Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-])=O)[C:6]1=2>C(O)C.C1COCC1.[Pd]>[NH2:17][C:16]1[C:6]2[N:5]([CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)CCN1C(=O)CCCc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCN1C(=O)CCCc2cccc(N)c21
Reaction time: 3 h

Procedure:
1-(2-(dimethylamino)ethyl)-9-nitro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (100 mg, 0.361 mmol) was stirred to dissolve in a mixture of ethanol (4 mL) and THF (3 mL). To this solution was added palladium on carbon, 10 wt %, (40 mg) as a solid. The black suspension was stirred under hydrogen gas for 3 h. When TLC analysis showed that the starting material was consumed the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated and then chromatographed on silica gel in 10% 2 N NH3/MeOH in dichloromethane. Yield 90 mg (quantitative). 1H NMR (DMSO-d6) δ 6.86 (d, 1H, J=8.1 Hz), 6.53 (d, 1H, J=3.0 Hz), 6.38 (dd, 1H, J=8.1, 3.0 Hz), 5.02 (brs, 2H), 2.50 (m, 2H), 2.25 (m, 2H), 1.8-2.2 (m, 10H); ESI-MS (m/z, %): 248 (MH+, 58), 203 (100).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[CH2:1]([O:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccn1
Reactant: OCc1ccccc1
Product: c1ccc(COc2ccccn2)cc1

Procedure:
The synthesis of 1 is illustrated in FIG. 8. Benzyl alcohol is coupled with 2-chloropyridine using a modification of a reported procedure to afford 2-benzyloxypyridine, compound 5, in high yield. A range of alkylating agents and solvents was investigated in search of preferred conditions for the irreversible covalent activation of 5. The preferred protocol is to add methyl triflate (bp 94-99° C.) to an ice-cold solution of compound 5 in toluene and allow the mixture to warm to ambient temperature. A white microcrystalline solid, compound 1, forms within minutes, as the solution warms. Analytically pure compound 1 (mp 82-86° C.) can be isolated by filtration or by evaporation of the supernatant under reduced pressure. Salt 1 is remarkably stable. It may be preferably stored under an argon atmosphere either in a refrigerator or on the laboratory bench-top at room temperature and the white crystals of compound 1 are routinely handled open to the air. No differences have been observed between freshly prepared crystals and those that were prepared three months prior.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:18][CH:19](Cl)[CH3:20])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(OC(C)C)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:18][CH:19]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[CH3:20])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCNCC
Reactant: Cc1cccc(C)c1N(CC(C)Cl)C(=O)c1ccccc1
Solvent: CC(C)OC(C)C
Product: CCN(CC)C(C)CN(C(=O)c1ccccc1)c1c(C)cccc1C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
A mixture of 6.0 g (20 mmoles) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-chloro-propane and 10.3 ml (7.3 g, 0.1 mole) of diethyl amine is heated at 160° C. for 12 hours in a steel bomb. The mixture is cooled and processed as described in Example 16. The resulting oily crude base, weighing 5.0 g, is dissolved in 30 ml of diisopropyl ether, the solution is allowed to stand for one day, and then the insolubles are filtered off. The filtrate is evaporated under reduced pressure. 4.35 g (64%) of 1-[N-(2,6-dimethylphenyl)-benzamido]-2-diethylamino-propane are obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([O:12]CC)=[O:11])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([OH:12])=[O:11])=[O:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CS(=O)Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CS(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 2-(4-fluorobenzylsulfinyl)acetate (1.60 g, 6.55 mmol) in THF (10.0 mL) and MeOH (20.0 mL) was added 1 N NaOH (20.0 mmol). The mixture was stirred at room temperature for 2 h. After removal of organic solvent under reduced pressure, the remaining aqueous solution was neutralized with 1 N HCl (25.0 mL). It was extracted with EtOAc (3×100 mL) and the combined organic layer was dried over MgSO4. The solution was then filtered and concentrated in vacuo to give 2-(4-fluorobenzylsulfinyl)acetic acid (1.25 g, 88% yield). MS(ESI+): m/z 217.05 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([F:19])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:20][C:9]1[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1cc(F)cc(F)c1
Product: O=Cc1cc(F)c(Oc2cc(F)cc(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3,5-difluorophenol.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[Na].[CH3:10][OH:11]>O>[Cl:1][C:2]1[C:7]([O:11][CH3:10])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: Clc1nccnc1Cl
Agent: [Na]
Solvent: O
Product: COc1nccnc1Cl

Procedure:
A mixture of 0.1 mole of 2,3-dichloropyrazine and 2.3 g. (0.1 mole) of sodium in 160 ml. of anhydrous methanol is refluxed 5-10 hours, and poured into water. The product is extracted with ether or chloroform and recrystallized from a suitable solvent such as ethanol to give pure 2-chloro-3-methoxypyrazine.
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[O:12][C:11]=2[C:10]([CH2:21][CH2:22][CH3:23])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[O:12][C:11]=2[C:10]([CH2:21][CH2:22][CH3:23])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: CCCc1c2c(c(OC)c3c(=O)cc(C(=O)O)oc13)CCCC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)CCCC2

Procedure:
A suspension of 5-methoxy-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylic acid (5 g) in 48% aqueous hydrobromic acid (130 ml) was heated under reflux for 7 hours. The reaction mixture was cooled and excess saturated aqueous sodium bicarbonate added. The resulting solution was filtered, the filtrate acidified with concentrated hydrochloric acid and then extracted with chloroform (100 ml). The chloroform solution was dried (Na2SO4) and evaporated leaving a residue which, when crystallised from acetone, gave the title compound as an orange crystalline solid mp 259°-260°.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1CCNCC1
Product: O=C1N=C(N2CCC(C(=O)O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1>>[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:13][CH:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 84.8 %

Procedure:
The title compound (D35) (1.5 g) was prepared according to the experimental procedure described in Description 34 starting from 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol) and 3-(Trifluoromethyl)phenol (0.640 ml, 5.34 mmol)
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].Cl.[OH:51][N:52]=[C:53]1[CH2:57][CH2:56][N:55]([C:58](=[NH:61])[CH2:59][SH:60])[CH2:54]1>C(#N)C.CS(C)=O.O1CCCC1.O.P([O-])([O-])([O-])=O.[C].[Pd].CCOCC>[OH:51][N:52]=[C:53]1[CH2:57][CH2:56][N:55]([C:58](=[NH:61])[CH2:59][S:60][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([OH:37])=[O:36])[CH2:54]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: N=C(CS)N1CCC(=NO)C1
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCC(=NO)C3)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
0.21 ml of diisopropylethylamine and 0.22 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 363 mg of p-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 5 ml of anhydrous acetonitrile, and the solution was stirred for one hour with ice-cooling. A solution of 0.18 ml of diisopropylethylamine and 282 mg of 2-(3-hydroxyiminopyrrolidin-1-yl)-2-iminoethylmercaptan hydrochloride in 3 ml of dimethylsulfoxide was added, and the mixture was then stirred for a further 20 minutes with ice-cooling. The reaction mixture was poured into 100 ml of anhydrous ether, and the solvent was decanted off from the gummy material which formed. This material was dissolved in a mixture of 20 ml of tetrahydrofuran, 7 ml of water and 23 ml of 0.1M phosphate buffer (pH 7.0), and the solution was catalytically hydrogenated at room temperature for 2 hours in the presence of 0.3 g of 10 % palladium-carbon. The product was worked up and purified in the same manner as in Example 2, giving 15 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:36][CH:35]=1)[C:9]1[N:20]2[C:16](=[CH:17][CH:18]=[N:19]2)[N:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][N:13]2[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:45]N1C(=O)CCC1=O>C1COCC1>[I:45][C:17]1[CH:18]=[N:19][N:20]2[C:16]=1[N:15]=[C:14]1[C:10]([CH2:11][CH2:12][N:13]1[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:36][CH:35]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4ccnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CC3)cc1
Solvent: C1CCOC1
Product: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4c(I)cnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CC3)cc1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a THF solution (1.5 mL) of tert-butyl (S)-3-(8-[tert-butoxycarbonyl-{4-(2-methoxyethoxy)phenyl}amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (110.6 mg, 0.182 mmol), N-iodosuccinimide (49.1 mg, 0.218 mmol) was added at room temperature and the mixture was stirred for 3 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was removed under reduced pressure and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (118.9 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH3:31])[CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[C:23]([O:30][CH3:31])[CH:22]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 3 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[CH2:31][CH2:32][O:28][C:29]3=[O:33])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 58.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 9 and oxazolidin-2-one (87 mg), the title compound (269 mg) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:31][CH2:32][CH2:33][CH2:34][NH2:35]>O.C(Cl)(Cl)Cl>[Cl:31][CH2:32][CH2:33][CH2:34][NH:35][S:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=3)[N:10]=[CH:9][N:8]=2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NCCCCl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reaction time: 1 h
Yield: 60 %

Procedure:
4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (11.7 g, 0.03 mole) was added portionwise to a well stirred mixture of sodium carbonate (45 g) in water (350 ml) and 3-chloropropylamine hydrochloride (3.9 g, 0.03 mole) in chloroform (350 ml) was added at 10° C. After about 1 hour at room temperature, the mixture was filtered and the solid was washed with water and then dried to give 7.4 g of the title compound. A sample was recrystallised from a mixture of ethanol and water to give the title compound, m.p. 168°-171° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]#[C:11][CH2:12][OH:13])=[N:6][C:7]=1[O:8][CH3:9].[H-].COCCO[Al+]OCCOC.[Na+].[H-].[I:28]N1C(=O)CCC1=O.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:10](/[I:28])=[CH:11]/[CH2:12][OH:13])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1nc(C#CCO)ccc1Cl
Reactant: O=C1CCC(=O)N1I
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1nc(/C(I)=C/CO)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of 3-(5-chloro-6-methoxypyridin-2-yl)prop-2-yn-1-ol (3.0 g) in tetrahydrofuran (50 mL) was stirred under ice-cooling in a nitrogen atmosphere, during which a solution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al(R)) in toluene (3.6 M, 7 mL) was added dropwise thereto. The mixture was stirred at room temperature for one hour. The reaction solution was cooled to an external temperature of −78° C. A solution of N-iodosuccinimide (6.2 g) in tetrahydrofuran (30 mL) was added dropwise and then the mixture was stirred at an external temperature of −78° C. for one hour. 1 M hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with a 10% sodium thiosulfate solution and brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→5:5) to give the title compound as a brown powder (3.79 g, 76%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:26])[O:9][CH2:10][C@H:11]2[O:16][CH2:15][C@@H:14]([CH3:17])[N:13]([C:18]3[CH:23]=[C:22](Cl)[N:21]=[C:20]([NH2:25])[N:19]=3)[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])#[N:28].C([O-])([O-])=O.[K+].[K+].Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[C:1]1([NH:7][C:8](=[O:26])[O:9][CH2:10][C@H:11]2[O:16][CH2:15][C@@H:14]([CH3:17])[N:13]([C:18]3[CH:23]=[C:22]([C:32]4[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[C:30]([F:38])[CH:31]=4)[N:21]=[C:20]([NH2:25])[N:19]=3)[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H]1CO[C@H](COC(=O)Nc2ccccc2)CN1c1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CO[C@H](COC(=O)Nc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Yield: 100.2 %

Procedure:
A biphasic suspension of [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methyl phenylcarbamate (123 mg, 0.326 mmol), (4-cyano-3-fluorophenyl)boronic acid (107 mg, 0.651 mmol), PdCl2(dppf).CH2Cl2 adduct (13.3 mg, 0.016 mmol), 2N aqueous K2CO3 (0.488 mL, 0.977 mmol), and 1,4-dioxane (3 mL) was heated in a microwave reactor for 10 minutes at 140° C. The reaction was poured into 0.1 N HCl (30 mL) and CH2Cl2 (50 mL) and the aqueous was extracted with CH2Cl2 (2×50 mL). The combined organics were dried over Na2SO4, and concentrated to yield the title compound (151 mg) as a dark brown oil. LC-MS (ES) m/z=463 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]([C:24](O)=[O:25])[C:16](O)([CH:20]([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.C(OCC)(=O)C>C(OC(=O)C)(=O)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[C:24]([O:18][C:17](=[O:19])[C:16]=2[CH:20]([CH3:21])[CH3:22])=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)C(O)(C(=O)O)C(C(=O)O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)C1=C([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)C(=O)OC1=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
3-(Trans-4-t-butyldimethylsilyloxycyclohexyl)-2-hydroxy-2-isopropylsuccinic acid (510 mg, 1.31 mmol) was dissolved in acetic anhydride (5.5 mL), and the solution was stirred at 120° C. for 18 h. The acetic anhydride was evaporated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 50:1) to give 293 mg of 2-(trans-4-t-butyldimethylsilyloxycyclohexyl)-3-isopropylmaleic anhydride as oil (yield: 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][OH:11])[C:6]=2[CH:12]=1.C12([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=3OC)[CH:26]=[O:27])CC3CC(CC(C3)C1)C2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:30]3[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=3)[C:6]=2[CH:12]=1
Reactant: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: OCc1coc2ccc(Cl)cc12
Product: O=Cc1ccc(OCc2coc3ccc(Cl)cc23)cc1
Yield: 9 %

Procedure:
When the product of Step A was substituted for 3-(1-admantanyl)-4-methoxy benzaldehyde in Example 32, Step B, the similar procedure afforded the title compound in 9% yield, as pale paste. 1H-NMR (CDCl3) 9.89 (s, 1H); 7.84 (d, 2H, J=8.74 Hz); 7.72 (s, 1H); 7.60 (d, 1H, J=2.07 Hz); 7.41 (d, 1H, J=8.76 Hz); 7.28 (dd, 1H, J=8.75, 2.09 Hz); 7.09 (d, 2H, J=8.73 Hz); 5.23 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([C:4]1([CH3:18])[CH2:8][NH:7][CH2:6][CH:5]1[C:9]1[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([OH:15])[CH:14]=1)[CH3:3].CCN(C(C)C)C(C)C.[CH3:28][C:29]1([CH3:37])[O:33][C@H:32]([C:34](Cl)=[O:35])[CH2:31][O:30]1>C(Cl)Cl>[CH3:28][C:29]1([CH3:37])[O:33][C@@H:32]([C:34]([N:7]2[CH2:6][C@@H:5]([C:9]3[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([OH:15])[CH:14]=3)[C@@:4]([C@H:2]([OH:1])[CH3:3])([CH3:18])[CH2:8]2)=[O:35])[CH2:31][O:30]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: COc1ccc(C2CNCC2(C)C(C)O)cc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H]2CN(C(=O)[C@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A round bottom flask equipped with a stir bar and rubber septum was charged with 5-[4-(1-hydroxy-ethyl)-4-methylpyrrolidin-3-yl)-2-methoxyphenol (2.4 g, 9.55 mmol), dry CH2Cl2 (50 mls), and DIEA (3.49 mls, 20.1 mmol) under a nitrogen atmosphere. The mixture was chilled to 0° C. and (S)-2.2-dimethyl-[1,3]dioxolane-4-carbonyl chloride (3.14 g, 19.1 mmol) in 15 ml of CH2Cl2 was added dropwise by syringe. The reaction mixture was allowed to gradually warm to room temperature over a 16-hour period. The mixture then was diluted with 50 ml of CH2Cl2, washed with 1N HCl (2×50 ml), saturated aqueous NaHCO3 (1×50 ml), dried over Na2SO4, and concentrated to 3.9 g of a tan foam. The material was taken up in 100 ml CH3OH and chilled to 0° C. Three equivalents of aqueous 1N LiOH then were added (29 ml, 29.0 mmol), the mixture was stirred at 0° C. for 2 hours, then warmed to room temperature for 2 hours. The reaction mixture next was concentrated under reduced pressure with the bath temperature at 30° C. to remove CH3OH. The remaining aqueous material was neutralized with saturated NH4Cl to pH 7 and extracted with EtOAc (2×100 ml). The extracts were dried over Na2SO4 and concentrated to 2.74 g of a tan foam (76%).
Reaction SMILES: C([O:3][P:4]([O:40]CC)([CH:6]([P:32]([O:37]CC)([O:34]CC)=[O:33])[CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:19](=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:23][CH3:24])[CH2:20][CH3:21])[CH:15]=[CH:16][C:17]=1[OH:18])=[O:10])=[O:5])C>C(#N)C>[P:4]([CH:6]([P:32]([OH:34])([OH:37])=[O:33])[CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:19](=[C:22]([C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)[CH2:23][CH3:24])[CH2:20][CH3:21])[CH:15]=[CH:16][C:17]=1[OH:18])=[O:10])([OH:40])([OH:5])=[O:3]
Reactant: CCOP(=O)(OCC)C(CCC(=O)Nc1cc(C(CC)=C(CC)c2ccc(O)cc2)ccc1O)P(=O)(OCC)OCC
Solvent: CC#N
Product: CCC(=C(CC)c1ccc(O)c(NC(=O)CCC(P(=O)(O)O)P(=O)(O)O)c1)c1ccc(O)cc1
Yield: 18.8 %

Procedure:
A crude product was obtained in the same manner as in Example 8 except for using 3-(3-(4,4-bis(diethoxyphosphinoyl)butyrylamino)-4-hydroxyphenyl)-4-(4-hydroxyphenyl)-3-hexene (0.48 g) obtained by the process described in Example 32, and then it was purified by a high-performance reversed phase column chromatography (a 0.1% aqueous trifluoroacetic acid solution:acetonitrile) to obtain 3-(3-(4,4-diphosphonobutyrylamino)-4-hydroxyphenyl)-4-(4-hydroxyphenyl)-3-hexene (74 mg, yield 19%).