Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:19]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O:31]=[C:32]1[C:41](=[O:42])[NH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([S:43](Cl)(=[O:45])=[O:44])[CH:38]=2)[NH:33]1>>[CH2:19]([O:26][C:27]([CH2:28][NH:29][S:43]([C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:31])[C:41](=[O:42])[NH:40]2)(=[O:44])=[O:45])=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(CNS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1)OCc1ccccc1
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 4.14 g (0.03 mole) of potassium carbonate in 25 ml of water 10.12 g (0.03 mole) of aminoacetic acid benzyl ester tosylate are added in small portions, under stirring. Then 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added to the mixture, it is stirred at room temperature for 6 hours and allowed to stand for 16 hours. The separated crystals are filtered off, washed with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated with water. Thus 3.50 g (45%) of N-(benzyl-oxycarbonylmethyl)-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide are obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28]O>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28][NH:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])=[CH:13][CH:12]=1
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=CO
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3ccc(Cl)cc32)cc1
Yield: 45.7 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-phenylamine (911 mg, 1.3 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (617 mg, 3.16 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (577 mg, 46%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[CH:31][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[CH:31][N:17]2[N:16]=1)[CH2:13][CH3:14])[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
{3-[1-(3-Benzyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (Example 47, 25 mg, 0.0569 mmol) in CHCl3 (10 mL) at 25° C. was treated with 4-chloro-benzoylchloride (31.5 μL, 0.248 mmol) and triethylamine (23.0 μL, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (17.2 mg, 52.3%) as a colorless film: LC/MS 86% at 3.74 min (ESI+) 578 (M++H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[C@H:18]([CH3:19])[C@H:17]3[N:14]([C:15](=[O:23])[C@@H:16]3[C@H:20]([OH:22])[CH3:21])[C:13]=2[C:24]([O:26]CC2C=CC([N+]([O-])=O)=CC=2)=[O:25])[CH2:8][N:7]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O.[H][H]>O1CCCC1.P([O-])([O-])([O-])=O.[OH-].[OH-].[Pd+2]>[F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[C@H:18]([CH3:19])[C@H:17]3[N:14]([C:15](=[O:23])[C@@H:16]3[C@H:20]([OH:22])[CH3:21])[C:13]=2[C:24]([OH:26])=[O:25])[CH2:8][NH:7]1
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](COCCF)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCF)C3)[C@H](C)[C@H]12
Yield: 45.2 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.80 g) in a mixture of tetrahydrofuran (50 ml) and 0.1M phosphate buffer (pH 5.8) (50 ml) was stirred at ambient temperature for 5 hours in the presence of 20% palladium hydroxide on carbon (0.3 g) under atmospheric pressure of hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to remove tetrahydrofuran. The resulting aqueous solution was washed with ethyl acetate (50 ml×2) and evaporated to remove the organic solvent. The residual solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (trademark, made by Mitsubishi Chemical Industries) (50 ml) and eluted with a mixture of acetone and water (5:95 V/V). The fractions containing the desired compound were combined and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.20 g).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH3:22].CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:36]([N:9]([CH3:8])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH3:22])=[O:37]
Reactant: CNc1cnccc1N1CCCCC1C
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)c1
Yield: 16 %

Procedure:
Methyl-(2-methyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester (60 mg, 0.20 mmol, example 20, intermediate b) was stirred in a solution of TFA (300 μL) and CH2Cl2 (2 mL) for 1 h after which all volatiles were removed under reduced pressure to give crude methyl-(2-methyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-3′-yl)-amine TFA salt. The crude TFA salt was dissolved in CH2Cl2 (2 mL) and treated with DIPEA (100 μL, 590 mmol) and 3,5-dichlorobenzoyl chloride (54 mg, 0.26 mmol, CAS RN 2905-62-6). The reaction mixture was loaded directly on a silica gel column and elution with 66% EtOAc in n-hexane gave the title product (12 mg, 16%). MS (ESI): m/z=378.0 [M+H]+.
Reaction SMILES: CN(C)C=O.[CH3:6][C@@:7]1([CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[N:13]=[C:12]2[S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][O:8]1.[N:29]1([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>C(OCC)(=O)C>[N+:16]([C:14]1[N:13]=[C:12]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[N:11]([CH2:10][C@:7]([OH:8])([CH3:6])[CH2:9][N:32]2[CH2:31][CH2:30][N:29]([C:35]([O:37][CH2:38][CH:39]=[CH:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:43][CH:42]=3)=[O:36])[CH2:34][CH2:33]2)[CH:15]=1)([O-:18])=[O:17]
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Sc2ccc([N+](=O)[O-])cc2)CO1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1ccc([N+](=O)[O-])cc1
Yield: 89.4 %

Procedure:
N,N-Dimethylformamide (0.5 ml) solution of (R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrophenylthio)imidazole (100 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazine-1-carboxylate (103 mg) was stirred at 60° C. for 1 day. Water and ethyl acetate were added to the reaction mixture, and the organic layer was taken by separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a silica gel column chromatography (eluent: dichloromethane/methanol=50/1 to 30/1) and a basic silica gel column chromatography (eluent: dichlomethane), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[4-nitro-2-(4-nitrophenylthio)imidazol-1-yl]-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (173 mg, yield: 90%) as pale yellow amorphous product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(O)cc2)C1=O
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 2c), the alkylation of the (S)-[1-(4-hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester with 4-fluorobenzylbromide in presence of potassium carbonate yields the title compound as a white solid; MS: m/e=401 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.O1CCCC1.CN(C)C(=O)C.[Cu]I.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:9]([C:5]1[CH:6]=[C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:2]([NH2:1])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc([N+](=O)[O-])cc1I
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
2-Amino-3-iodo-5-nitropyridine (10.0 g, 37.75 mmol) was dissolved in a mixture of triethylamine (250 mL), tetrahydrofuran (40 mL), N,N-dimethylacetamide (80 mL) and the solution was degassed and purged with nitrogen. Trimethylsilylacetylene (8.0 mL, 56.5 mmol), copper(I) iodide (0.145 g, 0.75 mmol) and bis(triphenylphosphino) palladium (II) chloride (0.53 g, 0.75 mmol) were added. The mixture was degassed and purged with nitrogen one more time, then stirred at ambient temperature for 16 h. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 15%-35% ethyl acetate/hexanes) to afford 5-nitro-3-trimethylsilanylethynyl-pyridin-2-ylamine (6.2 g, 70%) as a yellow solid: LC/MS m/e calcd for C10H13N3O2Si [M+H]+ 236.32, observed 236.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]=[CH2:10])=[CH:4][CH:3]=1.[ClH:12]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][Cl:12])=[CH:4][CH:3]=1
Reactant: Cl
Reactant: C=CC(O)c1ccc(F)cc1
Solvent: ClCCl
Product: Fc1ccc(C=CCCl)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
273.6 g (1.798 mol) of 1-(4-fluorophenyl)allyl alcohol were dissolved with stirring in 2,000 ml of methylene chloride. Subsequently, 101.0 g (2,770 mol) of hydrogen chloride were passed in over the course of 3 h, during which the temperature rose to 37° C. The mixture was then stirred for 1 h. After washing with 600 ml of ice-cold water and a mixture of 150 ml of saturated brine and 150 ml of water, the organic phase was dried over sodium sulfate and concentrated. 294.6 g (98%) of a brown oil were obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])[N:8]=1.O.CN([CH:24]=[O:25])C>>[Cl:6][C:7]1[C:12]([CH:24]=[O:25])=[N:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])[N:8]=1
Reactant: CC1CCCCN1c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCCCN1c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 57 %

Procedure:
Phosphoryl chloride (1.62 mL) was added dropwise to DMF (5 ml) at 0° C. The mixture was stirred for 15 min, and a solution of 2-chloro-6-(2-methylpiperidin-1-yl)pyrazine (1.85 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 80° C. for 16 hr, water (5 ml) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.18 g, 57%) as a colorless powder.
Reaction SMILES: [C:1]([N:3]=[C:4]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH2:11][C:10]=2[CH:24]=1)#[N:2].C1C=CC(OC(OC2C=CC=CC=2)=NC#N)=CC=1>C(O)(C)C.[H][H].[Pd]>[C:1]([N:3]=[C:4]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11][C:10]=2[CH:24]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(NC(=NC#N)Oc3ccccc3)cc2CC1
Reactant: [H][H]
Agent: [Pd]
Agent: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: N#CN=C(Nc1ccc2c(c1)CC[C@@H](N)CC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The single enantiomer was then BOC-protected, the nitro group reduced by treatment with H2/Pd and the primary aniline treated with diphenyl cyanocarbonimidate (slight excess) in 20 mL of isopropanol with stirring at ambient temperature overnight. The solid was filtered, washed with isopropanol and ether and dried to give phenyl (7S)—N′-cyano-N-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate, as a white solid in high yield (from the single enantiomer via transamination).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.CN(C=O)C.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].C(=O)([O-])[O-].[Na+].[Na+]>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.O>[F:27][C:28]1[CH:29]=[C:30]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:9]3[C:10]4[CH2:11][CH:2]([OH:1])[CH2:3][CH2:4][C:5]=4[CH:6]=[CH:7][CH:8]=3)=[O:21])=[CH:15][CH:16]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(I)cc1
Reactant: OB(O)c1ccc(F)c(F)c1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c1CC(O)CC2)c1ccc(-c2ccc(F)c(F)c2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 54.7 %

Procedure:
Next, to a solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-4-iodobenzamide (100 mg, 0.25 mmol) in a 3 to 1 mixture of DMF and H2O was added 3,4-difluorophenylboronic acid (80.3 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium(0) (8.82 mg, 0.01 mmol), and sodium carbonate (80.9 mg, 0.76 mmol). The mixture was stirred at 80° C. for 2.5 hours, and after cooled to room temperature, the product was extracted with diethyl ether. The organic layer was washed with water then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. After triturated with ethylacetate and hexane, the solid was filtered to afford 3′,4′-difluoro-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)biphenyl-4-carboxamide (51.9 mg, 54%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].I[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1c[nH]nn1
Reactant: ICCCc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc(CCCn3ccnn3)c2)cc1
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
In an argon atmosphere, 1H-1,2,3-triazole (0.9 g) was dissolved in DMF (20 ml); 65% oily sodium hydride (0.48 g) was added. After stirring for 30 minutes, a solution of benzyl 3-(3-iodopropyl)phenyl ether (3.53 g) in DMF (5 ml) was added, followed by stirring at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated saline. Under reduced pressure, the solvent was distilled off; the residue was subjected to column chromatography to yield the titled compound (1.1 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C(=O)C)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:13].C(N)C1C=CC=CC=1>C(O)C.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:13]
Reactant: CCC(CC)COC(=O)c1ccc(OC(C)=O)cc1F
Solvent: CCOCC
Solvent: NCc1ccccc1
Solvent: CCO
Product: CCC(CC)COC(=O)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
9.3 Grams (0.036 mol) of the compound prepared in the above (1) was dissolved in 250 ml of ethanol, and 7.7 g (0.0772 mol) of benzylamine was dropwise added. Further, the mixture was stirred at room temperature for 1 day, then diluted with 300 ml of ether, consecutively washed with diluted hydrochloric acid and with water, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified for isolation with a silica gel column chromatograph to give an end product in the yield of 95%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19].COCCO>O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]1[CH:8]([C:9]2=[O:14])[CH2:19][CH:18]=[CH:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Solvent: COCCO
Solvent: O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
A mixture comprising 10 g of the obtained 5-nitro-1,4-naphthoquinone, 3.3 g of 1,3-butadiene and 40 ml of ethylene glycol monomethyl ether was retained in a 100-milliliter autoclave at 50° C. for 6 hours with stirring. The reaction pressure was initially 1.2 atmospheres and 1.0 atmosphere when the reaction was over. Thereafter, 60 ml of water was added to the reaction mixture and cooled to 25° C. The precipitated crystals were filtered, washed with 30 ml of methyl alcohol and dried under reduced pressure to obtain 11.9 g of white 5-nitro-1,4,4a,9a-tetrahydroanthraquinone having a purity of 98%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.B(O)(O)[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCc3c(ncnc3Nc3ccc(C(F)(F)F)cc3)C2)cc1
Reaction time: 6 h
Yield: 9.8 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added p-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg,0.68 mmol) and triethylamine (0.68, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (12.8 mg, 10%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:30]1([NH:33][C:34](=[O:51])[NH:35][C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:30]1([NH:33][C:34]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:2]3[CH:7]=[C:6]([C:17]4[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=4)[N:5]=[C:4]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)[N:3]=3)=[CH:38][CH:37]=2)=[O:51])[CH2:32][CH2:31]1
Reactant: OB(O)c1cccnc1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2cc(-c3cccnc3)nc(N3CCOCC3)n2)cc1)NC1CC1
Temperature: 120 °C

Procedure:
4-(4,6-dichloropyrimidin-2-yl)morpholine (100 mg 0.43 mmol), pyridine-3-boronic acid (49 mg, 0.4 mmol), Cs2CO3 (280 mg, 0.86 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.025 mmol) were combined in dioxane (3 ml) and water (1 ml). The reaction mixture was then heated by microwave at 120° C. for 20 min. Without purification (4-(3-cyclopropylureido)phenyl)boronic acid pinacol ester (130 mg, 0.43 mmol), Cs2CO3 (280 mg, 0.86 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.025 mmol) were added and the reaction mixture was then heated by microwave at 120° C. for a further 20 min. The reaction mixture was partitioned between EtOAc and water. The organic layer was passed through a PTFE hydrophobic frit and the solvent removed in vacuo. Residual solid was triturated to give crude produect which was further purifed by prep LC/MS (low pH) to yield (9 mg, 5%).