Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:11](=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([O:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C.Br[CH2:50][C:51]([O:53][CH3:54])=[O:52]>O.CN(C)C=O>[ClH:1].[O:2]=[C:3]1[N:12]([CH2:13][C:14]([O:16][CH2:50][C:51]([O:53][CH3:54])=[O:52])=[O:15])[C:11](=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([O:28][CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)CBr
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COC(=O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A mixture of the hydrochloride of 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid obtained in Example 50 (0.58 g, 1.00 mmol), triethylamine (0.42 ml, 3.00 mmol) and N,N-dimethylformamide (2.0 ml) was stirred at 60° C. for 15 minutes, and methyl bromoacetate (0.11 ml, 1.20 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 6 hours, combined with an iced water, and then extracted with a solvent mixture of ethyl ether-ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with chloroform-methanol (20:1, v/v) to give a free form of the title compound (0.49 g, 80%) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:19][C@H:20]1[O:22][CH2:21]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:19]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:20]1[O:22][CH2:21]1
Reactant: COC(=O)c1cc2c(O)cccc2o1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC[C@@H]3CO3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution (60 ml) of methyl 4-hydroxybenzo(b)furan-2-carboxylate (3.6 g) in DMF were added (S)-glycidyl nosylate (5.1 g) and potassium carbonate (6.5 g) and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.1 g) as a yellow crystalline compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:10]C2N[C:7](=O)[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].CI.[CH3:25][N:26]([CH3:29])[CH:27]=[O:28]>O>[Br:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:10][C:25]2[N:26]([CH3:29])[C:27](=[O:28])[N:8]([CH3:7])[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2cc(Br)c(Oc3ccc(F)cc3F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(=O)n(C)c2cc(Oc3ccc(F)cc3F)c(Br)cc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of 5-bromo-6-(2,4-difluorophenoxy)-1,3-dihydro-2H-benzimidazol-2-one (0.106 g, 0.311 mmol) in N,N-dimethylformamide (2.2 mL) was treated with sodium hydride (0.0273 g, 0.684 mmol) and stirred at 20° C. for 30 min. The reaction mixture was treated with methyl iodide (0.0426 mL, 0.684 mmol) and stirred 20° C. for 30 min. The reaction mixture was diluted with water which resulted in the formation of a precipitate. The solid was filtered and washed with water to give the desired product (108 mg, 94%) which was used without further purification. LCMS calculated for C15H12BrF2N2O2 (M+H)+: m/z=369.0, 371.0. found: 368.9, 371.0.
Reaction SMILES: [CH3:1]C1C=C(C=CC=1C)C(Cl)=O.[C:12]1([N:18]2[C:22]3[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(Cl)(Cl)(Cl)=O>[Pd].C1(NC2C=C(C=CC=2OC)N)C=CC=CC=1>[C:12]1([N:18]2[C:22]3[CH:23]=[C:24]([O:27][CH3:1])[CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(-c2nc3ccc(O)cc3n2-c2ccccc2)cc1C
Reactant: Cc1ccc(C(=O)Cl)cc1C
Agent: [Pd]
Agent: COc1ccc(N)cc1Nc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(-c3ccc(C)c(C)c3)n(-c3ccccc3)c2c1

Procedure:
The nitro group of the above-described intermediate was then reduce to an amino group by catalytic hydrogenation using a palladium on activated carbon catalyst, essentially as previously described, resulting in 3-phenylamino-4-methoxyaniline with was then reacted with 3,4-dimethylbenzoyl chloride as previously described. This intermediate was then cyclized to the corresponding benzimidazole with phosphorous oxychloride as previously described to yield 1-phenyl-2-(3,4-dimethylphenyl )-6-methoxybenzimidazole.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[C:41]([O:14][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=5)[N:29]([CH3:39])[C:28]4=[O:40])[CH2:23][CH2:22]3)=[N:8][C:9]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:10]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Solvent: c1ccncc1
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
In 3 ml of pyridine was dissolved 360 mg (0.66 mmol) of Compound 47 obtained in Example 47, 0.12 ml (1.32 mmol) of acetic anhydride was added, and the mixture was stirred at room temperature for 4 hours. The solvent was removed at reduced pressure and water was added to the residue, the resulting precipitate was collected by filtration, washed with water, dried at heating and recrystallized from ethanol to give 205 mg (yield: 53%) of Compound 52 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6](Cl)[N:5]2[N:13]=[CH:14][CH:15]=[C:4]2[N:3]=1.C(N(CC)CC)C.[CH3:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>C(O)(C)C>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH3:23])=[CH:27][CH:28]=2)[N:5]2[N:13]=[CH:14][CH:15]=[C:4]2[N:3]=1
Reactant: CCOc1ccc(N)cc1
Reactant: OCCCc1c(Cl)nc2ccnn2c1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2c(CCCO)c(Cl)nc3ccnn23)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
To an isopropanol (3 mL) solution containing 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-1-ol (224 mg, 0.910 mmol), triethylamine (253 μL, 1.82 mmol) and phenethidine (128 μL, 1.00 mmol) were added, and this mixture was stirred at 40° C. for 5 hr. After the reaction, the solvent was distilled off, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (212 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35](OC1C=CC=CC=1)=[O:36].[CH2:44]([N:46]([CH2:51][CH3:52])[CH2:47][CH2:48][CH2:49][NH2:50])[CH3:45]>O1CCCC1>[C:1]1([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:35]([NH:50][CH2:49][CH2:48][CH2:47][N:46]([CH2:51][CH3:52])[CH2:44][CH3:45])=[O:36])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(Nc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Reactant: CCN(CC)CCCN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNC(=O)Nc1cc(Nc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Yield: 3 %

Procedure:
5-(2-Aminopyridin-4-ylamino)indole-1-carboxylic acid phenylamide (69 mg, 0.20 mmol, Production example 201-3) was dissolved in tetrahydrofuran (14 ml); triethylamine (0.055 ml, 0.40 mmol) was added thereto; and phenyl chloroformate (0.038 ml, 0.30 mmol) was added while stirring and cooled by ice. A portion of 7.0 ml of this reaction mixture was transferred to another vessel; and the remaining portion of the reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.0 ml); the similar reaction to Example 201 was performed using N,N-diethyl-1,3-diaminopropane (0.047 ml, 0.30 mmol); the crude product obtained was purified by a TLC plate (Fuji Silysia NH, developing solvent:ethyl acetate/ethanol=10/1); and the obtained crystals were suspended in ethyl acetate, filtered off, and dried to yield the title compound (3 mg, 0.006 mmol) as colorless crystals.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])C.[NH2:27][CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[OH:30]>>[OH:30][C@@H:29]([CH2:28][NH:27][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])[C:31]([OH:33])=[O:32]
Reactant: NC[C@H](O)C(=O)O
Reactant: CCOC(=O)c1ncc2cc(NC(=O)Nc3ccccc3)ccc2c1O
Product: O=C(Nc1ccccc1)Nc1ccc2c(O)c(C(=O)NC[C@H](O)C(=O)O)ncc2c1

Procedure:
(S)-2-Hydroxy-3-{[4-hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carbonyl]-amino}-propionic acid was prepared from 4-Hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carboxylic acid ethyl ester from under conditions analogous to Example 116(b) using (S)-isoserine. MS ESI(+) m/e: 411.0449 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:23][C:17]=4[CH2:16]3)[CH:12]3[CH:10]([CH2:11]3)[C:9]2=[O:30])=CC=1.C1(OC)C(=CC=CC=1)OC.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[C:24]1([C:22]2[O:23][C:17]3[CH2:16][N:15]([C:13]4[CH:12]5[CH:10]([CH2:11]5)[C:9](=[O:30])[NH:8][N:14]=4)[CH2:20][CH2:19][C:18]=3[N:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(CN2N=C(N3CCc4nc(-c5ccccc5)oc4C3)C3CC3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COc1ccccc1OC
Solvent: O=C(O)C(F)(F)F
Product: O=C1NN=C(N2CCc3nc(-c4ccccc4)oc3C2)C2CC12

Procedure:
320 mg (0.75 mmol) 3-(4-methoxy-benzyl)-5-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one, 1 ml (7.84 mmol) Veratrol and 6 ml TFA are heated to 100° C. in a pressure vessel for 24 h. The cooled mixture is combined with sat. sodium carbonate solution and extracted with DCM, the org. phase is concentrated by rotary evaporation i. V. and the residue is purified by silica gel (eluant: DCM/methanol).
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].[B].[CH3:10][C:11]1([CH3:23])[O:21][C:19](=[O:20])[NH:18][C:17]2[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]1=2>>[CH3:10][C:11]1([CH3:23])[C:12]2[CH:13]=[C:14]([C:6]3[NH:2][C:3]([C:7]#[N:8])=[CH:4][CH:5]=3)[CH:15]=[CH:16][C:17]=2[NH:18][C:19](=[O:20])[O:21]1
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: Cn1cccc1C#N
Agent: [B]
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21

Procedure:
In still a further embodiment, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile is prepared according to the present invention. This process includes reacting 1-methyl-pyrrole-2-carbonitrile and a boron agent; coupling the boronated carbonitrile with 6-bromo-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoazin-2-one (the Brofoxine™ reagent) to give 5-(4,4-dimethyl-2-oxo-1,4- dihydro -2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile. See, Scheme 8. Desirably, the boron agent is tri-isopropylborate. The boron agent is typically reacted with the carbonitrile in the presence of lithium di-isopropylamide (LDA) and tri-isopropylborate to give a boronate/borinate mixture which is not isolated. The coupling is typically performed in situ in the presence of a soluble palladium (0) catalyst to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile in an unpurified form.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CO[CH2:32][CH2:33]OC.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1.C(B1OB(C=C)OB(C=C)O1)=C>O>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([CH:32]=[CH2:33])[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1Br
Reactant: COCCOC
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1c(F)c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c1OC
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of N-[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (50 mg, 0.10 mmol, from Example 187, Step 7) in water (0.21 mL) was added 1,2-dimethoxyethane (0.7 mL), potassium carbonate (14 mg, 0.10 mmol), pyridine:trivinylboroxin (1:1) (26 mg, 0.10 mmol) and tetrakis(triphenylphosphine)Pd(0) (5.2 mg, 0.0045 mmol). The mixture was bubbled with nitrogen for five min and heated at 80° C. overnight. The reaction was diluted with water and EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification on silica gel using 0-100% EtOAc in hexane gave the desired compound (29 mg, 60%). LCMS calculated for C21H24ClFN5O2 (M+H)+: m/z=432.2. found: 432.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][C:15](=[O:29])[C@@H:16]([NH:18][C:19]1[N:24]=[C:23](Cl)[N:22]=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=1)[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[NH2:14][C:15](=[O:29])[C@@H:16]([NH:18][C:19]1[N:24]=[C:23]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[N:22]=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=1)[CH3:17]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(C(N)=O)nc(N2CCN(c3ccc(F)cc3)CC2)n1)C(N)=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 80.4 %

Procedure:
A mixture of 1-(4-fluorophenyl)piperazine (112 mg, 0.62 mmol), (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (150 mg, 0.62 mmol) and Cs2CO3 (235 mg, 0.62 mmol) in DMF (3.0 mL) was stirred at 100° C. for 14 hrs. The reaction was worked up with EtOAc and purified by silica gel flash chromatography (DCM/methanol) to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorophenyl)piperazin-1-yl)pyrimidine-4-carboxamide as a white solid (193 mg, 80%). 1H NMR (CD3OD): 6.90-7.1 (4H, m), 6.55 (1H, s), 4.3 (1H, m), 3.98 (4H, m), 3.10 (4H, m), 1.40 (3H, d, J=7.0 Hz). LC/MS: m/z=388 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]([C:12]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:15]3[C:16]([C:26]([NH:28][CH3:29])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[O:18][C:14]=3[CH:13]=2)[S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:44]1[CH:45]=[CH:46][C:47]2[O:60][CH2:59][N:50]3[C:51]4[CH:52]=[CH:53][CH:54]=[C:55]([F:58])[C:56]=4[CH:57]=[C:49]3[C:48]=2[N:61]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]([C:12]2[C:31]([C:44]3[CH:45]=[CH:46][C:47]4[O:60][CH2:59][N:50]5[C:51]6[CH:52]=[CH:53][CH:54]=[C:55]([F:58])[C:56]=6[CH:57]=[C:49]5[C:48]=4[N:61]=3)=[CH:30][C:15]3[C:16]([C:26]([NH:28][CH3:29])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[O:18][C:14]=3[CH:13]=2)[S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(Cl)cc3)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(Cl)cc3)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C

Procedure:
To a solution of 6-(N-(4-chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (0.15 g, 0.25 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (0.09 g, 0.33 mmol) and K3PO4.3H2O (0.15 g, 0.56 mmol) in dioxane/H2O (6 mL/12 drops) was added Pd2(dba)3 (12 mg, 0.013 mmol) and X-Phos (12 mg, 0.026 mmol) under N2. The mixture was stirred at 100° C. under reflux for 2 hours. Then it was filtered and extracted with EtOAc. The combined organic phases was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using flash gel chromatography (petroleum ether:EtOAc=2:1) to provide 6-(N-(4-chlorobenzyl)methylsulfonamido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide. 1H-NMR (CDCl3, 400 MHz) δ 7.90 (s, 1H), 7.82˜7.86 (m, 2H), 7.39 (s, 2H), 7.04˜7.19 (m, 10H), 6.76˜6.80 (m, 1H), 5.95 (s, 2H), 5.86 (s, 1H), 4.66˜4.78 (m, 2H), 2.89 (d, J=4.0 Hz, 3H), 2.74 (s, 3H). MS (M+H)+: 725.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25](O)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([NH:35][C@H:36]([C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([NH:35][C@H:36]([C:41]([N:43]1[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN1CCN(C(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CC1
Product: CN1CCN(C(=O)[C@H](CC(N)=O)NC(=O)CCc2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Yield: 0.1 %

Procedure:
Condensation of 3-(2,4-dibenzyloxyphenyl) propionic acid (961 mg) and 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-methylpiperazine (1.0 g) was carried out in the same manner as in Example 12 (i) to obtain colorless crystalline 1-[3-(2,4-dibenzyloxyphenyl) propionyl-L-asparaginyl]-4-methylpiperazine (1.39 mg). Melting point: 121°-123° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:60]1[CH:65]=[CH:64][C:63]([S:66]([CH3:69])(=[O:68])=[O:67])=[CH:62][CH:61]=1>C1(C)C=CC=CC=1>[CH3:69][S:66]([C:63]1[CH:64]=[CH:65][C:60]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:61][CH:62]=1)(=[O:68])=[O:67]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 110 °C

Procedure:
Piperazine (0.98 g, 11.5 mmol), Pd(II) acetate (0.017 g), sodium t-butoxide (0.37 g, 4.2 mmol) and BINAP (0.049 g) were stirred at room temperature in 10 mL dry toluene for 15 min. 1-Bromo-4-methanesulfonyl-benzene (0.9 g, 3.8 mmol) in 10 mL dry toluene was added into the reaction mixture. Then the reaction mixture was refluxed at 110° C. for 20 hrs. The reaction mixture was filtered through a celite bed and washed with toluene. The toluene was concentrated and the reaction mixture was taken in ethyl acetate and extracted with 1.5 (N) HCl solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate, concentrated and chromatographed (9/1-CHCl3/MeOH) to afford the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: OCc1cccc(Br)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: COCCOC
Solvent: O
Product: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C

Procedure:
A mixture 3-bromobenzyl alcohol (500 mg, 2.70 mmol), 4-(triflouromethyl)benzeneboronic acid (1.01 g, 5.35 mmol), Pd(PPh3)4 (68 mg, 0.06 mmol) and Na2CO3 (740 mg, 7.02 mmol) in a mixture of DME (20 mL) and water (10 mL) was heated at reflux for 3 hours. The mixture was allowed to cool to rt, and then partitioned between EtOAc and water. The layers were separated and the aqueous re-extracted with EtOAc (2×) and the combined organic layer washed with water and then brine, dried (Na2SO4), filtered and reduced to give an oil. Purification by flash chromatography (silica) eluting with cyclohexane:EtOAc (5:2) afforded the title compound as a clear oil which crystallised on standing (654 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]1[O:19][CH2:18][CH2:17][O:16]1)(=[O:9])=[O:8])[CH3:2].CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1.Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]([S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]1[O:16][CH2:17][CH2:18][O:19]1)(=[O:8])=[O:9])[CH2:38][C:37]1[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)[CH3:2]
Reactant: CCOC(=O)CNS(=O)(=O)c1sccc1C1OCCO1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1sccc1C1OCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.6 %

Procedure:
To a solution of the product from Example 10, Step A (2.80 g, 8.72 mmol) in anhydrous DMF (40 mL) at 0° C. was added a solution of potassium t-butoxide in t-butanol (1M, 9.16 mL, 9.16 mmol) followed by 4-methoxybenzyl chloride (1.78 g, 11.34 mmol). The solution was stirred at ambient temperature for 4 h, poured into 2N HCl (50 mL), diluted with water (150 mL) and extracted with ethyl acetate (2×120 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give a viscous oil (3.91 g) which was used in the next step.