Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O>CO.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C)c(N)c1

Procedure:
12.4 g of palladium-on-carbon are added to a solution of 132.9 g (0.759 mole) of 4-methyl-3-nitro-anisole in 1.1 liters of methanol and hydrogenation is carried out at room temperature. The catalyst is filtered off and the filtrate is concentrated in a vacuum rotary evaporator. Recrystallisation from isopropanol/water yields 3-amino-4-methylanisole having a melting point of 43°-44°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:15][C:16](O)=[O:17])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.C([O:39][C:40](=[O:43])[CH2:41][NH2:42])(C)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:15][C:16]([NH:42][CH2:41][C:40]([OH:43])=[O:39])=[O:17])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)C(CC(=O)NCC(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-carboxyethyl]aminocarbonyl-4-methoxyquinoline (50 mg, 0.11 mmol) in tetrahydrofuran (THF) (2 mL) was added glycine t-butyl ester hydrochloride (20 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (23 mg, 0.12 mmol), 1-hydroxybenzotriazole (HOBT) (16 mg, 0.12 mmol) and diisopropylethylamine (DIEA) (0.16 g, 0.12 mmol). The reaction was stirred at ambient temperature overnight. The resultant solution was partitioned between water and ethyl acetate. The organic layer was concentrated in vacuo to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(((carboxy)methyl)aminocarbonyl)ethyl]aminocarbonyl-4-methoxyquinoline as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:15]=3[N+:22]([O-:24])=[O:23])=[C:11]([C:26]([O:28]CC)=[O:27])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:15]=3[N+:22]([O-:24])=[O:23])=[C:11]([C:26]([OH:28])=[O:27])[N:10]=[N:9]2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1cc(C)c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(C)c(C)cc2[N+](=O)[O-])cc1

Procedure:
In the same manner as above, a solution of ethyl 1-(4-methoxybenzyl)-5-(4,5-dimethyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate (b-2) (2.48 g, 5.66 mmole) in tetrahydrofuran (30 ml) was hydrolyzed with a 1N aqueous sodium hydroxide solution (11.3 ml) at room temperature for 3 hours to give 1-(4-methoxybenzyl)-5-(4,5-dimethyl-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylic acid (c-2': MP) as a crude product of brownish oil (2.448
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[C:42](Br)[CH:41]=1)[CH3:36]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:35]([O:37][C:38](=[O:48])[CH2:39][C:40]1[CH:41]=[C:42]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:23][CH:22]=2)[C:43]([F:46])=[CH:44][CH:45]=1)[CH3:36]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1ccc(F)c(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, (3-bromo-4-fluoro-phenyl)-acetic acid ethyl ester, and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) were reacted to provide (4′-{-4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-6-fluoro-biphenyl-3-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCl.[W]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([Br:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Yield: 73.5 %

Procedure:
6-Methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.5 g, 5.10 mmol) prepared in Preparation Example 1 was dissolved in dichloromethane (80 mL), and N-bromosuccinimide (1.09 g, 6.12 mmol) and 2,2′-azobisisobutyronitrile (0.08 mg, 0.51 mmol) were added thereto. The mixture was stirred for 2 hrs at RT under the irradiation of a 375 W tungsten lamp. Upon the completion of the reaction, the mixture washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/n-hexane=1/20→1/9) to obtain 1.4 g of the titled compound (yield: 74%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li]CCCC.[O:23]1[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24]1.Cl>O1CCCC1.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C>[OH:23][C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[C:16]#[N:17]
Reactant: CCCCCC[C@@H]1CO1
Reactant: COc1ccc(-c2ccc(CC#N)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC[C@@H](O)CC(C#N)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 1.02 g (4.6 mmol) of 4-(4-methoxyphenyl)phenylacetonitrile in 40 ml of tetrahydrofuran (THF) was added, at -78° C., 1.5 M n-BuLi solution in hexane in an amount of 3.6 ml (5.5 mmol). This mixture was stirred for 1 hour. Thereto were added a solution of 705 mg (5.5 mmol) of (R)-1,2-epoxyoctane in 20 ml of THF and 5 ml of HMPA. The resulting mixture was warmed to room temperature, and then stirred overnight. The reaction mixture was neutralized with 3 M hydrochloric acid, and then subjected to extraction with 300 ml of ethyl acetate. The resulting ethyl acetate solution was washed with saturated sodium chloride aqueous solution, dried with anhydrous magnesium sulfate, filtered, and then concentrated. The residue was separated and purified by column chromatography (hexane/ethyl acetate=3/1), thereby obtaining 1.05 g (yield 65%) of (4R)-4-hydroxy-2-[4-(4-methoxyphenyl)phenyl]decanenitrile.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[CH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:4]=2[O:3]1.[H][H]>[Ni].C1COCC1>[NH2:12][C:11]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:7][CH2:6][C:5]=2[C:8]([CH3:15])=[CH:9][CH:10]=1
Reactant: Cc1ccc([N+](=O)[O-])c2c1CCC(C)O2
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(N)c2c1CCC(C)O2

Procedure:
A mixture of 27 g of 1D, 200 ml of THF and 2 g of activated Raney nickel catalyst was treated with hydrogen (40 psig) in a Parr shaker for 3 hours. The resulting mixture was dried (MgSO4), filtered and concentrated to dryness, to give 8-amino-3,4-dihydro-2,5-dimethyl-2H-1-benzopyran (1E), as an amber syrup.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:29]C(OCC1C=CC=CC=1)=O)[CH2:5][NH:6][C:7](=[O:28])[CH2:8][CH2:9][NH:10][C:11](=[O:27])[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH2:29])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][CH2:9][NH:10][C:11](=[O:27])[CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]1
Reactant: COC(=O)[C@H](CNC(=O)CCNC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H](N)CNC(=O)CCNC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound (0.578 g) obtained in the above (4) is dissolved in ethanol (15 ml), and thereto is added 10% palladium-carbon (50% wet, 0.4 g), and the mixture is stirred at room temperature for four hours under hydrogen atmosphere. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (398 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[C:9](O)=[O:10])[CH2:3][CH2:2]1>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: C1CCOC1
Product: OCc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a stirred solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (0.500 g, 1.936 mmol) in anhydrous THF (10 ml), BH3*THF complex (1M solution in THF, 3.87 ml, 3.87 mmol) was added drop wise at RT under nitrogen atmosphere. After 3 hours, the reaction was cooled to 0° C. and quenched with aqueous NH4Cl. The mixture was extracted with EtOAc and the organic phase was dried over Na2SO4 and evaporated under reduced pressure affording (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)methanol (0.450 g, 1.842 mmol, 95% yield, MS/ESI+ 227.1 [MH−H2O]+). This product was used without any further purification.
Reaction SMILES: [NH2:1][OH:2].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C@H:13]2[CH2:18][C@H:17]([C:19]([O:21]C)=O)[C@@H:16]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH2:15][CH2:14]2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]>CO>[C:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C@H:13]2[CH2:18][C@H:17]([C:19]([NH:1][OH:2])=[O:21])[C@@H:16]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH2:15][CH2:14]2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](OC2CCN(C(C)=O)CC2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Solvent: CO
Product: CC(=O)N1CCC(O[C@@H]2CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H](C(=O)NO)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 M of H2NOH in MeOH (0.75 ml) was added inTo a solution of methyl(1S,2S,5R)-5-[(1-acetylpiperidin-4-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate (0.1 mmol, 0.0001 mol) in 0.5 ml of MeOH. It was stirred at rt for 2 hrs. It was purified by Prep-HPLC. LCMS: (M+H)+=473.1.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:35])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:8][C:9]([C:11]1([NH:16][C:17](=[O:26])[C@@H:18]([S:22]C(=O)C)[CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([O:5][C:6](=[O:35])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:8][C:9]([C:11]1([NH:16][C:17](=[O:26])[C@@H:18]([SH:22])[CH:19]([CH3:20])[CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](SC(C)=O)C(C)C)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](S)C(C)C)CCCC1
Reaction time: 0.5 h

Procedure:
To a degassed solution of N-[[1-[(2-(S)-acetylmercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]-carbonyl]-L-tyrosine n-butyl ester (2.4 g, 4.74 mmole) in methanol at 0° C. is added dropwise 1N sodium hydroxide (4.74 ml, 4.74 mmole). The mixture is stirred for 30 minutes, neutralized to pH 3 with 1N hydrochloric acid and concentrated to dryness. The residue is dissolved in a mixture of water and ethyl acetate. The organic phase is separated, washed with brine, dried over magnesium sulfate and evaporated to dryness to yield N-[[1-[(2-(S)-mercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]-carbonyl]-L-tyrosine n-butyl ester, m.p. 182°-183° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccnc3)c(C)sc2n1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (100 mg, 0.232 mmol) (Example 61) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 3-Pyridinylboronic acid (42.7 mg, 0.347 mmol), tetrakis(triphenylphosphine)palladium(0) (26.8 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 120° C. for 15 min. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was then dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 5% MeOH in DCM, was followed by further purification by MDAP (basic conditions), to afford the title compound (32.7 mg). LCMS (A) m/z: 430 [M+1]+, Rt 0.83 min (basic), Rt 0.85 min (acidic).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][S:10][C:11](=[O:13])[CH3:12])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].C([O-])(=O)C.[NH2+]1CCCCC1.O>C1C=CC=CC=1>[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][S:10][C:11](=[O:13])[CH3:12])=[O:6])([O-:16])=[O:15]
Reactant: CC(=O)CC(=O)OCCSC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)SCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Yield: 85.7 %

Procedure:
A solution of 7.0 g of 2-acetylthioethyl acetoacetate, 5.14 g of 3-nitrobenzaldehyde and 0.99 g of piperidinium acetate in 100 ml of benzene was heated at reflux under azeotropic dehydration conditions for 2 hours. The reaction mixture was poured into water and extracted with benzene, and the extract was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 9.83 g of 2-acetylthioethyl 2-(3-nitrobenzilidene)acetoacetate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[Cl:12][CH2:13][C:14]([NH:16]O)=[NH:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:12][CH2:13][C:14]1[N:16]=[C:6]([C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:11]=[CH:10][CH:9]=2)[O:8][N:15]=1
Reactant: O=C(O)c1cccc(CO)c1
Reactant: N=C(CCl)NO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCc1cccc(-c2nc(CCl)no2)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
3-Hydroxymethylbenzoic acid, described in Reed, G. A.; Dimmel, D. R.; Malcolm, E. W. J. Org. Chem. 1993, 58 (23), 6372-6376, (175 mg, 1.15 mmol), 2-chloro-N-hydroxy-acetamidine (125 mg, 1.15 mmol) and HBTU was dissolved in anhydrous DMF (4 ml). Triethylamine (0.48 ml, 3.5 mmol) was added and the reaction was stirred at ambient temperature over night. The crude product was partitioned between dichloromethane and NaHCO3 (aq), the organic phase was dried (MgSO4) and the dichloromethane was removed in vacuo. The resulting DMF-solution was heated at 120° C. over night. The reaction mixture was concentrated in vacuo and the title compound (64 mg, 25%) was isolated by flash chromatography using 25-50% ethyl acetate in heptane. 1H NMR (CDCl3), δ (ppm): 8.15 (s, 1H), 8.06 (d, 1H), 7.62 (d, 1H), 7.53 (t, 1H); 4.80 (d, 2H), 4.66 (s, 1H); 1.99 (br. t, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[N:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)nc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 6-chloronicotinic acid ethyl ester (1.92 g) in N,N-dimethylformamide (1 ml), trimethylsilylacetylene (2.0 g), bistriphenylphosphine palladium dichloride (210 mg), cuprous iodide (60 mg) and triethylamine (1.2 g) were added successively and the mixture was stirred in a sealed tube at 100° C. for 2 hours. After cooling, the reaction solution was poured into a saturated aqueous sodium hydrogencabonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.38 g of the desired product as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[NH:9][CH2:8][CH:7]([N:14]([CH3:16])[CH3:15])[CH2:6]2.NC1C=CC=C2C=1NCC(N[C:29](=O)[O:30]C(C)(C)C)C2>>[CH3:16][N:14]([CH3:15])[CH:7]1[CH2:6][C:5]2[C:10]3=[C:11]([NH:13][C:29](=[O:30])[N:9]3[CH2:8]1)[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2
Reactant: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Reactant: COc1cc(N)c2c(c1)CC(N(C)C)CN2
Product: COc1cc2c3c(c1)[nH]c(=O)n3CC(N(C)C)C2

Procedure:
This compound was prepared by following the procedure of Example 44 part B, but substituting, 1,2,3,4-tetrahydro-6methoxy-N3,N3 -dimethyl- 3,8-quinolinediamine for t-butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]([NH2:14])=[O:13].N1C2C(=CC=CC=2)C(CCCC(O)=O)=[CH:16]1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]([CH3:16])[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: NC(=O)CCc1cc2ccccc2[nH]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(CC(N)=O)c1cc2ccccc2[nH]1
Yield: 96 %

Procedure:
This compound was prepared in the manner described above for (18a), using 3-indolebutyric acid and 1,1'-carbonyldimidazole. A 96% yield was obtained as a off-white solid: mp 86-87° C.
Reaction SMILES: [NH:1]([C:3](=[S:5])[NH2:4])[NH2:2].Cl[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>N1C=CC=CC=1>[NH2:4][C:3]([NH:1][NH:2][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[S:5]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: NNC(N)=S
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)NNC(N)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.9 %

Procedure:
To a suspension of hydrazinecarbothioamide (15.0 g, 165 mmol) in pyridine (100 mL) was added dropwise ethyl 3-chloro-3-oxopropanoate (24.8 g, 165 mmol) over 30 min at 0° C., and the reaction solution was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and methanol was added to the residue. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, THF and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over sodium sulfate, and concentrated. The residue was crystallized from ethyl acetate and isopropyl ether, and the obtained crystals were washed with isopropyl ether, and dried to give the title compound (14.2 g, 42%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][C:12]([C:15]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][CH2:25][CH2:24][C:23]=3[CH:27]=2)[CH2:17][CH3:18])=[CH:11][CH:10]=1>C1COCC1>[O:26]1[C:22]2[CH:21]=[CH:20][C:19]([C:16]([CH2:17][CH3:18])=[C:15]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[C:12]3[CH:13]=[N:14][C:9]([O:5][CH2:4][CH2:3][NH:2][CH3:1])=[CH:10][CH:11]=3)=[CH:27][C:23]=2[CH2:24][CH2:25]1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2c(c1)CCO2
Reactant: CNCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)nc1)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a stirred solution of 2-(methylamino)ethanol (875 mg, 10 eq) in 20 mL anhydrous THF was added NaH (373 mg, 8.0 eq) at 0° C., and the mixture was stirred at rt for 1 h, 4-(1-(6-Chloropyridin-3-yl)-2-(2,3-dihydrobenzofuran-5-yl)but-1-enyl)phenol (440 mg, 1.0 eq) was added. The mixture was refluxed for 16 h, cooled, quenched with sat. NH4Cl, and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (197 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=2.4 Hz, 0.5H), 7.60 (d, J=2.0 Hz, 0.5H), 7.32 (dd, J=8.4 Hz, 2.4 Hz, 0.5H), 7.07 (dd, J=8.4 Hz, 2.4 Hz, 0.5H), 7.03 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 0.5H), 6.78 (d, J=8.4 Hz, 1.5H), 6.69 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 0.5H), 6.59 (d, J=8.0 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.36 (d, J=8.4 Hz, 0.5H), 4.53 (t, J=8.4 Hz, 2H), 4.46 (t, J=5.2 Hz, 1H), 4.31 (t, J=5.2 Hz, 1H), 3.10 (t, J=8.4 Hz, 2H), 3.05 (t, J=5.2 Hz, 1H), 2.96 (t, J=5.2 Hz, 1H), 2.55 (s, 1.5H), 2.50 (s, 1.5H), 2.45 (q, J=7.6 Hz, 2H), 0.94 (t, J=7.2 Hz, 3H); m/z=417[M+1]+.