Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1)=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C@H:21]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1)[OH:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution consisting of (3aR,4R,5R,6aS)-4-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (4a, limiting reagent) in 2:1 THF-methanol (0.1 M) cooled to −40° C. is added CeCl3 heptahydrate. The reaction mixture is subsequently cooled to −78° C. and sodium borohydride (2 molar equivalents) is added and the solution is stirred for 1.5 hours. The reaction is quenched by the addition of acetone at −60° C. followed by the addition of a saturated aqueous ammonium chloride solution as the reaction mixture slowly warms to room temperature. The reaction mixture is diluted with brine and acidified with a small amount of 5% aqueous KHSO4. The product is extracted with ethyl acetate twice and the combined organic layers are dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 5a.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:42])[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: NC1CCC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclobutylamine according to conditions described in general procedure C. Mp: 110-112° C.; 1H NMR (400 MHz, CDCl3) δ 1.63 (s, 2 H), 1.73-1.80 (m, 2 H), 2.42 (s, 2 H), 3.19-3.29 (m, 4 H), 3.79-3.92 (m, 4 H), 4.30 (s, 1 H), 5.27 (s, 1 H), 6.08 (s, 1 H), 6.75-6.78 (m, 1 H), 7.05 (d, J=7.6 Hz, 1 H), 7.24-7.26 m, 1 H), 7.32 (s, 1 H), 7.47-7.57 (m, 2 H), 7.88-8.02 (m, 3 H), 8.16 (m, 1 H), 8.25 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:29])[C:15]([O:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([Cl:26])=[CH:21][C:20]=1[CH:27]=O)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:29])[C:15]([O:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([Cl:26])=[CH:21][C:20]=1/[CH:27]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:16]
Reactant: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (0.73 g, 4.4 mmol) and 2-(4-Chloro-5-fluoro-2-formyl-phenoxy)-2-methyl-propionic acid methyl ester (1 g, 3.65 mmol) in methanol (15 mL) was added pyrrolidine (0.26 g, 4.4 mmol) dropwise. Then the mixture was heated at 70° C. for 1 h. After cooled to room temperature, the mixture was concentrated to give the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16](O)=[O:17])=[CH:11][C:10]=3[N+:19]([O-:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:23][O:24][C:25](=[O:40])[CH2:26][C@@H:27]([NH2:39])[CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>>[CH3:23][O:24][C:25](=[O:40])[CH2:26][C@@H:27]([NH:39][C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([N+:19]([O-:21])=[O:20])[CH:11]=1)[NH:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:15]2)=[O:17])[CH2:28][S:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Reactant: COC(=O)C[C@@H](N)CSCc1ccc(OC)cc1
Agent: Cl
Product: COC(=O)C[C@H](CSCc1ccc(OC)cc1)NC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1

Procedure:
2-Phenyl-7-nitro-1H-indole-5-carboxylic acid prepared in Preparation 28 and (R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl ester hydrochloride prepared in Preparation 47 were reacted according to the same procedure as Example 92 to give the title compound.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([N:6]([C:22](=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[CH3:31])[N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1)=[O:5].[I-:33].[Na+]>CC(C)=O>[I:33][CH2:2][O:3][C:4]([N:6]([C:22](=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[CH3:31])[N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1)=[O:5]
Reactant: [I-]
Reactant: COc1cccc(C(=O)N(C(=O)OCCl)N(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(C(=O)N(C(=O)OCI)N(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Temperature: 30 °C

Procedure:
A solution of N′-tert-butyl-N′-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine carboxylic acid chloromethyl ester (15.0 g, 32.5 mmol) in 40 mL of acetone was added sodium iodide (9.8 g, 65.1 mmol)and heated to 30° C. for 3 h. The acetone was removed and the resulting slurry was treated with ether. The resulting white precipitated solids were filtered off, and the ether was then concentrated to afford yellow solids. Recrystallization from ether/hexanes afforded tannish crystals (20 g, 96%). 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.64 (s, 9H), 1.97 (bs, 3H), 2.25 (s, 6H), 3.79 (s, 3H), 5.76 (s, 2H), 6,78-7.1 (m, 6H). Mp=70-72° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:34][C:35]3[CH:36]=[N:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccc(C(F)(F)F)nc3)c3cc(Cl)ccc23)c1
Temperature: 0 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.050 g, 0.15 mmol) was dissolved in DMF:THF (1:1, 4 mL) and cooled to 0° C. Lithium bis(trimethylsilyl)amide solution (0.375 mL, 0.375 mmol, 1.0M in hexanes) was added. 3-(Chloromethyl)-6-(trifluoromethyl)pyridine (0.044 g, 0.225 mmol) was added and the reaction was allowed to warm to room temperature. After 20 minutes the reaction was heated to 50° C. for 1 hour and then submitted to aqueous workup to provide the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[ClH:11].[CH3:12][O:13][C:14](=[O:18])[C@H:15]([CH3:17])[NH2:16]>>[ClH:11].[CH3:12][O:13][C:14](=[O:18])[C@H:15]([CH3:17])[NH:16][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: O=C1Cc2ccccc2C1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC1Cc2ccccc2C1

Procedure:
By a procedure similar to that described in Reference Example 81, 2-indanone and L-alanine methyl ester hydrochloride give N-(2-indanyl)-L-alanine methyl ester hydrochloride. Melting point: 215° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[N:26]1([C:8]([C:7]2[CH:6]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:13]=[CH:12][CH:11]=2)=[O:10])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(C(=O)N2CCOCC2)c1
Reaction time: 4 h
Yield: 51 %

Procedure:
To a solution of 3-(aminosulfonyl)benzoic acid (6 g, 0.029 mol) in THF (100 ml) at 0° C. is added CDI (5.8 g, 0.035 mol) and the mixture is stirred for 4 h. To this mixture morpholine (7.8 ml, 0.089 mol) is added dropwise and the mixture is stirred at room temperature for 15 h. The solvent is removed under vacuum and the residue is diluted with EtOAc (100 ml), washed with a 10% solution of sodium bicarbonate, water and brine. The solvent is removed under vacuum and the residue is taken up with small amount of water (15 ml) and stirred for 15 min. The solid is collected by filtration to afford 4 g (50%) of the title compound as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.88-7.90 (1H, m), 7.83 (1H, s), 7.64-7.65 (2H, m), 7.47 (2H, bs), 3.56-3.64 (6H, m), 3.28-3.34 (2H, m); HPLC (Max plot) 98%, Rt, 4.09 min; LC/MS: (ES+): 206.2.
Reaction SMILES: C(OC(=O)[C:5]([C:13]#[N:14])=[C:6]([OH:12])[C:7]([O:9]CC)=[O:8])C.[OH-:16].[Na+]>>[NH2:14][C:13](=[O:16])[CH2:5][C:6](=[O:12])[C:7]([OH:9])=[O:8]
Reactant: [OH-]
Reactant: CCOC(=O)C(O)=C(C#N)C(=O)OCC
Agent: [Na+]
Product: NC(=O)CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
The 4-amino-2,4-dioxobutanoic acid was synthesized using the diethyl-2-cyano-3-hydroxy-butenedioate prepared as described above. A 5-liter Morton flask was equipped with an air condenser. Diethyl-2-cyano3-hydroxy-butenedioate (214.2.grams, 1.00 mole, 1.0 equivalent) was dissolved in aqueous sodium hydroxide (1.0 M, 1000 milliliters, 4.0 equivalents) at room temperature in the flask while stirring the contents of the flask. After about one minute, a heating mantle was placed underneath the flask. Using the heating mantle, the flask was heated sufficiently for reflux while the reaction mixture was stirred. After about 4½ hours at reflux, the heat was removed and the reaction mixture was allowed to cool to room temperature and was stirred overnight at room temperature. The reaction solution was placed into an ice-water bath and acidified using 6M HCl until the pH of was equal to about 1. Solids formed after about 5 minutes. The solids were filtered. The colorless solids (27 grams) were analyzed by NMR and were found to include carbonate (13C-NMR δ=162 ppm). The bulk of the water was evaporated using a rotary evaporator at about 40° C. The solids were stirred in acetone (1000 milliliters) and then filtered. The acetone was then removed under a vacuum using a rotary evaporator followed by a vacuum pump to yield the 4-amino-2,4-dioxobutanoic acid in 56% yield (74 grams) as a light yellow solid that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@@H:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](OS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In ethyl acetate (4 ml) was dissolved (2R,3S)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (0.18 g). To the solution were added triethylamine (0.10 ml) and methanesulfonyl chloride (84 mg) under ice-cooling. The mixture was stirred for 30 minutes at room temperature, to which was added ethyl acetate (10 ml). The reaction mixture was washed with water and dried (anhydrous magnesium sulfate), followed by concentration to give (2R,3S)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol as an oily product. This product was dissolved in methanol (6 ml), to which was added a 5.6% methanol solution of sodium methylate (0.76 ml) under ice-cooling. The mixture was stirred for 30 minutes at room temperature, which was then concentrated under reduced pressure. To the concentrate was added ethyl acetate (30 ml), which was washed with water and dried (anhydrous magnesium sulfate). The solvent was then distilled off, and the residue was purified by means of a silica gel chromatography (eluent: hexane-ethyl acetate=1:2) to afford (2R,3R)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (0.15 g) as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Nc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 44 %

Procedure:
To a 50 mL flask was added 10 (221 mg, 1 mmol) and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug, Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 105 mg (44%) of 11 as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8](I)=[CH:9][N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[NH:22][CH:23]=[CH:24]4)=[CH:9][N:10]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Br)cnc32)cc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3nc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 2-bromo-7-iodo-5-tosyl-5H-pyrrolo[3,2-b]pyrazine [Intermediate AU] (0.25 g, 0.52 mmol) and 1H-indol-5-ylboronic acid (0.10 mg, 0.62 mmol) in CH3CN (20 mL) was added 1 M Na2CO3 (20 mL) followed by bis(triphenylphosphine)-palladium(II) dichloride (60 mg, 0.086 mmol). The resulting mixture was stirred for 2 h at 60° C. The title compound was isolated as a yellow solid via filtration from the CH3CN layer (0.23 g, 94%). HPLC retention time: 3.23 minutes. MS ESI (m/z): 467.2/469.2 (M+H)+, calc. 466.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(OC)ccc4nc3OC)CC2)c1
Yield: 81 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 81%). MS(ESI) m/z 454 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][CH3:78])([CH2:75][CH3:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([NH:65][CH2:66][C:67]5[CH:68]=[CH:69][C:70]6[C:74]([CH2:75][CH3:76])([CH2:77][CH3:78])[O:73][B:72]([OH:79])[C:71]=6[CH:80]=5)=[O:26])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(F)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.23 mmol) and DIPEA (118 mg, 0.92 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (175 mg, 0.46 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]-oxaborol-1(3H)-ol hydrochloride (118 mg, 0.46 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title compound.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9][CH2:8]1)=[O:6])C.Cl.[NH2:29][OH:30].[OH-].[K+].CO>CO>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C:4]([NH:29][OH:30])=[O:3])[CH2:8][CH2:9]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)CC1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2CCN(C(=O)C(=O)NO)CC2)cc1OC1CCCC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-2-oxo-acetic acid ethyl ester (5.3 mmol, 2.0 g) in methanol (55 mL) was added hydroxylamine hydrochloride (21.2 mmol, 1.5 g) followed by potassium hydroxide/methanol solution (5M; 5.3 mL) dropwise at room temperature. A white solid precipitated out of solution as this reaction stirred overnight. The reaction mixture was diluted with H2O (250 mL), acidified with 1N HCl (60 mL) and extracted with EtOAc (2×500 mL). Each organic phase was washed with H2O (250 mL) and the combined organics were dried (Na2SO4) and concentrated in vacuo to give a tan solid. The residue was purified by flash chromatography (SiO2 : 1) 80% EtOAc/hexane, 2) EtOAc) to afford the title compound as a white solid, mp=123.5°-124° C. (2.5 mmol, 0.920 g, 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CO)cc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(CO)cc2)cc1N
Reaction time: 23.5 h
Yield: 108.1 %

Procedure:
{4-[(3,4-dinitrophenyl)oxy]phenyl}methanol (3.73 g, 12.9 mmol) was hydrogenated in approximately 100 ml of ethyl acetate under a balloon of hydrogen over 1.2 g of 10% Pd on carbon (wet, degussa type) for 2.5 hours. An additional 600 mg of 10% Pd on carbon (wet, degussa type) was added and the reaction was hydrogenated under a balloon of hydrogen for 14.5 hours. The catalyst was filtered away and the filtrate was concentrated. The residue was dissolved in 1:1 ethanol:ethyl acetate and hydrogenated under a balloon of hydrogen over 1.2 g of 10% Pd on carbon (wet, degussa type) for 23.5 hours to consume remaining reaction intermediates. The catalyst was filtered away and the filtrate was concentrated to give 3.21 g of crude {4-[(3,4-diaminophenyl)oxy]phenyl}methanol, which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:12]4[CH:25]=[CH:24][S:23][C:13]=4[C:14](=[O:22])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[O:20]C)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].BrB(Br)Br>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[C:12]4[CH:25]=[CH:24][S:23][C:13]=4[C:14](=[O:22])[NH:15][C:16]=3[CH:17]=[CH:18][C:19]=2[OH:20])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)=O)cc1
Agent: BrB(Br)Br
Product: CC(=O)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 73.4 %

Procedure:
Following General Procedure F, 9-(4-acetylphenyl)-8-methoxythieno[2,3-c]quinolin-4(5H)-one (450 mg, 1.3 mmol) was reacted with tribromoborane (15 mL) to afford the desired product (320 mg, 74%) as a light brown solid: 1H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 9.38 (s, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.74 (d, J=5.4 Hz, 1H), 7.44-7.39 (m, 3H), 7.18 (d, J=8.9 Hz, 1H), 5.90 (d, J=5.4 Hz, 1H), 2.68 (s, 3H); ESI MS m/z 336 [C19H13NO3S+H]+; HPLC 98.3% (AUC), tR=10.59 min.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>CS(C)=O>[CH2:18]([N:7]1[C:8](=[O:9])[CH:10]=[CH:11][N:4]([CH3:3])[C:5]1=[O:6])[CH2:17][CH2:16][CH2:15][CH:14]=[CH2:13]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCn1c(=O)ccn(C)c1=O
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
3-(5,6-Oxidohexyl)-1-methyluracil was synthesized as follows: A mixture of sodium hydride (86 mg, 3.6 mmol) and 1-methyluracil (500 mg, 4 mmol) in dimethyl sulfoxide (25 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (647 mg, 4 mmol) was added. After stirring for 20 hours, the reaction mixture was poured into water (50 ml) and extracted with 20% ethanol-dichloromethane (3×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml) and dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue which was purified by column chromatography (silica, ethyl acetate) to give 3-(5-hexenyl)-1-methyluracil (598 mg, 72% yield).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:17]1[C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=[C:18]1[C:25]([OH:27])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22]([C:21]1[S:17][C:18]([C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:19][CH:20]=1)=[O:24])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1ccc(C(=O)O)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)s1
Yield: 82.1 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) thiophene-2,5-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.84 g (84%) of the title compound as a yellow crystalline solid.