Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][NH:5]1)O.OP(O)(O)=O.[OH-].[Na+]>>[CH3:17][C:2]([CH:4]1[NH:5][CH2:6][CH2:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9]1)=[CH2:1]
Reactant: CC(C)(O)C1CN(Cc2ccccc2)CCN1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)C1CN(Cc2ccccc2)CCN1
Temperature: 140 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A mixture of 6.4 parts of α,α-dimethyl-4-(phenylmethyl)-2-piperazinemethanol and 50 parts of poly(phosphoric acid) was stirred for 1 hour at 140° C. After cooling, ice water was added and the whole was treated with a sodium hydroxide solution 50%. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated, yielding 5 parts (85.6%) of 3-(1-methylethenyl)-1-(phenylmethyl)piperazine as a residue (int. 47).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[CH:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>>[F:20][C:18]([F:19])([F:21])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:9][CH:10]=1)[O:22][C:23]1[CH:24]=[C:25]([CH3:31])[C:26]([C:40]2[CH:41]=[CH:42][C:37]([CH:34]([CH3:36])[CH3:35])=[CH:38][CH:39]=2)=[C:27]([CH3:29])[CH:28]=1
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)C)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. Isomer 1 MS: 554.2 [M−H]−; Isomer 2 MS: 554.2 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[N:7]([C:10]3[CH:11]=[C:12]([NH:24][C:25](=[O:27])[CH3:26])[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[F:23])[CH:15]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[CH:2].[CH2:30]([O:32][C:33](=[O:38])[CH2:34][N:35]=[N+:36]=[N-:37])[CH3:31].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:25]([NH:24][C:12]1[CH:11]=[C:10]([N:7]2[C:6]3[CH:28]=[CH:29][C:3]([C:1]4[N:35]([CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:38])[N:36]=[N:37][CH:2]=4)=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:13]=1)(=[O:27])[CH3:26]
Reactant: C#Cc1ccc2c(c1)ncn2-c1cc(NC(C)=O)cc(-c2ccc(F)cc2F)c1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1nncc1-c1ccc2c(c1)ncn2-c1cc(NC(C)=O)cc(-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
A mixture of N-(5-(5-ethynyl-1H-benzo[d]imidazol-1-yl)-2′,4′-difluorobiphenyl-3-yl)acetamide (258 mg, 0.6 mmol), ethyl-2-azidoacetate (180 mg, 0.8 mmol, 1.3 eq.), sodium ascorbate (125 mg, 0.6 mmol, 1.0 eq.) and copper sulfate pentahydrate (80 mg, 0.32 mmol, 0.5 eq.) in t-butanol and water (1:1, 3 ml) was stirred for 12 h at RT. The mixture was quenched with water and the precipitate formed was filtered and dried to give the product in 75% yield (250 mg).
Reaction SMILES: C([O:5][C:6]([C@:8]1([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:12][C@H:11]([C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([C:19]2[S:23][C:22](Cl)=[N:21][CH:20]=2)[N:9]1[C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[C:28]([O:36][CH3:37])[CH:27]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:25]([N:9]2[C@@H:10]([C:19]3[S:23][CH:22]=[N:21][CH:20]=3)[C@@H:11]([C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH2:12][C@@:8]2([CH2:39][CH:40]([CH3:41])[CH3:42])[C:6]([OH:7])=[O:5])=[O:38])=[CH:27][C:28]=1[O:36][CH3:37])([CH3:34])([CH3:35])[CH3:33]
Reactant: COc1cc(C(=O)N2[C@@H](c3cnc(Cl)s3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3cncs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1. Purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents, and analysis of the fractions by electrospray mass spectroscopy. This afforded the title compound as a solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1.C(Cl)Cl.C(N(C(C)C)CC)(C)C.[C:48]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])(=[O:51])[NH:49][NH2:50]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][C:33]([NH:50][NH:49][C:48]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:34])[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N(CCCC(=O)Cl)c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)CCCN(c1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-6-yl)methylsulfonamido)butanoyl chloride (51.9 mg, 0.101 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL) and anhydrous CH2Cl2 (1 mL) under nitrogen. Diisopropylethylamine (0.035 mL, 0.201 mmol) and tert-butyl carbazate (16.28 mg, 0.121 mmol) were added, and the mixture was stirred at 25° C. for 1 hour. Ethyl acetate (50 mL) was added, and the mixture was washed with H2O (3×10 mL) and brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The crude material was purified by SiO2 flash chromatography (Alltech Extract-Clean™ column, 10 g bed) eluting with 60:40 ethyl acetate/CH2Cl2, followed by 5% methanol/CH2Cl2 to afford the title compound as a white solid (41 mg, 0.067 mmol, 67%). MS (ESI+) m/z 612 (M+H)+, 1223 (2M+H); MS (ESI−) m/z 610 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([O:16]COC)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:3].Cl>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:3][CH:2]([C:4]1[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([OH:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:1]
Reactant: COCOc1c(-c2ccccc2)c(C(C)C)cc2cc(OC)ccc12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(O)c(-c3ccccc3)c(C(C)C)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3-(1-Methylethyl)-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}-2-phenyl naphthalene (71) (0.42 g, 1.24 mmol) was dissolved in dioxane (8 mL). 4 M HCl in dioxane (8 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (25 mL) and brine (25 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light yellow oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (20:1) to give 0.36 g (98%) of the title compound (72) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.16 (d, J=6.8 Hz, 6H), 2.79 (sept, J=6.8 Hz, 1H), 3.93 (s, 3H), 5.08 (s, 1H), 7.05-7.12 (m, 2H), 7.30 (s, 1H), 7.32-7.38 (m, 2H), 7.42-7.50 (m, 1H), 7.50-7.58 (m, 2H), 8.07 (d, J=9.0 Hz, 1H). LCMS (APCI): m/z 293 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=O)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([Br:18])=[CH:7][CH:8]=2)[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].CS(C)=O.O>C(O)C>[S:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:16]1[C:13]1[CH:14]=[C:15]2[C:10]([C:9]3[CH:8]=[CH:7][C:6]([Br:18])=[CH:5][C:4]=3[C:3]2([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:11][CH:12]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Reactant: Nc1ccccc1S
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(-c3nc4ccccc4s3)cc21
Temperature: 195 °C
Reaction time: 0.75 h
Yield: 80.3 %

Procedure:
A mixture of 9,9-diethyl-7-bromo-fluorene-2-carboxaldehyde (Example 3; 49.35 g, 0.15 mol), 2-aminothiophenol (20 mL, 0.187 mol, 1.25 eq.), and DMSO (110 mL) was heated in an oil bath to a bath temperature of 195° C., held there for 45 minutes, and then poured into water. The separated solids were collected, reslurried in 1:4 acetic acid-water (1000 mL), filtered, and washed with water and dilute sodium bicarbonate solution. These solids, 80.05 g, were then reslurried in hot ethanol (600 mL) cooled and filtered to get the product, 45.69 g, m.p. 133.6-135° C. An additional 6.6 g, m.p. 134.6-135.5° C., was obtained by chromatography of the ethanol filtrate. Total recovery 52.29 g. (80.3% yield). Mass Spec: m/z 433, 435, (M+). Analysis: Calculated for C24H20BrNS: C, 66.37%; H, 4.64%; Br, 18.40%; N, 3.23%; S, 7.37%. Found: C, 66.46%; H, 4.52%; Br, 18.54%; N, 3.14%; S, 7.19%.
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Cl)CCC.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([O:25]C)=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl:34][CH2:35][Cl:36].Cl>C(OCC)(=O)C.O.C1COCC1>[CH2:27]([C@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:15])([CH3:16])[CH3:17])[C:23](=[O:25])[CH:35]([Cl:36])[Cl:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Agent: CCCC[Mg]Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(Cl)Cl
Reaction time: 2 h
Yield: 33 %

Procedure:
Under nitrogen gas, diisopropylamine (19.92 g, 196.9 mmol) was added to n-butylmagnesium chloride (1.8 mol/kg, 99.4 g, 179 mmol) over 30 minutes at 40° C. and the mixture was further stirred for 2 hours at the same temperature to prepare a white slurry (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8 mmol), dichloromethane (6.09 g, 71.6 mmol) and THF (20 g) (liquor B). To this liquor B was added said liquor A over 1.5 hours at an internal temperature of about 5° C., and the reaction was conducted at 5° C. for 6 hours and at 20° C. for 16 hours. This reaction mixture was poured in a mixture of concentrated hydrochloric acid (43.12 g), water (100 g) and ethyl acetate (50 mL) over 10 minutes for hydrolysis. After phase separation, the organic layer was washed serially with water (100 mL) and saturated sodium hydrogencarbonate/H2O, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to recover 20.22 g of a reddish brown solid. This solid was recrystallized from ethyl acetate/hexane to provide yellow crystals of tert-butyl (S)-(1-benzyl-3,3-dichloro-2-oxopropyl)carbamate (3.921 g, 98.1 area %, yield 32%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:26]([CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:31][CH2:30][CH2:29][C:28]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([S:16][CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CSc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(SC)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylthiophenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters. The pure title compound was obtained by purification on a flash chromatogram.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].Cl.[CH2:14]([O:16]CC)C>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]=[C:14]=[O:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOCC
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C=Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-trifluoromethylaniline (2.16 g, 9 mmol) was dissolved in 20 mL diethylether and added concentrated hydrochloric acid (37%, 1.5 mL, 18 mmol). Upon stirring for 1 hour at 25° C. the solvent was removed in vacuo and the white solid was stripped with toluene (3×20 mL). Diphosgene (13 mL) was added to the ammonium chloride salt and the mixture was refluxed for 3.5 hours until no solid material precipitated on cooling. Excess diphosgene was removed in vacuo and the clear oil was stripped with toluene (3×20 mL). The obtained isocyanate was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]1[S:20][C:19]2[C:18](=[O:21])[N:17]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:16](=[O:28])[N:15]([CH2:29][C:30]3[N:31]=[N:32][N:33]([CH2:35][CH3:36])[N:34]=3)[C:14]=2[CH:13]=1.[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]1[S:20][C:19]2[C:18](=[O:21])[N:17]([CH:22]3[CH2:27][CH2:26][N:25]([C:56]([C:55]4[CH:59]=[CH:60][C:52]([C:46]5[C:47]6[CH:48]=[C:49]([O:50][CH3:51])[C:40]([O:39][CH2:37][CH3:38])=[CH:41][C:42]=6[C@H:43]6[CH2:64][S:63][CH2:62][CH2:61][C@H:44]6[N:45]=5)=[CH:53][CH:54]=4)=[O:57])[CH2:24][CH2:23]3)[C:16](=[O:28])[N:15]([CH2:29][C:30]3[N:31]=[N:32][N:33]([CH2:35][CH3:36])[N:34]=3)[C:14]=2[CH:13]=1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cc(OC)ccc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6cc(OC)ccc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(2,5-dimethoxyphenyl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (137 mg; compound B80) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C10) and HBTU (102 mg) in DCM (10 ml) in the presence of DIPEA (264 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=[O:17])[CH:2]=[CH2:3].[CH2:25](O)[CH2:26][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][CH2:41][CH3:42].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[CH:15]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:16]([O:18][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])=[O:17])[CH:2]=[CH2:3]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: C=CCOc1ccc(C(C)(C)C)cc1C(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOc1ccc(C(C)(C)C)cc1C(C(=O)OCCCCCCCCCCCCCCCCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 69.3 %

Procedure:
A solution of 3.24 g (10.0 mmol) of 2-(2-allyloxy-5-tert-butylphenyl)-2-phenylacetic acid (compound (105), Example 2) and 2.70 g (10.0 mmol) of stearyl alcohol (1-octadecanol) in 25 mol of dichloromethane is treated with 100 mg (0.82 mmol) of 4-dimethylaminopyridine and 2.20 g (10.7 mmol) of N,N'-dicyclohexylcarbodiimide, and the mixture is stirred for 60 hours at room temperature. The reaction mixture is filtered and concentrated on a vacuum rotary evaporator. Chromatography of the residue from silica gel using the diluent system dichloromethane/hexane=1:1 yields 4.0 g (69%) of stearyl 2-(2-allyloxy-5-tert-butylphenyl)-2-phenylacetate (compound (106), Table 1) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](/[CH3:14])=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1>[Pd].CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1
Reactant: CCOC(=O)/C=C(\C)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1cccnc1
Yield: 98.9 %

Procedure:
Palladium on carbon (600 mg, 10 wt. %) was added to a solution of (E)-ethyl 3-(pyridin-3-yl)but-2-enoate (0.60 g, 3.14 mmol) in EtOH (10 ml) and hydrogenated under balloon pressure for 3 h. The reaction mixture was filtered through a pad of celite and washed with EtOH. The filtrate was concentrated and dried under reduced pressure to afford 0.60 g (100%) of ethyl 3-(pyridin-3-yl)butanoate as colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]Cl.[C-:12]#[N:13].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1ccc(CCl)cc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC#N)cc1Cl
Reaction time: 6 h
Yield: 99 %

Procedure:
145 grams of 3-chloro-4-methoxybenzyl chloride was added to a solution comprising 40.6 grams of sodium cyanide in 230 ml of dimethylsulfoxide over a 40 minute time period at a temperature within the range of 40°-45° C. The reaction mixture was then stirred at this temperature for 6 hours and poured into 800 ml of water, the separated oil being extracted with 3 200 ml portions of ether. The ethereal solution was next washed with a dilute (1:1) hydrochloric acid solution in two 100 ml portions, with two 100 ml portions of water and dried over magnesium sulfate. The ether was then driven off, yielding 136.5 grams of crystalline 3-chloro-4-methoxy-phenylacetonitrile, m.p. 54°-56° C., which was refluxed for 16 hours with 420 ml of 48% hydrobromic acid. Following, the reaction mixture was cooled to -5° C. and, after two hours at this temperature, the precipitate filtered, triturated with ether in three 400 ml portions, dried over magnesium sulfate and boiled down to yield 137 grams (97.7%) of 3-chloro-4-hydroxyphenyl acetic acid, m.p. 101°-104° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])C([O-])=O.[Na+].Br[C:10]1[C:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[C:13]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[C:12]([F:34])[CH:11]=1>[Cu]I.CN(C)C(=O)C>[CH3:19][C:17]1([CH3:20])[O:16][C:15]2[C:10]([C:2]([F:7])([F:6])[F:1])=[CH:11][C:12]([F:34])=[C:13]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]3=[O:33])[C:14]=2[O:18]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c3c2OC(C)(C)O3)c1=O
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(C(F)(F)F)c3c2OC(C)(C)O3)c1=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a solution of 6.0 g (0.044 mole) of sodium trifluoroacetate, 4.18 g (0.022 mole) of copper(I)iodide, and 40 mL of N,N-dimethylacetamide under a nitrogen atmosphere at 140 ° C is added 4.83 g (0.011 mole) of 3-(7-bromo-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil (Example 3). The temperature is then raised to 150° C. at which the reaction mixture is stirred for three hours. After being cooled to ambient temperature, the reaction mixture is poured into ice and then extracted with diethyl ether. The combined extracts are dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure, leaving a residue which is purified using column chromatography on silica gel. The product-containing fractions are combined and the solvent evaporated under reduced pressure, leaving 3-(2,2-dimethyl-5-fluoro-7-trifluoromethyl- 1,3-benzodioxol-4-yi)- 1 -methyl-6-trifluoromethyluracil as a residue.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]([Mg]Cl)#[CH:9].[NH4+].[Cl-]>C1COCC1>[C:8]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[CH:9]
Reactant: C#C[Mg]Cl
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
A stirred solution of dihydro-2H-pyran-4(3H)-one (500 mg, 5.0 mmol) in dry THF (20 mL) was cooled to −70° C. and 0.5 M ethynylmagnesium chloride in THF (20 mL, 10 mmol) was added in a slow stream. The cooling bath was allowed to expire and the mixture was stirred as it warmed to rt. After 6 h, satd aq NH4Cl (20 mL) was added and the mixture was concentrated on the rotary evaporator. The aqueous residue was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to leave crude 4-ethynyltetrahydro-2H-pyran-4-ol (491 mg, 78%) as a brown oil. 1H NMR (CDCl3) 1.80 (m, 2H), 1.92 (m, 2H), 2.57 (s, 1H), 3.68 (m, 2H), 3.90 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16].[OH2:19]>C(O)(=O)C.N1C=CC=CC=1.[Ni]>[CH3:1][O:2][C:3]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:6]([CH:7]=[O:19])=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O
Reactant: COc1c(C(F)(F)F)cc(C#N)cc1C(F)(F)F
Agent: [Ni]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COc1c(C(F)(F)F)cc(C=O)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-methoxy-3,5-bis(trifluoromethyl)benzonitrile (868 mg, 3.23 mmol, 1.00 equiv), a solution of NaH2PO2.H2O in water (10.0 mL), acetic acid (10.0 mL), pyridine (20.0 mL), Raney-Ni (0.9 g). The resulting solution was stirred for 3 h at 45° C. in an oil bath. The reaction progress was monitored by GCMS. The solids were filtered out. 20.0 mL EtOAc and 20.0 mL H2O were added into the mixture. The organic phase was washed by H2O with 2*20 mL and dried over Na2SO4. The solvent was removed and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 0.43 g (49%) of 4-methoxy-3,5-bis(trifluoromethyl)benzaldehyde as yellow oil. Mass spectrum (GC, m/z): Calcd. for C10H6F6O2, 272.0 (M). found 272.0.
Reaction SMILES: [CH2:1]([N:5]1[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]>Cl>[CH2:1]([N:5]1[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC2(CC1)OCCO2
Agent: Cl
Product: CCCCN1CCC(=O)CC1

Procedure:
A mixture of 8-butyl-1,4-dioxa-8-azaspiro[4,5]decane (27.8 g, 140 mmol) and hydrochloric acid (8 M, 350 ml) was refluxed for 15 h. The mixture was evaporated and sodium hydroxide (200 ml, 1 M) was added. The mixture was extracted twice with diethyl ether (150 ml). The crude product was purified by column chromaography using dichloromethane, methanol, aqueous ammonia (89:10:1). The pure product was isolated as an oil. Yield 10.5 g, 48%.