Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([C:18]([CH3:20])=[CH2:19])=[CH:4][N:3]=1.[OH:21]O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:18]([CH3:20])[CH2:19][OH:21])=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[CH:7]=1
Reactant: OO
Reactant: C=C(C)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Solvent: O
Product: CC(CO)c1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a degassed solution of 2-(2-chloro-5-(prop-1-en-2-yl)pyridin-4-yl)-4-fluoro-1H-indole (50 mg, 0.17 mmol) was added BH3-DMS (0.5 mL) under N2 protection at 0° C., and the mixture was stirred for 1 hour. Then NaBO3.4H2O (60 mg, 0.34 mmol) and H2O2 (0.2 mL) was added under N2 protection at 0° C. for 0.5 hours, and the reaction mixture was stirred at RT for 2 hours. After diluted with H2O and extracted with EtOAc, the combined organic layer was washed with H2O, brine, dried over Na2SO4, and the residue was purified by prep-HPLC to give 2-(6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)propan-1-ol (20 mg, yield: 36%). 1H-NMR (CDCl3, 400 MHz) δ 10.86 (s, 1H), 8.17 (s, 1H), 7.33 (s, 1H), 7.18 (s, 1H), 7.06˜7.10 (m, 1H), 6.71˜7.76 (m, 2H), 4.10 (s, 1H), 3.95 (s, 1H), 3.75 (t, J=12.0 Hz 1H), 3.42˜3.51 (m, 1H), 1.14 (d, J=8.0 Hz, 3H). MS (M+H)+: 305/307.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>CCO.N1CCCCC1>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:16]([NH2:18])=[O:17])=[C:2]([N:1]=[CH:24][C:23]3[CH:26]=[CH:27][C:20]([OH:19])=[CH:21][CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(F)c(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2ccc(F)c(Cl)c2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 53 %

Procedure:
5-amino-3-((3-chloro-4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (45 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chloro-4-fluorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (147 mg, 53% yield).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:29][C:30]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)[C:2]([N:32]3[CH2:33][CH2:34][C:30]([F:35])([F:29])[CH2:31]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: FC1(F)CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC(F)(F)C2)c(-c2cncnc2)c1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 224 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Stage 247.1) and 3,3-difluoropyrrolidine hydrochloride (no extraction with citric acid). After purification by flash chromatography on Silica gel, the residue was suspended in iPr2O (10 mL) and stirred for 30 min. Crystals were filtrated off, washed with iPr2O (10 mL) and dried to afford the title product as a white solid. HPLC (Condition 10) tR=7.198 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=482 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.39 (spt, J=7.14 Hz, 2H) 3.37 (t, J=7.23 Hz, 2H) 3.62 (t, J=12.90 Hz, 2H) 7.36 (d, J=8.21 Hz, 2H) 7.87 (d, J=8.99 Hz, 2H) 8.15 (s, 1H) 8.82 (s, 1H) 8.94 (s, 2H) 9.23 (s, 1H) 10.28 (s, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]([N:34]([CH:42]([CH3:44])[CH3:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33])[CH3:30]>>[CH3:28][N:29]([CH2:31][C:32]([N:34]([C:35]1[CH:40]=[CH:39][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:8]3[C:7]\2=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:36]=1)[CH:42]([CH3:44])[CH3:43])=[O:33])[CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC(C)N(C(=O)CN(C)C)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C(=O)CN(C)C)C(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(dimethylaminomethylcarbonyl)-N-isopropyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H32N4O4
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOCCc1ccccn1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOCCc1ccccn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added 2-[2-(aminooxy)ethyl]pyridine 125 (0.12 g, 0.86 mmol, J. Med. Chem. 1997, 40(15), 2363-2373), 1-hydroxybenzotriazole (0.14 g, 1.10 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-[2-(pyridin-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 126 (0.26 g, 91%) as a clear thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C1(C)C(C)=CC=CC=1.CS(O)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:12])[N:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:13](=[O:15])[CH2:14]2)=[CH:6][CH:7]=1
Reactant: Nc1ccncc1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CC(c2ccc(Cl)cc2)CC(=O)N1c1ccncc1
Reaction time: 96 h

Procedure:
The starting material is prepared as follows: The mixture of 22.4 g of 3-(p-chlorophenyl)-glutaric anhydride, 10.3 g of 4-aminopyridine, 350 ml of xylene and 1.5 g of methane sulfonic acid is refluxed on a water separator while stirring for 4 days. After the first day an additional 0.5 g of methane sulfonic acid is added and the hot solution is finally decanted from some gummy material. The crystals formed on cooling are filtered off, triturated with hot ethanol, cooled, filtered off again and dried to yield the 4-(p-chlorophenyl)-1-(4-pyridyl)-piperidin-2,6-dione melting at 204°-206°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[O:28][CH:29]=1>>[F:41][C:38]([F:39])([F:40])[C:35]1[CH:36]=[CH:37][C:32](/[CH:31]=[CH:30]/[C:27]2[O:28][CH:29]=[C:25]([CH2:24][O:1][C:2]3[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[C:12]4[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=3)[N:26]=2)=[CH:33][CH:34]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: OCC(O)Cc1nccn1CCCc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCc1cccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)c1
Yield: 68.9 %

Procedure:
Using 3-{1-[3-(3-hydroxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol (194 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole (212 mg), the same reaction as Example 2 was carried out to yield the titled compound (255 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1C=CC=CC=1.[CH:40](OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)(C)C.C(OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C=C.C(OC1C=C(CC(NC(C2C=C(OC)C=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C>>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:25]=[C:26]([CH3:40])[CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OC(C)C)c1)c1ccccc1N1CCCCC1
Agent: C=CCOc1cc(CC(=O)NC(CCC)c2ccccc2N2CCCCC2)ccc1C(=O)O
Agent: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1cc(OC)ccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(C=C(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
The mixing ratio of 75/25 is obtained from the corresponding ratio of intensities of the particularly characteristic signals in the 400 MHz-1H-NMR spectrum (CDCl3). The position of the signals is: 3-methyl-2-buten-1-yl compound: olefinic H: 5.25 (d), CH3 : 1.64 (s) and 1.77 (s), benzylic >CH-- 6.00 (t). benzylic CH2 --: 3.52 ppm (s) 3-methyl-1-butyl compound: CH3 : 0.90 (d). benzylic >CH-- 5.35 (m), benzylic --CH2 --: 3.54 ppm (s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(Br)c1NC1CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 1-bromo-2-fluoro-3-nitrobenzene (4.1 g, 18.6 mmol) and cyclopropanamine (1.29 mL, 18.6 mmol) in THF (10 mL) was stirred under N2 at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water, filtered on a pad of Celite™, washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo. Purification of the residue by flash chromatography on a silica gel column using 30 to 50% gradient of DCM in hexane as eluent gave 2-bromo-N-cyclopropyl-6-nitroaniline: LC-MS (ESI) m/z 259.0 [M+H]+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[C:18]2[C:19](=[O:22])[O:20][CH2:21][C:17]=2[CH:16]=[C:15]([CH:23]=[CH2:24])[CH:14]=1>C(Cl)Cl>[F:12][C:13]1[C:18]2[C:19](=[O:22])[O:20][CH2:21][C:17]=2[CH:16]=[C:15]([CH:23]2[CH2:24][O:9]2)[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(F)c2c(c1)COC2=O
Solvent: ClCCl
Product: O=C1OCc2cc(C3CO3)cc(F)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
mCPBA (85%, 9.9 g, 48.9 mmol) was added to a solution of 7-fluoro-5-vinyl-2-benzofuran-1(3H)-one (2.9 g, 16.3 mmol) in 300 mL of DCM at 0° C. The mixture was stirred at room temperature for 16 hours before being cooled to 0° C. The mixture was washed sequentially with saturated NaHCO3 (50 mL), aqueous Na2SO3 (50 mL×2), 5% NaOH (50 mL) and brine, then concentrated. The residue was purified by column chromatography eluted with DCM to afford 7-fluoro-5-oxiran-2-yl-2-benzofuran-1(3H)-one as white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O-:11])=[O:10].[Na+]>>[C:1]([O:10][C:9](=[O:11])[CH:8]([NH2:7])[CH:12]([CH3:14])[CH3:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: CC(C)C(N)C(=O)[O-]
Agent: [Na+]
Product: CCCC(=O)OC(=O)C(N)C(C)C
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 6.39 g (60 mmol) of the prepared butyryl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 9.18 g (66 mmol) of sodium 2-amino-3-methylbutanoate. The round bottomed flask is placed in an ice bath and the butyryl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-3-methylbutanoic butyric anhydride.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][N:14]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]=2[C:27]=1[Cl:28])=[O:6].[C:29]([O-:32])(=[O:31])[CH3:30].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:29]([O:32][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][N:14]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]=2[C:27]=1[Cl:28])=[O:6])(=[O:31])[CH3:30]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(NC(=O)NCCCl)c2Cl
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 25 °C
Reaction time: 120 h

Procedure:
3.7 g 1-(2-chloroethyl)-3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea dissolved in 100 ml of acetonitrile are treated with 1.83 g of potassium acetate and 4.21 g of 18-crown-6. The mixture is then stirred at room temperature for 5 days, concentrated, treated with water/methylene chloride and the aqueous solution is extracted several times with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 350 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethanol/ether. There is obtained 2-[3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>CN(C=O)C.O>[F:24][C:23]([F:26])([F:25])[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxyl benzaldehyde (1.1 g, 8.7 mmol) and Cs2CO3 (4.3 g, 13.1 mmol) in DMF (16 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 mL, 10.5 mmol). The reaction mixture was stirred at rt for 1 h and then diluted with H2O, followed by extraction with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The NMR of the crude product obtained (1.8 g, 100%) was clean. 1H NMR (CDCl3, 400 MHz) δ 9.93 (s, 1H), 7.91-7.87 (m, 2H), 7.09-7.05 (m, 2H), 4.45 (q, J=8.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([OH:16])[CH:10]=3.Br[CH2:21][CH2:22][OH:23].BrCCOCC>>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([O:16][CH2:21][CH2:22][OH:23])[CH:10]=3
Reactant: OCCBr
Reactant: N#Cc1c(N)nc2c(c1N)Cc1ccc(O)cc1O2
Agent: CCOCCBr
Product: N#Cc1c(N)nc2c(c1N)Cc1ccc(OCCO)cc1O2

Procedure:
2,4-diamino-8-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in Example 10 using 2-bromoethanol in lieu of 2-bromoethyl-ethylether. The product was isolated as a tan solid (120 mg, 35% yield). 1H NMR (400 MHz, DMSO) δ 7.025 (d, 1H), 6.670 (d, 1H), 6.550 (d, 1H), 3.931 (t, 2H), 3.662 (t, 2H), 3.546 (s, 2H); m/z 413 (M+H).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].[CH3:11][O:12][CH:13](OC)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:11][O:12][CH:13]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1)[P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10]
Reactant: COc1cc(Cl)cc(C(OC)OC)c1
Reactant: CCOP(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(OC)c1cc(Cl)cc(OC)c1
Yield: 77 %

Procedure:
Triethyl phosphite (3.2 ml, 19 mmol) was added dropwise to a solution of acetal 7 (4.0 g, 18.5 mmol), boron trifluoride etherate (2.3 ml, 19 mmol) and CH2Cl2 (20 ml) at 0° C. After slowly warming the reaction to room temperature (30 min), the solution was partitioned with dilute NaHCO3, dried over Na2SO4, evaporated and purified on silica gel (40%-100% EtOAc/hexanes) to give 4.6 g (77.5%) of phosphonate 8 as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1-c1ccccc1
Temperature: 90 °C
Yield: 14.5 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml)/2M Na2CO3 (0.215 ml, 0.43 mmoles) was treated with phenylboronic acid (30 mg, 0.25 mmol) and Pd[PPh3]4 (14 mg, 0.012 mmol) for 12 hours at 90° C. Additional amounts of Pd[PPh3]4 (28 mg, 0.025 mmol) and 2M Na2CO3 (0.215 ml, 0.43 mmoles) were added and the mixture was stirred at 90° C. for another night. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (7.2 mg, 15%). MS m/e 405.26 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]O>>[CH3:20][O:18][C:17](=[O:19])[C@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
After 25.0 ml (19.8 wt %) of methanol was added to 100 g of oily N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine at room temperature (about 25° C.), the mixture was heated to 40° C. while stirring. When the temperature of liquid reached 40° C., methanol was evaporated under reduced pressure. Oily N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester was again obtained. Crystals of N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester prepared in Example 1 (1.0 g) were added to the oil as seed crystals. Cooling was gradually continued to 15° C. while stirring. The precipitated crystals were immediately separated by centrifuging, and were then washed with 5 ml of previously cooled methanol. After the obtained crystals were air-dried, the crystals were further dried at 30° C. overnight under reduced pressure to give 84.3 g of N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester as crystals. The powder X-ray chart for the crystals formed in this way resembled that shown in FIG. 1 for the crystals of Example 1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[C:8](Cl)([O:10][CH2:11][CH:12]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O>[NH2:7][C:5](=[O:6])[C@H:3]([NH:2][C:8](=[O:9])[O:10][CH2:11][CH:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:4]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Reaction time: 8 h
Yield: 120.4 %

Procedure:
A solution of D-Alaninamide hydrochloride (3 g) in 10% sodium carbonate solution (50 ml) and dioxan (50 ml) was treated with FMOC chloride (6.24 g) in dioxane (40 ml) and allowed to stir overnight. The mixture was diluted with water (500 ml) and the product collected by filtration and dried in vacuo to give 9.0 g of the subtitle compound.
Reaction SMILES: [CH2:1]([N:4]=[C:5]([C:7]1[C:24]2=[C:25]3[C:14]([C:15]4[C:26]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=5)[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([C:27]([OH:29])=[O:28])[C:10]3=[C:9]([C:30]([OH:32])=[O:31])[C:8]=1[C:33](=[N:35][CH2:36][CH:37]=[CH2:38])[OH:34])[OH:6])[CH:2]=[CH2:3].[CH3:39][Si:40]([CH3:50])([CH3:49])[O:41][Si:42]([CH3:48])([CH3:47])[O:43][SiH:44]([CH3:46])[CH3:45]>C1(C)C=CC=CC=1>[CH3:39][Si:40]([CH3:49])([CH3:50])[O:41][Si:42]([CH3:48])([CH3:47])[O:43][Si:44]([CH2:3][CH2:2][CH2:1][N:4]=[C:5]([C:7]1[C:24]2=[C:25]3[C:14]([C:15]4[C:26]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=5)[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([C:27]([OH:29])=[O:28])[C:10]3=[C:9]([C:30]([OH:32])=[O:31])[C:8]=1[C:33](=[N:35][CH2:36][CH2:37][CH2:38][Si:44]([CH3:46])([CH3:45])[O:43][Si:42]([CH3:48])([CH3:47])[O:41][Si:40]([CH3:50])([CH3:49])[CH3:39])[OH:34])[OH:6])([CH3:45])[CH3:46]
Reactant: C[SiH](C)O[Si](C)(C)O[Si](C)(C)C
Reactant: C=CCN=C(O)c1c(C(=O)O)c2c(C(=O)O)ccc3c4cccc5cccc(c(c1C(O)=NCC=C)c23)c54
Solvent: Cc1ccccc1
Product: C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCN=C(O)c1c(C(=O)O)c2c(C(=O)O)ccc3c4cccc5cccc(c(c1C(O)=NCCC[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C)c23)c54
Yield: 75.3 %

Procedure:
1.03 g (2.19 mmol) of perylene tetracarboxylic acid bis(allylimide) (compound (6), m=1, n=1) and 1.53 g (6.87 mmol) of 1,1,1,3,3,5,5-heptamethyl trisiloxane were dissolved in 100 ml of toluene, and 20 μl of a Karstedt catalyst (2 mol/l solution in xylene) was thereafter added thereto, which was then refluxed for 5 hours. The reaction solution thus obtained was then cooled and filtered, and the toluene was distilled off from a filtrate. The crude product thus obtained was purified by silica gel column chromatography (eluent: dichloromethane→dichloromethane-ethyl acetate (50:1)). The resultant crude product was dissolved in dichloromethane and re-precipitated with methanol. Thus, 1.51 g (1.65 mmol) of a red powder was obtained as an intended compound (1-1). A yield of the compound (1-1) was 75.3%. Values obtained by instrumental analysis of the compound (1-1) are shown below.