Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH2:13]([O:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ccc(CNOCc2ccccc2)cc1Cl
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(Cl)c(Cl)c2)OCc2ccccc2)O1
Yield: 78 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-benzyl-N-(3,4-dichlorobenzyl)-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (78% yield): mp 113-116° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.73 (6H, s, CH3), 4.73 (2H, s, CH2), 4.82 (2H, s, CH2), 6.34 (1H, s, CH), 7.18-7.41 (8H, m, aromatics). Anal. calcd for C21H19Cl2NO5: C, 57.81; H, 4.39; N, 3.21. Found: C, 57.92; H, 4.21; N, 3.12.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40].[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[N:52]=[CH:51][C:50](O)=[CH:49][CH:48]=2)=[CH:44][CH:43]=1>C(Cl)Cl.C1COCC1>[F:41][C:42]1[CH:43]=[CH:44][C:45]([O:46][C:47]2[N:52]=[CH:51][C:50]([O:34][C@@H:35]3[CH2:39][CH2:38][NH:37][C:36]3=[O:40])=[CH:49][CH:48]=2)=[CH:54][CH:55]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)nc1
Reactant: O=C1NCC[C@@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1NCC[C@H]1Oc1ccc(Oc2ccc(F)cc2)nc1

Procedure:
A mixture of THF (200 mL) and DCM (100 mL) under argon was added triphenylphosphine (polymer, 1.8 mmol/g, 20 g). Diisopropylazodicarboxylate (8.87 g) was added. After 5 minutes (S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and 6-(4-fluoro-phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutes the mixture was filtered and the filtrate concentrated. The residue was purified by chromatography (SiO2; DCM/MeOH 15:1) to provide the title compound. MS ESI+: m/z=289 [M+H]+.
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[C:54]3[C:53]([CH3:55])=[N:52][N:51]([CH:56]([CH3:58])[CH3:57])[C:50]=3[C:49](=[O:59])[N:48]2[C:60]2[CH:61]=[C:62]([CH3:70])[C:63]3[N:64]([C:66]([CH3:69])=[N:67][N:68]=3)[CH:65]=2)=[C:43]([F:71])[CH:42]=1>CC(O)C>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]2[C:54]3[C:53]([CH3:55])=[N:52][N:51]([CH:56]([CH3:58])[CH3:57])[C:50]=3[C:49](=[O:59])[N:48]2[C:60]2[CH:61]=[C:62]([CH3:70])[C:63]3[N:64]([C:66]([CH3:69])=[N:67][N:68]=3)[CH:65]=2)=[C:43]([F:71])[CH:42]=1
Reactant: Cc1nn(C(C)C)c2c1C(c1ccc(Cl)cc1F)N(c1cc(C)c3nnc(C)n3c1)C2=O
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CC(C)O
Product: Cc1nn(C(C)C)c2c1[C@@H](c1ccc(Cl)cc1F)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound (65 mg, 43% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: MGII preparative SFC; column: Chiralpak AD-H, 30×250 mm; mobile phase: scCO2/iPrOH 75:25; flow: 50 mL/min; temperature: 38° C.; detection UV: 220 nm) of the racemic mixture of 4-(4-chloro-2-fluorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-isopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 168).
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH3:13]>ClC1C=CC=CC=1>[I:12][C:9]1[CH:8]=[C:7]([CH3:13])[C:6]2[O:5][CH:4]=[CH:3][C:11]=2[CH:10]=1
Reactant: COC(COc1ccc(I)cc1C)OC
Solvent: Clc1ccccc1
Product: Cc1cc(I)cc2ccoc12
Yield: 50.2 %

Procedure:
To a 1 L 3-neck flask was added PPA (2.0 g), anhydrous chlorobenzene (300 ml) and the mixture was brought to reflux. Then 1-(2,2-dimethyoxy-ethoxy)-4-iodo-2-methyl benzene (11.16 g, 34.66 mmol) in chlorobenzene (80 ml) was slowly added by addition funnel over a 2 h period. The reaction was then cooled and passed through a silica plug (washed with chlorobenzene) and concentrated to a mixture of product plus 4-iodo-2-methylphenol. Column chromatography (100% hexane) afforded 4.49 g (53%) product as a clear oil: 1H NMR (300 MHz, DMSO-d6): δ 2.44 (3H, s), 6.91 (1H, d, J=2.2 Hz), 7.46 (1H, brs), 7.86 (1H, d, J=1.2 Hz), 8.00 (1H, d, J=2.2 Hz); MS (E) m/z 258 ([M]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:38])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27]C(=O)C4C=CC=CC=4)[CH2:24][O:23][C:22]3=[O:36])=[C:17]([F:37])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[Cl-].[Na+]>C(COC)OC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:38])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:36])=[C:17]([F:37])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)c(F)c2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)c(F)c2)CC1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
(R)-4-[4-(4-Benzoyloxymethyl-2-oxooxazolidin-3-yl)-3-fluoro-benzoyl]piperazine-1-carboxylic acid tert-butyl ester (1.45 g) described in Preparation Example 91 was dissolved in dimethoxyethane, 4N aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature. Under ice-cooling, the reaction mixture was neutralized with 1N hydrochloric acid, ethyl acetate and sodium chloride were added and the mixture was extracted with ethyl acetate, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (859 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C([Li])CCC.[C:27]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[OH:33][C:27]1([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccccn2)CC1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccccn2)C2(O)CCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of tert-butyl 4-(2-Pyridin-2-yl-ethyl)-piperazine-1-carboxylate (466 mg, 1.60 mmol) in dry tetrahydrofuran (6 mL) under nitrogen was cooled to −78° C. and treated dropwise with a solution of n-butyllithium (2.5 M in hexanes, 0.70 mL, 1.75 mmol). The resulting solution was stirred at −78° C. for 1 h. The reaction was then treated with a solution of cyclohexanone (174 mg, 1.77 mmol) in dry tetrahydrofuran (0.8 mL). The reaction was stirred at −78° C. for 45 min, after which time the reaction was then quenched by the addition of a saturated aqueous solution of sodium bicarbonate, and the tetrahydrofuran was removed in vacuo. The resulting residue was partitioned between water and ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo and the product was purified via Biotage Horizon (FLASH 25 M, silica, gradient from 0% methanol/EtOAc to 10% methanol/EtOAc) to yield 484 mg (78%) tert-butyl 4-[2-(1-hydroxy-cyclohexyl)-2-pyridin-2-yl-ethyl]-piperazine-1-carboxylate as a colorless oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([OH:22])[CH:13]2[O:19][C:18]([CH3:21])([CH3:20])[O:17][CH:14]2[CH:15]=[CH2:16])(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[O:22]1[CH:12]([CH:13]2[O:19][C:18]([CH3:20])([CH3:21])[O:17][CH:14]2[CH:15]=[CH2:16])[CH2:11]1
Reactant: C=CC1OC(C)(C)OC1C(O)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C=CC1OC(C)(C)OC1C1CO1
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
3,4-(Dimethylmethylenedioxy)-2-hydroxy-5-hexen-1-yl p-toluenesulfonate (17.88 g) was dissolved in ml of methanol, and 17.11 g of anhydrous sodium carbonate was added at room temperature, followed by stirring the mixture for 15 minutes. The reaction mixture was filtered through Celite, and crystals were washed with diethyl ether. After the filtrate was concentrated, the solid was filtered through a silica gel column. The filtrate was concentrated under reduced pressure to obtain 7.87 g of 1,2-epoxy-3,4-(dimethylmethylenedioxy)-5-hexene having the following properties.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:19]([S:21][C:22]1[C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:20]>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:28]([C:27]2[C:22]([S:21][CH2:19][CH3:20])=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:29])=[CH:4][CH:3]=1
Reactant: CCSc1ncccc1C(=O)Cl
Reactant: O=C1CCNc2cc(Cl)ccc21
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCSc1ncccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Temperature: 5 °C

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (25 g), pyridine (32 g) and dioxane (200 ml) was added dropwise 2-ethylthio-3-pyridylcarbonyl chloride (37 under cooling at 0 C. to 5° C. with stirring. The mixture was allowed to react at room temperature for additional 3 hours. The reaction mixture was subjected to the procedure described in example 1, and 43 g of 7-chloro-l-(2-ethylthio-3-pyridylcarbonyl)-2,3-dihydro-4(lH)-quinolinone was obtained as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23]([OH:25])=O)[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[C:5]([O:26][CH3:27])[CH:4]=1.Cl.Cl.Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C@@H:39]([N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)[CH3:40])[CH2:34][CH2:33]1>>[OH:47][C@H:44]1[CH2:45][CH2:46][N:41]([C@@H:39]([CH3:40])[CH2:38][N:35]2[CH2:34][CH2:33][CH:32]([NH:31][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][C:5]([O:26][CH3:27])=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:25])[CH2:37][CH2:36]2)[CH2:42][C@@H:43]1[CH3:48]
Reactant: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: COc1cc(OC)c2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(4,6-dimethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 126 (see example 99) and amine 56.
Reaction SMILES: [CH2:1]([C:9]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]2[CH:20]=[C:19]([C:22](O)=[O:23])[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:35])=O>>[CH2:1]([C:9]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]2[CH:20]=[C:19]([C:22]([Cl:35])=[O:23])[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)O)cc21
Reactant: O=S(Cl)Cl
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C(=O)Cl)cc21

Procedure:
9,9-Dioctyl-9H-fluorene-2-carboxylic acid (32.36 g, 74.5 mmole) was refluxed in thionyl chloride (93 g, 782 mmole) for 8 hrs. Unreacted thionyl chloride was distilled off and the residue material used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: Cc1ccc(CO)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
To a stirred solution of 4-methyl-2-nitrobenzoic acid (5 g, 27.6 mmol) in tetrahydrofuran (THF) (27 mL) was added borane tetrahydrofuran complex (35.9 mL, 35.9 mmol) and the mixture stirred at reflux for 3 hours. After cooling, the reaction mixture was extracted with water and DCM. The combined organic layers were dried over MgSO4 and then evaporated to dryness to give the alcohol (D139) as a pale yellow solid (4.52 g, 98%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:16][O:15][C:13](=[O:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: COC(=O)Cl
Reactant: Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1C
Yield: 81.4 %

Procedure:
4-Fluoro-2-methyl-phenol (25 g, 0.2 mol) was added to a solution of sodium hydroxide (9.7 g, 0.24 mol) in water (160 mL) and the resultant solution was cooled to 0° C. Methyl chloroformate (24.2 g, 0.26 mol) was added dropwise at 0° C. At the completion of the reaction, the pH was adjusted to pH 8 with saturated aqueous Na2CO3 and then the mixture was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to provide carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (30 g, 82% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.22-7.13 (m, 2H), 7.05 (m, 1H), 3.81 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>C(#N)C.C(OCC)(=O)C>[Br:35][C:14]1[CH:13]=[C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:26])[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]=1[OH:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(Cc1ccc(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cc(Br)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
402 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was dissolved in 5 ml acetonitrile, and 200 mg N-bromosuccimide was added. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate. The organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), 433 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was obtained.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].N1CCCCC1>[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.C1(C)C=CC=CC=1>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(C#C[Si](C)(C)C)cc2)OC1(C)C
Temperature: 35 °C
Yield: 88.4 %

Procedure:
To a toluene (40 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl) -5-(4-iodophenyl)-2,2-dimethyloxazolidine-3-carboxylate (2.0 g, 4.6 mmols) is added ethynyltrimethylsilane (451 mg, 4.6 mmols), copper (I)iodide (88 mg, 0.46 mmols, 0.1 equivs), Bis(triphenylphosphine)palladium(II) dichloride (165 mg, 0.23 mmols, 0.05 equivs) and piperidine (782 mg, 9.2 mmols, 2 equivs). The mixture is heated in an atmosphere of nitrogen at 35° C. for six hours. The mixture is filtered through a pad of Celite. The pad of Celite is washed with ethylacetate (2×15 ml). The combined organic filtrates were concentrated using rotary evaporation at reduced pressure to give a crude viscous oil. The oil is purified by flash column chromatography (grading from 100% hexanes to 15% EtOAc) to give the title compound (1.65 g): m/z (Cl) 306 ([M+H]+−Boc).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13](Br)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Li].C1(C)C=CC=CC=1.Br[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[N:30][CH:31]=1>[Zn+2].[Br-].[Br-].C1COCC1>[CH2:33]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C@H:13]2[CH2:14][CH2:15][C@H:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)=[CH:31][N:30]=1)[CH3:34]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](Br)CC2)CC1
Reactant: CCOc1ccc(Br)cn1
Agent: [Br-]
Agent: [Li]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(OCC)nc3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.02 m of trans-4-(trans-4-propylcyclohexyl)-cyclohexylbromide, 0.04 m of lithium, 0.01 m of ZnBr2, 40 ml of toluene and 12 ml of THF are stirred at 0°-10° for 2 hours under ultrasonic. The 0.02 m of 5-bromo-2-ethoxy-pyridine and 0.5 g Pd (Ph3P)4 as the catalyst are added, and the mixture is stirred for further 4 hours at room temperature. Customary work-up yields 2-ethoxy-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20](C)(=O)=O)=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:24])=[CH:4][CH:3]=1.CO.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([SH:20])=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCC(c2ccc(S)cc2)N1c1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of 2.5 g of 1-(4-chlorophenyl)-6-(4-methylsulfonylphenyl)-2-piperidone in 10 ml of methylene chloride, 15 ml of anhydrous trifluoroacetic acid was added, and the mixture was refluxed at 45° C. for 3 hours. After cooling, 100 ml of a mixture of methanol and triethylamine (1:1) was added, and the mixture was stirred at room temperature for 1 hour and then treated with a saturated aqueous ammonium chloride solution. The methylene chloride layer was washed with water, dried, and evaporated to give 2.2 g of 1-(4-chlorophenyl)-6-(4-mercaptophenyl)-2-piperidone as pale yellow oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(Br)cc1OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a suspension of 2.51 g (8.96 mmol) 3-benzyloxy-5-bromo-1H-pyridin-2-one and 2.48 g (17.9 mmol) K2CO3 in 45 mL DMF was added 1.12 mL (17.9 mmol) iodomethane at room temperature. After stirring overnight, 150 mL water was added with vigorous stirring causing precipitation of the product which was collected by filtration and dried in vacuo affording 2.3 g (87%) 3-benzyloxy-5-bromo-1-methyl-1H-pyridin-2-one
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH2:10])[C:4]=1[NH:11][C:12](=[O:28])[CH2:13][CH:14]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.[H][H]>O1CCCC1.[Pd]>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH:11][C:12](=[O:28])[CH2:13][CH:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:10]
Reactant: [H][H]
Reactant: C=Cc1cccc(OC)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cccc(OC)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Yield: 42.8 %

Procedure:
A solution of 258 mg (0.62 mmol) of N-(2-methoxy-6-vinylphenyl)-2-(9H-xanthen-9-yl)acetamide in 54 ml of tetrahydrofuran was vigorously stirred at room temperature for 10 hours in the presence of 20 mg of 10% palladium on charcoal in a stream of hydrogen. The reaction mixture was filtered with the aid of Celite and the catalyst was washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated. The residue was recrystallized from a mixture of dichloromethane and hexane to give 99 mg (57%) of the title compound as crystals.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(OC)cc3)CC2)n(-c2ccccc2)n1

Procedure:
122 mg (65%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(4-methoxyphenyl)piperazine (80 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>C1COCC1.C(O)C.[Fe]>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([C:22](=[O:26])[N:23]([CH3:24])[CH3:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cc(CCCC(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cc(CCCC(=O)OCc2ccccc2)ccc1N
Temperature: 100 °C
Yield: 89.2 %

Procedure:
To a mixed solution of 4-(3-dimethylcarbamoyl-4-nitrophenyl)butanoic acid benzyl ester (1.39 g) in THF (5 mL), ethanol (15 mL), and water (5 mL) was added ammonium chloride (1.0 g). After heating to 100° C., iron (838 mg) was added thereto in twice. The mixture was further heated for 1.5 hours under reflux, allowed to stand for cooling down to room temperature, and filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.14 g).