Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:15])[CH:9]=1)[C:4]([OH:6])=[O:5].[C:16](=[O:19])([O-:18])[O-].[K+].[K+].[C:22](Cl)(=[O:38])[O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2>O1CCOCC1.O>[CH:27]1[C:26]2[CH:25]([CH2:24][O:18][C:16]([NH:2][C@@H:3]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:22]([O:23][CH2:24][CH:25]4[C:37]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:31]5[C:26]4=[CH:27][CH:28]=[CH:29][CH:30]=5)=[O:38])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:6])=[O:5])=[O:19])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@H](Cc1ccc(O)c(Br)c1)C(=O)O
Agent: Br
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](Cc1ccc(OC(=O)OCC2c3ccccc3-c3ccccc32)c(Br)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.3 %

Procedure:
To a solution of (S)-2-amino-3-(3-bromo-4-hydroxyphenyl)propanoic acid, hydrobromide (3 g, 8.80 mmol) in 1,4-Dioxane (12 mL) and Water (48 mL) was added potassium carbonate (4.86 g, 35.2 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (2.276 g, 8.80 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and then treated with water (50 mL). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via silica gel chromatography (120 g column, 30-90% EtOAc:Hexanes, 20 column volumes) to give the product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3-bromophenyl)propanoic acid (3.42 g, 55.2% yield) as a light yellow solid. 1H NMR (400 MHz, chloroform-d) d 7.80 (t, J=7.9 Hz, 4H), 7.68 (d, J=7.6 Hz, 2H), 7.60 (d, J=7.3 Hz, 2H), 7.49-7.32 (m, 9H), 7.16 (br. s., 2H), 5.32 (s, 1H), 4.73 (br. s., 1H), 4.58 (d, J=7.3 Hz, 2H), 4.54-4.34 (m, 2H), 4.24 (t, J=6.6 Hz, 1H), 3.31-3.03 (m, 2H). ESI-MS (+) m/z=721 (M+H2O).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=1[F:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[CH:18][C:17]=1[F:25]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
1-(3,5-Dimethylpyridin-2-yl)piperazine (2.87 g) described in Preparation Example 47 was dissolved in N,N-dimethylformamide (38 ml), 4-bromo-3-fluorobenzoic acid (3.29 g), 1-hydroxybenzotriazole 1 hydrate (2.43 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.45 g) were added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into water under cooling, and extracted with ethyl acetate. The organic layer was washed twice with water, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane). Then, ethyl acetate and hexane were added and the mixture was stirred at room temperature. The solid was collected by filtration and dried under reduced pressure to give the title compound (3.97 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc(Br)n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(Br)n1
Yield: 82.2 %

Procedure:
6-bromopicolinic acid (1.99 g) in DMF (10 mL) was treated with potassium carbonate (1.40 g) and then methyl iodide (4 mL) at room temperature for 20 h. The reaction mixture was diluted with dichloromethane (60 mL) and filtered. The filtrate was extracted with brine (twice), dried (MgSO4), and concentrated under vacuum to give methyl 6-bromopicolinate as a pale yellow solid (1.75 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:22])[CH3:21]
Reactant: COC(=O)c1cc(N)ccc1Br
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methyl 5-amino-2-bromobenzoate (Reference Compound No. 1-(1), 21.0 g, 91.2 mmol) and triethylamine (19.0 mL, 137 mmol) were dissolved in anhydrous dichloromethane (450 mL), acetyl chloride (13.0 mL, 182 mmol) was added dropwise in this order over 30 minutes under ice cooling, and then the mixture was stirred at 0° C. for 2 hours. The reaction mixture was washed with water (200 mL, twice), saturated aqueous sodium hydrogen carbonate solution (200 mL, twice), and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with hexane-ethyl acetate (20:1) to give the titled reference compound (24.2 g) as a pale yellow solid. (Yield 98%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (5.0 g, 10 mmol) and (4-formylphenyl)boronic acid (2.35 g, 15.8 mmol) in dioxane/water (30 mL/10 mL) was added Na2CO3 (4.01 g, 37.9 mmol). The solution was purged with argon for 15 min., Pd(PPh3)4 (1.21 g, 1.05 mmol) and the mixture was heated at 100° C. for 2 h. The mixture was allowed to cool to room temperature, diluted with water and extracted with 10% MeOH/CH2Cl2. The combined organic layers were dried over sodium sulphate and the solvent removed under reduced pressure. The resulting crude material was purified by column chromatography over silica gel to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (3.5 g, 66%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[C:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:28]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1b using 5-cyclohex-1-enyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (Example 2b) and 3-(trifluoromethyl)-1,2,4-oxadiazole-5-methanamine (944905-93-5) as starting materials; MS (ESI) 451.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12.[Br:25][CH:26](Br)[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH:26]([Br:25])[C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=4)=[CH:31][CH:32]=3)[N:11]=[C:5]2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: Fc1ccc(-c2ccc(C(Br)Br)cc2)nc1
Reactant: CN1C(=O)c2c(n[nH]c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(nn(C(Br)c3ccc(-c4ccc(F)cn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (35 mg, 0.109 mmol), 2-(4-(dibromomethyl)phenyl)-5-fluoropyridine, and K2CO3 (15 mg, 0.109 mmol) in DMF (3 mL) is stirred at room temperature overnight. The mixture is filtered through a 0.45 μm microfilter, and the filtrate is purified by a semi preparative HPLC to give product as white powder. MS (ESI) m/z 585.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([CH2:31]Cl)[CH:28]=[CH:27][N:26]=1>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:31][C:29]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=3)[C:14]2=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C1=O
Reactant: ClCc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccnc(Cl)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
To a solution of 4.9 g of 3-[3-amino-4-(trifluoromethoxy)-phenyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage b) below in 200 mL of dimethylformamide are added, under argon, 0.68 g of 60% sodium hydride and stirring is continued for 20 minutes at room temperature. To this solution are added 2.85 g of 2-chloro-4-chloromethylpyridine obtained in stage b) of Example 3 dissolved in 20 mL of dimethylformamide, and the reaction mixture is then heated at 70° C. for 3.5 hours and then poured into 500 mL of ice-water and extracted with three times 300 mL of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in 500 mL of diethyl ether, washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum to give 6.8 g of 3-[3-amino-4-(trifluoromethoxy)phenyl]-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:17]2[C:18]3[N:9]([C:10](=[O:20])[CH:11]=[N:12][C:13]=3[CH:14]=[CH:15][C:16]2=[O:19])[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1>C(#N)C>[O:20]=[C:10]1[CH:11]=[N:12][C:13]2=[C:18]3[N:9]1[CH2:8][C@@H:7]([CH2:6][N:27]1[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]1)[N:17]3[C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: CS(=O)(=O)OC[C@@H]1Cn2c(=O)cnc3ccc(=O)n1c32
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A solution of [(1S)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl]methyl methanesulfonate (1.05 g, 3.53 mmol) in dry acetonitrile (50 ml) at room temperature under argon was treated with pyridine (0.343 ml, 4.24 mmol), followed by 1,1-dimethylethyl 4-piperidinylcarbamate (0.884 g, 4.24 mmol). The mixture was heated at 70° C. for 1.5 h and then at 90° C. for 3 h. LCMS showed ˜25% of product. So 0.5 eq of pyridine and 0.5 eq of 1,1-dimethylethyl 4-piperidinylcarbamate were added and the reaction was heated at 90° C. overnight and then stirred at room temperature for 2 days. The reaction was complete. The solvent was evaporated and the residue partitioned between sat NaHCO3 and 20% methanol/dichloromethane (100 ml/100 ml). The layers were separated and the aqueous layer was extracted with 20% methanol/dichloromethane again (2×100 ml). The combined organic extracts were dried on magnesium sulphate, filtered and evaporated to afford 1.7 g of crude which was purified by silica chromatography using a 0-5% methanol/dichloromethane gradient to afford the product as a yellow solid (0.57 g, 40.2%).
Reaction SMILES: BrC1C=CC([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13](O)=[C:14](OC)[CH:15]=3)[N:10]=[CH:9]C=2)=C(F)C=1.OCCCN1CCCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:65]>>[ClH:65].[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:6][CH:9]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ccnc2cc1O
Reactant: ClCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C1CCCN1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl
Product: c1ccc2ncncc2c1
Yield: 67 %

Procedure:
Using a method analogous to that in Example 47, 4-(4-bromo-2-fluoroanilino)7-hydroxy-6-methoxyquinoline (146 mg, 0. mmol) in methylene chloride (5 ml) was treated with 1-(3hydroxypropyl)-2-pyrrolidinone (86 mg, 0.6 mmol), triphenylphosphine (314 mg, 1.2 mmol) and diethyl azodicarboxylate (209 mg, 1.2 mmol) and was purified and isolated to give 4-(4-bromo-2-fluoroanilino)-methoxy-73(oxopyrrolidin-1-yl)propoxy)quinazoline hydrochloride (140 mg, 67%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:4][O:3]1.[C:12]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2C(N[C:23](=[O:24])[C:18]=12)=O)(OCC)=[O:13].C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1([CH3:11])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][N:10]2[C:12](=[O:13])[C:17]3[C:18](=[CH:19][CH:25]=[CH:26][CH:27]=3)[C:23]2=[O:24])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CCCN)O1
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OCC(CCCN2C(=O)c3ccccc3C2=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)propylamine (1.05 g, 6.60 mmol) and carboethoxyphthalimide (1.45 g, 6.60 mmol) in acetonitrile (10 mL) at room temperature was added triethylamine (0.92 mL, 6.60 mmol) in one portion and the resuting mixture was stirred at room temperature for 18 hours, evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with brine, 10% citric acid solution and brine, then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave an oil which was purified by column chromatography on silica using ethyl acetate-petroleum ether mixture as eluent to afford a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.8 %

Procedure:
A mixture of 5-chloro-2-[(2-chlorophenoxy)methyl]benzoic acid (step 2, 85 mg, 0.28 mmol), methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5, 73 mg, 0.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (107 mg, 0.56 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (76 mg, 0.56 mmol) and triethylamine (117 μL, 0.84 mmol) in dichloromethane (3 mL) was stirred at room temperature for 19 hours. Water (5 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (10 mL×2) and the combined organic extracts were dried (sodium sulfate). After removal of solvent, the residue was purified by pTLC eluting with hexane/ethyl acetate (2/1) to afford 105 mg (82%) of the title compound:
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:34][CH2:35][CH3:36])(=[O:33])[C:30]#[C:31][CH3:32].O>CN(C)C=O>[OH:22][CH2:21][C:17]1[C:16]2[N:15]([N:14]=[C:31]([CH3:32])[C:30]=2[C:29]([O:34][CH2:35][CH3:36])=[O:33])[CH:20]=[CH:19][CH:18]=1
Reactant: CC#CC(=O)OCC
Reactant: N[n+]1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2cccc(CO)c12
Reaction time: 12 h
Yield: 26.9 %

Procedure:
To a solution of 1-amino-3-(hydroxymethyl)pyridinium 2,4-dinitrobenzenolate (200 g, 0.650 mol) in dimethylformamide (1.3 L) was added potassium carbonate (224 g, 1.62 mol). To the mixture was added ethyl 2-butynoate (72.8 g, 0.650 mol) at room temperature, and the mixture was stirred for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (41.0 g, yield 27%).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.O=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[NH4+].[Cl-]>C1COCC1>[CH2:2]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of MePh3PBr (37.1 g, 104 mmol) in THF (500 mL) at 0° C. was added slowly LDA (1.2 eq) over 1 h. The resulting orange solution was stirred for 30 min before ethyl 4-oxocyclohexanecarboxylate (16.1 g, 94.4 mmol) was added dropwise. The resulting suspension was warmed to rt and stirred overnight. A saturated NH4Cl (aq) was added and THF was removed. The aqueous residue was extracted with EtOAc (100 ml×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by passing through a short silica gel plug (hexanes/EtOAc 7:1). After being concentrated, ethyl 4-methylenecyclohexanecarboxylate was obtained as a pale yellow oil (12.1 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (200 mg, crude) in dioxane (6 mL) was added benzofuran-2-ylboronic acid (113.0 mg, 0.70 mmol), K3PO4 (220.0 mg, 1.04 mmol), Pd(PPh3)4 (20.1 mg, 0.02 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford (S)-methyl 2-(benzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a red oil (100.0 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]1=2.[I-].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:29][C:26]4[CH:27]=[CH:28][C:20]5[O:19][CH2:24][CH2:23][O:22][C:21]=5[CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cccnc1N1CCc2c(ncnc2Nc2ccc3c(c2)OCCO3)C1
Temperature: 150 °C
Yield: 81.7 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.095 g, 0.00034 mol), 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.10 g, 0.00068 mol) and sodium iodide (0.02 g, 0.0001 mol) in acetonitrile was heated at 150° C. by microwave in a sealed tube for 10 minutes. After cooling to r.t., the mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate and concentrated to leave an oil. Residue purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.110 g of a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)(=[O:4])=[O:3].O.[Br:14]Br.[OH-].[Na+]>C(O)(=O)C>[Br:14][C:10]1[CH:9]=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:5]=1[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: COc1cccc(S(C)(=O)=O)c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(S(C)(=O)=O)c1
Reaction time: 15 h
Yield: 45 %

Procedure:
1-Methanesulfonyl-3-methoxy benzene was dissolved in 90 mL glacial acetic acid. 100 mL water was added. A solution of bromine (4.79 g, 30 mmol) in 10 mL acetic acid was added dropwise at 10° C. The stirring was continued at rt for 15 h. The pH of the mixture was adjusted to pH 8 with aqueous NaOH solution, and extracted with EtOAc (3×200 mL) and dried over Na2SO4. The crude compound was purified by column chromatography (SilicaGel 230-400 mesh; 20% EtOAc in hexanes as an eluent) to give 1-bromo-2-methanesulfonyl-4-methoxy benzene (2.4 g, 45%).