Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(P(CCCC)CCCC)CCC.[C:30]1([C@@H:36]([NH:38][C:39](=[O:48])[CH2:40][C@H:41]([CH2:46]O)[CH2:42][CH2:43][CH2:44][CH3:45])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>O1CCCC1>[CH2:42]([C@H:41]1[CH2:46][N:38]([C@H:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:37])[C:39](=[O:48])[CH2:40]1)[CH2:43][CH2:44][CH3:45]
Reactant: CCCC[C@@H](CO)CC(=O)N[C@@H](C)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCCC[C@@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.5 %

Procedure:
To a solution of di-t-butyl azodicarboxylate (2.1 g, 9.1 mmol) in tetrahydrofuran (25 mL) under argon was added tributylphosphine (2.27 mL, 9.1 mmol). The mixture was stirred for 5 minutes and was added slowly to a solution of (R)-3-hydroxymethylheptanoic acid, (S)-1-phenylethylamide (1.84 g, 7.0 mmol) in dry THF (10 mL) at 0° C. The reaction was warmed up to rt and stirred overnight. Saturated NaHCO3 (100 mL) was added and the resulting mixture was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 1:4 EtOAc/hexanes) to afford 1.4 g (82%) of (R)-4-butyl-1-[(S)-1-phenylethyl]pyrrolidin-2-one as a colorless oil: 1H NMR (CDCl3) δ 7.33 (m, 5 H), 5.48 (q, 1 H), 3.06 (t, 1 H), 2.92 (t, 1 H), 2.53 (q, 1 H), 2.06 (m, 2 H), 1.51 (d, 3 H), 1.20-1.46 (m, 6 H), 0.88 (t, 3 H). MS(ES) m/e 246 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:13][C:10]1([F:12])[O:9][C:8]2[CH:14]=[CH:15][C:5]([CH2:3][OH:2])=[CH:6][C:7]=2[O:11]1
Reactant: COC(=O)c1ccc2c(c1)OC(F)(F)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g) dissolved in 20 mL of anhydrous tetrahydrofuran (THF) was slowly added to a suspension of lithium aluminum hydride (4.10 g, 106 mmol) in anhydrous THF (100 mL) at 0° C. The mixture was then warmed to room temperature. After being stirred at room temperature for 1 hour, the reaction mixture was cooled to 0° C. and treated with water (4.1 g), followed by sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting slurry was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by silica gel column chromatography to give (2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol, 76% over two steps) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Yield: 42.8 %

Procedure:
2-Fluoronitrobenzene (4.2 ml, 40 mmol), methyl 3 -hydroxyphenylacetate (5 g, 32.5 mmol) and potassium carbonate (6.9 g, 50 mmol) were heated together in DMF (100 ml) at 100° C. for 36 hrs. After evaporation of the solvent, the residue was partitioned between water (100 ml) and dichloromethane (100 ml), and the aqueous phase further extracted with dichloromethane (2×100 ml). The combined organics were dried and evaporated, and the residue chromatographed on silica, eluting with 25% ethyl acetate/60°-80° petrol to yield methyl 3-(2-nitrophenyloxy)phenylacetate (4 g); δH (CDCl3) 3.62 (2H, s, CH2CO2Me), 3.69 (3H, s, CO2Me), 6.94 (1H, d, J 7.2 Hz, ArH), 7.00-7.04 (2H, m, ArH), 7.09 (1H, d, J 8.3 Hz, ArH), 7.19 (1H, t, J 8.3 Hz, ArH), 7.32 (1H, t, J 7.9 Hz, ArH), 7.50 (1H, t, J 7.2 Hz, ArH), 7.94 (1H, d, J 8.2 Hz, ArH).
Reaction SMILES: C([O:5]C(N[C@@H](CCOC1C=CC=C(C#N)C=1)C(OCC1C=CC=CC=1)=O)=O)(C)(C)C.[CH3:31][N:32]([CH3:66])[C:33]([C:35]1[CH:65]=[CH:64][C:38]([C:39](N[C@@H](CCOC2C=CC=C(C#N)C=2)C(OCC2C=CC=CC=2)=O)=[O:40])=[CH:37][CH:36]=1)=[O:34]>>[CH3:66][N:32]([CH3:31])[C:33]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([OH:40])=[O:5])=[CH:64][CH:65]=1)=[O:34]
Reactant: CN(C)C(=O)c1ccc(C(=O)N[C@@H](CCOc2cccc(C#N)c2)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1cccc(C#N)c1)C(=O)OCc1ccccc1
Product: CN(C)C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was obtained in the same manner as in step 6 in Example 1 by treating benzyl (2S)-2-t-butoxycarbonylamino-4-(3-cyanophenoxy)butyrate (the compound in step 1 in Example 91) and benzyl (2S)-2-(4-dimethylcarbamoylbenzoylamino)-4-(3-cyanophenoxy)butyrate obtained in the same manner as in step 2 in Example 91 from 4-dimethylcarbamoylbenzoic acid as the starting material.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:40]=[CH:39][C:22]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.[ClH:41]>ClCCl.O1CCOCC1>[ClH:41].[N:1]1[N:2]=[C:3]([C:19]2[CH:40]=[CH:39][C:22]([C:23]([N:25]3[CH2:26][CH2:27][CH:28]([NH2:31])[CH2:29][CH2:30]3)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(-c3nnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CCN(C(=O)c2ccc(-c3nnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a solution of tert-butyl (1-(4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoyl)piperidin-4-yl)carbamate (0.25 g, 0.47 mmol) in dichloromethane (10 mL) was added 4N HCl in dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 20 hours. The solids were filtered off, washed with ether and dried under vacuum, yielding (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)(4-aminopiperidin-1-yl)methanone hydrochloride as a yellow solid (0.21 g, 88%). M.p.=258-263° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.83 (br.s, 1H), 8.25-8.18 (m, 3H), 7.97 (dd, J=7.6, 1.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.48-7.42 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.20 (dd, J=8.0, 1.2 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 6.94 (dd, J=8.0, 4.4 Hz, 1H), 4.55-4.4 (m, 1H), 3.7-3.65 (m, 1H), 3.35-3.25 (m, 1H), 3.22-3.05 (m, 1H), 3.0-2.8 (m, 1H), 2.2-1.85 (m, 2H), 1.6-1.4 (m, 2H); LCMS [M+H]: 438.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[CH:14][C:15](N)=[N:16][C:17]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.S(=O)(=O)(O)[OH:26].[OH-].[Na+]>O>[F:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[CH:14][C:15](=[O:26])[NH:16][C:17]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cnc(-c2ccncc2F)c(-c2cccnc2)[nH]1
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of sodium nitrite (0.248 g, 3.6 mmol) in water (2.5 mL) was added dropwise to a stirred, cooled (ice-bath) mixture of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) (0.80 g, 3.0 mmol) and 5% aqueous sulphuric acid (18 mL). After 1 hour, the mixture was taken to pH 5-6 with aqueous sodium hydroxide solution with external cooling. The mixture was concentrated to low bulk then extracted with chloroform. The organic layer was dried (MgSO4) and concentrated in vaccuo to give the title compound (0.793 g, 99%) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]([N:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:33])[C:27]=3[C:26]3=[N:34][O:35][C:36]([CH3:37])=[C:25]3[C:24]2=[O:38])[CH2:20][CH:19]([CH2:39][NH2:40])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(CC)CC.C(Cl)(Cl)Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]([N:23]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:33])[C:27]=3[C:26]3=[N:34][O:35][C:36]([CH3:37])=[C:25]3[C:24]2=[O:38])[CH2:20][CH:19]([CH2:39][NH:40][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CC(CN)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1CC(CNC(=O)c3ccccc3)CN(C(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Temperature: 25 °C
Yield: 52.6 %

Procedure:
Add benzoyl chloride (0.11 mL, 0.98 mmol) to a solution of 3-aminomethyl-5-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.89 mmol) in CH2Cl2 (10 mL). Add Et3N (0.4 mL, 2.67 mmol) and DMAP (5 mg, cat.). Stir 4 H at room temperature then add CHCl3. Wash 2× with sat. aq NaHCO3, wash 2× with 1N HCl, wash 2× with brine, dry over Na2SO4, filter and concentrate to dryness. Purify by radial chromatography using a MeOH/CHCl3 gradient as eluant. Purify again via radial chromatography using an EtOAc/hexane gradient as eluant and concentrate to dryness to afford the title compound (0.258 g, 53%) as a white foam as a mixture of cis isomers. MS(IS) 551.3 (M+). Purify via chiral HPLC (Chiralcel OD 4.6×250 mm. Eluant: 35% IPA, 65% heptane. Flow: 1.0 mL/min. UV: 240 nM). Chromatography affords isomer 1 of the title compound (59 mg, 23%) as a white solid. MS(IS) 551.3 (M+); Rt=7.0 min. Chromatography affords isomer 2 of the title compound (124 mg, 48%) as a white solid. MS(IS) 551.3; Rt=15.0 min.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:15][CH2:14][C@@H:4]1[CH2:3][C:2]([F:1])([F:16])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a CH2Cl2 (22 ml) solution of (S)-tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.65 g, 11.2 mmol) and Et3N (2.3 ml, 16.8 mmol), at 0° C., methylsulfonyl chloride (0.95 ml, 12.3 mmol) was added dropwise over ˜2 minutes, ice bath was removed after 15 minutes, and stirring was continued at room temperature for another 30 minutes. Reaction went to completion as monitored by LC-MS. The reaction mixture was cooled to 0° C. and was quenched by addition of saturated aqueous solution of NaHCO3 (˜30 ml), stifling was continued at 0° C. for 5 minutes and at room temperature for 15 minutes. Two layers were separated, aqueous layer was extracted with CH2Cl2 (˜30 ml). Organic layers were combined, washed with brine (˜25 ml), dried (Na2SO4), filtered, solvent was removed in vacuo. Compound ((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl methanesulfonate was obtained as a very light yellow oil: 3.40 g (96% crude yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[CH2:17][C@H:16]([CH2:18]O)[O:15][CH2:14][C@:12]2([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:29]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C.O1CCCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[CH2:17][C@H:16]([CH2:18][F:29])[O:15][CH2:14][C@:12]2([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@H]2CS1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate (C24) (82 mg, 0.20 mmol) was dissolved in a mixture of acetonitrile (0.8 mL) and tetrahydrofuran (0.2 mL). 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonyl fluoride (71.1 μL, 0.396 mmol) was added, followed by triethylamine trihydrofluoride (64.4 μL, 0.395 mmol), and then triethylamine (0.166 mL, 1.19 mmol), and the reaction mixture was allowed to stir at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The combined organic extracts were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via preparative thin layer chromatography on silica gel (Eluent: 5% methanol in dichloromethane) afforded the product as a pale yellow foam. Yield: 22 mg, 0.053 mmol, 27%. LCMS m/z 415.4 (M−1). 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 1.53 (s, 9H), 1.87-1.99 (m, 1H), 2.57 (dd, J=12.9, 2.8 Hz, 1H), 2.93 (dd, J=12.9, 3.8 Hz, 1H), 3.01-3.10 (br m, 1H), 3.79 (br d, J=12 Hz, 1H), 3.91-4.03 (m, 1H), 4.15 (dd, J=11.9, 1.9 Hz, 1H), 4.42 (ddd, half of ABXY pattern, J=46.7, 9.9, 3.6 Hz, 1H), 4.50 (ddd, half of ABXY pattern, J=47.7, 9.9, 6.4 Hz, 1H), 6.85 (ddd, J=12.4, 8.4, 2.4 Hz, 1H), 6.89-6.96 (m, 1H), 7.28-7.36 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]=[CH:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.[CH:20](Br)([Br:22])[Br:21].C(OCC)(=O)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Cl-].[Na+].O>[Br:21][C:20]1([Br:22])[C@H:10]2[C@@H:11]1[CH2:12][O:13][C:14]1[C:9]2=[CH:8][CH:7]=[C:6]([CH2:5][O:4][CH3:3])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: BrC(Br)Br
Reactant: COCc1ccc2c(c1C(=O)OC)OCC=C2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1ccc2c(c1C(=O)OC)OC[C@H]1[C@@H]2C1(Br)Br
Temperature: 60 °C

Procedure:
Aqueous sodium hydroxide solution (50% w/v, 1.63 mL) was added slowly to a vigorously stirred mixture of methyl 7-methoxymethyl-2H-chromene-8-carboxylate (Intermediate 9, 0.875 g), benzyltriethylammonium chloride (0.173 g) and bromoform (15 mL). The resultant mixture was vigorously stirred and heated at 60° C. for 3 hours. After cooling, the mixture was poured into a mixture of brine and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of TBME and cyclohexane with a gradient of 0-35% to give methyl cis-(1aRS,7bSR)-1,1-dibromo-5-methoxymethyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (1.06 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: COCCN
Product: COCCNc1ccc(C(=O)c2sc(Nc3ccc(N4CCN(C)CC4)cc3)nc2N)cc1[N+](=O)[O-]

Procedure:
This compound was prepared from the compound of Example 15 and 2-methoxyethanamine (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=512.
Reaction SMILES: [C@@H:1]12[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]1[CH2:4][NH:3][CH2:2]2.Br[C:16]1[CH:17]=[C:18]([Cl:23])[C:19]([Cl:22])=[N:20][CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:18]1[CH:17]=[C:16]([N:3]2[CH2:4][C@@H:5]3[C@@H:1]([CH2:7][N:6]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2]2)[CH:21]=[N:20][C:19]=1[Cl:22]
Reactant: Clc1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H]2CN(c3cnc(Cl)c(Cl)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 L flask with mechanical stirrer was charged with a solution of tert-butyl (1R,5S)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (10.0 g, 50 mmol, product of Example 1L) and 5-bromo-2,3-dichloropyridine (14.0 g, from Example 2D) in toluene (400 mL). The flask was evacuated and purged three times with nitrogen. Xantphos (1.74 g, 3 mmol), Pd2(dba)3 (916 mg, 1 mmol) and sodium tert-butoxide (7.20 g, 75 mmol) were added successively to the flask against a purge of nitrogen gas. The flask was again evacuated and purged with nitrogen (3 times) and the mixture heated to 85–90° C. under N2. After 2 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (1000 mL) and water (200 mL), and stirred for 5 minutes. The organic phase was separated, washed with brine (200 mL), dried (MgSO4), filtered through Celite® (diatomaceous earth) and the filtrate concentrated under vacuum to provide the title compound which was used in the next step without further purification. 1H NMR (MeOH-d4, 300 MHz) δ 1.45 (s, 9H), 2.94 (dd, J=11.6, 4.4 Hz, 1H), 3.04 (dd, J=10.2, 6.4 Hz, 1H), 3.3 (m, 1H), 3.58 (m, 1H), 3.78 (d, J=10.5 Hz, 1H), 3.90 (d, J=10.8 Hz, 1H), 4.05 (m, 1H), 4.83 (m, 1H) 7.39 (d, J=2.7 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H); MS (DCI/NH3) m/z 344/346/348 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([OH:6])=[O:5].[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1.O>CCO>[C:18]1([CH3:17])[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:25])=[O:26])=[CH:22][CH:23]=1.[CH2:17]([NH:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([OH:6])=[O:5])[CH3:18]
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCNC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O

Procedure:
Acid 2-1b (13.20 g, 54.1 mmol) was suspended in 500 mL EtOH, p-TsOH--H2O (11.3 g, 59 mmol) was added and the mixture was heated at reflux overnight. After distilling off the solvent, fresh EtOH was added and distilled off, then more EtOH was added and the mixture was distilled to 100 mL at which point 800 mL ether was added. After cooling to 4°, solvent was decanted from the gum which was rinsed with additional ether, and dried, providing 35-2 as a hygroscopic glass. Additional 35-2 was recovered from the solvent phase by concentration and triturating with ether (2×).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[OH2:2].[O:25]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3cccnc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3cccnc3c2)cc1
Yield: 178 %

Procedure:
A mixture of alpha-oxo-4-[[2-(7-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester (0.5 g) in hot methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (2.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was dissolved in hot water. Cold 2N hydrochloric acid (1.0 mL) was added dropwise and the product was allowed to crystallize and was filtered, washed with water and dried to give 0.45 g of alpha-oxo-4-[[2-(7-quinolyloxy)ethyl]oxy]benzeneacetic acid monohydrate as a colorless solid, mp 229°-231° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10](B2OC(C)(C)C(C)(C)O2)=[C:9]1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Br[C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][C:39]=1[F:49].[OH-].[Na+]>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([N:8]1[C:12]([C:13]([F:15])([F:14])[F:16])=[C:11]([CH3:17])[C:10]([C:38]2[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][C:39]=2[F:49])=[C:9]1[C:27]([N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(OC(F)(F)F)ccc1Br
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)c(C(=O)N2CCOCC2)n(Cc2ccccc2)c1C(F)(F)F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OC(F)(F)F)cc2F)c(C(=O)N2CCOCC2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Under an nitrogen atmosphere (1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone (50 mg, 0.106 mmol) was dissolved in DMF (0.5 mL) and LiOH (2 mg, 0.106 mmol), bis(tri-tert-butylphosphine)palladium (0) (3 mg, 0.007 mmol) and 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene (24 mg, 0.096 mmol) were subsequently added. The reaction mixture was stirred at 80° C. under microwave irridation for 1 h. The mixture was cooled to RT and the reaction was stopped by addition of 1M NaOH solution (2 mL). The crude product was extracted with EtOAc (2×3 mL) and the combined organic layers were washed with water (3×1 mL), dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude mass was purified by flash chromatography to give SC-262 (34 mg, 66.8%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.