCc2c1cc(C)c(CC#N)c2C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCN1CCCc2c1cc(C)c(CC(N)=O)c2C
Temperature: 40 °C
Reaction time: 10 h
Yield: 32.6 %

Procedure:
1-Acetyl-6-cyanomethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline (2.7 g) was dissolved in ethanol (30 ml), and a solution of NaOH (4.4 g) in water (10 ml) was added, which was followed by refluxing for 10 hr under nitrogen. The solvent was evaporated under reduced pressure, and the residue was extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 6-carbamoylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline was dissolved in N,N-dimethylformamide (10 ml), and octyl bromide (1.6 g), potassium carbonate (1.2 g) and potassium iodide (166 mg) were added, which was followed by stirring at 40° C. for 10 hr in nitrogen. The reaction mixture was extracted with ethyl acetate (100 ml). After washing with water, the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/ methanol=50/1−10/1) to give 600 mg of 1-octyl-6-carbamoylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]([C:12]1[CH:17]=[C:16]([NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:15]=[C:14]([CH3:24])[N:13]=1)[CH2:6][CH2:5]2.[Cl:25]N1C(=O)CCC1=O>C(#N)C>[Cl:25][C:17]1[C:12]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[Cl:11])[CH2:5][CH2:6]2)=[N:13][C:14]([CH3:24])=[N:15][C:16]=1[NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(CC)Nc1cc(N2CCc3cc(Cl)cc(Cl)c32)nc(C)n1
Solvent: CC#N
Product: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1Cl
Yield: 98.7 %

Procedure:
4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (140 mg, 0.38 mmol) and N-chlorosuccinimide (60 mg, 0.45 mmol) were stirred in dry acetonitrile (5 mL) at 20° C. for 20 h. The reaction mixture was stripped in vacuo and the residue was chromatographed on silica gel using 20% EtOAc/hexanes to give the product, 5-chloro-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (150 mg, 99% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCC(CN)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCN(C)CC3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-methlpiperidin-4-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22-1.29 (m, 1H) 1.32-1.46 (m, 2H) 1.80 (d, J=3.54 Hz, 1H) 1.91 (d, J=13.64 Hz, 2H) 2.44 (s, 3H) 2.71-2.84 (m, 3H) 2.85-3.00 (m, 2H) 3.23 (t, J=6.19 Hz, 2H) 3.45 (br. s., 1H) 7.67 (d, J=7.83 Hz, 1H) 7.71-7.90 (m, 2H) 8.22 (d, J=13.64 Hz, 1H) 8.43 (br. s., 2H) 8.82 (br. s., 1H) 8.93 (dd, J=2.02, 0.76 Hz, 1H) 9.28 (br. s., 1H) 13.23 (br. s., 1H). MS m/z [M+H]+ 431.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17]C(=O)C2C=CC=CC=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.O1CCCC1>[OH-].[Na+]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][OH:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCCO)C(=O)O)cs1
Yield: 61 %

Procedure:
A solution of ethyl 2-(2-aminothiazol-4-yl)-2-(2-benzoyloxyethoxyimino)acetate (syn isomer, 8.5 g.) in a mixture of 1N aqueous sodium hydroxide (34 ml.), methanol (40 mI.) and tetrahydrofuran (40 ml.) was treated in a similar manner to that of Example C-(4) to give 2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetic acid (syn isomer, 3.3 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:24][CH3:25])=[N:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[C:18]([Si](C)(C)C)[N:17]=[N:16]3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.N(CC1C=C(C2C=CC=C(Cl)C=2)C(OC)=NC=1)=[N+]=[N-].C([Si](C)(C)C)#C.C(N(C(C)C)CC)(C)C>C1COCC1.O.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:24][CH3:25])=[N:10][CH:11]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(Cn2cc([Si](C)(C)C)nn2)cc1-c1cccc(Cl)c1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Agent: COc1ncc(CN=[N+]=[N-])cc1-c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(Cn2ccnn2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
3-(3-Chlorophenyl)-2-methoxy-5-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine. To a solution of 5-(azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (directly used from previous reaction) and ethynyltrimethylsilane (75.1 mg, 0.77 mmol) in THF (3 mL), water (1 mL), was added copper (I) iodide (19.4 mg, 0.10 mmol) and diisopropylethylamine (132 mg, 1.02 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted in to DCM. The organic layers were combined, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification (FCC, SiO2, 0-50% EtOAc/hexanes) afforded the title compound (92 mg, 48%). [M+H]=373.2.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][OH:24])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CO[Si](C)(C)C(C)(C)C)cc2cccnc12)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cc(CO)cc2cccnc12)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl cyclopropyl{[6-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-8-quinolinyl]methyl}carbamate (1 eq.) from the previous step in THF (0.12 M) was added TBAF (1.0 M in hexane, 1.6 eq.). The resulting solution was stirred at RT for 2 h before the volatiles were removed in vacuo. The resulting residue was partitioned between ether and water. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]1([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CCOC(=O)CCN(C(=O)Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.115.1, starting from 4-chlorophenylacetyl chloride and ethyl N-phenyl-3-aminopropionate, ethyl 3-[2-(4-chlorophenyl)-N-phenylacetamido]propanoate was obtained as light tan oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[O:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].CCOCC>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]([OH:14])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC1(C)COc2c(C=O)cc(Br)cc21
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)COc2c(C(O)C(C)(C)C)cc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A stirred, cooled (ice-bath) solution of 5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran-7-carbaldehyde (Intermediate 30, 1.72 g, 6.74 mmol) in 15 mL of anhydrous tetrahydrofuran was treated with a 1M solution of tert-butyl magnesium chloride solution in ether (6.74 mL, 6.74 mmol). The reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an oil that on flash column chromatography using 5% ethyl acetate in hexane as the eluent afforded the title compound (0.95 g, 45%).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH2:19]([N:26]1[CH2:49][CH:48]([C:50]([OH:52])=O)[O:47][C:28]2([CH2:33][CH2:32][N:31]([C:34](=[O:46])[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[C:37]([CH3:45])[CH:36]=3)[CH2:30][CH2:29]2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O[N:54]=[C:55]([NH2:57])[CH3:56].C(N(CC)CC)C>CC1CCCO1>[CH2:19]([N:26]1[CH2:49][CH:48]([C:50]2[O:52][N:57]=[C:55]([CH3:56])[N:54]=2)[O:47][C:28]2([CH2:33][CH2:32][N:31]([C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:43])[CH3:44])=[C:37]([CH3:45])[CH:36]=3)=[O:46])[CH2:30][CH2:29]2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(N)=NO
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(C(=O)O)O3)ccc1OC(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: Cc1noc(C2CN(Cc3ccccc3)CC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)n1
Temperature: 75 °C
Yield: 39.1 %

Procedure:
T3P (546 mg, 510 μL of 50% w/w, 0.86 mmol) was added to a solution of 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (160 mg, 0.34 mmol), N′-hydroxyacetamidine (25 mg, 0.34 mmol) and triethylamine (173 mg, 239 μL, 1.71 mmol) in 2-methyltetrahydrofuran (800 μL) and the reaction mixture was heated at 75° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 0-30% EtOAc in DCM as eluent to afford [8-benzyl-10-(3-methyl-1,2,4-oxadiazol-5-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (67 mg, 39%) as a white solid. ESI-MS m/z calc. 504.6. found 505.3 (M+1)+; Retention time: 1.63 minutes (3 min run).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][O:8][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23])[NH2:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](N)CO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
L-Serine methyl ester hydrochloride (7.09 g) was suspended in dichloromethane (100 mL), and to the suspension 4-(dimethylamino)pyridine (700 mg) and triethylamine (9.69 g) were added, and tert-butyldimethylchlorosilane (7.0 g) were added portionwise at 0° C. to the mixture to conduct stirring at room temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]\[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.O.BrN1C(=[O:30])CCC1=O>C(COC)OC>[CH3:20][C:19]([CH:18]([OH:30])[CH2:17][CH2:16]/[C:15](/[CH3:22])=[CH:14]\[CH2:13][CH2:12]/[C:2](/[CH3:1])=[CH:3]/[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[CH2:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)=CCC/C(C)=C\CC/C(C)=C/COC1CCCCO1
Solvent: O
Solvent: COCCOC
Product: C=C(C)C(O)CC/C(C)=C\CC/C(C)=C/COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g (0.0065 mol) of tetrahydro-2-[[(2E,6Z)-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran dissolved in 13 ml of monoglyme and 2.6 ml of water is treated portionwise at -10° with 1.3 g of N-bromosuccinimide. The mixture is subsequently stirred at 0° for 1/4 hour and at room temperature for 2 hours. The reaction solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing tetrahydro-2-[[(2E,6Z)-10-bromo-11-hydroxy-3,7,11-trimethyl-2,6,10-dodecatrienyl]oxy]-2H-pyran, is dissolved in 18 ml of methanol and treated with 600 mg of potassium carbonate. The suspension is stirred at room temperature for 1.5 hours under argon. After removing the methanol on a rotary evaporator the residue is treated with 500 ml of ether and 200 ml of water. The organic phase is washed with saturated sodium chloride solution. After drying and removing the solvent the residue, containing (6Z,10E)-2,3-epoxy-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)-oxy]-6,10-dodecadiene, is dissolved in 30 ml of toluene and treated with 1.35 g of aluminum isopropylate. The reaction mixture is boiled at reflux for 17 hours. After cooling to room temperature the reaction mixture is poured into 200 ml of an ice-water mixture. After acidification with 1N hydrochloric acid the mixture is extracted with 3×150 ml of hexane. The organic phase is washed with 500 ml of saturated sodium chloride solution. After drying and removing the solvent the residue is chromatographed on silica gel with a 1:2 ether-hexane mixture which additionally contains 0.1% triethylamine. There is obtained (6Z,10E)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol which has the following bands in the IR spectrum: 3447 cm-1, 1644 cm-1, 1443 cm-1, 1379 cm-1, 909 cm-1.