Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(-c2ccc(Br)cc2)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
(4′-Bromobiphenyl-4-yl)methanol (0.70 g, 2.7 mmol) and imidazole (0.54 g, 8.0 mmol) were dissolved in tetrahydrofuran (20 mL), and tert-butyldimethylchlorosilane (1.2 g, 8.0 mmol) was added under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate, and subsequently washed sequentially with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.90 (hexane/ethyl acetate=9/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.92 g, 2.4 mmol) as a white solid (yield 91%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[F:22])[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Fc1ccccc1S
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1cc(Sc2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 23.3 %

Procedure:
To 2.2 ml of chloroform were added 0.29 ml of diisopropylethylamine, 0.2 g of 4-(2-butynyloxy)-6-chloropyrimidine, and 0.17 g of 2-fluorothiophenol, followed by stirring at room temperature for 7 hours. Then, a saturated aqueous ammonium chloride solution was poured into the reaction mixture, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 4-(2-butynyloxy)-6-(2-fluorophenylthio)pyrimidine (the present compound (146)).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]#[N:10])=[C:5]([CH3:11])[CH:4]=[C:3]1[OH:12].[K].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[C:14]([NH:1][N:2]1[C:7](=[O:8])[C:6]([C:9]#[N:10])=[C:5]([CH3:11])[CH:4]=[C:3]1[OH:12])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(O)n(N)c(=O)c1C#N
Reactant: O=C(Cl)c1ccccc1
Agent: [K]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)n(NC(=O)c2ccccc2)c(=O)c1C#N
Reaction time: 1 h

Procedure:
To a solution of 10.16 g (50 mmol) of potassium 1-amino-5-cyano-2-hydroxy-4-methyl-6-pyridone in 50 ml of water was added a solution of 7.03 g (50 mmol) of benzoyl chloride in 50 ml of methylene chloride. The mixture was stirred rapidly for 1 hr, and then filtered. The solid was washed with isopropanol and air dried. The yield of product was 3.90 g (29.0%); mp: 256° C. dec. The NMR spectrum was consistent with the proposed structure. Anal. Calcd. for C14H11N3O3: C, 62.5; H, 4.1; N, 15.6. Found: C, 62.23; H, 4.31; N, 15.85.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[SH:21][CH:22]([CH3:30])[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24]>>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:3][C:2]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][S:21][CH:22]([CH3:30])[C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[O:1])=[CH:12][CH:13]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: CC(S)C(=O)NCC(=O)O
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Product: CC(SSc1ccccc1C(=O)Nc1ccc(S(N)(=O)=O)cc1)C(=O)NCC(=O)O
Yield: 92.3 %

Procedure:
This compound was prepared according to the method of Example 132 using 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzenesulfonamide and 0.25 g (1.5 mmol) of 2-mercapto-propionylglycine. The product was washed with ether and dried in vacuo to give 0.65 g of the title compound, mp 254°-256° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][N:24]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Clc1cc(I)ccn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(Cl)c3)n2)cc1

Procedure:
The title compound was prepared from 2-bromo-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyridine (example A.19) (1.11 g, 3.0 mmol), commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (740 mg, 3.1 mmol) and i-PrMgCl/ZnCl2 according to the general procedure IVc protocol a. Obtained as a white solid (0.601 g, 50%). MS (ISP) 403.3 [(M+H)+] and 405.2 [(M+2+H)+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N+:11]([O-])=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C[Si]([C:20]#[N:21])(C)C.CN(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:20]#[N:21])[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)c1ccc2c(ccc[n+]2[O-])c1
Agent: CN(C)C
Solvent: CC#N
Product: CC(C)(C)c1ccc2nc(C#N)ccc2c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture of 6-tert-butylquinoline 1-oxide (310 mg, 1.54 mmol), trimethylsilylcyanide (458 mg, 4.62 mmol), trimethylamine (312 mg, 3.08 mmol) in acetonitrile (3 ml) was stirred for 15 minutes at 120° C. under microwave irradiation. The mixture was applied to a silica gel column chromatography and eluted with hexane/EtOAc (20:1) to furnish the title compound (295 mg, 91% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.44 (9H, s), 7.68 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.2 Hz), 7.94 (1H, d, J=2.2, 8.8 Hz), 8.11 (1H, d, J=8.8 Hz), 8.26 (1H, d, J=8.8 Hz) MS (ESI): m/z 211 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:27][C:28](=[O:31])[CH2:29][CH3:30])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:23])[C:17]1=[O:26])[CH2:27][C:28](=[O:31])[CH2:29][CH3:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)O)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCOCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoic acid (0.035 g) in DCM (2 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.044 g), HOBT (0.031 g) and triethylamine (0.064 ml) and the mixture was stirred at room temperature for 30 min. Morpholine (0.02 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.008 g) as a white solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][F:13])=[CH:8][C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:6]([F:20])[CH:5]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][C:36](O)=[O:37])[N:27]=1>>[Cl:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][F:13])=[CH:8][C:7]([N:14]2[CH2:15][CH2:16][N:17]([C:36](=[O:37])[CH2:35][N:28]3[C:29]4=[N:30][CH:31]=[CH:32][CH:33]=[C:34]4[C:26]([C:22]4[NH:21][CH:25]=[CH:24][N:23]=4)=[N:27]3)[CH2:18][CH2:19]2)=[C:6]([F:20])[CH:5]=1
Reactant: FCCOc1cc(N2CCNCC2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2cc(OCCF)c(Cl)cc2F)CC1

Procedure:
The title compound was prepared following Protocol A. 1-[4-Chloro-2-fluoro-5-(2-fluoroethoxy)phenyl]-piperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (2% to 3.5% MeOH in CH2Cl2) to provide 1-{4-[4-chloro-2-fluoro-5-(2-fluoroethoxy)phenyl]piperazin-1-yl}-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H, J=8.0, 1.8 Hz), 8.67 (d, 0.4H, J=6.4 Hz), 8.57-8.55 (m, 1H), 7.30-7.25 (m, 1H), 7.11-7.06 (m, 2H), 6.63 (d, 0.6H, J=7.6 Hz), 6.57 (d, 0.4H, J=7.6 Hz), 6.54 (d, 1H, J=7.6 Hz), 5.45 (s, 0.7H), 5.43 (s, 1.3H), 4.83-4.80 (m, 1H), 4.71-4.68 (m, 1H), 4.31-4.18 (m, 2H), 3.82-3.76 (m, 3H), 3.50 (t, 1H, J=5.2 Hz), 3.23-3.04 (m, 4H); LC/MS m/z (M+H)+ 502.4.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].S(C1C=CC(C)=CC=1)(O[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH:14]1([CH2:13][O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Oc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccccc1OCC1CCCC1
Yield: 44 %

Procedure:
This compound was prepared in 44% yield from catechol and cyclopentylmethyl tosylate according to the general procedure for 2p in Example IX, except that potassium carbonate was used in place of cesium carbonate. Yellow oil; 1H NMR (CDCl3): δ 1.33 (m, 2H), 1.58-1.69 (m, 4H), 1.82-1.89 (m, 2H), 2.40 (s-7, J=7.70 Hz, 1H), 3.91 (d, J=7.15 Hz, 2H), 5.66 (s, 1H), 6.81-6.88 (m, 3H), 6.92-6.94 (m, 1H); 13C NMR (CDCl3): δ 25.53, 29.54, 39.11, 73.20, 111.78, 114.49, 120.16, 121.40, 145.90, 146.16.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])[NH:20][C:19]=1[CH:32]=O>>[CH3:17][C:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])[NH:20][C:19]=1[CH:32]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21

Procedure:
4-Piperidin-4-yl-1,3-dihydro-indol-2-one (45 mg, 0.2 mmol) was condensed with 3-methyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (52 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7][OH:8])[NH:5][C:4]1=[O:9])[CH3:2].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][O:8][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[NH:5][C:4]1=[O:9])[CH3:2]
Reactant: CC[C@@H]1C(=O)N[C@@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H]1C(=O)N[C@@H]1CO[Si](C)(C)C(C)(C)C

Procedure:
187 mg of (±)-cis-3-ethyl-4-hydroxymethyl-2-azetidinone, 300 mg of imidazole, and 300 mg of t-butyldimethylsilyl chloride in 3 ml dry dimethylformamide (DMF) were stirred at room temperature for 2 hours. The mixture was concentrated to dryness and 25 ml of H2O:EtOAc (2:3) were added. The mixture was washed 3 times with 3 ml of H2O to remove DMF and imidazole and then dried over Na2SO4 and concentrated to yield the titled compound as white crystals. NMR (CDCl3): δ0.06 (6H, s), 0.89 (9H, s), 1.06 (3H, t), 1.48-1.88 (2H, m), 3.14 (1H, m), 3.56-3.90 (3H, m), 5.86 (1H, brs).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[NH:11][C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]1=2)=[O:7].ClC1C=C[C:29]2NC3C=CC=C[C:33]=3[C:32](=O)[NH:31][C:30]=2C=1.BrCCCCC(Cl)=O>>[Cl:24][C:21]1[CH:22]=[CH:23][C:9]2[N:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:31]([CH2:32][CH3:33])[CH2:30][CH3:29])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[NH:11][C:10]=2[CH:20]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: O=C1Nc2cc(Cl)ccc2N(C(=O)CCCCBr)c2ccccc21
Agent: O=C(Cl)CCCCBr
Product: CCN(CC)CCCCC(=O)N1c2ccc(Cl)cc2NC(=O)c2ccccc21

Procedure:
The 5-(5-bromovaleryl)-8-chloro-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one, used as starting material, is synthesized similarly to the starting material described in Example 1, from 8-chloro-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one and 5-bromovaleryl chloride.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:27][C:17]1[C:18]2[C:19](=[O:25])[NH:20][CH2:21][CH2:22][C:23]=2[NH:24][C:16]=1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[N:15]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([CH3:26])=[N:8]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2cccc(-c3[nH]c4c(c3Br)C(=O)NCC4)c2nc1NC(C)(C)C
Yield: 61.6 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.30 g, 0.86 mmol) and 1-bromopyrrolidine-2,5-dione (0.23 g, 1.28 mmol) in CHCl3 (8.6 mL) was stirred at RT for 3 h. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (3×150 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was directly injected onto the column and was purified via automated flash chromatography (silica gel) with 1-4% of 2 M NH3 in MeOH/DCM to give 3-bromo-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (349) (228 mg, 0.53 mmol, 62% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.60 (s, 9H) 2.55 (s, 3H) 2.97 (t, J=6.85 Hz, 2H) 3.61 (td, J=6.85, 2.74 Hz, 2H) 4.85 (s, 1H) 5.51 (br. s., 1H) 7.44 (t, J=7.92 Hz, 1H) 7.74 (dd, J=8.02, 1.37 Hz, 1H) 8.71 (dd, J=7.63, 1.37 Hz, 1H) 12.28 (br. s., 1H). MS (ESI, pos. ion) m/z: 428.0/430.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[P:9]([O-:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([O:10][P:9]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: Fc1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(F)cc1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
4-Bromo-fluorobenzene (10.95 g, 62.57 mmol) was added to diethyl phosphite (8.86 mL, 68.8 mmol) at ambient temperature, followed by the addition of triethylamine (9.6 mL, 68.8 mmol). The resulting solution was degassed with nitrogen followed by the addition of tetrakis(triphenylphosphine)-palladium (3.0 g, 2.6 mmol). The resulting mixture was heated at 90° C. overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The crude product was purified by vacuum distillation (ca. 98° C., 0.6 Torr) to yield 8.956 g of 4-fluorophenyl-phosphonic acid diethyl ester (38.6 mmol, 94% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.88-7.80 (m, 2H); 7.20-7.14 (m 2H); 4.22-4.04 (m, 4H); 1.36-1.32 (t, 6H); ESMS (m/z): M+1)+ found, 233.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[CH3:26]I.O>C1COCC1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)c1ccc(C(C)(C)C)cc1
Yield: 101 %

Procedure:
23.3 mL of lithium bis (trimethylsilyl) amide (1.0 M, 23 mmols) was added dropwise to 4.75 g (23 mmols) of methyl 4-tert-butylphenylacetate in 100 mL of dry THF at −78° C. while stirring under nitrogen. The mixture was stirred at this temperature for 45 minutes, then 1.5 mL (24 mmol) methyl iodide was added dropwise and the solution was stirred for an additional 1 hour at −78° C. The mixture was poured into 200 mL of H2O and the desired product was extracted with 500 mL diethyl ether. The organic layer was backwashed once with 500 mL H2O, dried over K2CO3, and concentrated under reduced pressure to yield 5.12 g of a dark oil. The oil was purified via silica gel chromatography eluting with a solvent gradient of hexane to hexane/ethyl acetate 19:1. The fractions containing the desired product were combined and concentrated under reduced pressure to yield the title compound 2.65 g (53%).
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)CO)=O)C=C(F)C=1.N[C@H]1C(=O)NC2C=CC=CC=2S[C@H]1C1C=C(F)C=CC=1F.CN1CCOCC1.[F:47][C:48]1[CH:49]=[C:50]([CH2:55][C:56]([NH:58][C@@H:59]([CH2:83][OH:84])[C:60]([NH:62][C@H:63]2[C:69](=[O:70])[NH:68][C:67]3[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=3[S:65][C@H:64]2[C:75]2[CH:80]=[C:79]([F:81])[CH:78]=[CH:77][C:76]=2[F:82])=[O:61])=[O:57])[CH:51]=[C:52]([F:54])[CH:53]=1>ClCCl>[F:47][C:48]1[CH:49]=[C:50]([CH2:55][C:56]([NH:58][C@@H:59]([CH2:83][OH:84])[C:60]([NH:62][C@@H:63]2[C:69](=[O:70])[NH:68][C:67]3[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=3[S:65][C@@H:64]2[C:75]2[CH:80]=[C:79]([F:81])[CH:78]=[CH:77][C:76]=2[F:82])=[O:61])=[O:57])[CH:51]=[C:52]([F:54])[CH:53]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@@H](CO)C(=O)N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Agent: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Agent: O=C(Cc1cc(F)cc(F)c1)N[C@@H](CO)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1cc(F)cc(F)c1)N[C@@H](CO)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1cc(F)ccc1F
Reaction time: 0.08 h

Procedure:
To a solution N-[(3,5-difluorophenyl)acetyl]-L-serine (4b (75 mg) in dichloromethane (15 mL) at 0° C. under N2, was added racemic 2,3-cis-3-amino-2-(2,5-difluorophenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one-HCl (1d) (100 mg) followed by the HOBt-hydrate (97 mg) and NMM (32 μL). Reaction stirred for 5 min. and then added EDAC-HC1 (84 mg) and NMM (50 μL). The reaction mixture was stirred 2 H at 0° C. under N2, concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, saturated aqueous sodium bicarbonate, brine, dried, filtered and evaporated to yield a mixture of the title compound and (2S)-2-{[(3,5-difluorophenyl)acetyl]amino}-N-[(2S,3S)-2-(2,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-3-hydroxypropanamide. The crude product (165 mg) was purified by flash chromatography (80% ethyl acetate/hexanes) to afford the title compound (60 mg, 73%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ(d, 3H), 3.48 (s, 2H), 4.21 (q, 1H), 4.74, (t, 1H), 4.85 (bs, 1H), 5.50 (d, 1H), 6.93 (d, 2H), 7.09 (m, 1H), 7.18-7.35 (m, 4H), 7.45-7.55 (m, 2H), 7.71 (t, 2H), 8.17(d, 1H), 10.68 (s, 1H). MS APCI, m/z=548 (M+1). LC/MS: 2.34 min.
Reaction SMILES: C([Li])CCC.[CH2:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([C:18]=2[NH2:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:8][CH2:7]1.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23].O>O1CCCC1>[CH2:16]1[C:17]2[C:12](=[N:11][C:10]3[C:19]([C:18]=2[NH:20][C:22](=[O:23])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:13][CH2:14][CH2:15]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: CCCCCCCCOC(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
n Butyllithium, 0.033 mol, is added to a suspension of 6.5g (0.033 mol) of 1,2,3,4-tetra -hydro-9-acridinamine (Petrow, V., Journal of the Chemical Society, pages 634 to 637 (1947)) in 200 ml of tetrahydrofuran at 0° C. The mixture is stirred at 0° C. for 20 minutes, the cooling bath removed and 6.36 g (0.033 mol) of octyl chloroformate added and the solution stirred over the weekend. Water, 200 ml, is added and the mixture extracted with ethyl acetate. The ethyl acetate layer is separated and evaporated to afford a yellow oil. Chromatography (elution with isopropanol-chloroform (5:95)) affords 6.59 g of octyl (1,2,3,4-tetrahydro-9-acridinyl)carbamate, as a yelIow solid; mp 96-99° C.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:4]=1[O:5][CH:6]([OH:8])[CH3:7].[N-:14]=[C:15]=[O:16].[K+]>O>[OH:2][C:3]1[CH:12]=[C:11]([NH:13][C:15]([NH2:14])=[O:16])[CH:10]=[CH:9][C:4]=1[O:5][CH:6]([OH:8])[CH3:7]
Reactant: [N-]=C=O
Reactant: CC(O)Oc1ccc(N)cc1O
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(O)Oc1ccc(NC(N)=O)cc1O

Procedure:
0.03 mol (6.16 g) of 2-hydroxy-4-aminophenoxyethanol hydrochloride is dissolved in 34 ml of water at 15° C. 0.03 mol (2.43 g) of potassium isocyanate dissolved in 7.5 ml of water is added to this solution, with stirring. The temperature of the reaction medium rises to 25° C. After stirring for 30 minutes, the expected product which has precipitated is filtered off. It is washed with a normal solution of hydrochloric acid and then with water. After recrystallization from acetic acid and drying in vacuo, the product melts at 191° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[OH:7].Br[C:9]1[S:10][CH:11]=[C:12]([Br:14])[N:13]=1>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[Br:14][C:12]1[N:13]=[C:9]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[S:10][CH:11]=1
Reactant: Oc1ccccn1
Reactant: Brc1csc(Br)n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1csc(Oc2ccccn2)n1
Temperature: 140 °C
Yield: 37.9 %

Procedure:
According to Scheme 3, Step 2: Pyridin-2-ol (4.12 mmol, 0.39 g) and then silver carbonate (4.94 mmol, 1.36 g) were added to a solution of 2,4-dibromothiazole (4.12 mmol, 1.00 g) in DMF (18 mL) and the reaction mixture was heated at 140° C. overnight. After evaporation of the solvent, the reaction mixture was dissolved in DCM and was filtered through celite. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 2-(4-bromothiazol-2-yloxy)pyridine (1.56 mmol, 400 mg, 34%).