Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)([CH2:4][CH2:5][CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:2]1.[C:21]([O:25][C:26](=[O:37])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:21]([O:25][C:26](=[O:37])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:36])[C@H:33]([CH3:35])[NH:34][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1([O:19][CH2:20][CH2:1][O:2]1)[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)CCCC1(c2cccs2)OCCO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCCC1(c2cccs2)OCCO1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Ethyl 6,6-ethylenedioxy-2-oxo-6-(2-thienyl)-hexanoate (3 g.) and L-alanyl-L-proline t-butyl ester (2.5 g.) were added to a suspension of freshly activated 4 Å molecular sieve (15 g.) in ethanol (35 ml.) and the mixture was stirred at laboratory temperature for 1 hour. Acetic acid (1.25 ml.) was added, and sodium cyanoborohydride (0.625 g.) was then added in portions during 1 hour. The mixture was stirred at laboratory temperature for 48 hours and then filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on a silica gel column using a 40:1 v/v mixture of dichloromethane and methanol as eluant. There was thus obtained as an oil N-[1-ethoxycarbonyl-5,5-ethylenedioxy-5-(2-thienyl)pentyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: N[CH2:2][CH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:16]([CH3:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#[N:38].[Na+]>CO>[CH3:29][O:28][C:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]([CH2:2][C:3]([NH2:38])([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)[OH:4])[CH3:30])=[CH:20][CH:21]=1)=[O:27]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc2ccccc12
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)CC(N)(O)c2cccc3ccccc23)cc1
Yield: 30.1 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of 2-amino-1-(1-naphthyl)ethanol (prepared as described in Preparation 10), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 3 g of sodium cyanoborohydride, 1.9 g of the title compound were obtained having an Rf=0.35 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: C([O:3][CH2:4][CH3:5])=O.O.Cl.[CH2:8]([Mg]Br)[CH2:9][CH2:10][CH2:11][CH3:12]>>[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:4]([OH:3])[CH2:5][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[Mg]Br
Reactant: CCOC=O
Agent: Cl
Solvent: O
Product: CCCCCC(O)CCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of n-pentylmagnesium bromide in tetrahydrofuran synthesized in Example 2, 162 mL (2.0 mol) of ethyl formate was added dropwise in a nitrogen atmosphere and the mixture was stirred overnight at room temperature. After careful addition of water, the reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and thereafter concentrated to give 340.8 g of 6-undecanol.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH:13]=[CH2:14])=[CH:7][C:5]=1[NH2:6])([O-])=O.O>C1C=CC=CC=1.[Fe]>[CH2:12]([S:11][C:8]1[CH:9]=[CH:10][C:4]([NH2:1])=[C:5]([NH2:6])[CH:7]=1)[CH:13]=[CH2:14]
Reactant: C=CCSc1ccc([N+](=O)[O-])c(N)c1
Agent: [Fe]
Solvent: c1ccccc1
Solvent: O
Product: C=CCSc1ccc(N)c(N)c1

Procedure:
To a solution of 4 g of 2-nitro-5-(2-propenylthio)aniline in 200 ml of benzene there is added 4.0 g of activated iron (Sandler and Karo, Organic Functional Group Preparations, Vol. 1, 1968, pp. 339-340), and the mixture is refluxed for three hours. During the reflux period, water is added in small portions every 15 minutes until a total of 20 ml is reached. The solvent is decanted. The iron sludge is extracted with hot benzene and the combined dried benzene fractions are evaporated in vacuo. The resulting residue is stored under nitrogen at 0°.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[C:22]([N:26]6[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]6)[CH:23]=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (408 mg, 2 mmol) to give 5-{3-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: CC([O-])(C)C.[K+].[O:7]([CH2:14][C:15]([NH:17][CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:19]([O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([O:23][C:24](=[O:34])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:17]([CH3:18])[C:15](=[O:16])[CH2:14][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[S:33])=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CNC(=O)COc1ccccc1
Reactant: CCCCOC(=O)c1ccc(N=C=S)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOC(=O)c1ccc(NC(=S)N(C)C(=O)COc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
t-BuOK (0.55 mL of 1.0 N solution) in THF is added to a solution of phenoxy-N-methylacetamide (83 mg, 0.5 mmol) in THF (5 mL). After 5 minutes, butyl-4-isothiocyanatobenzoate (118 mg, 0.5 mmol) is added in one portion and the resultant mixture is stirred overnight. The crude mixture is filtered through a silica pad. After purification on silica eluting with 25% EtOAc in hexane, the desired acylthiouraea is obtained as a yellow oil (20 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[OH:10][C@@H:11]([CH3:15])[C:12](O)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12]([C@@H:11]([OH:10])[CH3:15])=[N:9][N:8]=2)[N:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: C[C@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](O)c1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), (S)-2-hydroxypropanoic acid (1.06 g, 10 mmol, i.e. L-lactic acid, 85% in water) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was poured off, and the oil residue was suspended in water (10 mL), then basified with 3 N aq. NaOH to pH=10. This aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation under reduced pressure afforded the title compound as an off-white solid. MS (ES+): 199/201 (3/1) [MH+]. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=6.8 Hz, 3H), 2.94 (d, J=6.6 Hz, 1H, —OH), 5.51 (m, 1H), 7.15 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([O:27][CH2:28][C@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][N:30]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(N(CC)CC)C>[CH2:20]([O:27][CH2:28][C@H:29]1[CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:32][CH2:31][N:30]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1COCc1ccccc1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 85 °C
Yield: 84.7 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (450 mg, 1.66 mmol) in 10 mL DMF was added a solution of (R)-tert-butyl 2-((benzyloxy)methyl)piperazine-1-carboxylate (610 mg, 1.99 mmol) in DMF and triethylamine (0.46 mL). The reaction mixture was then refluxed at 85° C. for 30 minutes, quenched with water, extracted twice with CH2Cl2, dried over Na2SO4, and concentrated to give (R)-tert-butyl 2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate (760 mg, 85%). This material was used in the next step without further purification. LC/MS: m/z 541.5 (M+H)+ at 3.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.N1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[OH2:18]>>[C:7]([CH2:6][C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:12]([CH:13]2[CH:4]([CH:5]([CH3:9])[CH3:6])[CH2:3][CH2:2][CH:15]([CH3:16])[CH2:14]2)=[O:18])=[CH:3][CH:4]=1)#[N:8]
Reactant: c1ccncc1
Reactant: N#CCc1ccc(N)cc1
Reactant: O
Agent: [Cl-]
Product: CC1CCC(C(C)C)C(C(=O)Nc2ccc(CC#N)cc2)C1
Reaction time: 24 h

Procedure:
To a flask, were added 6.6 g (50 mmol) of 4-aminobenzyl cyanide, 4.04 mL of pyridine and 100 mL MtBE. To this mixture, 10 g of p-menthane-3-carbon*yl chloride were added dropwise over 5 minutes. The reaction mixture was stirred for 24 h. To the reaction mixture, 50 mL of water were added. The mixture was separated. The organic layer was washed with 50 mL of water and 50 mL of brine. The organic layer was dried over MgSO4. The solvent was evaporated in vacuo to afford the crude product, which was recrystallized from hexanes to afford 10.1 g of the desired product with the following spectroscopic properties:
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[P:28](=[O:32])([OH:31])([OH:30])[OH:29]>>[P:28]([O-:32])([OH:31])([OH:30])=[O:29].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=P(O)(O)O
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: O=P([O-])(O)O
Yield: 75.4 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and phosphoric acid (0.19 mL, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium dihydrogenphosphate as a crystalline white solid (0.95 g, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[I:9].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1>[Br:10][CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=1
Reactant: Cc1cnc(Cl)c(I)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: Clc1ncc(CBr)cc1I
Yield: 64 %

Procedure:
4.60 g (18.15 mmol) of 6-chloro-5-iodo-3-methylpyridine (Setliff et al., J. Chem. Engineering Data (1976), 21(2), 246-7), 3.39 g (19.06 mmol) of N-bromosuccinimide and 0.30 g (1.82 mmol) of 2,2′-azobis(2-methylpropanenitrile) in 500 ml of chlorobenzene are boiled under reflux for about 16 hours. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:10) gives 3.86 g (38% of theory) of 3-bromomethyl-6-chloro-5-iodopyridine.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14](N3C4C=CC([Sn](CCCC)(CCCC)CCCC)=CC=4N=C3)[CH:13]=C[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:39]1[CH:40]=[N:41][CH:42]=[N:43][CH:44]=1.[CH3:45][N:46]([CH:48]=O)[CH3:47]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:11]=[C:45]([N:46]3[C:47]4[CH:4]=[CH:3][C:2]([C:39]5[CH:40]=[N:41][CH:42]=[N:43][CH:44]=5)=[CH:1][C:7]=4[N:9]=[CH:48]3)[CH:13]=[CH:14][N:15]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cncnc4)ccc32)n1)c1ccccc1
Temperature: 100 °C

Procedure:
To a stirred solution of 2-[(S)-1-phenylethylamino]-4-[5-(tributylstannyl)-benzimidazol-1-yl]pyrimidine (27.7 mg) in THF (3 mL) was added 5-bromopyrimidine (22 mg), Pd2DBA3 (0.26 mg) and tri-o-tolylphosphine (0.47 mg). The mixture was heated and maintained at reflux for 2 h. Thin layer chromatographic analysis indicated there was mostly starting material present. DMF (3 mL) was added and the THF was removed under a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (1 mg) was added and the mixture was heated under nitrogen and maintained at 100° C. overnight. The mixture was then cooled and poured into 100 mL of 3:1 ether/ethyl acetate and washed 2× with water and then brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography eluting with methanol in dichloromethane to give 11.3 mg of the title compound. Mass spectrum (ESI): 394.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[CH3:11][C:12]1([CH2:33]C(=C2C(=O)OC(C)(C)OC2=O)O)[CH2:17][CH2:16][C:15]2[C:18]([CH3:32])=[C:19]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=2[O:13]1>C1(C)C=CC=CC=1>[CH3:10][CH:2]([O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:33][C:12]1([CH3:11])[CH2:17][CH2:16][C:15]2[C:18]([CH3:32])=[C:19]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=2[O:13]1)/[CH:1]=[CH:20]/[CH2:19][C@H:18]([CH3:32])[CH2:15][CH2:16][CH2:17][CH:12]([CH3:33])[CH3:11]
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(O)=C1C(=O)OC(C)(C)OC1=O)O2
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(=O)CC(=O)OC(C)/C=C/C[C@H](C)CCCC(C)C)O2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.40 g (5.0 mmol) of Meldrum's acid adduct i.e. rac.-5-[2-[3,4-dihydro-2,5,7,8-tetramethyl-6-phenylmethoxy-2H-1-benzopyran-2-yl]-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione and 1.19 g (6.0 mmol) of alcohol (2RS,3E,6R)-6,10-dimethyl-3-undecen-2-ol in 4 mL of dry toluene was degassed by 3 cycles of evacuating/purging with argon and then heated under argon to 100° C. CO2 evolution started at ca 90° C. and ceased after ca. 30 minutes. The light yellow solution was stirred for another 2 hours at 100° C. The cooled solution was diluted with hexane, washed with water, sat. NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated to leave 3.6 g of a brown oil. Chromatography on 250 g of silica gel (hexane/ethyl acetate 5%-6%) afforded 2.33 g (81 %) of [2R,S)-3-oxo-4-[3,4-dihydro-2,5,7,8-tetramethylβ-oxo-6-(phenylmethoxy)-2H-1-benzopyran-2-yl-butanoic acid-1,5,9-trimethyl-2-decenyl ester as a colorless very viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:29]1[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[C:31]([CH2:41][S:42][C:43]2[S:44][C:45]([CH2:48][CH3:49])=[N:46][N:47]=2)[N:30]=1)[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:17]=1)[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].O1CCCC1>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:29]1[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[C:31]([CH2:41][S:42][C:43]2[S:44][C:45]([CH2:48][CH3:49])=[N:46][N:47]=2)[N:30]=1)[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:17]=1)[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)Nc1cccc(C(CCC(=O)OC)N(C(=O)OC(C)(C)C)c2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Nc1cccc(C(CCCO)N(C(=O)OC(C)(C)C)c2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-[N-tert-butoxycarbonyl-N-{3-methoxycarbonyl-1-[3-(2-propenyloxycarbonylamino)phenyl]propyl}amino]-6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholinopyridine (100 mg) obtained in Example 138-(2) was dissolved in tetrahydrofuran (3 ml), and a 2 M lithium borohydride-tetrahydrofuran solution (0.1 ml) was added thereto, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the above identified compound (66 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH2:13]([Mg]Cl)[CH:14]=[CH2:15].Cl.C(OCC)C.[CH2:24]1[CH2:28]OC[CH2:25]1>CCCCCC.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:12])([CH2:28][CH:24]=[CH2:25])[CH2:13][CH:14]=[CH2:15]
Reactant: C=CC[Mg]Cl
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCC(O)(CC=C)c1ccc2ccccc2c1
Yield: 42 %

Procedure:
First, 16 g of 2-naphthaldehyde was dissolved in 150 mL of THF, and 150 mL of allyl magnesium chloride (a 2.0 M THF solution) was slowly added thereto. The resulting mixture was reacted at a temperature of about 45° C. for 8 hours. After the reaction, the reactant was slowly neutralized in an extreme amount of thin hydrochloric acid solution. Then, the extract was extracted therefrom using diethyl ether and purified through column chromatography (hexane:ethyl acetate=3:1), preparing 10 g of 4-(naphthalen-2yl)hepta-1,6-dien-4-ol monomer (yield: 42%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[CH:25]=[C:24]([C:26](=O)[NH2:27])[CH:23]=[CH:22][C:10]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])(=O)[NH2:7]>O>[C:6]([C:9]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:10]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])#[N:7]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(N)=O)cc2C(N)=O)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2C#N)cc1
Temperature: 50 °C
Yield: 60 %

Procedure:
Phosphorus oxychloride (5.00 g) was added to 2′,4′-dicarbamoyl-p-toluenesulfonanilide (0.30 g (0.90 mmol), and the mixture was heated at 50° C. for 4 hours with stirring. After cooling, addition of water, and stirring brought about precipitation of an insoluble solid. These crystals were filtered, washed with water and recrystallized from ethyl acetate-hexane to give 0.16 g (60%) of 2′,4′-dicyano-p-toluenesulfonanilide as pale brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A solution of 4-aminobenzoic acid (5.0 g, 36 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (7.27 g, 3.16 mL, 36 mmol) was then added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 7.46 g (81%) of the title compound as a white solid, mp 241°-243° C.: 1H NMR (DMSO-d6) δ12.79 (bs, 1H), 10.68 (s, 1H), 7.91 (d, J=9.2, 2H), 7.69 (d, J=9.2, 2H), 4.06 (s, 2H); 13C NMR (DMSO-d6) δ166.79, 165.28, 142.56, 130.47, 125.70, 118.53, 30.29; MS (EI, m/z) 259 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1.NN.O.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(OCCCCCN)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A suspension of 4-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentyloxy]-benzoic acid methyl ester (1 g, 2.72 mmol, Example 283: step a) and hydrazine (98.4 μL, 3.13 mmol) in MeOH:H2O (10 mL, 4:1) was heated to 65° C. for 2 hrs. Additional hydrazine was added (171 μL, 5.44 mmol) to the reaction mixture at rt. The reaction mixture was heated to 70° C. for 2 hrs then stirred overnight at rt. Potassium carbonate (30 mL, 1N aqueous) and methylene chloride (200 mL) were added to the reaction. The organic layer was dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a white solid (500 mg, 77%). 1H-NMR (CDCl3): δ 7.95–8.00 (m, 2H), 6.88–6.92 (m, 2H), 4.02 (t, 2H, J=6.43 Hz), 3.88 (s, 3H), 2.71–2.76 (m, 2H), 1.79–1.86 (m, 2H), 1.49–1.56 (m, 4H).