Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH2:11].C(N(CC)CC)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:44][C:45]1([CH3:52])[C:49]([CH3:51])([CH3:50])[O:48][BH:47][O:46]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:47]2[O:48][C:49]([CH3:51])([CH3:50])[C:45]([CH3:52])([CH3:44])[O:46]2)=[C:3]([NH2:11])[CH:4]=1
Reactant: COc1cc(C)c(Br)c(N)c1
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)c(N)c1
Yield: 99 %

Procedure:
A solution of 2-bromo-5-methoxy-3-methyl-phenylamine ((Example 198: step c) 2.04 g, 6.18 mmol) in dry dioxane (100 mL) was treated with triethylamine (5.26 mL, 37.7 mmol), 2-(dicyclohexylphosphino)biphenyl (0.662 g, 1.89 mmol), and Pd(OAc)2 (0.106 g, 0.472 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (4.09 mL, 28.3 mmol) was added slowly and the mixture heated to reflux for 1 h. The dioxane was evaporated in vacuo. The residue was taken up in EtOAc and washed with water (2×75 mL). The organic layer was filtered by gravity to remove the palladium residue, dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (10–25% EtOAc in hexanes raised in 5% increments) afforded the product 5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.61 g, 98%) as a light brown solid. 1H NMR (CDCl3): δ 7.361 (d, 1H, J=7.6 Hz), 7.279 (d, 1H, J=8.0 Hz), 3.815 (s, 3H), 2.46 (s, 3H), 1.356 (s, 12H).
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:19]1[O:23][CH:22]([CH:24]=[CH:25][P:26]([O:30]C)([O:28]C)=[O:27])[CH:21]([O:32]C(=O)C2C=CC=CC=2)[CH:20]1[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:42]1C(C)=CC=CC=1C.C[Si](Br)(C)C.C(N(CC)CC)C>CC#N.CO>[NH4+:9].[NH4+:42].[C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:19]1[O:23][CH:22]([CH:24]=[CH:25][P:26](=[O:27])([O-:28])[O-:30])[CH:21]([OH:32])[CH:20]1[F:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)n1
Reactant: COP(=O)(C=CC1OC(n2cnc3c(NC(=O)c4ccccc4)ncnc32)C(F)C1OC(=O)c1ccccc1)OC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ncnc2c1ncn2C1OC(C=CP(=O)([O-])[O-])C(O)C1F)c1ccccc1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Compound 55.5 (92 mg, 0.16 mmol) in CH3CN (3.0 mL) was treated with 2,6-lutidine (183 μL, 1.6 mmol) and TMSBr (102 μL, 0.79 mmol) at 0° C. for 30 min. The mixture was warmed to r.t. and stirred for 30 min. The mixture was cooled to −40° C. and treated with triethylamine (446 μL, 3.2 mmol) in MeOH (2 mL). The mixture was warmed to r.t. and concentrated in vacuo. The residue was dissolved in concentrated NH4OH (1.5 mL) and warmed to 60° C. The solution was stirred for 2 h and then concentrated in vacuo. The residue was subjected to reverse phase HPLC eluting with 5-50% CH3CN-water gradient to give 55.6 (26 mg, 48% yield): white solid (bis-ammonium salt); 1H NMR (D2O, 300 MHz) 8.01 (s, 1H), 7.96 (s, 1H), 6.24 (m, 2H), 6.01 (app t, J=16 Hz, 1H), 5.23 (d, J=52.2 Hz, 1H), 4.44 (m, 2H), 4.31 (m, 1H); 31P NMR (D2O 121.4 MHz) 7.7; 19F NMR (D2O, 282 MHz) −203 (m, 1F); MS (ESI) m/z 345 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:10][N:11]([CH2:13][CH2:14]Cl)[CH3:12].CN(CCOC1C=CC(Br)=CC=1)C>>[CH3:10][N:11]([CH2:13][CH2:14][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:12]
Reactant: Oc1cccc(Br)c1
Reactant: CN(C)CCCl
Agent: CN(C)CCOc1ccc(Br)cc1
Agent: Cl
Product: CN(C)CCOc1cccc(Br)c1
Yield: 73.7 %

Procedure:
3-Bromophenol (5.0 g, 28.9 mmol) and 2-(N, N-dimethylamino)ethyl chloride, hydrochloride (6.24 g, 43.3 mmol) were reacted by the general procedures as described in the preparation of N,N-dimethyl-2-(4-bromophenoxy)ethylamine. The residue was chromatographed on silica gel (dichloromethane/methanol 100:0 to 90:10) to give the title compound (5.2 g, 74%) as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(Nc1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
3-Bromobenzenesulfonyl chloride (51a) (1.0 g, 3.9 mmol) was added to a mixture of aniline (0.47 g, 5.1 mmol) in acetonitrile (10 ml) and sodium carbonate (1.3 g, 12.3 mmol) in water (10 ml). The mixture was stirred at ambient temperature for 1 hour and the reaction product was extracted with ethyl acetate (30 ml). The extract was dried (Na2SO4) and solvents were removed under reduced pressure to give the title compound (1.15 g, 94%) as an oil wich solidified upon standing. M.p. 98-100° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.94-7.48 (5H, m, C6H5); 7.50-7.96 (4H, m, C6H4); 10.36 (1H, s, NH).
Reaction SMILES: [C:1]([C:4]1C=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[C:7](C(=O)C)=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:9]2)(=[O:3])C.C1C[O:27][CH2:26]C1.C([O-])([O-])=O.[K+].[K+].Cl>CO>[OH:3][C:1]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([C:14]1[CH:15]=[CH:16][C:17]([CH2:26][OH:27])=[CH:18][CH:19]=1)=[CH:7][C:6]2=[O:23]
Reactant: C1CCOC1
Reactant: CC(=O)c1c(-c2ccccc2)oc2cccc(C(C)=O)c2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1cc(-c2ccc(CO)cc2)oc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
In a 100 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2′-hydroxy-5′-acetoxyacetophenone (2.63 g, 13.54 mmol), 4-acetoxymethyl benzoic acid (2.63 g, 13.54 mmol) and pyridine (20 mL). POCl3 (2.07 g, 13.54 mmol) was added slowly on cooling. Then the reaction mixture was stirred for 24 h at rt under nitrogen. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried and concentrated to give product (3.0 g, 60%). A solution of this product (3.0 g, 8.10 mmol) in THF (50 mL), was added potassium t-butoxide (1.187 g, 9.72 mmol) and the reaction mixture was stirred for 24 h at rt under N2. The reaction mixture was poured into saturated aqueous solution of NH4Cl. The organic layer was separated, washed with water, dried and concentrated to give crude diketone (3.0 g, 99%). The mentioned diketone (3.0 g, 8.10 mmol) was taken into a mixture of 48% HCl (2 mL) and AcOH (25 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried and concentrated to give the di-acetyl flavone (1.2 g, 74%). To a solution of the di-acetyl flavone (228 mg, 0.676 mmol) in methanol:THF (5 ml:5 mL), K2CO3 (112 mg, 0.811 mmol) was added and stirred for 2 h at rt, then the reaction mixture was neutralized by dilute HCl and extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated to give a crude product, which was purified by column chromatography using 2% MeOH in dichloromethane, to give 100 mg of 6-hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one (50%). MS (ES) m/z: 269.90 (M+1), 268.91 (M); Mp. 262-265° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:18](=O)[CH3:19])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.N.C([BH3-])#[N:25].[Na+].C(Cl)Cl>CO.C(O)(=O)C>[NH2:25][CH:18]([CH3:19])[CH:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Benzyl 2-(4-chlorobenzyl)-3-ketobutyrate (317 mg, 1 mmole, obtained from Step A) was added to a cooled mixture of 7M ammonia in MeOH (2.42 mL) and glacial acetic acid (1.6 mL). To this solution, at ˜10° C., was added sodium cyanoborohydride (101 mg, 1.75 mmol) in small portions. This mixture was stirred at room temperature for 40 h. The excess sodium cyanoborohydride was destroyed by the addition of 6M HCl (to pH 1). The residue obtained after removal of volatiles was taken up in a minimal amount of water and extracted with ether. The aqueous layer was basified to pH 10 using solid KOH. This layer was then saturated with sodium chloride and then extracted with EtOAc. Further analyses of the ether and the EtOAc layers suggest that the desired product resides the EtOAc layer. This material was used in the ensuing coupling reaction without further purification. Proton NMR spectrum show that the two pairs of diastereomers are obtained in ˜1:1 ratio, homogeneous by TLC, Rf=0.4 in 95:5 CH2Cl2:MeOH. LC/MS m/e=318 (M+1). 400 MHz 1H NMR (CDCl3) δ 1.27, 1.29 (2 d, J=7Hz, 3H), 2.85 (m, 1H), 3.03 (m, 1H), 3.15 (m, 1H), 3.55 (m, 1H), 4.85 (br, 2H), 5.00-5.18 (m, 2H), 7.0-7.2 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C(=O)CCC1=O.N>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution (20 mL) of 2-chloro-4,5-difluorobenzoic acid (1.0 g) in N,N-dimethylformamide were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.15 g) and N-hydroxysuccinimide (717 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 28% aqueous ammonia solution (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-chloro-4,5-difluorobenzamide as a colorless solid (yield: 760 mg, yield: 76%). To a solution (5 mL) of 2-chloro-4,5-difluorobenzamide (300 mg) in N,N-dimethylformamide was added pyridine (0.253 mL), and oxalyl chloride (0.20 mL) was added dropwise thereto under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a colorless solid (yield: 250 mg).
Reaction SMILES: C(O[C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38]C)=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([CH2:59][CH2:60]O)=[CH:55][CH:54]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(Cl)CCl.[CH3:99][C:100]1[O:101][C:102]([CH3:108])=[C:103](C(O)=O)[N:104]=1>C(Cl)Cl>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([CH2:59][CH2:60][O:51][C:48]2[CH:49]=[CH:50][C:45]([C@H:43]3[CH2:42][O:41][C:13]4=[CH:14][C:15]5[CH2:16][C@@H:17]([C:18]([NH:19][C@@H:20]([CH2:21][C:22]6[CH:27]=[CH:26][C:25]([C:28]7[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=7[CH3:35])=[CH:24][CH:23]=6)[C:36]([OH:38])=[O:37])=[O:40])[N:8]([C:6]([C:103]6[N:104]=[C:100]([CH3:99])[O:101][C:102]=6[CH3:108])=[O:7])[CH2:9][C:10]=5[CH:11]=[C:12]4[O:44]3)=[CH:46][CH:47]=2)=[CH:57][CH:58]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)CO3
Reactant: OCCc1ccc(Cl)cc1
Reactant: Cc1nc(C(=O)O)c(C)o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCCc3ccc(Cl)cc3)cc2)O4)c(C)o1
Temperature: 25 °C

Procedure:
(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (30 mg) was dissolved in DCM and 2(4-chloro-phenyl)-ethanol (5 equiv), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) added. The mixture stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) added the mixture used in the following reaction sequence. In a separate vial EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. This solution was added to the above mixture stirred 12 hours. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 842.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:31][C:12]3=[N:13][C:14]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:15][C:16](=[O:17])[N:11]3[N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:32](C(OC(C)(C)C)=O)[CH2:33][C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([C:9]2[S:31][C:12]3=[N:13][C:14]([N:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)=[CH:15][C:16](=[O:17])[N:11]3[N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cc(N)cc(Br)c4)sc3n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCC(=O)Nc1cc(Br)cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.5 %

Procedure:
To a solution of tert-butyl 4-(2-(3-amino-5-bromophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (30.0 mg, 0.059 mmol) in DMF (2 ml) are added Boc-Gly-OH (20.7 mg, 0.118 mmol), HATU (45.0 mg, 0.118 mmol) and i−Pr2NEt (31 μl, 0.177 mmol). The mixture is stirred at room temperature for 2 h. EtOAc (10 ml) is added and the solution is washed with H2O and brine. The organic layer is dried over Na2SO4. After removing EtOAc, the residue is purified by Biotage column chromatography (MeOH/DCM: 1/100 to 1/20 gradient) to give the desired product (33 mg, 84%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)=[CH:2]1.CN(C)C=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:38][O:39][CH:40]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=2)[CH2:41]1>O1CCCC1>[CH3:38][O:39][CH:40]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([S:51]([N:1]3[C:9]4[C:4](=[N:5][CH:6]=[CH:7][CH:8]=4)[C:3]([C:10]4[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=4)=[CH:2]3)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=2)[CH2:41]1
Reactant: COC1CCN(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cccnc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1CCN(c2cccc(S(=O)(=O)n3cc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4ncccc43)c2)C1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Into a 1-Neck round-bottom flask tert-butyl 4-(1H-pyrrolo[3,2-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.000334 mol) was stirred in tetrahydrofuran (3 mL, 0.04 mol) and N,N-dimethylformamide (3 mL, 0.04 mol) at 5° C. and 1.0 M of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.50 mL) was added. The reaction was stirred for 20 minutes at 5° C. 3-(3-Methoxypyrrolidin-1-yl)benzenesulfonyl chloride (138 mg, 0.000501 mol) in tetrahydrofuran (3 mL, 0.04 mol) was added by syringe at 5° C. and the reaction was stirred for 30 minutes. The reaction was extracted with ethyl acetate and was washed with water and brine. The solvent was rotovaped.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][C:26]([NH:29][C:37](=[O:39])[CH3:38])([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(N)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC1(c2ccccc2)CCN(C(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 71 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine (1 eq, 35.3 mg, 0.066 mmol) was stirred in a mixture of acetic anhydride (2 mL) and pyridine (2 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)acetamide (27 mg, 71%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.01 (s, 3H) 2.05-2.19 (m, 2H) 2.21 (s, 3H) 2.34 (d, J=14.60 Hz, 1H) 2.66 (d, J=13.85 Hz, 1H) 3.15-3.34 (m, 1H) 3.52 (t, J=11.68 Hz, 1H) 4.26 (d, J=13.75 Hz, 1H) 4.54 (d, J=13.75 Hz, 1H) 6.10 (s, 1H) 7.03-7.11 (m, 2H) 7.14-7.19 (m, 1H) 7.19-7.41 (m, 8H) 7.44 (d, J=2.17 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:26][CH2:27][C:28](O)=[O:29].C(Cl)(Cl)Cl.Cl>CO>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[C:3]3[C:2](=[CH:7][CH:6]=2)[NH:1][C:28](=[O:29])[CH2:27][CH2:26]3)[CH2:9][CH2:10]1)=[O:25]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc(N)c(CCC(=O)O)c3)CC2)cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
3-{2-Amino-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]phenyl}propionic acid (1 g) was dissolved in a mixed solvent consisting of chloroform and methanol, and 1 ml of concentrated hydrochloric acid was added to the solution. The resulting mixture was stirred for 1 hour at room temperature. After distilling off the solvent, the residue was recrystallized from ethanol-chloroform to give 500 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 238°-239.5° C., colorless granules.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](Cl)=[O:4].Cl.[F:20][C:21]([F:33])([C:29]([F:32])([F:31])[F:30])[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)=[O:23].CN1CCOCC1>C(Cl)Cl>[F:33][C:21]([F:20])([C:29]([F:30])([F:31])[F:32])[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:3]([CH:2]1[CH2:6][CH2:7][CH2:8][N:1]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:4])=[O:23]
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(C1CCCN1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)N1CCCC1C(=O)N1CCCC1C(=O)C(F)(F)C(F)(F)F

Procedure:
Methylene chloride (10 ml) was added to CBZ-L-Pro-Cl which was then reacted under argon with a suspension of 2-(2,2,3,3,3-pentafluoro-1-oxopropyl)pyrrolidine hydrochloride (compound from Example IC; 2.49 mmol) and N-methylmorpholine (0.54 ml; 4.98 mmol) dissolved in methylene chloride (7 ml). After 2.5 hours the reaction was concentrated and brought up in methylene chloride (1 ml) and the product purified by flash chromatography on silica gel column eluting with ethyl acetate/hexane (50:50). Product fractions were collected and concentrated to give the desired product (0.52 g) as a colorless oil.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=2)[N:9]=1.[Cl-:22].[NH4+:23]>>[ClH:22].[NH:23]=[C:3]1[NH:9][CH:8]([CH2:10][CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(C=CCC2CCCCC(OC)=N2)o1
Reactant: [Cl-]
Product: COC(=O)c1ccc(C=CCC2CCCCC(=N)N2)o1
Product: Cl

Procedure:
The product of Example 178 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:12][CH2:13][O:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCCOc1ccc2cc[nH]c2c1
Temperature: 75 °C
Yield: 71.8 %

Procedure:
A mixture of 1H-indol-6-ol (4.0 g, 30.0 mmol), 1-bromo-2-methoxyethane (3.53 mL, 37.6 mmol), and cesium carbonate (11.75 g, 36.1 mmol) in DMF (50 mL) was heated at 75° C. for 16 hr. DMF was removed under vacuum with a oil pump. The residue was diluted with ethyl acetate (200 mL), washed sequentially with 1 N NaOH solution (50 mL), water (2×50 mL), and brine (50 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The desired product (4.68 g, 21.54 mmol, 71.7% yield) was isolated as a white solid by ISCO (300 g silica gel, solid loading, 10-50% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:18]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:18]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: ClI
Solvent: CC(=O)O
Product: Cc1ccc2nc(-c3ccc(N)c(I)c3)sc2c1
Yield: 66.6 %

Procedure:
2-(4'-Aminophenyl)-6-methylbenzothiazole (0.6 g, 2.5 mmol) was treated with iodine monochloride (0.5 g, 3.02 mmol) in acetic acid according to the above-described general procedure for iodination. Crude product was purified by flash chromatography on silica gel, using ethyl acetate-hexane (1:3) as eluent, to give brown small crystals (0.61 g, 66.7%), m.p. 176.2-177.9° C.