Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:32])[CH2:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:14].Cl.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][N:42]1[C:46]([CH2:47]Cl)=[CH:45][N:44]=[C:43]1[S:49][CH2:50][CH2:51][CH3:52].[Cl-].[NH4+]>O1CCCC1.CN(C)C=O>[CH2:13]([O:15][C:16](=[O:32])[C@H:17]([CH2:47][C:46]1[N:42]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[Cl:34])[C:43]([S:49][CH2:50][CH2:51][CH3:52])=[N:44][CH:45]=1)[N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:14]
Reactant: CCCSc1ncc(CCl)n1Cc1ccccc1Cl
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCCSc1ncc(C[C@H](N=C(c2ccccc2)c2ccccc2)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
A solution of diisopropylamine (8.4 mL) in tetrahydrofuran (100 mL) was cooled to -78° C. under argon and a solution of n-butyl lithium (30 mL of 2.5M in hexane) was added. The mixture was stirred at -78° C. for 30 minutes and at 0° C. for 10 minutes. After being recooled to -78° C., a solution of N-(diphenylmethylene)-glycine ethyl ester (Tetra. Lett., (1978), 2541, 4625) (15.4 g) in tetrahydrofuran (50 mL) was added, the mixture was stirred for 1 hour at -78° C. and a solution of 1-(2-chlorophenyl)methyl-5-chloromethyl-2-propylthio-1H-imidazole hydrochloride (9.4 g) in dry dimethylformamide (20 mL) was added. The mixture was then stirred at ambient temperature for 18 hours, poured into saturated ammonium chloride solution and the aqueous layer was extracted with methylene chloride. The organic extracts were washed with water, dried with magnesium sulfate concentrated and chromatographed over silica gel with 1% methanol in methylene chloride to afford 6.88 g of 3-[(2-chlorophenyl)methyl]-2-propylthio-N-(diphenylmethylene)histidine ethyl ester. This product (2.59 g) was dissolved in methylene chloride (52 mL), aqueous 1N hydrochloric acid solution (52 mL) was added and the misture was stirred at 25° C. for 18 hours. The aqueous layer was separated, neutralized to pH 10.5 with sodium carbonate and the product was extracted into methylene chloride. The organic extract was dried with magnesium sulfate and concentrated to give 1.29 g (71%) of 3-[(2-chlorophenyl)methyl]-2-propylthio-histidine ethyl ester as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]([O:22]CC4C=CC=CC=4)=[O:21])=[CH:16][CH:15]=3)[C:7]=2[CH:30]=1)#[N:2].C(N(CCCC)CCCC)CCC>[Pd].C(O)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[C:7]=2[CH:30]=1)#[N:2]
Reactant: CC1(C)C=C(c2ccc(C(=O)OCc3ccccc3)cn2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: O=CO
Solvent: CCCCN(CCCC)CCCC
Product: CC1(C)C=C(c2ccc(C(=O)O)cn2)c2cc(C#N)ccc2O1
Yield: 35.8 %

Procedure:
5.06 g of benzyl 6-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylate were heated at 100° C. with 7.8 ml of tributylamine, 244 mg of 10% palladium-on-charcoal and 0.9 ml of formic acid. After 12 hours a further 7.8 ml of tributylamine and 10 ml of formic acid were added. After 24 hours a further 2 ml of tributylamine and 3 ml formic acid were added. After 26 hours a further 170 mg of 10% palladium-on-charcoal, 2 ml tributylamine and 3 ml of formic acid were added. After 28 hours the mixture was evaporated and filtered. The filtrate was evaporated and the residue obtained was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) and ethyl acetate for the elution. There were obtained 1.4 g of 6-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylic acid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1([CH2:14][CH3:15])[C:7](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13].C(N1C(=O)C(C)(N2[C:33](=[O:34])[C:32]3[C:27](=[C:28]([F:38])[C:29]([F:37])=[C:30]([F:36])[C:31]=3[F:35])[C:26]2=[O:39])C(=O)NC1=O)C>>[CH2:14]([C:2]1([N:1]2[C:26](=[O:39])[C:27]3[C:32](=[C:31]([F:35])[C:30]([F:36])=[C:29]([F:37])[C:28]=3[F:38])[C:33]2=[O:34])[C:7](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13])[CH3:15]
Reactant: CCC1(N)C(=O)NC(=O)N(C(C)C)C1=O
Reactant: CCN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Product: CCC1(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C(=O)NC(=O)N(C(C)C)C1=O

Procedure:
Compound 19g was prepared from 5-amino-5-ethyl-1-isopropylbarbituric acid (0.32 g, 1.50 mmol) using the same procedure described for 19f. The crude product was recrystallized from EtOH to give 5-ethyl-1-isopropyl-5-(tetrafluorophthalimido)barbituric acid (19g) as white crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]1[CH2:18][O:19][CH3:20])[CH3:2].[CH3:21]OC(C1OC=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]1[CH:18]([O:19][CH3:20])[CH3:21])[CH3:2]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Reactant: COC(C)c1occc(=O)c1OCc1ccccc1
Product: CCn1ccc(=O)c(OCc2ccccc2)c1C(C)OC
Yield: 29.6 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one using 2-(1-methoxyethyl)-3-benzyloxy-pyran-4(1H)-one 3.12 g (12 mmol, 1 eq.) yielded the title compound (1.03 g, 29.6%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].[SnH4]>O1CCCC1>[N:12]1([CH2:11][C:9]2[CH:8]=[CH:7][N:6]3[C:2]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:3][N:4]=[C:5]3[N:10]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: Brc1cnc2nc(Cn3cncn3)ccn12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [SnH4]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(Cn3cncn3)ccn12
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of 3-bromo-7-([1,2,4]triazol-1-ylmethyl)-imidazo[1,2-α]pyrimidine (0.42 g, 1.50 mmol) in tetrahydrofuran (15 ml) was added isopropylmagnesium chloride (0.82 ml of a 2M solution in tetrahydrofuran, 2.37 mmol). Mixture was allowed to warm to −45° C. and stirring at this temperature was continued for 0.5 h. Mixture was recooled to −78° C., tributyltin chloride (0.47 ml, 1.72 mmol) added in a dropwise fashion, stirred for 10 min at −78° C. and then allowed to warm to ambient temperature. This process of Grignard formation with subsequent transmetallation to the stannane intermediate was repeated to encourage completion of the reaction giving 7-([1,2,4]triazol-1-ylmethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine as a solution in tetrahydrofuran (ca. 0.1M); m/z (ES+) 487, 489, 490 (M++H).
Reaction SMILES: [Na].[OH:2][C:3]1(C2C=CC=CC=2)[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[C:11]1([C:4]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:3](=[O:2])[NH:7][C:6]([S:8][CH:4]([CH3:3])[CH2:5][CH3:6])=[C:5]2[C:9]#[N:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CC1=C(c2ccccc2)C(O)(c2ccccc2)NC1=S
Agent: [Na]
Solvent: CCO
Product: CCC(C)SC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.8 g. Sodium is dissolved in 150 ml. absolute ethanol, 10.0 g. 5-hydroxy-4,5-diphenyl-2-thioxo-3-pyrroline-3-carbonitrile are added thereto and the reaction mixture is boiled for 30 minutes. The solvent is thereafter removed on a rotary evaporator and the residue is taken up in 100 ml. dimethylformamide. 5.1 g. sec.-Butyl bromide are added thereto, the reaction mixture is stirred for 24 hours at ambient temperature, a further 3.0 g. of the alkylating agent are again added thereto and stirring is continued for 24 hours. Thereafter, the solvent is distilled off under water pump vacuum and the residue is triturated with water. The precipitate is filtered off with suction, washed with water and crystallised from ethanol. There are obtained 7.0 g. of the desired product in the form of colourless crystals; m.p. 155°-156° C.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.C(Cl)Cl>[C:1]1([C:11]([Cl:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2ccccc12
Reaction time: 24 h
Yield: 100.2 %

Procedure:
a mixture of 17.2 g (0.1 mole) 1-naphthoic acid, 14 g (0.11 moles) oxalyl chloride, 150 ml methylene chloride and three drops DMF (dimethylformamide) were stirred for about 24 hours. The clear reaction mixture was stripped to give about 19.1 g of the 1-naphthoyl chloride as a brown liquid which was used in step (b) without further isolation.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([Cl:30])[N:24]=2)=[CH:18][C:17]=1[CH2:31][CH2:32][C:33]1[CH:34]=[C:35]([NH:39]C(=O)OC(C)(C)C)[CH:36]=[N:37][CH:38]=1)=O)(C)(C)C>CO>[ClH:29].[ClH:1].[ClH:29].[NH2:39][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][C:17]2[CH:18]=[C:19]([NH:22][C:23]3[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([Cl:30])[N:24]=3)[CH:20]=[CH:21][C:16]=2[NH2:15])[CH:38]=[N:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cncc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2N)c1
Yield: 73 %

Procedure:
A solution of 4.0 M of hydrogen chloride in 1,4-dioxane (30 mL, 120 mmol), tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (860 mg, 1.49 mmol) and methanol (15 mL) was stirred at 25° C. for 1 hour. The solvent was removed in vacuo. The crude residue was dissolved in DCM and triturated with ether to give the desired product (0.57 g, 73%). LCMS calculated for C17H17Cl2N6(M+H)+: m/z=375.0, 377.0.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH2:24][CH2:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[NH2:30][C:26]1([CH2:25][NH:24][C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:29][O:28][CH2:27]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: NCC1(N)COC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(NCC3(N)COC3)cc1OCC2

Procedure:
Following the procedures of Example 551, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 3-(aminomethyl)oxetan-3-amine were reacted to give 524. LC/MS (ESI+): m/z 396.3 (M+H)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][NH2:29].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][NH:29][C:17]([C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:4]2[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)[CH2:12]1)=[O:19]
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(Cl)cc3Cl)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.5 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (100 mg, 0.377 mmol) was added [(2,4-dichlorophenyl)methyl]amine (82 mg, 0.47 mmol), DMAP (10 mg, 0.08 mmol) and EDCI (108 mg, 0.56 mmol). The mixture was stirred at room temperature for 4 h. The mixture was filtered and the filtrate concentrated. The crude product was purified by HPLC to provide 55 mg (0.13 mmol, 35% yield) of the desired material as a single major racemic diastereomer. MS (ES+): m/e 423.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6]C)=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[CH:22]=3)[N:17]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[CH:22]=3)[N:17]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2C1CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CN1CCC(n2cc(-c3ccc(F)cc3)c3cc(C)ccc32)CC1

Procedure:
A solution of ethyl bromoacetate in acetone was added during 15 min to a mixture of 3-(4-fluorophenyl)-5-methyl-l-(4-piperidyl)-1H-indole 3d (5.0 g), K2CO3 (2.5 g) and acetone (100 ml) at room temperature. After another 2 h the solvents were evaporated, water was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with brine and dried (Na2SO4). Evaporation of the solvent afforded the crude methyl 4-[3-(4-fluorophenyl)-5-methyl-1H-indol-1-yl]1-piperidinacetate (6.0 g), which was used without further purification.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10](=[O:29])[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][CH:19]=[CH:18]2)([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C.C(OCC)(=O)C>[C:5]([O:9][C:10](=[O:29])[N:11]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][CH2:19][CH2:18]2)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1cccc2cc[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1cccc2c1NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
Add sodium cyanoborohydride (3.0 g, 47.6 mmol) to a solution of benzyl-(1H-indol-7-ylmethyl)carbamic acid tert-butyl ester (10.0 g, 29.8 mmol) in acetic acid. Stir the mixture at ambient temperature for 3 hours. Dilute with ethyl acetate and cool in an ice bath. Wash the mixture with aqueous 3.0 N sodium hydroxide until pH is 8. Dry the organic layer with magnesium sulfate and concentrate. Purify by chromatography (silica gel; hexane/ethyl acetate; 3:1 to 0:1) to afford a solid as the title compound (5.0 g, 50%). MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([N:23]=[C:24]=[S:25])(=O)[C:16]1C=CC=CC=1>C1COCC1>[S:25]1[CH:16]=[CH:15][N:23]=[C:24]1[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccs2)CC1
Yield: 94 %

Procedure:
To a solution of N-Boc-4-aminopiperidine (6.0 g) in THF (100 ml) was added benzoyl isothiocyanate (4.1 ml), and mixed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol, potassium carbonate was added thereto, and mixed at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and then the residue was dissolved in ethyl acetate. The mixture was washed with 1 N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a pale yellow solid (7.3 g, 94%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][O:16]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)C1=Cc2ccc(OCc3ccccc3)cc2OC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Yield: 62.4 %

Procedure:
tert-butyl 7-(benzyloxy)-2H-chromene-3-carboxylate (13 g) was dissolved in ethyl acetate (15 ml) and methanol (5 ml) in a hydrogenation bottle. Pd—C (10%) (1 g) was added and the reaction mixture was hydrogenated (H2, 70 psi & RT) for overnight. After the completion of the reaction, catalyst was filtered and washed with 100 ml of ethyl acetate. Solvent was evaporated and the crude product was purified using column chromatography and ethyl acetate hexane mixture to give 6 g of pure product (48.3% overall for 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][Br:12])=[CH:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
3.0 g (0.0217 mol) of p-methoxybenzyl alcohol were dissolved in 50 ml of ether and treated with 14.4 g (0.0433 mol) of carbon tetrabromide. 11.4 g (0.0433 mol) of triphenyl-phosphine were added while cooling with ice. The mixture was stirred at room temperature for 3 hrs. After removal of the solvent the residue was filtered over a short silica gel column with ether/hexane (1:1) as the eluent. The filtrate was subjected to a bulb-tube distillation. 2.05 g (47%) of 4-methoxybenzyl bromide were obtained as a colorless oil; b.p. 120°-140°(22 Torr). MS: me/e (% basic peak)=202, 200 (C8H9BrO+, 3), 121 (C8 H9O+, 100).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>C(O)C.[Pd]>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([C:13](=[O:15])[CH3:14])=[CH:5][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1cc(C(C)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCNc1cc(C(C)=O)ccc1N
Reaction time: 2 h

Procedure:
10% Pd/C (100 mg) is added to a Parr bottle containing 1-(3-ethylamino-4-nitro-phenyl)-ethanone (0.98 g, 4.7 mmol) in ethanol (40 mL). The Parr bottle is sealed in a mechanical shaker, evacuated, and then purged with nitrogen followed by hydrogen. The system is pressurized to 50 PSI of hydrogen at room temperature and mechanical shaking engaged. After 2 hours, shaking is stopped, and the system purged with nitrogen prior to opening the vessel. The reaction mixture is filtered through celite, concentrated in vacuo, to give 1-(4-amino-3-ethylamino-phenyl)-ethanone.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C=CCCCCC(=O)O)cc1
Agent: [Pd]
Product: CCCCc1ccc(CCCCCCC(=O)O)cc1
Yield: 90.7 %

Procedure:
This compound was synthesized from 7-(p-butylphenyl)-6-heptenoic acid (1.30 g, 5 mmol) by a hydrogenation reaction using Pd/C (130 mg). Crystallization (petroleum ether) afforded the product (1.19 g, 97%) as white crystals (mp 32-33° C.). IR: 3400-2500, 1718 cm-1 ; 1H-NMR:0.92 (t, 3 H), 1.35 (m, 6 H), 1.60 (m, 6 H), 2.32 (t, 2 H), 2.55 (m, 4 H), 7.02 (s, 4 H), 9.70 (bs, 1 H). Anal. Calcd. for C17H26O2 : C, 77.82, H, 9.99%; Found: C, 77.73, H, 10.01%.
Reaction SMILES: [OH:1][C:2]1([C:6]2[N:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.Cl.Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=[N:21][C:22]=1[NH2:23].S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C(OCC)(=O)C.O.C(O)C>[OH:1][C:2]1([C:6]2[N:11]=[C:10]([C:12]3[NH:23][C:22]4=[N:21][C:20]([N:24]5[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]6[CH2:36][CH2:35][CH2:34][CH2:33]6)=[O:31])[CH2:25]5)=[CH:19][CH:18]=[C:17]4[N:16]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:3][O:4][CH2:5]1
Reactant: O=Cc1cccc(C2(O)COC2)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(C5(O)COC5)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C

Procedure:
Into a flask was added 6-(3-hydroxyoxetan-3-yl)picolinaldehyde (54 mg, 0.30 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3) (76 mg, 0.24 mmol) and ethanol (1.2 mL). Then sodium dithionate (0.20 g, 1.2 mmol), triethylamine (82 μL, 0.59 mmol) and water (1.0 mL) were added. The solution was heated to 110° C. for 18 h. The mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water, washed with a saturated aqueous solution of ammonium chloride, washed with a saturated aqueous solution of sodium bicarbonate and washed with brine. The organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dried under high vacuum to give a green oil which was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 448.9; HPLC retention time 1.89 min (Method A).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Brc1ccccn1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccccn2)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
3-Hydroxybenzyl alcohol (1.0 g, 8.2 mmol) was dissolved in pyridine (20 mL). 2-Bromopyridine (1.6 g, 9.8 mmol) and potassium carbonate (2.3 g, 16.4 mmol) were added thereto, and then the mixture was stirred at 90° C. for 10 minutes. Copper oxide(II) (1.6 g, 20.5 mmol) was further added thereto, and the reaction mixture was heated under reflux for 2 days. The reaction solution was filtered, and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (1.0 mg, yield 61%).
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCN
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Product: COC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(=O)C(C)(C)C

Procedure:
The (E)-2-pivaloylthiomethyl-3-phenylpropenoic acid described in Example 8 (step B) is coupled with methyl β-alaninate according to the experimental procedure described in Example 1 (step D).