Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][C:8]([CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[CH3:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][C:8]([CH3:18])=[CH:7][C:3]=1[C:4]([NH:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=1[CH3:34])=[O:6]
Reactant: Cc1cc(C(=O)O)c(F)c(-c2cccc(F)c2)c1
Reactant: Cc1ccc(O)c(C)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2c(C)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of 2-fluoro-3-(3-fluorophenyl)-5-methyl-benzoic acid (intermediate III(e)) (597 mg, 2.4 mmol, 1.1 eq) in CH2Cl2 (15 mL) was added (COCl)2 (916 mg, 7.2 mmol, 3.3 eq) and DMF (5 drops). The reaction mixture was stirred at room temperature for 2 h, then the solvent and excess reagent were removed under reduced pressure. The residue obtained was dissolved in THF (20 mL) and added dropwise to a mixture of 3-amino-2,4-dimethylphenol (intermediate X(c)) (300 mg, 2.2 mmol, 1.0 eq) and NaHCO3 (920 mg, 10.9 mmol, 5.0 eq) in THF (20 mL) at 0° C. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for a further 1 h. The reaction was then poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 500:1 to 300:1) to give the title compound as a white solid (588 mg, 73%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:3][P:4]([C:9]1[O:13][C:12]([CH:14]=[N:16][OH:17])=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOP(=O)(OCC)c1ccc(C=O)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccc(C=NO)o1

Procedure:
A solution of 5-diethylphosphono-2-furaldehyde (1 mmole) in ethanol was treated with hydroxylamine (1.1 mmole) and sodium acetate (2.2 mmole) at 25° C. for 12 h. Extraction and chromatography gave 5-diethylphosphono-2-furaldehyde oxime.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[C:11](=[O:20])[CH:12]([CH2:17][C:18]#[CH:19])[CH2:13][C:14]=2[O:15][CH3:16])=[C:4]([Cl:21])[CH:3]=1.[C:22](O)(=O)[C:23]#[C:24]C.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CCOC(C)=O.ClCCl.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.O.CS(C)=O>[Cl:21][C:4]1[CH:3]=[C:2]([C:22]#[C:23][CH3:24])[CH:7]=[C:6]([O:8][CH3:9])[C:5]=1[C:10]1[C:11](=[O:20])[CH:12]([CH2:17][C:18]#[CH:19])[CH2:13][C:14]=1[O:15][CH3:16]
Reactant: CC#CC(=O)O
Reactant: C#CCC1CC(OC)=C(c2c(Cl)cc(Br)cc2OC)C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C#CCC1CC(OC)=C(c2c(Cl)cc(C#CC)cc2OC)C1=O
Temperature: 110 °C
Yield: 32.1 %

Procedure:
A microwave vial was charged with 2-(4-bromo-2-chloro-6-methoxy-phenyl)-3-methoxy-5-prop-2-ynyl-cyclopent-2-en-1-one (0.147 g, 0.398 mmol), but-2-ynoic acid (0.0368 g, 0.437 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0141 g, 0.0199 mmol) and 1,4-bis-(diphenylphosphino)butane (0.0170 g, 0.0398 mmol) was sealed and dimethyl sulfoxide (2 mL) was added via syringe followed by tetrabutylammonium fluoride (1 mol/L) in tetrahydrofuran (0.795 mL, 0.795 mmol) and then the solution was heated under microwave irradiation at 110°C. for 40 minutes. The reaction was cooled to room temperature, poured into water (20 ml) and diluted with EtOAc (10 ml). The phases were separated and the aqueous phase was extracted into ethyl acetate (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give a yellow gum, 230 mg. The residue was dissolved in dichloromethane, adsorbed onto silica and purified by flash chromatography over silica using an EtOAc/isohexane gradient to give the desired compound as a yellow gum (42 mg, 32%) as a seperable mixture of atropisomers with identical spectral data. 1H NMR (400 MHz, CDCl3) δ ppm 7.09 (s, 1H), 6.82 (s, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 3.11-3.09 (m, 1H), 2.74-2.51 (m, 4H), 2.05 (s, 3H), 1.99 (s, 1H).
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].C(Cl)C(=C)C.ClC1C=C[CH:27]=[C:26]([C:30]([O:32]O)=O)[CH:25]=1>ClCCl.O.CN(C)C=O>[O:32]1[C:26]([CH3:27])([CH2:25][O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:30]1
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCOCC1(C)CO1
Temperature: 60 °C
Reaction time: 15 h
Yield: 79.5 %

Procedure:
A 200-ml flask equipped with a stirrer was charged with 10 g (46.6 mmol) of tetradecanol, 50 ml of dimethylformamide, 2.86 g (71.5 mmol) of 60% NaH and 5.96 g (65.8 mmol) of methallyl chloride. The contents were stirred at 60° C. for 15 hours. After completion of the reaction, the reaction mixture was added with water and subjected to extraction with hexane, and the solvent was distilled off under reduced pressure. The resultant residue was charged into a 300-ml flask equipped with a stirrer, and 12.24 g (70.9 mmol) of m-chloroperbenzoic acid and 200 ml of dichloromethane were added thereto. The resultant mixture was stirred at room temperature for 19 hours. Solids formed were separated by filtration, and the resultant solution was concentrated under reduced pressure and then purified by column chromatography on silica gel, thereby obtaining 10.54 g (yield: 79.4%) of 1,2-epoxy-2-methyl-3-tetradecyloxypropane as an intermediate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][CH:11]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([CH3:38])[CH:36]=2)([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:22][CH2:23]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of benzyl N-tert-butoxycarbonyl-isonipecotate (8.02 g, 25.11 mmol) in anhydrous THF (80 mL), a solution of sodium bis(trimethysilyl)amide (35 mL, 35 mmol; 1 M) in THF was added over a period of 10 min. The resulting orange solution was stirred at −78° C. for 1 h. and then treated dropwise with 3-methylbenzyl bromide (4.1 mL, 30.6 mmol). The reaction mixture was allowed to warm to room temp., and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with ethyl acetate. The organic extracts were combined, washed with brine, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:20]=[O:21])[C:6]2[N:10]=[N:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH:19]=1.[BH4-].[Na+]>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH2:20][OH:21])[C:6]2[N:10]=[N:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:7]=2[CH:19]=1
Reactant: C[Si](C)(C)CCOCn1nnc2c(C=O)cc(C(F)(F)F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nnc2c(CO)cc(C(F)(F)F)cc21
Reaction time: 0.25 h

Procedure:
To a solution of 6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole-4-carbaldehyde (165 mg, 0.478 mmol) in ethanol (5 mL) at 0° C. was added sodium borohydride (18.1 mg, 0.48 mmol). The ice bath was removed. After 15 min, the reaction was recooled to 0° C., quenched by the cautious addition of saturated ammonium chloride, and poured into ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 165 mg (99%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.67 (s, 1H), 6.02 (s, 2H), 5.30 (s, 2H), 3.70 (s, 1H), 3.56 (m, 2H), 0.89 (m, 2H), −0.09 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 145.6, 135.1, 132.3, 130.4 (q, J=33 Hz), 124.0 (q, J=273 Hz), 118.5 (q, J=2.9 Hz), 107.4 (q, J=4.8 Hz), 77.3, 67.6, 61.0, 17.7, −1.5.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:41]=[C:42]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:43][NH:44][C:45](=[O:59])[C:46]1[CH:51]=[CH:50][C:49]([O:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:48][CH:47]=1>CN(C=O)C.O>[C:10]([N:63]1[CH2:62][CH2:61][N:60]([C:42](=[O:41])[CH2:43][NH:44][C:45](=[O:59])[C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:50][CH:51]=2)[CH2:65][CH2:64]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
DIPEA (0.138 mL, 0.80 mmol) was added drop wise to benzoic acid (39 mg, 0.32 mmol) in DMF (5 mL). EDCI (127 mg, 0.67 mmol) and HOBT (43 mg, 0.32 mmol) were added consecutively. After 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded N-[2-(4-benzoyl-piperazin-1-yl)-2-oxo-ethyl]-4-phenoxy-benzamide in 57% yield. LC-MS purity: 99%, 1H NMR (DMSO-D6): δ 8.6 (t, 1H), 7.9 (d, 2H), 7.5 (m, 7H), 7.2 (t, 1H), 7.1 (m, 4H), 4.2 (d, 2H), 3.6 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11]C)=O)[CH:5]=[N:6][C:7]=1I.[C:13]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:11])[CH:5]=[N:6][C:7]=1[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cnc(I)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncc(C=O)cc1Br
Temperature: 110 °C
Yield: 55.2 %

Procedure:
To a mixture of methyl 5-bromo-6-iodo-3-pyridinecarboxylate (232 mg, 0.679 mmol), tetrakis(triphenylphosphine)palladium (0) (39.2 mg, 0.034 mmol), and K2CO3 (281 mg, 2.036 mmol) in dioxane (5 ml), trimethylboroxin (0.095 ml, 0.679 mmol) was added under N2. The reaction mixture was heated at 110° C. and more tetrakis(triphenylphosphine)palladium (0) was added in several portions until starting material was not detected by HPLC. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude of reaction was purified by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc to afford the title compound (75 mg, 48%) as a yellow solid.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:58])[N:37]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=2)[CH:40]=1)(O)=[O:33]>>[Cl:57][C:54]1[CH:53]=[CH:52][C:51]([CH2:50][N:37]2[C:36](=[O:58])[C:35]([CH2:32][OH:33])=[CH:40][C:39]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=3)=[N:38]2)=[CH:56][CH:55]=1
Reactant: COc1ccc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: COc1ccc(-c2cc(CO)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Yield: 20.4 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as pale yellow needles (yield: 20.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:16]/[C:15]([OH:19])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)cc1

Procedure:
A solution of 17 g (96 mmol) of (E)-4-(4-methoxyphenyl)but-3-en-2-one and 8.9 g (96 mmol) of glyoxylic acid monohydrate in 25 ml of glacial acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether/hexane yielded (E,E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 138°-139°.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:51][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=4)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccccn1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.4 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1 -piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (70 mg, 0.13 mmol) in CH2Cl2 (1 mL) were added N,N-diisopropylethylamine (85 μL, 0.49 mmol), 2-(aminomethyl)pyridine (17 mg, 0.16 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol), and 1 -hydroxybenzotriazole (24 mg, 0.18 mmol). The suspension was allowed to stir at r.t. for 22 hr, filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→15% MeOH in CH2Cl2) to afford the title compound as a yellow solid (43 mg, 51% yield). LC/MS (ESI) retention time: 1.57 min, m/z 643 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.15-1.27 (m, 3 H) 1.29-1.45 (m, 3 H) 1.48-1.58 (m, 1 H) 1.61-1.70 (m, 1 H) 1.71-1.81 (m, 2 H) 1.86-1.97 (m, 1 H) 1.98-2.15 (m, 3 H) 2.27 (t, J=11.08 Hz, 1 H) 2.38 (s, 4 H) 2.60-2.77 (m, 2 H) 2.78-2.89 (m, 1 H) 3.61 (s, 4 H) 4.40 (s, 1 H) 4.79 (d, J=4.53 Hz, 2 H) 5.09 (s, 1 H) 6.81 (s, 1 H) 7.18-7.22 (m, 1 H) 7.36 (t, J=8.18 Hz, 2 H) 7.41-7.49 (m, 2 H) 7.50-7.59 (m, 2 H) 7.62-7.73 (m, 2 H) 7.89 (d, J=8.56 Hz, 1 H) 8.05 (s, 1 H) 8.56 (d, J=4.53 Hz, 1 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.S(=O)(=O)(O)O>C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Reaction time: 1 h

Procedure:
1.1 g (29 mmol) of lithium aluminium hydride are initially introduced in 50 ml of THF, and a solution of 8.0 g (24.1 mmol) of 3-(3′-benzyloxy-biphenyl-3-yl)propionic acid in 50 ml of THF is added. The batch is stirred at room temp. for 1 h, heated under reflux for 1 h, added to water and acidified using dil. sulfuric acid. The aqueous phase is separated off and extracted with MTB ether. The combined org. phases are washed with water and sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is employed in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:5][C:6]2[N:12]=[CH:11][C@@H:10]3[CH2:13][CH2:14][CH2:15][N:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1.[C:35]([O-:38])([O-])=O.[Ca+2]>C(#N)C.O.Cl[Hg]Cl>[CH3:1][O:2][C:3]1[C:4]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[C:23]3[CH:24]=[CH:25][C:26]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:7]=4)=[CH:27][C:28]=3[C:29]3[C:34]2=[CH:33][CH:32]=[C:31]([C:24]2[CH:23]=[CH:28][C:27]([O:38][CH3:35])=[CH:26][CH:25]=2)[CH:30]=3)=[CH:5][C:6]2[N:12]=[CH:11][C@@H:10]3[CH2:13][CH2:14][CH2:15][N:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1OCCCn1c3ccccc3c3ccccc31)N=C[C@@H]1CCCN1C2=O
Agent: Cl[Hg]Cl
Agent: [Ca+2]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)c2cc(-c4ccc(OC)cc4)ccc2n3CCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2C=N3)cc1
Yield: 58 %

Procedure:
This compound was prepared according to the method described for the compound 6a employing 9d (764.89 mg, 1.0 mmol) and HgCl2 (582 mg, 2.26 mmol), CaCO3 (230 mg, 2.46 mmol) in acetonitrile-water (4:1) to obtain the pure product 10d (373 mg, 58% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([O:11]C(=O)C)[CH2:7][CH2:8][C:9]=2[CH:10]=1.[OH-].[Na+].CCCCCCC.C(OCC)(=O)C>CO.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([OH:11])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: CC(=O)OC1CCc2cc(Cl)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CO
Solvent: O
Product: OC1CCc2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
A solution of acetic acid 3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl ester (1.57 g, 7.42 mmol) in methanol (35.7 ml) was treated with a solution of sodium hydroxide (1M; 8.9 ml). The mixture was stirred at room temperature for 1.5 hours. The reaction was followed by TLC (silica gel, heptane:ethyl acetate=1:1; UV detection 254 nm). After completion, the reaction mixture was treated with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, then evaporated leaving a dark red liquid (1.15 g, 91% yield) which crystallised on standing. Following NMR the product was pure enough for the next step of the synthesis. MS (ISP): m/z=170 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>ClCCl>[CH2:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][C:21](=[O:24])[CH2:22][CH2:23]1)=[O:17])[CH2:12][C:13]#[CH:14]
Reactant: C#CCCOC(=O)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCOC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
25 ml of oxalyl chloride was added to 500 ml of dichloromethane, into which 4 ml of dimethyl sulfoxide was gradually dropped in a stream of nitrogen at a temperature of from -50° C. to -70° C. Subsequently, 10.3 g of N-(3-butynyloxycarbonyl)-4-hydroxypiperidine was dissolved in 50 ml of dichloromethane, followed by gradually dropping into the reaction mixture. Finally, 120 ml of triethylamine was dropped, followed by gradually increasing the temperature up to room temperature. The reaction solution was charged into a saturated saline solution, extracted three times with dichloromethane and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resultant residue was purified by the use of silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1), thereby obtaining 8.9 g of the intended compound.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:28][Si](C)(C)C>CC(CC)=O>[ClH:28].[CH3:27][N:2]([CH3:1])[C:3]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:4][CH2:5][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCc2ccccc2)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1.5 h

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexyl)-N-phenethylacetamide (220 mg, 0.6 mmol) was dissolved in ethyl methyl ketone with gentle heating and chlorotrimethylsilane (0.113 ml, 0.9 mmol) was added. After 1.5 h it was possible to isolate a colourless, hygroscopic solid in a yield of 80% (191 mg).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH2:13]C([O-])=O.[K+]>C1(C)C=CC=CC=1>[C:1]1([C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[CH:13]/[C:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[O:6]1)=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)/C=C1\OC(=O)c2ccccc21
Yield: 52 %

Procedure:
14.8 g (0.1 mol) of phthalic anhydride and 9.9 g (0.05 mol) of potassium tert-butyl malonate are added to 200 ml of toluene, and the reaction mixture is heated under reflux for 6 hours. After terminating the reaction, 100 ml of water is added, and an organic layer is separated out. The organic layer is washed with 100 ml of 5%-aqueous ammonium bicarbonate solution, and toluene is distilled off under a reduced pressure. The residue thus obtained is purified by column chromatography, to give 6.4 g (0.026 mol) of tert-butyl (Z)-3-phthalidylideneacetate. The yield is 52.0%.