Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O[C:8]1([CH2:14][C:15]2([C:20]([O:22]CC)=O)[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1.[OH:25]S([O-])(=O)=O.[Na+]>CCOCC>[OH:25][CH:14]([C:15]1([CH2:20][OH:22])[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(CC2(O)C=CC=CC2)CCCC1
Reactant: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1(C(O)c2ccccc2)CCCC1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Lithium aluminum hydride (1.05 g, 27.6 mmol) was suspended in ether (80 ml) and the mixture was cooled to −20° C. to −30° C. Thereto was added dropwise a solution of ethyl 1-(1-hydroxyphenylmethyl)cyclopentanecarboxylate (14.118.4 mmol) in ether (10 ml) while maintaining the solution at not higher than −20° C. The mixture was stirred at −20° C. for 1 h and at room temperature for 3 h, cooled to −20° C. and 10% NaHSO4 aqueous solution (40 ml) was added dropwise. The mixture was stirred at 0° C. for 30 min and an insoluble material was removed by decantation. This was washed twice with ether (100 ml), and the organic layer was combined, washed with water and dried over anhydrous sodium sulfate. This was concentrated to dryness to give a colorless oil (3.12 g).
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.CO>O>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([NH2:17])=[O:16]
Reactant: CC(C(N)=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: O
Solvent: CO
Product: CC(C(N)=O)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 50 °C
Yield: 80 %

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is dissolved in 50 ml. of methanol and 5 ml. of N-hydrochloric acid is added. The mixture is heated to 50° C. for 30 minutes then cooled and added to water. The solution is extracted with ethyl acetate and the extract washed, dried and evaporated to yield 80% of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide which is recrystallized from methanol, m.p. 158°-159° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide.
Reaction SMILES: N1CCCCC1.[CH2:7]([N:9]([CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=O)[CH2:10][CH3:11])[CH3:8].C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH2:7]([N:9]([CH2:12][C:13]1[CH:14]=[C:15](/[CH:16]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:10][CH3:11])[CH3:8]
Reactant: CCN(CC)Cc1cc(C=O)ccc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 49.4 %

Procedure:
Piperidine (97 μL, 0.99 mmol) was added to a suspension of 3-((diethylamino)methyl)-4-methoxybenzaldehyde (0.22 g, 0.99 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.20 g, 0.90 mmol) in toluene (5 mL) and treated according to Procedure 2, neutralizing with 20% AcOH. The resulting precipitate was filtered and washed with water providing (E)-2-[[3-(3-((diethylamino)methyl)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.17 g, 50%) as a colourless crystalline solid; mp 202-205° C.; δH (400 MHz, DMSO-d6) 1.14 (t, J=7.2 Hz, 4H, CH2CH3), 2.87 (q, J=7.2 Hz, 6H, CH2CH3), 3.79 (s, 3H, OCH3), 3.98 (s, 2H, NCH2), 6.51 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.03 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.34 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.46 (d, J=15.6 Hz, 1H, CH═CHCO), 7.57 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.76 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.98 (d, J3,4=8.0 Hz, 1H, H3), 8.54 (d, J5,6=8.0 Hz, 1H, H6), 13.34 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 9.38, 46.4, 49.8, 55.6, 111.4, 118.9, 121.2, 121.5, 122.1, 126.9, 130.2, 130.8, 130.9, 139.2, 140.7, 158.8, 163.3, 169.7; HRMS (ESI) calculated for C22H26N2O4 [M+H]+ 383.1965. found 383.1964; vmax 823, 1264, 1366, 1500, 1579, 1609, 1674, 2943, 3478 cm−1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].O[CH2:11][CH:12]([CH2:14]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O>O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:7]([CH:11]=[CH:12][CH:14]=[N:6]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: OCC(O)CO
Reactant: CCc1cccc(N)c1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: CCc1ccc2cccnc2c1
Yield: 93.3 %

Procedure:
In a similar fashion using route 10 general procedure 20, 3-ethylaniline (1 g, 8.25 mmol), glycerol (2.35 g, 25.6 mmol), 3-nitro benzenesulfonic acid sodium salt (2.42 g, 10.7 mmol), H2SO4:H2O (3.5 ml:2.5 ml) gave the title compound (1.21 g, 93%) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:25]([Cl:26])=[C:24]([C:27](Cl)=[O:28])[S:23][N:22]=1.O>CN(C)C=O>[Cl:20][C:21]1[C:25]([Cl:26])=[C:24]([C:27]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[O:28])[S:23][N:22]=1
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(C(=O)c2snc(Cl)c2Cl)c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of N-(4-chlorophenyl)-4-methoxybenzenesulfonamide (1.98 g) in unhydrous N,N-dimethylformamide (20 ml) 60% sodium hydride (0.24 g) was added at room temperature. After stirring the reaction mixture at the same temperature for 1 hour, a solution of 3,4-dichloro-5-isothiazolecarbonyl chloride (1.1 g) in unhydrous N,N-dimethylformamide (10 ml) was added thereto dropwise. After finishing the addition, the reaction mixture was stirred at room temperature for 18 hours and poured into water. The mixture was extracted with ethyl acetate and the organic phase was washed with water and dried with unhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from ethanol to obtain N-(3,4-dichloro-5-isothiazolecarbonyl)-N-(4-chlorophenyl)-4-methoxybenzenesulfonamide (0.89 g). mp 154-158° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)[CH:15]=[CH:14][C:13]=2[NH2:28])=[N:2]1.C(N(CC)CC)C.[CH3:36][C:37]1[CH:41]=[CH:40][S:39][C:38]=1[C:42](Cl)=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:23]3)[CH:15]=[CH:14][C:13]=2[NH:28][C:42]([C:38]2[S:39][CH:40]=[CH:41][C:37]=2[CH3:36])=[O:43])=[N:2]1
Reactant: CS(=O)(=O)C1CCN(c2ccc(N)c(C=Cc3n[nH]c4ccccc34)c2)CC1
Reactant: Cc1ccsc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(N2CCC(S(C)(=O)=O)CC2)cc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a similar manner to Example 2, said crude 3-{2-[5-(4-methanesulfonylpiperidin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (0.23 g, 0.54 mmol) obtained in Step 1 was dissolved in ethanol (7.0 mL) and 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenylamine was obtained from tin (0.19 g, 1.6 mmol) and concentrated hydrochloric acid (1.0 mL) at room temperature. In a similar manner to Example 29, a solution of 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenylamine (0.22 g, 0.54 mmol) in THF (10 mL) was added with triethylamine (0.23 ml, 1.6 mmol) and 3-methylthiophenecarbonyl chloride (0.09 g, 0.54 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure to obtain crude (E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenyl}-3-methylthiophene-2-carboxamide. Further, Compound 227 (68 mg, 22%) was obtained using 4 mol/L hydrogen chloride-methanol solution (1.0 mL).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:51])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:26]([S:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)(=[O:37])=[O:36])[CH2:25][CH:24]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C(O)C>[Pd].C(Cl)Cl.CO>[C:47]([O:46][C:44]([CH:24]1[CH2:25][CH:26]([S:35]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)(=[O:37])=[O:36])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:51])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)C1CC(S(=O)(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC(S(=O)(=O)N2CCOCC2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 59.4 %

Procedure:
A The process is performed as described in Example 2A, but starting with 2.5 g of (2RS,4SR,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-morpholinosulphonylpyrrolidine, 0.25 g of 10% palladium-on-charcoal and 100 cm3 of ethanol under a hydrogen atmosphere (130 kPa). After treatment, 1.3 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-morpholinosulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid are obtained [Rf=0.43; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: [SH:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CC#N.ClCCl>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:12][S:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[CH3:18]
Reactant: Sc1nc2ccccc2[se]1
Reactant: CCOC(=O)C(=O)CBr
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C(=O)CSc1nc2ccccc2[se]1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a suspension of 2-mercaptobenzselenazole (418 mg, 2 mmol) in 4 mL of MeCN and 4 mL of dichloromethane with vigorous stirring was added dropwise, ethyl bromopyruvate (290 mg, 2 mmol). The resulting mixture was stirred for 5 h. It was allowed to settle for 30 min and then filtered. The solid was washed with EtOAc/hexanes (1:1, 2×8 mL) and dried in high vacuum to afford 3-(benzoselenazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester as a white powder (582 mg, 89%). 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 8.14-8.10 (m, 1H), 7.95-7.92 (m, 0.7H), 7.75-7.73 (m, 0.3H), 7.52-7.45 (m, 1H), 7.36-7.30 (m,1H), 7.07 (s, 0.7H), 4.69 (s, 0.6), 4.37-4.27 (m, 2H), 1.32 (t, J=7 Hz, 3H). MS(ESI) m/z: 330(M+H+, 55), 348 M++H2O, 58), 362 (M++MeOH, 100).
Reaction SMILES: [O:1]=C[C@@H]([C@@H]([C@@H](CO)O)O)O.O[C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH:13]1[C:22]#[C:23]C1N=C3C(NC=N3)=C(N)N=1)[CH2:19]2.OC12CC3CC(CC(C3)C1C#CC1N=C(N)C3N=CN(C=3N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)C2.[OH-].[Na+]>CO.Cl>[C:22]([C:13]1([OH:1])[CH:14]2[CH2:20][CH:18]3[CH2:17][CH:16]([CH2:21][CH:12]1[CH2:19]3)[CH2:15]2)#[CH:23]
Reactant: Nc1nc(C#CC2C3CC4CC(C3)CC2(O)C4)nc2nc[nH]c12
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Agent: Nc1nc(C#CC2C3CC4CC(C3)CC2(O)C4)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: CO
Product: C#CC1(O)C2CC3CC(C2)CC1C3

Procedure:
Representative procedure for ribose cleavage: 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine. A solution of 2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenosine (3.486 g, 7.896 mmol) in methanol (100 mL) and 1.0 M HCl (10.0 mL) was stirred at 90° C. in a pressure apparatus for 18–50 h. The pH was adjusted to 4.2 with 5.0 M NaOH and the volume was reduced to half under reduced pressure. After cooling the resulting precipitate was filtered and washed with methanol to afford the pure product as a white solid: yield 2.153 g, 88%. 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 7.25 (br s, 2H), 5.56 (s, 1H), 2.18–2.09, 1.94–1.89, 1.82–1.64, 1.52–1.45 (4×m, 12H). LRMS ESI (M+H+) 310.1.
Reaction SMILES: Br[CH:2]1[CH2:20][CH2:19][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:21].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@@H:32]([O:34][CH2:35][CH3:36])[CH2:31][C@H:30]1[C:37]([OH:39])=[O:38])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH2:35]([O:34][C@@H:32]1[CH2:33][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[C@H:30]([C:37]([O:39][CH:2]2[CH2:20][CH2:19][C:5]3=[CH:6][C:7]4[C:8]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=5[CH2:10][O:11][C:12]=4[CH:13]=[C:4]3[C:3]2=[O:21])=[O:38])[CH2:31]1)[CH3:36]
Reactant: CCO[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C1c2cc3c(cc2CCC1Br)-c1ccc(Cl)cc1CO3
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(Cl)ccc2-4)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a slurry of 9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.50 g, 6.8 mmol) in MeCN (20 mL) was added (2S,4S)-1-(tert-butoxycarbonyl)-4-ethoxypyrrolidine-2-carboxylic acid (2.68 g, 10.3 mmol) and DIPEA (1.3 mL, 7.5 mmol). The reaction was heated with stirring to 50° C. for 18 h. The reaction was then cooled to room temperature and diluted with EtOAc. The solution was washed with HCl (1N) and brine. The aqueous layers were backextracted with EtOAc and the resulting organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (15% to 50% EtOAc/Hexanes) to afford (2S,4S)-1-tert-butyl 2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 4-ethoxypyrrolidine-1,2-dicarboxylate (2.08 g, 56%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH:13][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[O:15])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(NCc1cccc(F)c1)NNC(=O)c1ccc2c(c1)CCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(CNc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Yield: 11.1 %

Procedure:
A solution of 2-(2,3-dihydro-1-benzofuran-5-ylcarbonyl)-N-(3-fluorobenzyl)hydrazinecarboxamide (0.50 g, 2.81 mmol), polystyrene resin-immobilized triphenylphosphine (2.15 mmol/g, 0.76 g, 1.64 mmol), triethylamine (0.17 mL, 1.22 mmol) and carbon tetrachloride (0.12 mL, 1.22 mmol) in tetrahydrofuran (5 mL) was stirred at 80° C. for 4 hr. The reaction mixture was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (97 mg, yield 51%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.S(Br)([Br:27])=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][Br:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Br)Br
Reactant: OCCN(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: BrCCN(Cc1ccccc1)Cc1ccccc1
Reaction time: 15 h
Yield: 55 %

Procedure:
To N,N-dibenzyl-2-aminoethanol (18.47 g) was added hexane (150 ml) and DMF (0.3 ml), and thereto was added dropwise thionyl bromide (15.91 g) at 0° C. The mixture was stirred for 15 hours, and to the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution in an ice-bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×2) and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane) to give the title compound (12.80 g).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[C:12]([SiH2:16][O:17][C:18]([CH3:33])([CH3:32])[C:19]1[CH:20]=[C:21]([NH2:31])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[C:19]([C:18]([CH3:33])([CH3:32])[O:17][SiH2:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:20]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(N)ccc1N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(Nc2ncc(Br)n3ccnc23)ccc1N1CCOCC1
Yield: 21.5 %

Procedure:
In the same way as described in the general procedure for amine displacement using 5,8-dibromo-imidazo[1,2-a]pyrazine (0.534 g, 1.94 mmol), 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-morpholin-4-yl-phenylamine (0.751 g, 2.33 mmol), N,N-diisopropyethylamine (0.31 mL, 1.8 mmol) and iso-propanol (10 mL). Purification by silica gel column chromatography eluting with 7:3 petroleum ether:ethyl acetate followed by trituration with diethyl ether affords the title compound (0.216 g, 17%).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[O:47][CH3:48])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:50]1[S:54][C:53]([C:55]([O:57][CH3:58])=[O:56])=[CH:52][C:51]=1[CH3:59].N#N.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:19]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37]([C:50]4[S:54][C:53]([C:55]([O:57][CH3:58])=[O:56])=[CH:52][C:51]=4[CH3:59])[CH:36]=[CH:35][C:34]=3[O:47][CH3:48])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C)c(Br)s1
Reactant: COc1ccc(B2OCC(C)(C)CO2)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4S,5R)-3-({6-azetidin-1-yl-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]pyridin-2-yl}methyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (27 mg, 0.040 mmol) and methyl 5-bromo-4-methyl-2-thiophene carboxylate (18.74 mg, 0.080 mmol) in THF (0.5 mL) was degassed with N2 at 25° C. 1N K2CO3 (0.5 mL) was added followed by 1,1-bis(di-tert-butylphosphino) ferrocene palladium dichloride (2.60 mg, 3.99 mmol) and the reaction was stirred vigorously at 25° C. under N2 overnight. The reaction was diluted with water and extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by preparative TLC (20×20, 1000 μm, hexanes/EtOAc (70/30)) to give methyl 5-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}-4-methylthiophene-2-carboxylate. LCMS calc.=719.2. found=720.2 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.86 (s, 1H); 7.73 (s, br, 2H); 7.62 (s, 1H); 7.47 (d, J=8.6 Hz, 1H); 7.35 (d, J=8.6 Hz, 1H); 7.33-7.23 (m, 1H); 7.03 (d, J=8.6 Hz, 1H); 6.31 (d, J=8.3 Hz, 1H); 5.74-5.31 (m, 1H); 4.87 (d, J=16.2 Hz, 1H); 4.24 (s, br, 1H); 4.23-3.97 (m, 5H); 3.88 (s, 3H); 3.87 (s, 3H); 2.47-2.41 (m, 2H); 2.33 (s, 3H); 0.75-0.53 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH:18]=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.CO[C:23](C)(C)[CH3:24]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:16][CH2:17][CH:18]=[CH:23][CH3:24]
Reactant: N#Cc1ccc([C@H]2CC[C@H](CCCC=O)CC2)cc1
Reactant: COC(C)(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: CC=CCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3.16 g of ethyl-triphenylphosphonium bromide in 50 ml of dry t-butyl methyl ether was treated with 960 mg of potassium t-butylate while gassing with argon at -10° C. and the mixture was stirred for a further 45 minutes at 0° C. Thereafter, the mixture was cooled to -20° C., treated within 5 minutes with a solution of 1.45 g of 4-[trans-4-(p-cyanophenyl)cyclohexyl]butyraldehyde (purity 90%) in 20 ml of t-butyl methyl ether and the mixture was stirred for a further 30 minutes while warming to room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of water, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave p-[trans-4-(4-hexenyl)cyclohexyl]benzonitrile (4Z: 4E=88:12) as a colourless oil. Additional low-pressure chromatography (0.5 bar) of this material on 140 g of silver nitrate-coated silica gel (prepared according to Example 2) with hexane/diethyl ether (vol. 3:1) yielded 750 mg of p-[trans-4-(4Z-hexenyl)cyclohexyl]benzonitrile. Two-fold recrystallization from methanol finally gave 468 mg of colourless crystals with m.p. (C--I) 27.4° C. and cl.p. (N--I) 4.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].C(=O)([O-])[O-].[K+].[K+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: Fc1cnccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2ccncc2F)cc1
Yield: 121.1 %

Procedure:
To a stirred suspension of (4-nitrophenyl)boronic acid (1.6 g), 4-chloro-3fluoropyridine (1.11 g), and tetrakis (triphenylphosphine) palladium (462 mg) in 1,2-dimethoxyethane (25 mL) was added 0.8M potassium carbonate aqueous solution (25 mL) and the mixture was refluxed under nitrogen for 20 hours. After cooling, 1,2-dimethoxyethane was removed in vacuo. To the residue was added ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated to afford 3-fluoro-4-(4-nitrophenyl)pyridine (2.23 g) as a brown solid.