Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[S:30](=[O:33])(=[O:32])[CH2:31][C:22]=3[C:21]([C:34](OCC)=[O:35])=[N:20]2)[CH:16]=[CH:17][CH:18]=1.O>C1COCC1>[N:5]1([C:34]([C:21]2[C:22]3[CH2:31][S:30](=[O:32])(=[O:33])[C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:23]=3[N:19]([C:15]3[CH:14]=[C:13]([CH2:12][OH:11])[CH:18]=[CH:17][CH:16]=3)[N:20]=2)=[O:35])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1nn(-c2cccc(CO)c2)c2c1CS(=O)(=O)c1ccccc1-2
Reactant: C1COCCN1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1nn(-c2cccc(CO)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of aluminium chloride (5.13 g; 38.49 mmol; 4.93 eq.) in THF (30 mL) stirred for 25 min at 4° C. is added morpholine (5.40 ml; 61.36 mmol; 7.86 eq.) and the reaction mixture is stirred at 4° C. for 1 h. Ethyl 1-[3-(hydroxymethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (3.11 g; 7.81 mmol; 1 eq.) is added and the reaction mixture is allowed to warm up to rt. After 22 h, the reaction mixture is cooled down to 0° C. then water is added slowly (total volume 25 mL). After 30 min stirring, the product is extracted with DCM. The organic phase is washed with an aqueous solution of Rochelle salts (˜0.7 m; pH=5), brine then dried over MgSO4. The solvent is removed under reduced pressure to afford 3.39 g (99%) of the title compound as a pale yellow solid. HPLC (max plot) 95.6%; Rt 3.08 min. MS (ESI+): 440.0.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: N#Cc1ccccc1CBr
Reactant: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2ncc3cnn(Cc4ccccc4C#N)c3n2)cn1

Procedure:
A solution of N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (100 mg, 0.46 mmol), 2-(bromomethyl)benzonitrile (1.1 eq) and potassium carbonate (2 eq) in DMF (2 mL) was stirred at rt for 18 h. The resultant mixture was diluted with EtOAc and washed with H2O, then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography (petroleum ether: EtOAc) to give the title product. 1H NMR (d6-DMSO) δ 9.94 (s, 1H), 8.93 (s, 1H), 8.09 (s, 2H), 7.91 (dd, 1H), 7.67 (td, 1H), 7.51-7.54 (m, 2H), 7.36-7.38 (m, 1H), 5.76 (s, 2H), 3.82 (s, 3H); LC-MS method B, (ES+) 331.0, RT=8.04 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.[CH3:41][C:42](=O)[CH3:43].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH:42]([CH3:43])[CH3:41])[CH2:22][CH2:23]3)[S:17][C:10]=12
Reactant: CC(C)=O
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)N1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 35.0 mg, 0.0625 mmol), propan-2-one (36.3 mg, 0.625 mmol), NaBH(OAc)3 (66.3 mg, 0.313 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford crude product. The crude product was further purified by preparative reverse phase HPLC to afford product (5.8 mg, 15.4%). LRMS (APCI pos): >99% purity, 254 nm, m/e 602 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.52 (d, 1H), 8.39 (d, 1H), 8.26 (d, 1H), 8.05 (m, 1H), 7.69 (m, 2H), 7.61 (m, 1H), 7.52 (m, 1H), 7.34-7.46 (m, 3H), 6.70 (d, 1H), 3.12-3.41 (m, 6H), 2.33 (m, 2H), 1.97 (m, 2H), 1.28 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH:44]([C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1)([CH2:46][CH3:47])[CH3:45]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:52][C:51]1[CH:53]=[CH:54][C:48]([CH:44]([CH2:46][CH3:47])[CH3:45])=[CH:49][CH:50]=1)=[O:6]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(N)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCC(C)c1ccc(NC(=O)c2cc(S(C)(=O)=O)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-amino-5-methanesulfonyl-benzoic acid (0.750 g, 3.48 mmol) in THF (50 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.730 g, 3.83 mmol), 1-hydroxybenzotriazole (0.510 g, 3.83 mmol), and 4-methylmorpholine (0.380 g, 3.83 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then 4-sec-butyl-aniline (0.780 g, 5.22 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo, water was added, and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo and the residue was washed with ether to obtain 2-amino-N-(4-sec-butyl-phenyl)-5-methanesulfonyl-benzamide as white solid. Yield: 0.75 g (62%).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@H:38]3[CH2:43][CH2:42][C@H:41]([N:44]4[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]4)[CH2:40][CH2:39]3)[N:19]=[C:20]([C:21]3[C:26]([F:27])=[CH:25][C:24]([NH:28]C(=O)OC(C)(C)C)=[C:23]([O:36][CH3:37])[CH:22]=3)[C:13]=12>ClCCl>[NH2:28][C:24]1[C:23]([O:36][CH3:37])=[CH:22][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([C@H:38]3[CH2:43][CH2:42][C@H:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)[CH2:40][CH2:39]3)[N:19]=2)=[C:26]([F:27])[CH:25]=1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 7 mL) was added to a solution of trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)carbamate (250 mg, 0.451 mmol) in dichloromethane (4.0 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 4 hours. Solvent was then evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added to adjust the pH to 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (179 mg, 87%). 1H NMR (CDCl3) δ 1.56 (m, 2H), 2.15 (m, 7H), 2.31 (s, 3H), 2.51 (m, 4H), 2.67 (m, 4H), 3.88 (s, 3H), 4.16 (bs, 2H), 4.74 (m, 1H), 5.64 (bs, 2H), 6.56 (d, J=10.84 Hz, 1H), 6.88 (d, J=6.55 Hz, 1H), 8.33 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+ =455.2, Rt=0.63 min.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C@@H:8]([CH3:12])[C:9]([OH:11])=O.[C:13]([O:17][C:18](=[O:26])[CH2:19][CH:20]([NH2:25])[CH:21]([OH:24])[CH2:22][F:23])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:13]([O:17][C:18](=[O:26])[CH2:19][CH:20]([NH:25][C:9](=[O:11])[C@@H:8]([N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[CH3:12])[CH:21]([OH:24])[CH2:22][F:23])([CH3:16])([CH3:14])[CH3:15]
Reactant: C[C@@H](C(=O)O)n1ccccc1=O
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CN(C)c1ccncc1
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF)n1ccccc1=O
Temperature: 0 °C
Yield: 91.5 %

Procedure:
A stirred mixture of (S)-2-(2-Oxo-2H-pyridin-1-yl)-propionic acid (70 mg, 0.42 mmol), 3-Amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (91 mg, 0.44 mmol), HOAt (63 mg, 0.46 mmol) and DMAP (59 mg, 0.48 mmol) and anhydrous THF (5 ml) was cooled to 0° C. then EDC (88 mg, 0.46 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (3% methanol in ethyl acetate) to afford the title compound as a white foam (137 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 1.3-1.5 (9H, 2×s), 2.5-2.7 (2H, m), 3.4-3.7 (1H, m), 3.9-4.6 (4H, m), 5.4-5.6 (1H, m), 6.2-6.3 (1H, m), 6.5-6.6 (1H, m), 7.1-7.6 (3H, m); 19F NMR (376 MHz, CDCl3) δ −230.14, −230.14, −230.17, −230.95, −231.07.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28]CC3C=CC([N+]([O-])=O)=CC=3)=[O:27])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].I[CH2:42][C:43]([NH2:45])=[O:44].C(OCC)(=O)C>CC(C)=O>[C:43]([CH2:42][N+:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:19][C:16]1[N:17]=[CH:18][N:13]2[CH:12]=[C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:39](=[O:40])[N:6]4[C:7]=3[C:26]([O-:28])=[O:27])[S:15][C:14]=12)(=[O:44])[NH2:45]
Reactant: NC(=O)CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(Sc5ccccn5)c4s3)[C@H](C)[C@H]12
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(Sc5cccc[n+]5CC(N)=O)c4s3)[C@H](C)[C@H]12
Temperature: 40 °C
Reaction time: 96 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-2-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (42.2 mg) was dissolved in 2 ml of acetone. 2-Iodoacetamide (140 mg) was added to the solution. The mixture was stirred at 40° C. for 4 days. Ethyl acetate (4 ml) was added to the reaction solution, and the resultant precipitate was collected, and was reacted in the same manner as in Example 1c). The reaction product was purified by column chromatography on Cosmosil 40C18-PREP (a 10 to 25% aqueous methanol solution). In this case, the first eluted fraction in two major products was collected to prepare 1.44 mg of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH2:13][CH2:12]1>C(O)=O>[CH:5]([NH:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH2:13][CH2:12]1)=[O:7]
Reactant: NCCN1CCn2nccc21
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCCN1CCn2nccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of acetic anhydride (4.96 ml) and formic acid (2.51 ml) was stirred for 45 minutes at room temperature. The mixture was cooled to 5° C., and 1-(2-aminoethyl]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (4.0 g) was added to the mixture. The mixture was stirred for an hour under ice-cooling. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. Fractions containing the object compound were combined and evaporated to give 1-(2-formamidoethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (2.6 g) as crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-quinoline carboxylic acid (1.2 eq.) in DMF at 0° C. was treated with EDC (1.4 eq.). The mixture was stirred at 0° C. for 1 to 2 h and then N-hydroxysuccinimide (1.0 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 60% sat. NaHCO3 and the product filtered: 1H NMR (CDCl3, 300 MHz, ppm) 8.35 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 7.87 (d, 1H), 7.80 (m, 1H), 7.68 (m, 1H), 2.91 (s, 4H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[CH:7]2>>[Br:1][C:5]1[C:4]([F:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH3:14])=[N:10]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: BrBr
Product: Cc1ccc2c(Br)c(F)ccc2n1

Procedure:
reacting bromine with 6-fluoro-2-methylquinoline to give 5-bromo-6-fluoro-2-methylquinoline, and
Reaction SMILES: C(OC(N1CCC(C(O[C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[CH3:44][O:45][C:46](=[O:52])[CH:47]([OH:51])[CH2:48][CH2:49][Br:50].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>O1CCOCC1.CCOC(C)=O>[CH3:44][O:45][C:46](=[O:52])[CH:47]([O:51][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[CH2:48][CH2:49][Br:50]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)C(O)CCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C(CCBr)Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (2.8 g, 8.5 mmol), 4-bromo-2-hydroxybutyric acid methyl ester (2.5 g, 12.7 mmol) and triphenylphosphine (3.77 g, 14.3 mmol) in dioxane (30 mL) was added DIAD (2.8 ml, 14.3 mmol) and the reaction mixture was stirred at RT for 1 h. Additional amounts of DIAD (1.67 mL) and of triphenylphosphine (2.23 g) were added and stirring was continued for 1 h. The mixture was diluted with EtOAc and washed with aq. NaOH (1N). The aqueous phase was further extracted with EtOAc (×3). The combined organic layers were then washed with brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc followed by Si-PCC, gradient 0-10% MeOH in DCM) affording 4-Bromo-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]butyric acid methyl ester (2.5 g, 58%). 1H NMR (CDCl3, 400 MHz): δ 8.43 (1H, d, J=9.01 Hz), 7.57 (1H, s), 6.74 (1H, d, J=9.15 Hz), 6.55 (1H, d, J=2.56 Hz), 5.95-5.83 (1H, m), 4.92 (1H, dd, J=8.80, 3.97 Hz), 4.51-4.31 (4H, m), 3.79 (3H, s), 3.65-3.53 (2H, m), 2.58-2.36 (5H, m), 1.58-1.51 (6H, m)
Reaction SMILES: O[CH2:2][CH2:3][N:4]([S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][OH:8].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>N1C=CC=CC=1.C(Cl)Cl>[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([CH2:2][CH2:3][N:4]([S:9][C:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][CH2:6][CH2:7][O:8][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: OCCCN(CCO)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCN(CCCOS(=O)(=O)c2ccc(C)cc2)SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
N-(2-hydroxyethyl)-N-tritylsulfenyl-3-amino-1-propanol (5.0 g, 12.64 mmol) is dissolved in pyridine (100 mL) and cooled to 0° C. p-Toluensufonylchloride (2.65 g, 13.9 mmol) is dissolve in CH2Cl2 (50 mL) and added to the reaction mixture at 0° C. via dropping funnel. The reaction is monitored by TLC to completion. The reaction mixture is concentrated in vacuo and the resultant residue is dissolved in EtOAc and washed with H2O (3×50 mL) and brine (2×50 mL). The EtOAc is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography using EtOAc/hexanes as eluent. The appropriate fractions are pooled and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:51][C:52](OC(C)=O)=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:52](=[O:53])[CH3:51])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution containing 35 (228 mg, 0.4 mmol), DIPEA (104 mg, 0.8 mmol) and DMAP (cat) in DCM (5 mL) was cooled to 0° C., followed by the addition of Ac2O (50 mg, 0.48 mmol). After 1 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with saturated aqueous NaHCO3, 1N HCl, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford crude 38 which was used without further purification. Mass spectrum, m/z [615.1] (M+H)+.
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:18]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[NH:21][C:20]([CH3:29])=[C:19]2[C:30]([O:32][CH3:33])=[O:31])[CH:14]=[CH:15][C:16]=1[F:17])C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH2:50][NH2:51])[CH2:44][CH2:43]2)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C>[F:17][C:16]1[CH:15]=[CH:14][C:13]([CH:18]2[C:19]([C:30]([O:32][CH3:33])=[O:31])=[C:20]([CH3:29])[NH:21][C:22]([CH3:28])=[C:23]2[C:24]([O:26][CH3:27])=[O:25])=[CH:12][C:11]=1[NH:10][C:5]1[C:6](=[O:9])[C:7](=[O:8])[C:4]=1[NH:51][CH2:50][CH2:49][CH2:48][N:45]1[CH2:44][CH2:43][CH:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=2)[CH2:47][CH2:46]1
Reactant: COc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCOc1c(Nc2cc(C3C(C(=O)OC)=C(C)NC(C)=C3C(=O)OC)ccc2F)c(=O)c1=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(F)c(Nc2c(NCCCN3CCC(c4cccc(OC)c4)CC3)c(=O)c2=O)c1

Procedure:
The compound of Example 2 (98.3 mg, 0.215 mmol) and 4-(3-methoxyphenyl)piperidine-1-propanamine (64 mg, 0.258 mmol) were stirred in 2 mL DMF at room temperature for 64 hours. The crude reaction mixture was evaporated to dryness under high vacuum (0.1 mmHg) at 50-55° C. The resulting gum was triturated with methylene chloride followed by the addition of hexanes. The titled compound precipitated out as fine creamy white crystalline solid (120 mg, 84.6%): mp 205-207° C.; 1H NMR (DMSO-d6) δ 9.38 (br. s, 1H), 8.96 (br. s, 1H), 8.04 (br. t, 1H, J=3 Hz), 7.80 (d, 1H, J=7.2 Hz), 7.10 (m, 2H), 6.77 (m, 4H), 4.85 (s, 1H), 3.71 (s, 3H), 3.65 (q, 2H, J=6.0 Hz), 3.53 (s, 6H), 2.95 (d, 2H, J=10.5 Hz), 2.40 (m, 3H), 2.25 (s, 6H), 1.97 (m, 2H), 1.67.(m, 6H), 13C NMR (DMSO-d6) δ 184.94, 179.65, 169.52, 167.32, 163.03, 159.26, 147.95, 146.23, 145.07, 129.25, 126.76, 126.62, 119.68, 118.81, 114.66, 114.40, 112.41, 111.35, 100.93, 55.14, 54.83, 53.73, 50.60, 32.93, 27.84, 18.31. Anal Calcd. for C36H41 FN4O7•0.14 H2O: C, 65.19; H, 6.27; N, 8.45. Found: C, 65.20; H, 6.28; N, 8.37.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([CH2:24][C:25](=[O:27])[NH2:26])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3].[C:28]([OH:36])(=[S:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:35][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([CH2:24][C:25](=[O:27])[NH2:26])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(CC(N)=O)c1
Reactant: OC(=S)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCn1cnc(CC(N)=O)c1

Procedure:
(2R,4R)-1-Allyloxycarbonyl-2-{2-(4-carbamoylmethyl-imidazol-1-yl) ethyl}-4-methanesulfonyloxypyrrolidine (2.74 g) were reacted with thiobenzoic acid (1.69 ml) and potassium t-butoxide (1.54 g) in substantially the same manner as Preparation 19-2) to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[2-(4-carbamoylmethyl-imidazol-1-yl) ethyl]pyrrolidine (2.30 g) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][OH:9].[Br:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:21]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COc1ccc(CO)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(F)cc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
Sodium hydride (80% disp. in oil; 933 mg, 31.1 mmol) was added, all at once to 3,4-dimethoxybenzyl alcohol (3.48 g, 20.7 mmol) in DMF (40 mL) at 0° C. and under Ar. After 5 min., the mixture was allowed to warm to r.t. After 1 h, 1-bromo-3,5-difluorobenzene (4 g, 20.7 mmol) in DMF (5 mL) was added dropwise at r.t. The resulting mixture was kept at this temperature for 16 h and slowly poured into H2O (500 mL). It was extracted with EtOAc (3×) and the combined organics were washed with 25% NH4OAc buffer (1×), H2O (2×) and brine. The solution was dried (MgSO4) and concentrated to give a pale yellow solid that was purified by column chromatography on silica gel (EtOAc:hexane, 10:90-15:85) to afford the title compound as a white solid (5.85 g, 83%).