Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1I.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])#[CH:20]>CN(C)C=O.[Cu](I)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:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:20]#[C:19][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27]
Reactant: C#Cc1ccccc1F
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(C#Cc2ccccc2F)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.2 ml, 1.43 mmol) was added to a suspension of 1-Chloro-2-iodo-4-nitro-benzene 69 (Step 1) (100 mg, 0.354 mmol), 1-ethynyl-2-fluorobenzene (100 mg, 0.832 mmol), copper iodide (100 mg, 0.525 mmol), Pd(PPh3)2Cl2 (100 mg, 0.142 mmol) in dimethylformamide (2 ml) at room temperature, then stirred at 70° C. for 2 hours. Reaction was cooled to room temperature and extracted with ether (50 ml), washed with water (20 ml), dried (MgSO4), filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 20% v/v MeCl2/hexanes yielding title product 70 as pale yellow solid (80 mg, 82%).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])(=O)=O.[CH3:14][C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[OH-].[Na+]>[OH:5][C:6]1[CH:11]=[C:10]([C:15]([CH3:20])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18])[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: COc1ccccc1OS(C)(=O)=O
Reactant: CC(C)=CC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(C)(C)CC(=O)O)cc1O
Temperature: 25 °C
Yield: 37.9 %

Procedure:
A mixture of 2-methanesulfonyloxy anisole (240 g) and 3-methylcrotonic acid (39 g) was stirred, and to the thus mixed solution, aluminum chloride (104 g) was added, and the mixture was stirred for 5 hours at 70° C., and then further stirred for 2 hours at 100° C. The obtained solution was cooled to about room temperature, and then 6N hydrochloric acid (HCl) solution (390 ml) was added thereto, and the mixture was stirred for 3 hours vigorously. The solution obtained was extracted with the use of methylene chloride (300 ml), and the organic layer separated was further extracted with the use of two normal (2N) sodium hydroxide (NaOH) aqueous solution (400 ml). Subsequently, 6N hydrochloric acid (HCl) solution was further added to the aqueous layer separated, to acidify, the solution. The obtained aqueous solution was extracted with methylene chloride (300 ml) twice, and thereafter, thus obtained organic layer was concentrated under reduced pressure to obtain a residue. Subsequently, to the residue thus obtained, 6N NaOH aqueous solution (300 ml) was added, and the mixture was stirred for 4 hours at 100° C. for mixing. The obtained reaction solution was cooled to a room temperature, and then 6N HCl solution was added thereto, to acidify the solution. The obtained solution was extracted with ethyl acetate. From the organic solution separated, the solvent therein was removed by distillation under reduced pressure, and thereafter, the obtained crude crystals were recrystallized with toluene to obtain 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid as objective (33.2 g; yield: 37.9% to the 3-methylcrotonic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:14]1[O:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=1)([O-])=O.O>CS(C)=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[O:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
To a solution of 4-chlorophenol (4.4 g, 33.6 mmol) in dimethylsulfoxide (30 mL) was added sodium hydride (1.34 g, 33.6 mmol, 60% in oil), and the solution was stirred at room temperature for 10 minutes. 5-Nitrofuran-2-carbaldehyde (4.0 g, 28 mmol) was added to this reaction solution, and the solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed with water 6 times. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane, then hexane:ethyl acetate=10:1, then 4:1), and the title compound (3.3 g, 14.9 mmol, 53.0%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[Cl:18][C:12](=[O:14])[CH2:11][N:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnn(CC(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the compound (2.0 g) obtained in Example 115b in dichloromethane (20 mL) was cooled in an ice bath, and oxalyl chloride (2.5 g) and N,N-dimethylformamide (2 drops) were added. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([O:49][CH2:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:54]4[CH2:55][CH2:56][CH:51]([CH2:50][O:49][CH2:47][CH3:48])[CH2:52][CH2:53]4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCOCC1CCNCC1
Product: CCOCC1CCN(C(=O)CC2CCN(C(=O)N3C(c4cnc(C(C)(C)C)cc4OCC)=N[C@@](C)(c4ccc(Cl)cc4)[C@@]3(C)c3ccc(Cl)cc3)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-(ethoxymethyl)-piperidine (VWR) to give the title product. LC-MS (ES+) 790 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].[OH:31][C:32]1[CH:42]=[CH:41][C:35]2[C:36](=[O:40])[CH2:37][CH2:38][O:39][C:34]=2[C:33]=1[CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:31][C:32]2[CH:42]=[CH:41][C:35]3[C:36](=[O:40])[CH2:37][CH2:38][O:39][C:34]=3[C:33]=2[CH2:43][CH2:44][CH3:45])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCCC(=O)c1ccc(CCCCCCBr)c(CCC(=O)OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCCc2ccc(C(=O)CCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 89 °C
Yield: 91.5 %

Procedure:
A mixture of 0.43 g (0.89 mmol) of 4-(6-bromohexyl)-3-(3-ethoxy-3-oxopropyl)-δ-oxobenzenepentanoic acid ethyl ester from the preceding example, 0.188 g (0.91 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.398 g (2.88 mmol) of anhydrous granular potassium carbonate in 10 mL of 2-butanone was stirred and heated at 89° C. for 19.3 hr. The mixture was filtered with suction and the solid was washed with ether and ethyl acetate. The filtrate was concentrated in vacuo and the crude product was flash chromatographed on 80 g of silica gel, eluting with hexane-ethyl acetate (5:2). There was obtained 0.496 g (91.5%) of the title compound as a colorless oil.
Reaction SMILES: C([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]4=[O:35])=[CH:21][C:20]=3[F:36])[CH2:16]2)[CH2:12]1)(OCC1C=CC=CC=1)=O.C(Cl)Cl>[Pd].CO>[C@@H:17]12[CH2:16][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]4=[O:35])=[CH:21][C:20]=3[F:36])[CH2:14][C@@H:13]1[CH2:12][NH:11][CH2:18]2
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)OCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CNC[C@H]4C3)c(F)c2)C(=O)O1

Procedure:
(S)-N-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (150 mg, 0.30 mmol), methylene chloride (5 mL), and methanol (10 mL) are combined with 10% palladium on carbon (30 mg) and placed under a hydrogen atmosphere (balloon) for 15 hours. The reaction is filtered through celite and concentrated in vacuo to give crude (S)-N-[[3-[4-[cis- 3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. To the crude (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (115 mg, 0.30 mmol) dissolved in pyridine (5 mL) at 0° C. is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70 mg, 0.35 mmol), 4-dimethylaminopyridine (5 mg, 0.05 mmol), and isoxazole-5-carboxylic acid (40 mg, 0.35 mmol). The reaction is warmed to ambient temperature, stirred 15 hours, diluted with methylene chloride (30 mL). The organic phase is washed with 1N HCl (20 mL) and saline (20 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.16, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 172-175° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:25][NH2:26]>CCO>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:25][NH2:26])=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 61.3 %

Procedure:
Synthesized according to General Procedure C: 51i (4.00 g, 11.6 mmol, 1.0 equiv.), anhydrous hydrazine (1.5 mL, 46.4 mmol, 4.0 equiv.), EtOH (25 mL, 0.5 M). 46i (2.35 g, 61.4%) was obtained as a white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.09 (br s, 1H), 7.62 (d, 2H, J=8.0 Hz), 7.45 (d, 2H, J=8.0 Hz), 3.88 (br s, 2H) 3.75 (br s, 2H), 3.35 (br s, 2H), 3.07 (s, 2H), 2.56 (br s, 2H), 2.42 (br s, 2H). 13C-NMR (125 MHz, CDCl3) δ169.8, 168.9, 139.1 131.8 (q, JC-F=32.1 Hz), 127.5, 125.7 (q, JC-F=3.6 Hz), 123.7 (q, JC-F=271.1 Hz), 60.5, 53.7 (br), 53.2 (br), 47.6 (br), 42.2 (br). 19F-NMR (470 MHz, CDCl3) δ
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:22]([N:25]([C:19](=[O:20])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1)[NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1cccnc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.696 mmol), N′-isopropylnicotino hydrazide (187.14 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried, so that ivory (E)-tert-butyl 3-(3-(1-isopropyl-2-nicotinoyl hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (83 mg, 26.6%).
Reaction SMILES: CO[CH:3]1[CH2:6][CH2:5][C:4]21[CH:15]([CH3:16])[CH2:14][C:13]1[C:8](=[C:9]([CH3:20])[C:10]([CH3:19])=[C:11]([OH:18])[C:12]=1[CH3:17])[O:7]2>CO.Cl>[CH3:16][C:15]1[C:4]2([CH2:5][CH2:6][CH2:3]2)[O:7][C:8]2[C:13](=[C:12]([CH3:17])[C:11]([OH:18])=[C:10]([CH3:19])[C:9]=2[CH3:20])[CH:14]=1
Reactant: COC1CCC12Oc1c(C)c(C)c(O)c(C)c1CC2C
Agent: Cl
Solvent: CO
Product: CC1=Cc2c(C)c(O)c(C)c(C)c2OC12CCC2
Yield: 91.6 %

Procedure:
To a stirred solution of methoxy-3,5,7,8-tetramethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (50 mg) in 10 mL of MeOH was added 5 drops of conc. HCl. The reaction mixture was concentrated, and the residue was purified by flash chromatography eluted with 20% ethyl acetate in hexane to give 40.5 mg of the desired product 3,5,7,8-tetramethylspiro[chromene-2,1′-cyclobutan]-6-ol as a white solid. 1H-NMR (300 MHz, CDCl3) δ=6.27 (s, 1H, =CH), 4.28 (s, 1H), 2.39 (t, 2H), 2.22 (s, 3H), 2.17 (s, 6H), 2.03 (s, 3H), 2.10-1.70 (m, 4H) ppm. 13C-NMR (75 MHz, CDCl3) δ=145.7, 143.7, 136.0, 122.3, 121.6, 119.9, 116.6, 115.1, 81.3, 33.3, 19.1, 14.2, 12.7, 11.8, 11.4 ppm. MS: (m/z)=245.1 (M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]2[C:8]=1[C@@H:9]1[CH2:27][C:26]([CH3:28])=[CH:25][CH2:24][C@H:10]1[C:11]([CH3:23])([CH3:22])[O:12]2)(=O)=O.C(Cl)Cl.[CH3:34][C:35]1([CH3:42])[C:39]([CH3:41])([CH3:40])[O:38][BH:37][O:36]1.C(N(CC)CC)C>ClC(Cl)C>[CH3:34][C:35]1([CH3:42])[C:39]([CH3:41])([CH3:40])[O:38][B:37]([C:7]2[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[C:13]3[C:8]=2[C@@H:9]2[CH2:27][C:26]([CH3:28])=[CH:25][CH2:24][C@H:10]2[C:11]([CH3:22])([CH3:23])[O:12]3)[O:36]1
Reactant: CCCCCc1cc2c(c(OS(=O)(=O)C(F)(F)F)c1)[C@@H]1CC(C)=CC[C@H]1C(C)(C)O2
Reactant: CC1(C)OBOC1(C)C
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1cc2c(c(B3OC(C)(C)C(C)(C)O3)c1)[C@@H]1CC(C)=CC[C@H]1C(C)(C)O2
Temperature: 80 °C
Yield: 95.5 %

Procedure:
A solution of (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl trifluoromethanesulfonate (S30) (410 mg, 0.92 mmol, 1 equiv) in anhydrous dichloroethane (20 ml) was degassed with a steady stream on N2 for 20 min. To the solution was added PdCl2dppf.CH2Cl2 (113 mg, 0.19 mmol, 0.2 equiv), 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (400 μl, 2.76 mmol, 3 equiv) and triethylamine (770 μl, 5.52 mmol, 6 equiv). The mixture was heated to 80° C. under an atmosphere of N2 for 11 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with benzene/hexanes 4/6 (v/v) to afford 373 mg of the title compound as white semi solid (92% yield). Rf=0.32 (benzene/hexanes 1:1 (v/v)). 1H NMR (600 MHz, CDCl3, 20° C., δ): 7.09 (d, J=2 Hz, 1H) 6.71 (d, J=2 Hz, 1H) 5.44 (bd, J=4 Hz, 1H) 2.99 (dt, J=5 Hz, J=11 Hz, 1H) 2.60 (bdd, J=5 Hz, J=15 Hz, 1H) 2.49−2.52 (m, 2H) 2.10−2.17 (m, 1H) 1.83−1.90 (m, 2H) 1.74 (dt, J=5 Hz, J=12 Hz, 1H), 1.68 (s, 3H) 1.59 (p, J=8 Hz, 2H) 1.38 (s, 3H) 1.36 (s, 6H) 1.34 (s, 6H) 1.28−1.33 (m, 4H) 1.14 (s, 3H) 0.88 (t, J=7 Hz, 3H) 13C NMR (100 MHz, CDCl3, 22° C., δ): 152.9, 141.4, 134.5, 128.5, 128.1, 120.0, 119.9, 83.5, 76.1, 45.5, 40.4, 35.4, 33.5, 31.7, 30.9, 28.2, 27.5, 25.1, 24.6, 23.2, 22.6, 18.5, 14.0 (C-B not observed). 11B NMR (96 MHz, CDCl3, 22° C., δ): 29.9. Mass Spectrometry: HRMS-FIA (m/z): Calcd for [C27H41BO3+H], 425.32215. Found, 425.32224.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][CH2:40][O:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=O)=[CH:44][N:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][CH2:40][O:41][C:42]2[N:43]=[CH:44][C:45]([CH2:46][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:49][CH:50]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 64.7 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (22 mg) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][Cl:7].S([O-])([O-])(=O)=[O:9].[Mg+2].OO.[C:16]([OH:21])(=[O:20])[C:17]([OH:19])=[O:18]>CC(C)=O.C[Re](=O)(=O)=O.C(OCC)(=O)C>[C:16]([OH:21])(=[O:20])[C:17]([OH:19])=[O:18].[Cl:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][Cl:7])[OH:9]
Reactant: ClCCNCCCl
Reactant: O=S(=O)([O-])[O-]
Agent: C[Re](=O)(=O)=O
Agent: O=C(O)C(=O)O
Agent: OO
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: ON(CCCl)CCCl
Yield: 108 %

Procedure:
Bis(2-chloroethyl)amine (3.0 g, 0.0211 mole) was added with ethyl acetate (15 ml) and anhydrous magnesium sulfate (3 g), and the mixture was stirred under ice cooling. A solution of methyltrioxorhenium (0.0104 g, 0.0417 mmole) dissolved in 35% aqueous hydrogen peroxide (2.5 g, 0.025 mole) was added dropwise to the mixture over 1 hour so as to keep internal temperature at from 5° C. to 10° C. After the reaction mixture was stirred at room temperature for 1 hour, the magnesium sulfate was removed by filtration, and the filtrate was added with a solution of oxalic acid (1.9 g, 0.0211 mole) dissolved in acetone (7 ml). The mixture was stirred for 30 minutes under ice cooling, and the precipitated crystals were collected by filtration to obtain oxalic acid salt of N,N-bis(2-chloroethyl)hydroxylamine (3.6 g, yield: 68.0%) having melting point of 134-135° C. Structure of the product was analyzed by 1H-NMR and mass spectrometry. 1H-NMR (DMSO-D6) σ (ppm) (multiplicity, integrated value): 8.57-7.80 (br, 1H), 5.95-4.96 (br, 1H), 3.71 (t, 4H), 2.92 (t, 4H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)[CH2:5]P(=O)(OC)OC.[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH:37]=O)[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>O1CCCC1.O.C(OC)(C)(C)C>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][C@@H:29]([NH:28][C:26]([O:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:27])/[CH:37]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]1[CH:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH3:36]
Reactant: COP(=O)(CC(=O)Cc1cc(C)cc(C)c1)OC
Reactant: CCOC(=O)CC[C@H](C=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC[C@H](/C=C/C(=O)Cc1cc(C)cc(C)c1)NC(=O)OC(C)(C)C
Yield: 64.7 %

Procedure:
Under atmosphere of argon, a suspension of 60% sodium hydride (50 mg) was added by a solution of dimethyl (2-oxo-3-(3,5-dimethylphenyl)propyl)phosphonate (373 mg) in tetrahydrofuran (5 mL) at the temperature of 0° C. The mixture was stirred for an hour and then a solution of ethyl (4R)-4-(tert-butoxycarbonylamino)-4-formylbutanoate (298 mg) in tetrahydrofuran (5 mL) was added to the mixture. The mixture was stirred for an hour. To the mixture, metyl tert-butyl ether and water were added, and then 1N a solution of sodium hydroxide was added. The organic layer was washed with saturated brine, dried over an anhydrous magnesium sulfate, concentrated and was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (300 mg) having the following physical data.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.F[B-](F)(F)F.[O:27]=[N+:28]=[O:29]>C(#N)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:28]([O-:29])=[O:27])=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CCC(c2nc(-c3ccncc3)cc(=O)n2C)CC1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CN1CCC(c2nc(-c3ccncc3)c([N+](=O)[O-])c(=O)n2C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-2-(1-methyl-piperidin-4-yl)-6-pyridin-4-yl-3H-pyrimidin-4-one (0.64 mmol) in acetonitrile (2.5 mL) at 0° C. was added 2.5 mL 0.5M solution of nitronium tetrafluoroborate. After 30 min, the reaction product was isolated and purified on silica. M+1=329.
Reaction SMILES: [Br:1][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:25].[Br-].[Li+].C(=O)([O-])[O-].[Ca+2]>CC(N(C)C)=O>[Br:1][C@@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:25]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.1 %

Procedure:
A solution of 2β-bromo-3α-hydroxy-5α-pregnane-11,20-dione (2.5 g.) in dry dimethyl acetamide (70 ml.) was treated with lithium bromide (9.3 g.) and finely divided calcium carbonate (7.1 g.), and the mixture was stirred on a steam bath for 41/2 hr. The reaction mixture was cooled to room temperature, filtered, treated with 2N HCl to pH 4, and the product was extracted with methylene chloride. The extract was washed with water, dried (Na2SO4), and evaporated in vacuo. The residue (2.3 g.) was subjected to preparative t.l.c. The most polar fraction was 3α-hydroxy-5α-pregn-1-ene-11,20-dione (305 mg., 15%), with a nuclear magnetic resonance spectrum resembling that of the product of Example 17. The least polar fraction, after crystallisation from methyl acetate/petrol, gave 2α-bromo-3α-hydroxy-5α-pregnane-11,20-dione (53 mg.), m.p. 168°-170°, [α]D + 134.5°.