Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[C:26]([O:31][CH3:32])[C:25]=3[O:33][CH2:34][CH2:35][OH:36])[C:5]2=[CH:4][CH:3]=1.C[Si]([C:42]#[CH:43])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:42]#[CH:43])[CH:27]=[C:26]([O:31][CH3:32])[C:25]=3[O:33][CH2:34][CH2:35][OH:36])[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(I)cc(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1OCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1cc(OC)c(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 11 %

Procedure:
In a manner similar to the method described in example 193, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-iodo-3-methoxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in example 196c (0.3 g, 0.46 mmol) was reacted with trimethylsilyl acetylene (0.65 mL, 4.6 mmol), CuI (10 mg), triethylamine (1.9 mL, 13.8 mmol), and dichlorobis(triphenylphosphine)palladium (32 mg, 0.046 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(2-hydroxy-ethoxy)-3-methoxy-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a light brown solid (Yield 28 mg).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[C:14]([N:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([Br:42])[CH:33]=3)[C:25]3[C:20](=[CH:21][C:22]([O:45][CH3:46])=[C:23]([O:43][CH3:44])[CH:24]=3)[C:19]2=[O:47])[CH:15]=[CH:16][CH:17]=1.O>C(OCC)(=O)C>[CH3:44][O:43][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:45][CH3:46])[C:19](=[O:47])[N:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][CH:1]=[O:2])[CH:13]=1)[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([Br:42])[CH:33]=1
Reactant: COC(=O)c1c(-c2cc(Br)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1cccc(N)c1
Reactant: O=CO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(-c2cc(Br)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1cccc(NC=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To formic acid (3 ml) is added acetic anhydride (3 ml), and the mixture is stirred at room temperature for four hours. To the reaction mixture is added the compound obtained in Example 176 (500 mg), and the mixture is stirred at room temperature overnight. The mixture is further stirred at 60° C. overnight. After the reaction is complete, to the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=10:1) to give 6,7-dimethoxy-2-[3-(formylamino)phenyl]-4-(3-bromo-4,5-dimethoxyphenyl)-3-methoxycarbonyl-1(2H)-isoquinolinone as listed in Table 16.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH2:12][C:13]2[C:18]([CH2:19][C:20]=1OC)=[CH:17][CH:16]=[C:15]([O:23][CH3:24])[C:14]=2[O:25][CH3:26])(C)(C)C.[ClH:28]>CO>[ClH:28].[CH3:26][O:25][C:14]1[C:13]2[CH2:12][CH:11]3[C:20]([CH2:19][C:18]=2[CH:17]=[CH:16][C:15]=1[O:23][CH3:24])=[N:7][CH2:8][CH2:9][CH2:10]3
Reactant: COC1=C(CCCNC(=O)OC(C)(C)C)Cc2c(ccc(OC)c2OC)C1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1OC)CC1CCCN=C1C2

Procedure:
Compound 8 (1.52 g from the previous step) was dissolved in MeOH (20 mL). 37% HCl (3.5 mL) was added, and the mixture was refluxed for 4 h. The volatiles were removed in vacuo, using toluene to azeotropically remove the water. This provided impure compound 9 (0.89 g) as an yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[N:32]1([CH2:29][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:8]4[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=4[CH3:13])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:31])[CH:15]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=2)[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: C1CNCCNC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCNCC3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using product of Example 75 step i) and [1,4]diazepane.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH:11]=2)[CH:2]=1.[NH3:31]>CO>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[CH:11]=2)[CH:2]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 130 °C
Reaction time: 7 h

Procedure:
A mixture of 1.40 g of methyl 5-(3H-imidazo[4,5-c]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B1b) and 65 ml of a saturated solution of ammonia in methanol were stirred in an autoclave at 130° C. for 7 h. The mixture was allowed to cool down to room temperature and concentrated to about half of the volume. The precipitated solid was filtered, widely dissolved in 500 ml of methanol upon heating and filtered again. The filtrate was concentrated to about 25 ml upon which solid precipitated. It was filtered, dissolved in acetonitrile containing small amounts of water and finally the solution was lyophilized to give the title compound as a colorless powder.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([O:18][CH3:19])[CH:11]=[CH:10]2.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>CCCCC.C1COCC1.[Cl-].[Zn+2].[Cl-].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.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.[Pd]>[CH3:19][O:18][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:8]=2)[N:13]=1
Reactant: COc1ccc2cc(Br)cc(C)c2n1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2cc(-c3cccnc3)cc(C)c2n1

Procedure:
t-Butyl lithium (8.0 cm3 of a 2.0M solution in pentane) was added dropwise to a stirred solution of 6-bromo-2-methoxy-8 -methylquinoline (2.0 g) in THF (20 cm3) at -70° under nitrogen. After 10 minutes the mixtures was treated with a solution of anhydrous zinc chloride (1.09 g) in THF (10 cm3) and the resulting solution was warmed to 0°. A solution containing 3-bromopyridine (1.26 g) and tetrakis(triphenylphosphine) palladium(O) (0.05 g) in THF (10 cm3) was then added and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, concentrated in vacuo, treated with chloroform (100 cm3) and a solution of ethylenediaminetetraacetic acid disodium salt (6 g) in water (100 cm3). The aqueous phase was extracted further with chloroform (3×50 cm3) and the combined and dried (MgSO4) extracts were concentrated in vacuo to give an oil. This oil was chromatographed on silica (Merck "MK 60.9385") eluting with ethyl acetate. The fractions containing the product were combined and evaporated to afford a solid which was recrystallised from hexane to afford 2-methoxy-8-methyl-6-(3-pyridyl)quinoline, m.p. 117°-118.5°, (1.12 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[OH:1][C@H:2]1[CH2:3][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH3:7])[CH2:5]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (50 mg, 0.09 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and extracted with 5% MeOH/CH2Cl2 (2×). The combined organics were concentrated and triturated with EtOAc to afford 19 mg (50%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-hydroxy-cyclobutyl)-ethyl]-amide as a light yellow solid. MS: (M+H)+=409; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.09 (s, 1H), 8.42 (s, 1H), 8.39 (dd, J=8.7, 5.3 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.71 (dd, J=9.6, 2.1 Hz, 1H), 7.26 (td, J=9.1, 1.9 Hz, 1H), 4.96 (br. s., 1H), 4.14 (s, 3H), 4.07-4.26 (m, 2H), 2.23-2.41 (m, 1H), 1.98-2.19 (m, 3H), 1.84-1.98 (m, 1H), 1.20 (d, J=6.4 Hz, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH:13]=[O:14])[C:7]([OH:9])=[O:8].[CH3:15]I.Cl>CN(C=O)C>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[C:4]([F:3])[CH:5]=1
Reactant: O=Cc1ccc(C(=O)O)cc1F
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% NaH (0.14 mol) is added portionwise to a solution of 3-fluoro-4-formyl benzoic acid (3, 0.12 mol) in dry DMF (330 mL). The mixture is stirred at room temperature for 30 min. Methyl iodide (0.14 mol) is added dropwise to the mixture. After stirring at room temperature for 5 h, the reaction mixture is poured into 1 N HCl (ca. 1000 mL) and extracted twice with EtOAc. The combined organic layers are washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and evaporated in vacuo to give crude 3-fluoro-4-formyl benzoic acid methyl ester (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.Br[CH2:15][CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C.[H-].[Na+].[Cl-].[NH4+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CN(C)C=O.C(OCC)(=O)C>[OH:18][CH2:17][CH2:16][CH2:15][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(CCCO)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 145.4 %

Procedure:
6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one (1.0 g, 5.64 mmol) was dissolved in N,N-dimethylformamide (15 mL), (3-bromopropoxy)(tert-butyl)dimethylsilane (2.62 mL, 11.3 mmol) and 55% sodium hydride (259 mg, 5.93 mmol) were added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (5 mL), a 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution (22.5 mL, 22.5 mmol) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (1.93 g; yield, 100%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[C:18]([CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1)(O)=[O:19].C(P(=O)(OCC)OCC)#N>O1CCCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:25][CH:24]=2)=[O:19])=[C:3]([N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:4]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(O)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(O)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A mixture of t-butyl N-(2-amino-5-hydroxyphenyl)-N-methylcarbamate (0.43 g), 5-(4-carboxymethoxybenzyl)thiazolidine-2,4-dione (0.51 g), diethyl cyanophosphonate (0.29 g) triethylamine (0.18 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 8 hours. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=2:3 as the eluant to afford t-butyl N-{5-hydroxy-2-[4-(2,4-dioxothiazolidin-5-ylmethyl) phenoxymethylcarbonylamino]phenyl}-N-methylcarbamate (0.75 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=[C:2]([CH:13]2[CH2:15][CH2:14]2)[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)cc(Cl)c1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: FC(F)(F)c1cc(Cl)cc(C2CC2)c1
Yield: 87.1 %

Procedure:
3,5-Dichlorobenzotrifluoride (1.10 g, 5.1 mmol) and cyclopropylboronic acid (440 mg, 5.1 mmol) were reacted using K3PO4 (3.8 g, 17.9 mmol), tricyclohexylphosphine (145 mg, 0.51 mmol), Pd(OAc)2 (60 mg, 0.27 mmol) as described in example 100 to give 1-chloro-3-cyclopropyl-5-trifluoromethyl-benzene (980 mg, 87%) after purification by flash chromatography on silica gel.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[B:24](OC)([O:27]C)[O:25]C.Cl>C1COCC1.BrCCBr>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([B:24]([OH:27])[OH:25])=[CH:4][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COB(OC)OC
Reactant: CCCCCCCCCCCCCCOc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCCCCCCCCCCCCCOc1ccc(B(O)O)cc1
Temperature: -78 °C

Procedure:
Magnesium turnings (1.84 g, 0.08 mol) were added to a stirred solution, at room temperature under dry nitrogen, of compound 31 (15.00 g, 0.040 mol) in dry THF (150 ml) containing 1,2-dibromoethane (2 drops). The reaction mixture was maintained under these conditions for 1 h and then heated under reflux for 1 h. The reaction mixture was cooled to -78° C. and a solution of trimethyl borate (5.75 g, 0.08 mol) in dry THF (50 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight and then stirred for 1 h with 10% hydrochloric acid (100 ml). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[C:25]([F:28])([F:27])[F:26])[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.033 g, 4.69 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.188 g, 4.69 mmol) dissolved in water (2.4 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.3 mL, 4.90 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 20 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (40 mL, 240.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Product was pale yellow oil. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (1.32 g, 70%) was isolated as a colorless foam. 1H NMR (600 MHz, cdcl3) δ 1.84-1.99 (m, 3H), 1.99-2.10 (m, 1H), 2.62 (dd, 1H), 2.82 (dd, 1H), 2.92-3.06 (m, 1H), 3.10-3.19 (m, 1H), 3.59 (s, 3H), 3.93-4.03 (m, 1H), 4.19-4.34 (m, 1H), 5.73 (s, 1H), 6.91-6.99 (m, 2H), 7.46 (t, 1H). MS m/z 403 (M+H)+
Reaction SMILES: [CH2:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:16]=[CH:17][CH:18]=1>[OH-].[K+]>[CH2:1]([C:4]1([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3]
Reactant: CCCC1C(=O)CCC1=O
Reactant: C=CC(=O)CCCc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCC1=O
Yield: 79.6 %

Procedure:
Condense 2-propylcyclopentane-1,3-dione (13.1 g) in 0.12% methanolic potassium hydroxide solution (90 cc) with 6-m-methoxyphenyl-hex-1-en-3-one (19.0 g), to obtain crude 2-n-propyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (25.5 g). Submit this Michael condensation product (23.4 g) to double cyclodehydration by heating with toluene-p-sulfonic acid, and distil the product at 200°/10-4 mm; crystallize the distillate from ethanol to obtain the tetracyclic diene ketone 13β-propyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one, m.p. 82°-84°; ultraviolet absorption peak at 310 mμ (ε24,700).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([OH:39])[C:10]1([OH:43])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:46](OC)([CH3:48])[CH3:47].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CC(C)=O>[CH2:1]([O:8][CH:9]1[C:10]2([CH2:40][CH2:41][CH3:42])[CH:11]([O:39][C:46]([CH3:48])([CH3:47])[O:43]2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:14]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: CCCC1(O)C(O)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCC12OC(C)(C)OC1C(OCc1ccccc1)C(OCc1ccccc1)C(OCc1ccccc1)C2OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.6 %

Procedure:
21 (0.22 g, 0.37 mmol) was dissolved in 20 mL dry acetone. 5 mL (40.8 mmol) 2.2-dimethoxypropane and 48 mg (0.25 mmol) p-toluene sulfonic acid were added an the solution was stirred for three days at room temperature. Then the reaction was stopped by adding 150 μL (1.08 mmole) triethylamine. All volatile components were removed under reduced pressure and the residue was dissolved in t-butylmethyl ether and washed with 0.5 M phosphate buffer pH=7 and brine. The organic phase was dried over Na2SO4, filtered and dried under reduced pressure. The residue was purified by preparative HPLC (RP18, 94% MeOH, 40 mL/min, tRet=35.10 min) to give 22 (160 mg, 0.25 mmol, 69.3% yield) as a slightly yellow oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:16][CH2:17][N:18]([CH3:32])[CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)=O.C(P(CCCC)CCCC)CCC.Cl>CCOC(C)=O>[CH3:32][N:18]1[CH2:19][CH2:20][N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[CH2:16][CH2:17]1
Reactant: CN(CCO)CC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 0 °C
Yield: 79 %

Procedure:
A solution of diisopropyl azodicarboxylate (51.4 mmol, 1.3 eq) in EtOAc (20 mL) was added to N2-(2-hydroxyethyl)-N2-methyl-N1-(3-nitrophenyl)glycinamide (10 g, 39.5 mmol) and tributylphosphine (13 mL, 51.4 mmol, 1.3 eq.) in EtOAc (50 mL) over a 60-min period during which time the internal reaction temperature was maintained between 25° C. and 30° C. Ethanolic HCl (2.0 M solution, 20 mL) was added dropwise and the resulting slurry was cooled to 0° C. and stirred for an additional hour. The solid was collected by filtration, washed with isopropanol and dried in vacuo at 40° C. for 18 h to give the desired 1-methyl-4-(3-nitrophenyl)piperazine, which was used in the next step without further purification (8.43 g, 79% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (1H, br s) 8.28 (1H, t, J=2.15 Hz) 8.20 (1H, ddd, J=8.08, 2.27, 1.01 Hz) 7.85 (1H, d, J=2.02 Hz) 7.84 (1H, d, J=2.02 Hz) 7.77 (1H, t, J=8.08 Hz) 4.04 (3H, br. s.) 3.66 (1H, br. s.) 3.56 (1H, br. s.) 2.92 (4H, s).