Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:6][CH:5]([CH2:24][OH:25])[CH:4]1[CH3:26])[CH3:2].[CH2:27]([CH:29]1[CH:34]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[C:33]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)=[CH:32][CH:31]([CH2:50][OH:51])[CH:30]1[CH3:52])[CH3:28]>C(Cl)Cl.C(OCC)(=O)C.O.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:7]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:6][CH:5]([CH2:24][OH:25])[CH:4]1[CH3:26])[CH3:2].[CH2:27]([CH:29]1[CH:30]([CH3:52])[CH:31]([CH2:50][OH:51])[CH2:32][CH:33]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[CH:34]1[C:35]1[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=1)[CH3:28]
Reactant: CCC1C(c2ccc(O)cc2)C(c2ccc(OC)cc2)=CC(CO)C1C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCC1C(c2ccc(O)cc2)=C(c2ccc(OC)cc2)CC(CO)C1C
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C(C)C(CO)CC(c2ccc(OC)cc2)C1c1ccc(O)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To the above mixture of 4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-1-enyl]-phenol and 4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-2-enyl]-phenol (380 mg) in DCM (10 mL) at −10° C. was added TiCl4 (0.180 mL) and the mixture was stirred for 3 h at −10° C. The reaction mixture was diluted with ethyl acetate/H2O (200/100 mL). The organic layer was dried and purified on SiO2 to yield two products 4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-1-enyl]-phenol and 4-[2-ethyl-4-hydroxymethyl-6-(4-methoxy-phenyl)-3-methyl-cyclohexyl]-phenol.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]=O.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1/[CH:8]=[N:16]/[S@@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15]
Reactant: Cn1ncc(C=O)c1Cl
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Product: Cn1ncc(/C=N/[S@](=O)C(C)(C)C)c1Cl
Temperature: 25 °C
Yield: 87.3 %

Procedure:
5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde (1130 mg, 7.82 mmol) was suspended in THF (20 ml), Ti(OEt)4 (4.29 ml, 16.4 mmol) was added followed by (R)-(+)-2-methyl-2-propanesulfinamide and the reaction heated to reflux for 18 hours. The reaction was then cooled to room temperature, poured onto EtOAc:Brine (20 ml: 20 ml) filtered through celite and washed through with EtOAc (2×20 ml). The organic layer was then separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to give the title compound as a brown viscous oil (1690 mg, 87.3% yield). 1H NMR (400 MHz, CDCl3) 1.22-1.23 (9H s) 3.88 (3H s) 7.92 (1H s) 8.43 (1H br. s) MS (ESI/APCI) m/z 248 (M+H)+
Reaction SMILES: S(C)C.[CH:4]([Li])([CH3:6])[CH3:5].[C:8]([NH:27][C@H:28]([CH2:31][CH3:32])[CH:29]=[O:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][CH:4]([CH:29]([OH:30])[C@H:28]([NH:27][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:31][CH3:32])[CH3:6]
Reactant: [Li]C(C)C
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added isopropyllithium (0.7 M in pentane, 17.29 mL, 4 eq, 12.1 mmol) dropwise, and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 1 h, then allowed to warm to −55° C. and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel gradient column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a colourless oil. Yield: 0.53 g (47%). (50% de 3S,4R: 50% de 3R,4R) 1H-NMR (d6-DMSO, 250 MHz): δ 0.44 (t, 3H, J=7.03 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.52 & 0.77 (2×d, 6H, J=6.48 Hz, —NHCH (CH2CH3)CH(CH(CH3)2)OH), 0.79-1.13 (m, 2H, —NHCH(CH2CH3)CH (CH(CH3)2)OH), 1.72 (m, 1H, —NHCH(CH2CH3)CH (CH(CH3)2)OH), 2.11 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)OH), 2.77 (m, 1H, —NHCH(CH2CH3)CH (CH(CH3)2)OH), 2.99 (m, 1H, —NHCH(CH2CH3)CH(CH (CH3)2)OH), 4.55 (d, 1H, J=5.21 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 7.15-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11]O.[BrH:13].[Br-].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C.C(Cl)Cl.C1C=CC=CC=1>[Br-:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Br
Reactant: O=[N+]([O-])c1ccc(Cl)c(CO)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 63 %

Procedure:
Bromination of (2-chloro-5-nitrophenyl)methanol with 30% HBr in acetic acid, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 112, gave the phosphonium salt (564) (63%) as a white solid, mp (CH2Cl2/benzene) 239–243° C. 1H NMR (CDCl3) δ 8.22 (br s, 1H), 8.07 (br d, J=8.7 Hz, 1H), 7.87–7.65 (m, 15H), 7.41 (d, J=8.9 Hz, 1H), 5.80 (d, J=14.8 Hz, 2H). Found: C, 58.56; H, 3.93; N, 2.73. C25H20BrClNO2P requires C, 58.47; H, 3.98; N, 2.66.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:29])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[N:22][NH:23][C:24]=3[Si](C)(C)C)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.CO>[NH3:8].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:29])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[N:22][NH:23][CH:24]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cccc(-c3nn[nH]c3[Si](C)(C)C)c2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(c2cccc(-c3c[nH]nn3)c2)CCN(Cc2ccccc2)CC1
Product: N
Yield: 186.9 %

Procedure:
A solution of 1-benzyl-4-methyl-4-(3-(5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine (Example 37, assume 1.03 mmol) in 2 N hydrochloric acid:methanol (1:1, 20 mL) was heated at 90° C. overnight. After allowing to cool, the reaction mixture was adjusted to pH 9 using aqueous 2 N sodium hydroxide. The aqueous mixture was extracted with ethyl acetate (3×20 mL) and the extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with a gradient of ethyl acetate:hexane:0.88 ammonia (50:50:1 to 100:0:1) to give the title compound as a white solid (320 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(-c2ccccc2Br)c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 2′-bromo-biphenyl-3-carbonitrile (200 mg, 0.77 mmol), sodium azide (66 mg, 1.01 mmol) and triethylamine hydrochloride (139 mg, 1.01 mmol) in toluene (2 ml) was heated at 90° C. for 24 hours. A further portion of sodium azide (66 mg, 1.01 mmol) and triethylamine hydrochloride (139 mg, 1.01 mmol) was added and heated for a further 24 hours. After cooling, the mixture was extracted with water (3×2 ml). The combined extracts were acidified and the precipitate filtered off and dried. (163 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH:26]=[C:9]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C=C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of (3-tert-butoxycarbonylamino-2-oxo-propyl)-carbamic acid tert-butyl ester (310 mg, 1.08 mmol) in benzene (20 mL) was added (carbethoxymethylene)-triphenyl phosphorane (825 mg, 2.37 mmol) and the reaction mixture was stirred at 45° C. overnight. Then the mixture was cooled to room temperature and the solvent concentrated down. Purification by radical chromatography on silica gel (2 mm plate, using CH2Cl2) afforded the desired compound as a yellow oil (290 mg, 75%). 1H NMR (CDCl3) δ 1.26 (t, 3H, J=9.0 Hz), 1.42 (s, 18H), 3.87 (d, 2H, J=6.0 Hz), 4.09 (d, 2H, J=6.0 Hz), 4.15 (q, 2H, J=9.0 Hz), 5.34 (br s, 1H), 5.85 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: COB(OC)OC.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:27]2[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:26]=2[C:25]2[C:24]3[CH:23]=[C:22]([NH:33][CH:34]=O)[CH:21]=[CH:20][C:19]=3[N:18]([CH3:36])[C:17]=2[CH:16]=1.O1CCCC1>CO>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:27]2[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:26]=2[C:25]2[C:24]3[CH:23]=[C:22]([NH:33][CH3:34])[CH:21]=[CH:20][C:19]=3[N:18]([CH3:36])[C:17]=2[CH:16]=1
Reactant: Cn1c2ccc(NC=O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2C)C(=O)NC3=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Borane methylsulphide complex (0.074 mL, 0.78 mmol) and trimethylborate (0.089 mL, 0.78 mmol) were added at 0° C. under an atmosphere of nitrogen to a solution of amide (920) (0.105 g, 0.26 mmol) prepared as described in example 469 dry tetrahydrofuran (10 mL) After stirring at 0° C. for 30 min. the solution was allowed to warm to room temperature over 16 h. Methanol (200 mL) was added and the reaction mixture was stirred for 12 h. The solvent was removed under reduced pressure and the yellow residue was purificatied by column chromatography on silica, eluting with petroleum ether:ethyl acetate (100:0 to 0:100) to give (922) as a red solid (0.053 g, 45%), mp 293–296° C. 1H NMR δ [(CD3)2SO] 11.01 (br s, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.69 (s, 1H), 7.57 (dd, J=7.1, 2.0 Hz, 1H), 7.42–7.52 (m, 4H), 7.02 (dd, J=8.8, 2.3 Hz, 1H), 5.61 (q, J=5.2 Hz, 1H), 3.90 (s, 3H), 2.81 (d, J=5.2 Hz, 3H). EIMS found: M+=389.0929, 391.0905. C22H16ClN3O2 requires 389.0931, 391.0902.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].CCN(CC)CC>C(Cl)Cl>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]

Procedure:
Combine phenyl boronic acid (7.32 g, 60 mmol), 4-methyl-3-nitrophenol (4.5 g, 30 mmol), and Cu (oAC)2-H2O (6 g, 30 mmol) in 30 mL CH2Cl2 and treat with 6 g 4A molecular sieves powder. Add Et3N (15.18 g, 150 mmol) dropwise, and stir the reaction at ambient temperature for 8 days. Dilute with 100 mL CH2Cl2 and filter through celite and concentrate to dryness. Purification by chromatography using 2% EtOAc in hex anes gave the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[CH3:23][NH2:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:24][CH3:23])[C:11]=2[CH:10]=[CH:9]1
Reactant: CN
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21
Product: CNc1nc2c(C)cccc2c2c1ccn2-c1ccccc1C

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methylpyrrolo[3,2-c]quinoline (1.5 g, 4.9 mmol) and methylamine (33% in ethanol, 50 ml) were heated to 150° C. in a pressure vessel for 16 hours, then the solvent evaporated. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from aqueous ethanol yielded 1-(2-methylphenyl)-4-methylamino-6-methylpyrrolo[3,2-c]quinoline (0.62 g),m.p. 129°-130°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[Na+].[C:12]1([S:18]([O-:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[CH:6]=[O:7])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: O=Cc1ccc(Cl)cc1S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared by the method of Preparation 5a using 4-chloro-2-fluorobenzaldehyde and benzene sulfinic acid sodium salt.
Reaction SMILES: C([O:5][C:6](=[O:27])[NH:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(O[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=O.C(=O)([O-])O.[Na+]>>[CH2:46]([O:5][C:6](=[O:27])[NH:7][N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:12][CH2:13]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC1(CN2CCN(NC(=O)OCc3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
A mixture of tert-butyl[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 493-(150 mg, 0.39 mmol) and trifluoroacetic acid (4 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (4 ml) and neutralized with triethylamine (4 ml, 28.7 mmol). Subsequently, to the solution, benzyl chloroformate (100 mg, 0.59 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 2 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added. The mixture was extracted with methylene chloride. The extract was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=1/1) to afford benzyl[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate (6.5 mg, yield 4%) as a light yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>C(O)C>[CH2:22]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 137 g (0.55 mol) of n-dodecyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter separated therefrom was concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 178-180° C./0.5 Torr), yielding 110 g of 4-n-dodecyloxyphenyl bromide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.O.CCOC(C)=O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCN(C(=O)OC(C)(C)C)C4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 72.9 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (233 mg, 0.681 mmol), 3-amino-1-N-Boc-piperidine (136 mg, 0.680 mmol) and TEA (0.200 mL, 1.44 mmol) in dioxane (5 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (251 mg).
Reaction SMILES: [CH2:1]([O:11][CH:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].P(Br)(Br)[Br:21].CO.C(=O)([O-])O.[Na+]>C(OCC)C>[CH2:1]([O:11][CH:12]([Br:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: BrP(Br)Br
Reactant: C=CCCCCCCCCOC(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: C=CCCCCCCCCOC(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 223.9 %

Procedure:
First, 16.05 g (0.061 M) of 9-decenoxybenzyl alcohol (compound (23)) prepared in Synthetic example 1-2 was dissolved in 85 mL of diethyl ether, and the solution was cooled to 0° C. After cooling, 6.76 g (0.022 M) of phosphorus tribromide (compound (21)) was added dropwise thereto at 5° C. or less. The mixture was aged at 5° C. for 2 hours and then at 15° C. for 1.5 hours. After aging, the solution was cooled to 5° C. Then, 38 mL of methanol was added dropwise at 5° C. or less. After dropwise addition, 73.4 g of a sodium hydrogen carbonate aqueous solution (1 M) was added dropwise at 10° C. or less, and then phase separation was performed. After the separation, the separated organic layer was washed with 32 mL of deionized water and then concentrated. Thereby, 18.19 g of 9-decenoxybenzyl bromide (compound (24)) was produced (yield: 91.6%).
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][C:5](=O)[NH:6][CH:7]=1.[ClH:10].O=P(Cl)(Cl)[Cl:13]>>[Br:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]([Cl:10])=[N:6][CH:7]=1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc(Br)c(Cl)n1
Yield: 82 %

Procedure:
5-bromouracil (30 g, 0.16 mole) was added to a flask containing 130 ml of POCl3. The mixture was heated at reflux for 4 days. During this time the reaction contents were protected from atmospheric moisture; HCl gas was evolved and the solution became homogeneous. Excess POCl3 was removed by distillation at atmospheric pressure. Continued distillation at reduced pressure afforded the title compound, bp 85°-90°/4 mm (29.7 g, 82% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-fluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=579.6)=93%.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C:15](=[O:32])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]COC)=[C:20]([O:28]COC)[CH:19]=1>Cl.CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:15](=[O:32])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:28])[CH:19]=1
Reactant: COCOc1ccc(C(=O)CCc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Agent: Cl
Solvent: CO
Product: O=C(CCc1ccc(O)c(O)c1)c1ccc(O)cc1O
Temperature: 0 °C
Yield: 15.1 %

Procedure:
Then, 4.94 g of 1-[2,4-bis(methoxymethoxy)phenyl]-3-[3,4-bis(methoxymethoxy)phenyl]-1-propanone was dissolved in 48 ml of a hydrochloric acid/methanol reagent, and the solution was refluxed for 8 minutes and the reaction liquid was poured into ice water and extracted with ethyl acetate two times. The organic layer was washed with water three times, shaken with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the column chromatography (400 g of 230-400 mesh silica gel, n-hexane/ethyl acetate=3/2, 0.5 kg/cm2). Fractions of 50 ml were collected, and the 96th to 120th fractions were combined and the solvent was removed by distillation. The residue was recrystallized from n-hexane and chloroform to obtain 453.6 mg (yield=39.0%) of 1-(2,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)-1-propanone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH:13]12CC(C=C1)CC2CO.C1(C)C=CC=CC=1>[OH-].C([O-])(=O)C.[Zr+4].C(OCC)(=O)C>[CH:12]12[CH2:5][CH:4]([CH:3]=[CH:2]1)[CH2:10][CH2:11]2.[CH3:13][C:3]1[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([O-:9])=[O:8]
Reactant: O=C(O)C=Cc1cccc(F)c1
Reactant: OCC1CC2C=CC1C2
Agent: [Zr+4]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C1=CC2CCC1C2
Product: Cc1c(F)cccc1C=CC(=O)[O-]
Temperature: 145 °C
Yield: 54 %

Procedure:
5 g (43 mmol) of 3-fluoro-cinnamic acid, 5.35 g (43 mmol) of 5-norbornene-2-methanol, and 0.21 g (0.02 eq.) of zirconium(IV) acetate hydroxide were added to 50 ml of toluene and stirred. The mixture was heated to 145° C. under N2 atmosphere and azeotropically refluxed for 24 hours. After the reaction, the mixture cooled down to room temperature and was added with 100 volume % of ethyl acetate. The resulting product was extracted by 1M HCl and washed again with water. The organic layer was dried with Na2SO4 and the solvent was evaporated out to give a highly viscous material. (Yield: 54%, Purity (GC): 73%)