Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]1[CH:9]=[C:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C:17]2=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[C:28]3[CH2:29][CH2:30][CH2:31][N:27]3[CH3:26])[C:17]2=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1Cl
Reactant: CN1CCCC1=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)cc1Cl

Procedure:
By the procedure of Example B1, except that ethyl acetate was used as eluant and ether to crystallize the product, 1-(3-chloro-4-methoxyphenyl)-2(1H,3H)-indolone (1.05 g, 3.84 mole) and N-methyl-2-pyrrolidone (0.62 ml, 6.42 mmoles) were converted to title product, 0.58 g, m.p. 126°-127.5°.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[CH2:6][C:7](=[O:9])[N:17]([C:15]2[CH:16]=[C:11]([Cl:10])[CH:12]=[CH:13][C:14]=2[CH3:20])[C:18]1=[S:19])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCCCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 40.6 %

Procedure:
A mixture of N-butyl glycine (12.0 g), 5-chloro-2-methylphenyl-isothiocyanate (9.15 g), triethyl amine (12.0 g) and chloroform (200 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was treated with diethyl ether (400 mL). The mixture was filtered. The solid was washed with diethyl ether then discarded. The filtrate was evaporated to dryness. Crystallization from ethanol afforded the title compound (6.0 g) as a tan solid, m.p. 102°-103° C. Anal. Calcd. for. C14H17Cl N2O S: C, 56.65; H, 5.77; N, 9.44. Found: C, 56.41; H, 5.97; N, 9.36. Mass spectrum (EI, M.+) m/z 296/298.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][O:13]CC#C)[NH:6][C:5]2(CCC[CH2:8][CH2:7]2)[O:4][CH2:3]1.Cl>O>[NH2:6][C:2]([CH3:1])([CH2:3][O:4][CH2:5][C:7]#[CH:8])[CH2:12][OH:13]
Reactant: C#CCOCC1(C)COC2(CCCCC2)N1
Agent: Cl
Solvent: O
Product: C#CCOCC(C)(N)CO
Temperature: 25 °C
Yield: 102.7 %

Procedure:
3-Methyl-3prop-2-ynyloxymethyl-1-oxa-4-aza-spiro[4.5]decane (1.83 g) in an aqueous solution of HCl (6N) (2.73 ml) were refluxed for 1 hr. The reaction mixture was cooled down to room temperature, diluted with water and extracted thrice with ethyl ether. The two layers were separated. The aqueous layer was concentrated under reduced pressure and further co-evaporated with toluene to yield 2-amino-2-methyl-3-prop-2-ynyloxy-propan-1-ol hydrochloric salt (1.205 g) as a white beige solid which was used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH:21]1([CH:24]=[O:25])[CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[OH:25])[CH2:23][CH2:22]1
Reactant: O=CC1CC1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)C2CC2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a stirred −78° C. solution of 5-bromo-2-methoxypyridine (3.70 g, 19.79 mmol) in tetrahydrofuran (10 mL) was added 2.6 M n-butyllithium solution in hexane (8.4 mL, 21.84 mmol). The mixture was allowed to stir at −78° C. for 30 min, and then cyclopropanecarboxaldehye (1.70 g, 23.74 mmol) was added in one portion. The cooling bath was removed, and the mixture was allowed to warm to room temperature. After 2 h, the mixture was quenched by the addition of saturated aqueous ammonium chloride solution (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. Chromatographic purification of the residue (silica gel, 20% ethyl acetate in petroleum ether elute) afforded 2.90 g (80%) of cyclopropyl(6-methoxypyridin-3-yl)methanol as a yellow oil.
Reaction SMILES: C[Li].CN(C)P(N(C)C)(N(C)C)=O.[CH3:14][C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[C:16]=1[CH:22]=[CH:23][C:24]#[C:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1.Cl[Si](C)(C)[CH3:39]>CSC.[Cu]Br.C1COCC1>[CH3:14][C:15]1([CH3:39])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]1/[CH:22]=[CH:23]/[C:24]#[C:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc(C#CC=CC2=C(C)CCCC2=O)cc1
Agent: [Cu]Br
Agent: [Li]C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)c1ccc(C#C/C=C/C2C(=O)CCCC2(C)C)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A 1.3M solution of methyllithium (2.2 mL, 2.85 mmol) was added to a stirring suspension of copper (I) bromide-dimethyl sulfide (293 mg, 1.43 mmol) and 6 mL of THF at -78° C. The solution was warmed to -40° C. over 30 minutes and then recooled to -78° C. Freshly distilled hexamethylphosphoramide (0.37 mL, 2.14 mmol) was added, and the solution was stirred at -78° C. for 30 min. A solution of ethyl 4-(4-(3-methyl-2-cyclohexen-1-on-2-yl)but-3-ene-1-yn-1-yl)benzoate (Compound 5, 220 mg, 0.713 mmol), chlorotrimethylsilane (0.271 mL, 2.14 mmol) and 1.5 mL of THF was added. The solution was stirred at -78° C. for 1 hour, and warmed slowly to -30 ° C. The reaction was then quenched by the addition of saturated aqueous NH4Cl and ethyl acetate. The layers were separated and the aqueous layer extracted 3× with ethyl acetate. The combined organic layers were washed with 10% aqueous HCl until all of the enol ether was hydrolyzed. The layers were separated and the organic layer was washed with water, and brine, and dried (MgSO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (10:1, hexane:ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:72](=O)([O-:74])[O-:73].[K+].[K+].O>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[F:29])[C:72]([OH:74])=[O:73])([CH2:27][F:28])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Temperature: 90 °C
Yield: 21.7 %

Procedure:
To a mixture of N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (2.19 g, 4.59 mmol), bis(tri-t-butylphosphine)palladium(0) (0.23 g, 0.46 mmol), xantphos (0.53 g, 0.92 mmol), potassium carbonate (1.90 g, 13.76 mmol) in DMF (15 mL) and water (0.83 ml, 45.9 mmol) was bubbled CO gas for 10 min. The mixture was heated at 90° C. for 4 h, then was allowed to cool to rt. 1N HCl was added until pH˜4. Water was then added and a precipitate was formed. The solid was filtered, washed with water, and dried. The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatographed, eluting with a gradient of 1% to 8% MeOH in 0.5% AcOH/DCM, to provide the acid as a white solid (0.44 g, 21.45% yield). MS m/z=443 [M+H]+. Calculated for C20H15F5N2O4: 442.3.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:25]([CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])(=[O:27])=[O:26])[CH:20]=[CH:19]2)=O)C>C1(C)C=CC=CC=1>[CH3:31][Si:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][S:25]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([CH2:14][OH:13])=[CH:24][CH:23]=2)[CH:19]=[CH:20]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)c1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(CO)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of diisobutylaluminum hydride (82.9 mL, 1M in toluene, 82.9 mmol) was added slowly at 0° C. to the solution of 1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indole-5-carboxylic acid ethyl ester (8.81 g, 25.9 mmol) in toluene (200 mL). After it was stirred at 0° C. for 45 min, the reaction was quenched by the addition of methanol (26 mL), pulverized sodium sulfate decahydrate (194 g) and celite (26 mL). The mixture was warmed up to room temperature in 1 h and filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a very viscous liquid, which solidified upon cooling. A white solid (8.08 g, 100% yield). 1H-NMR (CDCl3, 500 MHz) δ 7.87 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J=3.7 Hz, 1H), 7.35 (dd, J=8.6, 1.5 Hz, 1H), 6.66 (d, J=3.7 Hz, 1H), 4.79 (s, 2H), 3.18-3.14 (m, 2H), 1.73 (s, 1H), 0.85-0.82 (m, 2H), −0.06 (s, 9H). Mass spec. 312.14 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:44])[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][C:32]=3[CH2:40][CH2:41][CH2:42][CH3:43])=[CH:26][CH:25]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])C.[OH-].[Na+].Cl>C(O)C>[CH2:40]([C:32]1[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:31]=1[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:44])=[O:3])[CH:9]=2)=[CH:25][CH:26]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(NC(=O)C(=O)OCC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(NC(=O)C(=O)O)c2)cc1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
A solution of N-[4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamic acid ethyl ester (120 mg, 0.204 mmol) in ethanol (3 mL) was treated with aq 1 N NaOH (0.3 mL, 1.5 equiv., 0.306 mmol) and stirred at room temperature. After stirring 1 h, the solution was acidified to pH<4 with 10% HCl, concentrated and purified by prep thin layer chromatography (10% methanol in dichloromethane) afforded N-[4′-(2-Butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamic acid (32 mg, 28%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.CON(C)[C:15]([C:17]1[O:21][CH:20]=[N:19][C:18]=1[CH3:22])=[O:16].[Cl-].[Na+]>C(OCC)C.C(O)C>[CH3:22][C:18]1[N:19]=[CH:20][O:21][C:17]=1[C:15]([C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)=[O:16]
Reactant: CON(C)C(=O)c1ocnc1C
Reactant: Brc1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1ncoc1C(=O)c1ccoc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Bromofuran (2.5 g) in dry diethylether was stirred and cooled to -70° C. under an atmosphere of dry nitrogen and n-butyllithium (2.5M solution in hexane, 6.8 ml) was added dropwise. After 30 minutes, N-methoxy-N-methyl-4-methyl-5-oxazolecarboxamide (2.89 g) in dry diethylether was added dropwise. After a further 30 minutes the mixture was allowed to warm to room temperature. Ethanol (5 ml) was added followed by saturated aqueous sodium chloride. The mixture was extracted with dichloromethane and the material thus obtained was purified by flash chromatography to give the title compound. M.p. 82°-83.5° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([OH:27])=O)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>S(Cl)(Cl)(=O)=O>[N:1]1([C:25]([CH:24]=[CH:23][C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:13]=3)=[CH:22][CH:21]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Solvent: O=S(=O)(Cl)Cl
Product: O=C(C=Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 141.9 %

Procedure:
A solution of 3-[4′-(3-piperidinopropoxy)biphenyl-4-yl]acrylic acid (1 g) in sulfonyl chloride (5 mL) is stirred at a temperature close to 40° C. for two hours, then concentrated under reduced pressure. The concentrate is dissolved in dichloromethane (10 mL) and piperidine (4 mL) is added dropwise. The mixture is stirred at room temperature for one hour, washed with water, then a normal aqueous solution of hydrochloric acid, dried over magnesium sulfate, concentrated and purified by chromatography over silica gel using a gradient dichloromethane/methanol from 100/0 to 95/5. Fractions containing the expected product are pooled and concentrated under reduced pressure to afford 840 mg of 1-(3-{[4′-(2-piperidinocarbonylethen-1-yl)biphenyl-4-yl]oxy}propyl)piperidine as beige crystals melting at 146-150° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:2].[CH2:9]([OH:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>CCCCCC.O.[Cl-].[Na+].O>[CH2:9]([O:11][C:1](=[NH:2])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH3:10]
Reactant: COC(=O)CCC#N
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: CCOC(=N)CCC(=O)OC
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A solution of methyl 3-cyanopropanoate (1.5 g, 13.3 mmol) and ethanol (0.61 g, 13.3 mmol) in n-hexane (15 mL) was cooled to −30° C., and anhydrous hydrogen chloride was bubbled into the solution for 1 h. The mixture was allowed to stand overnight at about −15° C., then at 5-10° C. for 16 h. The solvent was decanted, and the residue was diluted with diethyl ether (30 mL×2) and a solution of K2CO3 (3.67 g, 26.6 mmol) in water (25 mL), the organic layer was washed with water (20 mL) and brine (10 mL), dried, and concentrated to give a colorless oil (1.34 g). MS (ESI): m/z 160 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2ccc(F)cc2)o1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2ccc(F)cc2)c1=O
Reaction time: 24 h

Procedure:
2-(4-Fluorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(4-fluorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:14])([F:13])[CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10].[CH3:15]O>>[F:5][C:6]([F:14])([F:13])[CH2:7][CH:8]([OH:12])[C:9]([O:11][CH3:15])=[O:10]
Reactant: O=C(O)C(O)CC(F)(F)F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(O)CC(F)(F)F
Temperature: 70 °C

Procedure:
Thionyl chloride (0.139 ml, 1.90 mmol) was added dropwise to a solution of 12-2 (200 mg, 1.27 mmol) in MeOH (2 ml) at room temperature. After addition was complete, the reaction was heated in a sealed vessel at 70° C. for 2 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with 7N NH3/MeOH (3 mL) and filtered to remove insolubles. The filtrate was concentrated to dryness to afford 12-3 as a clear oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:15][NH2:16])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=O.O1CCCC1>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:15][N:16]=[CH:17][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NN)cc(C(C)(C)C)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(C=NNc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc1
Yield: 58.2 %

Procedure:
3.5g (15 mmoles) of 3,5-di-t-butylphenylhydrazine and 2.6g (15 mmoles) of methyl 4-formylbenzoate were stirred for 1 hour under reflux in 150ml of a 1:1 mixture of tetrahydrofuran and ethanol. After evaporation of the solvent the residue was digested with ethanol at the boil and then cooled, filtered off in vacuo and rinsed with ethanol. After drying in vacuo at ambient temperature, there were obtained 3.2g of the above compound, m.p. 215°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:24]([O:26][C:27](=[O:39])[C:28]([C:36](Cl)=[O:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[CH3:25].C(N(CC)CC)C>>[CH2:24]([O:26][C:27](=[O:39])[C:28]([CH3:29])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=1)=[O:37])[CH3:25]
Reactant: COc1ccc(NCCc2ccc(C(F)(F)F)cc2)cc1OC
Reactant: CCOC(=O)C(C)(C(=O)Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(OC)c(OC)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
A mixture of 97.5 mg (0.3 mmol) (3,4-dimethoxy-phenyl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine (intermediate 1), 101 mg (0.45 mmol) 2-chlorocarbonyl-2-phenyl-propionic acid ethyl ester (Journal of Organic Chemistry (1959), 24 109-10) and 121 mg (1.2 mmol) triethylamine 15 mL DCM was stirred for 16 h at room temperature. The mixture was evaporated and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid, the product containing fractions were evaporated to yield 71.5 mg (45%) of the title compound. MS(m/e): 530.2 (MH+).
Reaction SMILES: [CH2:1]([N:8]([C@@H:19]1[CH2:26][N:25]2[C:27]3[CH:28]=[C:29]([C:40]([NH:42][S:43]([N:46]([CH2:48][CH:49](OC)[O:50]C)[CH3:47])(=[O:45])=[O:44])=[O:41])[CH:30]=[CH:31][C:32]=3[C:33]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:24]2[C:23]2[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:22]=2[O:21][CH2:20]1)[CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[NH2:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:19]1[CH2:26][N:25]2[C:27]3[CH:28]=[C:29]([C:40]([NH:42][S:43]([N:46]([CH3:47])[CH2:48][CH:49]=[O:50])(=[O:45])=[O:44])=[O:41])[CH:30]=[CH:31][C:32]=3[C:33]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:24]2[C:23]2[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:22]=2[O:21][CH2:20]1
Reactant: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(CCNC(=O)OC(C)(C)C)Cc1ccccc1)COc1cc(F)ccc1-3)OC
Agent: Cl
Solvent: C1CCOC1
Product: CN(CC=O)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(CCN)Cc1ccccc1)COc1cc(F)ccc1-3
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Tert-butyl [2-(benzyl{(7R)-14-cyclohexyl-11-[({[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}amino)carbonyl]-3-fluoro-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl}amino)ethyl]carbamate was dissolved in THF (50 mM) and 3M aqueous HCl (10 eq) was added. The solution was warmed to 60° C. and stirred for 2 h. The solution was then used directly in the next step. (ES+) m/z 676 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:35][C:36]1[C:41](B(O)O)=[CH:40][C:39]([CH3:45])=[CH:38][N:37]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:13]1[C:12]2[O:11][C:10]3[C:19](=[CH:20][C:7]([C:41]4[C:36]([F:35])=[N:37][CH:38]=[C:39]([CH3:45])[CH:40]=4)=[CH:8][CH:9]=3)[C@@:18]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:17]=2[CH:16]=[C:15]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:14]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(N3CCOCC3)cc12
Reactant: Cc1cnc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(F)c(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(N4CCOCC4)cc(F)c2O3)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A resealable vial was charged with (S)-2-amino-4′-fluoro-2′-morpholino-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (130 mg, 0.258 mmol; prepared as described in Method BB40), tetrakis(triphenylphosphine)palladium(0) (29.8 mg, 0.026 mmol), 2-fluoro-5-methylpyridin-3-ylboronic acid (64.0 mg, 0.413 mmol), DMF (1.3 mL) and 2 M aqueous sodium carbonate (387 μL, 0.775 mmol). The vial was sealed and the mixture stirred for 2 hr at 85° C. The mixture was cooled and diluted with EtOac (6 mL) and water (2 ml). The organic layer was filtered through celite, concentrated, and purified by reverse phase HPLC (Gilson, 15-90% MeCN in 0.1% aq. TFA). The fractions containing product were concentrated in vacuo, neutralized with saturated sodium bicarbonage and extracted with ethyl acetate. Organic layer was washed with brine, and concentrated. The residue was redissoved in ˜1 mL 1:1 MeCN/water and liophilized to afford (S)-4′-fluoro-7′-(2-fluoro-5-methylpyridin-3-yl)-2′-morpholino-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][C:6]([CH3:9])([CH3:8])[CH3:7]>CO.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)C=CC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCC(C)(C)C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
4,4-Dimethyl-pent-2-enoic acid methyl ester (8.52 g, 60.0 mmol) was dissolved in MeOH (30 mL) and ethyl acetate (30 mL). Palladium on carbon (10 wt %) (˜50 mg) was added to the reaction and was placed under a H2 balloon (1 atm). The reaction was allowed to stir for 12 hours, flushed with nitrogen and filtered over a pad of celite. Evaporated to provide 4,4-dimethyl-pentanoic acid methyl ester (7.0 g, 48.5 mmol, 81%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H), 3.67 (s, 3H).