Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3.[C:27]([O-])(O)=[O:28].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CO>[OH:26][C@H:4]1[CH2:3][C@@:2]2([CH3:1])[C@@H:7]([CH2:8][CH2:9][C@:10]2([OH:15])[C@@H:11]([OH:12])[C:13]([O:28][CH3:27])=[O:14])[C@H:6]2[C@H:5]1[C@:24]1([CH3:25])[C:18]([CH2:17][CH2:16]2)=[CH:19][C:20](=[O:21])[CH:22]=[CH:23]1
Reactant: O=C([O-])O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 0.33 h

Procedure:
Prednisolone (10 g) was dissolved in 750 ml of methanol and 2.25 g cupric acetate in 750 ml of methanol was added. The solution was mixed and set aside for 20 min. While stirring, the reaction was continued with airation for 1 weak. After adding 500 ml of 0.1% NaHCO3 solution containing 4.5 g EDTA, methanol was evaporated under vacuum. The solution was extracted with ethyl acetate (1,000 ml), dried on anhydrous sodium sulfate and evaporated to dryness (7.5 g). The residue was dissolved in 150 ml methanol and 375 ml water containing 3.75 g NaHSO3 was added. After refluxing for 1 hour, water was evaporated and the residue was extracted with ethyl acetate (500 ml), washed with distilled water, dried on sodium sulfate and evaporated to dryness (3.5 g), which was purified with silica gel column with acetone:dichloromethane:hexane (3:2:5) as a mobile phase. The pooled fraction was evaporated to dryness. Recrystallization four times from methanol gave 1.1 g of methyl (20R)-11β,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate (Product 9A) as a colorless platelet, m.p.=254°-255° C., 1H-NMR (Me2SO-d6) δ1.05(s,3H,13-CH3), 1.40(s,3H,10-CH3), 3.62(s,3H,21-OCH3), 4.06(s,1H,20-H), 4.21(m,1H,11-H), 5.91(s,1H,4-H), 6.15(dd,1H,J=10 and 2 Hz,2-H), 7.32(d,1H,J=10 Hz,1-H); MS, m/e 390(M+). The combined remaining solution was evaporated. After dissolving in small amount of methanol, the solution was subjected to preparative HPLC using methanol:water (6:4) as a mobile phase. The eluate was evaporated and crystallized to give 0.8 g of methyl (20S)-11β,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate (Product 9B) as a white prism, m.p.=171°- 173° C. 1H-NMR (CDCl3) δ1.15(s,3H,13-CH3), 1.45(s,3H,10-CH3), 3.31(s,3H,21-OCH3), 4.36(s,1H,20-H), 4.43(m,1H,11-H), 6.01(s,1H,4-H), 6.28(dd,1H,J=10 and 2 Hz,2-H), 7.28(d,1H,J=10 Hz,1-H); MS, m/e 390(M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>ClCCl>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:2][C:3]2[CH:7]=[C:6]([CH3:8])[O:5][N:4]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(CBr)no1
Solvent: ClCCl
Product: Cc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 3-bromomethyl-5-methylisoxazole (0.102 g, 0.58 mmol) in dichloromethane (6 ml) was added 1-BOC-piperazine (0.240 g, 1.30 mmol). The reaction mixture was stirred at room temperature for 18 h under argon, then concentrated in vacuo. The resulting residue was absorbed on silica and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of ethyl acetate (30 to 70%) in petroleum ether (60-80° C.) afforded the title compound as a white solid (0.124 g, 76%). 1H-NMR (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.32 (t, J=5.1 Hz, 4H, piperazine N(CH2)2), 2.38 (s, 3H, isoxazole 5-CH3), 3.35 (br t, 4H, piperazine N(CH2)2), 3.50 (s, 2H, NCH2 isoxazole), 6.17 (s, 1H, isoxazole 4-H); LC (Method B)-MS (ESI, m/z): Rt=2.60 min—282 [(M+H)+, 5%], 226 [(M-tBu)+, 100%].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH3:30][C:31]1[N:32]=[CH:33][C:34]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:35][CH:36]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCCCC5)CC4)cc3n2)cn1

Procedure:
1′-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl (Example 24) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine in General Procedure A. Purification on silica yielded 132. NMR (CDCl3): 1.62 m, 10H, 5×CH2), 1.70 (m, 2H, CH2), 2.13 (t, 2H, CH2, J=11.07 Hz), 2.36 (m, H, CH), 2.58 (m, 2H, CH2), 2.66 (s, 3H, CH3), 3.06 (d, 2H, CH2, J=11.5 Hz), 3.83 (s. 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 4.06-4.08 (m, 4H, 2×CH2), 7.25 (d, H, ArH, J=8.1 Hz), 7.31 (s, H, ArH), 8.58 (dd, H, ArH, J=2.14 Hz, 8.09 Hz), 9.52 (d, H, ArH, J=1.9 Hz). MS: (ESI+): MH+=493.45
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:17]4[NH:21][C:20]([C@@H:22]5[CH2:26][CH2:25][CH2:24][N:23]5[C:27](=[O:37])[C@@H:28]([NH:32][C:33](=[O:36])[O:34][CH3:35])[CH:29]([CH3:31])[CH3:30])=[N:19][CH:18]=4)=[CH:10][C:11]=3[C:12]2([F:16])[F:15])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[CH:48][C:49]3[N:53]=[C:52]([C@@H:54]4[C@@H:59]5[CH2:60][C@@H:56]([CH2:57][CH2:58]5)[N:55]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[NH:51][C:50]=3[CH:68]=2)O1.C(=O)(O)[O-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[F:16][C:12]1([F:15])[C:13]2[CH:14]=[C:2]([C:47]3[CH:46]=[CH:68][C:50]4[N:51]=[C:52]([C@@H:54]5[C@@H:59]6[CH2:60][C@@H:56]([CH2:57][CH2:58]6)[N:55]5[C:61]([O:63][C:64]([CH3:66])([CH3:65])[CH3:67])=[O:62])[NH:53][C:49]=4[CH:48]=3)[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][C:9]([C:17]1[NH:21][C:20]([C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27](=[O:37])[C@@H:28]([NH:32][C:33]([O:34][CH3:35])=[O:36])[CH:29]([CH3:30])[CH3:31])=[N:19][CH:18]=1)=[CH:8][CH:7]=2
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Temperature: 95 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
A mixture of methyl (S)-1-((S)-2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (192 mg, 0.33 mmol), (1R,3S,4S)-tert-butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (177 mg, 0.40 mmol), 1M aqueous sodium bicarbonate solution (1.27 mL, 1.27 mmol), triphenylphosphine (9 mg, 0.03 mmol), palladium(II) acetate (4 mg, 0.02 mmol) and dimethoxyethane (3.5 mL) was degassed with a stream of argon for twenty minutes. The reaction was heated to 95° C. After four hours, the reaction was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield (1R,3S,4S)-tert-butyl 3-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (204 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CN(C=O)C.[Cl-].[NH4+]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][N:9]2[CH2:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)n[nH]c2c1
Reactant: CC(=O)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C)nn(CC(C)=O)c2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of the product from Step A (1.1 g, 6.7 mmol) in DMF (10 ml) was added sodium hydride (60% in oil, 0.41 g, 10.2 mmol) at room temperature. After stirring for 30 min, chloroacetone (0.79 ml, 10.2 mmol) was added, and the solution heated at 60° C. for 6 h. The reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (10 ml) and extracted with ethyl acetate (3×65 ml). The combined extracts were washed with brine (10 ml), dried (MgSO4), and evaporated to give a residue which was purified by chromatography (silica, 20% to 30% ethyl acetate in hexane) to give an oil (1.3 g, 88%): MS (ES) m/z 219 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:23])[CH2:21][CH3:22]
Reactant: CCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCC(=O)Cl
Product: CCCN1CCC(c2c[nH]c3ccc(NC(=O)CC)nc23)CC1
Yield: 684.5 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1-propylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.040 mL (0.046 mMol) propionyl chloride, 0.099 gm (81%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][NH:22]3)=[CH:18][CH:17]=2)=[O:15])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[S:37](Cl)(=[O:39])=[O:38]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6](=[O:25])[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[S:37]([C:31]3[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:30]=3[O:29][CH3:28])(=[O:39])=[O:38])=[CH:18][CH:17]=2)=[O:15])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2ccc(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A suspension of 4-[(1H-indole-6-carbonyl)-amino]-benzoic acid tert-butyl ester (200 mg, 0.595 mmol) and tetrabutylammonium hydrogensulfate (20 mg, 0.059 mmol) was treated with 50% aq. sodium hydroxide solution (0.30 mL, 7.4 mmol), then after 5 min 2-methoxy-5-methylbenzenesulfonyl chloride (0.197 mg, 0.892 mmol) was added, and the two-phase mixture was stirred for 1 h at room temperature. The reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-benzoic acid tert-butyl ester (309 mg, 100%). Off-white solid, MS (ISP): m/e 521.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(Br)cc1
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To a solution of 2.0 g (10 mmol) 4-bromobenzaldehyde in 20 ml CH2Cl2 at rt was added 1.3 g (10 mmol) (S)-(−)-2-methylpropane-2-sulfinamide and 2.4 g (10 mmol) copper (II) sulfate. After 24 h at room temperature, the reaction mixture was filtered through celite and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-40% EtOAc:hexane) afforded 2.8 g (90%) N-[(1E)-(4-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide. ES-MS [M+1]=289.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:36]=[N:35][C:34]([O:33][CH3:32])=[N:39][CH:38]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: COc1ncc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: COc1ncc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 51.8 %

Procedure:
To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 2-methoxypyrimidine-5-boronic acid (0.233 g, 1.517 mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.200 g, 51% yield). MP: 224-227° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.72(s,2H), 8.09(s,1H), 8.04(dd, J=7.9,1.4 Hz, 1H),7.84(m,1H),7.69(d, J=8.3 Hz, 1H),7.52(t, J=7.8 Hz, 1H),7.32(m,1H), 7.12-6.95(m,5H), 6.03(q, J=7.1 Hz, 1H),1.90(d, J=7.0 Hz, 3H). Mass: 509.99(M+).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[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>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(F)cc1F
Yield: 55.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2,4-difluorophenylboronic acid (0.079 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.056 g (55%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]1[OH:13].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:22][S:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@H:12]1[OH:13]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(S)ncnc32)[C@@H](O)[C@@H]1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CSc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
6-mercapto-9-(β-D-arabinofuranosyl)purine is reacted at room temperature with methyl iodide in dimethyl sulphoxide in the presence of anhydrous potassium carbonate to give 6-methylthio-9-(β-D-arabinofuranosyl)purine, m.p. 99°-101° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:29][CH2:28][CH2:27][C@@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]1>>[CH2:25]([O:24][C:22]([C@@H:21]1[CH2:27][CH2:28][CH2:29][N:19]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20]1)=[O:23])[CH3:26]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: CCOC(=O)[C@@H]1CCCNC1
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (R)-(−)-nipecotic acid, ethyl ester (TCI America, Portland Oreg., USA) in the same manner as the R isomer. Colorless solid (220 mg, 70%). LC/MS 6.76 min, [M+1]+ 417.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][OH:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.CS(C)=O>CCOC(C)=O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]=[O:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1
Reactant: OCc1nn(C2CCCCO2)c2cc(Cl)ccc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1nn(C2CCCCO2)c2cc(Cl)ccc12
Yield: 98 %

Procedure:
A solution of [6-Chloro-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-methanol (1.75 g, 6.58 mmol), IBX (2.76 g, 9.87 mmol) and DMSO (27 mL) was stirred overnight. The reaction was diluted in EtOAc and water. The layers were separated, and the aqueous was extracted with EtOAc (3×100 mL). The organics were combined and washed with saturated NaCl (100 mL). The organic was dried over MgSO4, filtered, and then concentrated to a solid. The solid was dissolved in CH2Cl2, and filtered. The organic was evaporated to yield the desired product (1.707 g, 92%).
Reaction SMILES: [N:1]#[N:2].C([O:5][C:6](=[O:41])[CH2:7][N:8]([C:13](=[O:40])[C@H:14]([CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])[NH:15][S:16]([C:19]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:31][CH3:32])[CH:25]=2)[CH:20]=1)(=[O:18])=[O:17])[CH2:9][CH2:10][O:11][CH3:12])C>C(O)C.[OH-].[Na+]>[N:1]#[N:2].[CH3:30][O:29][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:31][CH3:32])[CH:25]=2)[CH:20]=[C:19]([S:16]([NH:15][C@H:14]([C:13]([N:8]([CH2:9][CH2:10][O:11][CH3:12])[CH2:7][C:6]([OH:41])=[O:5])=[O:40])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])(=[O:18])=[O:17])[CH:28]=1
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cc(OC)c2cc(OC)ccc2c1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCN(CC(=O)O)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cc(OC)c2cc(OC)ccc2c1
Yield: 55.4 %

Procedure:
A solution of 2.5 g of N2 -(4, 6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester in 5 ml of ethanol and 7 ml of 1N NaOH solution was stirred for 30 hours at room temperature. At the end of this period, the solution was concentrated to 5 ml, chromatographed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness, and the residue was purified by reprecipitation with ethanol-diethyl ether to give 1.32 g (72 percent) of N2 -(4, 6-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine as an amorphous solid, I.R. (KBr): 3,360, 3,180, 1,610 cm-1. Analysis Calcd. for C23H33N5O8S (percent): C, 51.20; H, 6.17; N, 12.98 Found (percent): C, 51.31; H, 6.01; N, 12.67.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8]([C:10]2[S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[N:9]=[C:8]([C:10]2[S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:6][CH:5]=1)=[O:29])[CH3:2]
Reactant: CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
2-[6-(Ethylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.10 g, 0.33 mmol) was dissolved in chloroform (50 ml). A solution of 3-chloroperbenzoic acid (ca. 77%, 0.075 g, 0.33 mmol) in chloroform (10 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (0.050 g, 47%) as pale yellow crystals.
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[P:25](Cl)([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH:22]1([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][N:11]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:23][CH2:24]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: CCOP(=O)(Cl)OCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reaction time: 0.17 h

Procedure:
A suspension of 2.816 g (8.5 mmol) of ciprofloxacin base in 100 ml of dry CH2Cl2 was stirred under argon as 3.46 g (17 mmol) of N,O-bis(trimethylsilyl)-acetamide was added. After the solid had dissolved (2-3 hours), 1.47 g (8.5 mmol) of diethyl chlorophosphate was added. After 24 hours at approximately 23° the solution was evaporated, finally at 0.03 mm for 15 hours. Washing of the solid residue with water gave a white solid which was dried and then recrystallized from CH2Cl2 -toluene, boiling out te CH2Cl2 within 10 minutes to avoid thermal degradation. The product was 3.74 g (94%) of cream-colored solid, m.p. 192°-193° C.; NMR (CDCl3, 80 MHz) δ 1.36 (t, CH3), 3.30 (s, CH2N), 4.06 (5 peaks, OCH2); IR (KBr) 1028(P=O), 1630 (--COOH), 1724 cm-1 (C=O).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[N:9][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[Cl:32].CO>CN(C=O)C>[Cl:32][C:26]1[C:27]([Cl:31])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]2[C:15]1=[O:16]
Reactant: O=C1NCCn2c1nnc2-c1cnccn1
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1c2nnc(-c3cnccn3)n2CCN1Cc1cccc(Cl)c1Cl
Reaction time: 5 h
Yield: 88.8 %

Procedure:
To a slurry of Intermediate 1 (60 mg, 0.18 mmol) and cesium carbonate (237 mg, 0.73 mmol) in DMF (1.4 mL) was added 1-(bromomethyl)-2,3-dichlorobenzene (65 mg, 0.27 mmol). After 5 h, the reaction was quenched with sat aq NH4Cl, poured into brine, and extracted with 20% IPA/CHCl3 (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give a brown sludge. Trituration with MeOH provided the desired product as a beige powder (60 mg, 88%). MS (ESI): mass calcd. for C16H12Cl2N6O, 374.0; m/z found, 375.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.77 (s, 2H), 7.57 (dd, J=7.9, 1.2 Hz, 1H), 7.49-7.38 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 4.86-4.75 (m, 4H), 3.90-3.81 (m, 2H).