Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH2:41]O)([CH3:35])([CH3:34])[CH3:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH2:41][O:12][C:3]1[C:4]([F:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[F:1])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a solution of 2,6-difluoro-3-nitrophenol (170 mg, 0.971 mmol) and triphenylphosphine (383 mg, 1.46 mmol) in THF (8 mL) was added a solution of (3-hydroxypropyl)carbamic acid tert-butyl ester (204 mg, 1.165 mmol) in THF (1 mL). The mixture was cooled in an ice bath and a solution of diethyl azodicarboxylate (255 mg, 1.46 mmol) in THF (1 mL) was added. The reaction was stirred at RT for 30 min, then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 25-40% EtOAc in cyclohexane) affording the title compound as a colourless gum (296 mg, 92%). 1H NMR (CDCl3, 300 MHz): 7.81 (1H, ddd, J=9.4, 7.8, 5.3 Hz), 7.04 (1H, dt, J=9.4, 2.2 Hz), 4.77 (1H, bs), 4.27 (2H, t, J=6.0 Hz), 3.37 (2H, q, J=6.4 Hz), 2.00 (2H, quintet, J=6.3 Hz), 1.45 (9H, s)
Reaction SMILES: C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:25]([O:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][C:32]([N:38]=[C:39]=[O:40])=[CH:31][C:30]=1[CH:41]([CH3:43])[CH3:42])(=[O:27])[CH3:26].[NH2:44][C:45]1[CH:46]=[N:47][C:48]2[C:53]([C:54]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[Cl:61])=[CH:52][C:51]([CH3:62])=[CH:50][C:49]=2[CH3:63]>C1C=CC=CC=1.C(OCC)(=O)C>[C:25]([O:28][C:29]1[C:30]([CH:41]([CH3:43])[CH3:42])=[CH:31][C:32]([NH:38][C:39](=[O:40])[NH:44][C:45]2[CH:46]=[N:47][C:48]3[C:53]([C:54]=2[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[Cl:61])=[CH:52][C:51]([CH3:62])=[CH:50][C:49]=3[CH3:63])=[CH:33][C:34]=1[CH:35]([CH3:37])[CH3:36])(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1c(C(C)C)cc(N=C=O)cc1C(C)C
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C(C)C)cc(NC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1C(C)C
Reaction time: 0.67 h

Procedure:
Triethylamine (0.15 ml) was dropwise added to a mixture of 4-acetoxy-3,5-didiisopropylbenzoic acid (238 mg), diphenylphosphoryl azide (300 mg) and benzene (10 ml) under stirring. The mixture was further stirred for 30 mins. at room temperature, and for 40 mins. under reflux to prepare a solution of 4-acetoxy-3,5-diisopropylphenylisocyanate. After cooling, to the solution were added a solution of 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (255 mg) in benzene (255 mg) and then triethylamine (0.15 ml). The whole was stirred for 2 hrs. at room temperature, then for 3 hrs. under reflux, and thereto was added ethyl acetate. The organic layer was separated, washed with 2N-hydrochloric acid and water successively, and dried over anhydrous magnesium sulfate and then distilled to remove the solvent. The residue was recrystallized from a mixture of acetone and isopropyl ether to give 3-[3-(4-acetoxy-3,5-diisopropylphenyl)ureido]-4-(2-chlorophenyl)-6,8-dimethylquinoline as colorless needles. Yield 367 mg (74.9%). m.p. 248°-249° C.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[CH:10]=2)[C:4](=O)[O:3]1.[CH3:22][NH:23][NH2:24]>C(O)C>[OH:20][C:17]1[CH:18]=[CH:19][C:14](/[CH:13]=[CH:12]/[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[C:4](=[O:3])[N:23]([CH3:22])[N:24]=[CH:2]3)=[CH:15][CH:16]=1
Reactant: COc1ccc(/C=C/c2ccc3c(c2)C(O)OC3=O)cc1
Reactant: CNN
Solvent: CCO
Product: Cn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O

Procedure:
Trans-3-Hydroxy-5-[2-(4-methoxyphenyl)ethenyl]phthalide (15 g) was dissolved in refluxing ethanol (85 ml) and methylhydrazine (10 ml) was added slowly. The resulting suspension was refluxed for 3 hours, then cooled and filtered to give the 2-methyl-1(2H)-phthalazinone, mp 223°-225° C. The methoxy phthalazinone (10 g) was mixed with pyridine hydrochloride (35 g) and heated to 180° C. for 10 hours. The mixture was diluted with water, filtered and washed with isopropanol to give the desired phenol (4.3 g), mp 282°-284° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:25])[CH:17]=2)=[N:7]1)=[O:5].[OH-].[Na+:35]>O>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([O-:22])=[O:21])=[C:18]([OH:25])[CH:17]=2)=[N:7]1)=[O:5].[Na+:35]
Reactant: O=C(O)c1ccc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3cccc(F)c23)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1ccc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3cccc(F)c23)cc1O

Procedure:
To a suspension of compound 26A (48 mg, 0.1 mmol) in H2O (20 mL) was added 0.1 M NaOH (1 mL), and the mixture was sonicated for ˜10 mins. The mixture was then dried under lyophilizaiton to give the title compound. LCMS (ESI) calc'd for C22H11ClF4N2NaO4 [M+H]+: 501. found: 501; 1H NMR (400 MHz, MeOD) δ 8.45 (1H, d, J=8.0), 7.91-7.76 (5H, m), 7.31 (1H, q, J=8.0 Hz), 7.20-7.17 (2H, m).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:14](=[O:26])[N:13]([CH2:27][C:28]4[O:32][N:31]=[C:30]([CH2:33][CH3:34])[N:29]=4)[C:12]=3[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[CH2:35]([O:37][C:38]1[C:47]([O:48][CH3:49])=[CH:46][C:45]2[C:44]([C:50]3[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=3)=[N:43][C@@H:42]3[CH2:59][CH2:60][S:61][CH2:62][C@@H:41]3[C:40]=2[CH:39]=1)[CH3:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH:20]4[CH2:21][CH2:22][N:23]([C:54]([C:53]5[CH:57]=[CH:58][C:50]([C:44]6[C:45]7[CH:46]=[C:47]([O:48][CH3:49])[C:38]([O:37][CH2:35][CH3:36])=[CH:39][C:40]=7[C@H:41]7[CH2:62][S:61][CH2:60][CH2:59][C@H:42]7[N:43]=6)=[CH:51][CH:52]=5)=[O:55])[CH2:24][CH2:25]4)[C:14](=[O:26])[N:13]([CH2:27][C:28]4[O:32][N:31]=[C:30]([CH2:33][CH3:34])[N:29]=4)[C:12]=3[CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)c(F)c4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)c(F)c6)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(3,4-difluorophenyl)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (228 mg; compound B89) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (191 mg; compound C10) and HOBt (74 mg) and EDCI (92 mg) in DMF (10 ml) according to the procedure described in example 46 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/ethanol, 100/0/to 95/5 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH:25]=[C:24](B(O)O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:6][N:7]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Brc1ccc(-c2ncccn2)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncccn3)cn2)CC1

Procedure:
Refluxed mixture of 2-(6-Bromo-pyridin-3-yl)-pyrimidine (1Q) (200 mg, 0.85 mmol), N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (290 mg, 0.93 mmol); Cesium Carbonate (500 mg, 1.538 mmol); PdCl2dppf (30 mg) in dioxane/H2O (10 ml v/v 4/1) for 4 hours. Cooled reaction, then evaporated solvent. Extracted with EtOAc (200 ml) washed with H2O (50 ml), dried over MgSO4, filtered and solvent evaporated yielding a solid which chromatographed on silica gel eluting with 30% v/v acetone/hexanes yielding 2Q as a white solid (110 mg, 38%) ESMS (MH, 339).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)[N:3]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl.O>[CH3:43][S:44]([N:17]1[CH2:16][CH2:15][N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:6]3[C:2]([CH3:1])=[N:3][C:4]([C:20]4[O:24][N:23]=[C:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=5)[N:21]=4)=[N:5]3)[CH:9]=2)[CH2:19][CH2:18]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCNCC2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCN(S(C)(=O)=O)CC2)c1
Temperature: 25 °C

Procedure:
To a solution of 5-(5-methyl-1-(3-(piperazin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 81; 110 mg, 0.23 mmol) and Et3N (70 mg, 0.69 mmol) in DCM (5 mL) at 0° C. was added methanesulfonyl chloride (34 mg, 0.30 mmol). The reaction mixture was allowed to warm to RT over 2 h, then diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by prep-HPLC (10% to 30% MeCN/H2O containing 0.1% trifluoroacetic acid) to give the title compound as an off-white solid; MS (ES+) C24H24F3N7O4S requires: 563. found: 564 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ 8.22 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.24 (m, 1H), 6.96 (m, 2H), 6.70 (d, J=7.5 Hz, 1H), 5.49 (s, 2H), 3.98 (m, 4H), 3.25 (m, 4H), 2.92 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:24]=[C:25]([O:32][CH3:33])[C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:27][N:28]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5CCC[C@@H]5C)C4)sc3c2)c(OC)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 19A for the product of Example 1E and substituting 2,6-dimethoxy-5-pyrimidineboronic acid for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (s, 1H) 7.91-8.03 (m, 2H) 7.55 (dd, J=8.44, 1.69 Hz, 1H) 4.06 (s, 3H) 4.05 (s, 3H) 3.55-3.70 (m, 1H) 3.15-3.29 (m, 1H) 3.02-3.14 (m, 1H) 2.72-2.88 (m, 1H) 2.60-2.71 (m, 1H) 2.43-2.56 (m, 3H) 2.30-2.40 (m, 1H) 1.91-2.02 (m, 1H) 1.79-1.88 (m, 1H) 1.66-1.77 (m, 1H) 1.44-1.55 (m, 1H) 1.16 (s, 3H). MS: (M+H)+=411.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]([CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)(C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Cl>C(O)C>[C:3]([NH:6][CH:7]([CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnccn1)(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cc1cnccn1)NC(C)=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
12 cm3 of 6N sodium hydroxide are added dropwise to a solution of 14 g of diethyl 2-acetylamino-2-(2-pyrazinylmethyl)malonate in 240 cm3 of ethanol and the mixture is then stirred at a temperature in the region of 20° C. After 1 hour, the reaction medium is neutralized with 6 cm3 of 12N hydrochloric acid. After stirring for 2 hours at a temperature in the region of 20° C., the reaction medium is filtered and the filtrates are then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is taken up in 200 cm3 of dioxane, refluxed for 2 hours and concentrated as above. 8.5 g of ethyl (2RS)-2-acetylamino-3-(2-pyrazinyl)propanoate are obtained in the form of a cream-coloured solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6 δ in ppm): 1.13 (t, J=7 Hz: 3H); 1.80 (s: 3H); 3.12 (dd, J=14 and 8.5 Hz: 1H); 3.22 (dd, J=14 and 6 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.71 (mt: 1H); 8.36 (d, J=8 Hz: 1H); 8.52 (d, J=2.5 Hz: 1H); from 8.55 to 8.65 (mt: 2H]).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[C:24]([Br:28])[C:25]=1[O:26][CH3:27])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[C:24]([Br:28])[C:25]=1[O:26][CH3:27])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1c(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)sc(-c2ccnn2C)c1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(=O)NC(CN)Cc2ccccc2)sc(-c2ccnn2C)c1Br
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part e) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:28][C:29]1[S:30][C:31]([Cl:34])=[CH:32][N:33]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[Cl:34][C:31]1[S:30][C:29]([NH:28][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:33][CH:32]=1
Reactant: Nc1ncc(Cl)s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(Cl)s2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (300 mg, 1.01 mmol) and dry N,N-dimethylformamide (2 drops) in methylene chloride (3 mL) was cooled to 0° C. and then treated dropwise with oxalyl chloride (115 μL, 1.32 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo. The resulting yellow oil was dissolved in a small amount of methylene chloride and then slowly added to a solution of 2-amino-5-chlorothiazole hydrochloride (259 mg, 1.52 mmol) and triethylamine (424 μL, 3.04 mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was then stirred at 25° C. for 15 h. The reaction mixture was then partitioned between water (50 mL) and ethyl acetate (50 mL), and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (50 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded the N-(5-chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide (106 mg, 25%) as a tan foam: mp 76-79° C. (foam to gel); EI-HRMS m/e calcd for C18H21ClN2O3S2 (M+) 412.0682, found 412.0683.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[CH:12]=[C:13]([NH2:20])[C:14]4[N:15]([N:17]=[N:18][N:19]=4)[N:16]=3)[CH2:7][S:8][C@H:3]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[Cl:38][CH2:39][C:40](=[O:45])[CH2:41][C:42](Cl)=[O:43].C(O)(C)C>CN(C)C=O.C(Cl)Cl>[NH2:20][C:13]1[C:14]2[N:15]([N:17]=[N:18][N:19]=2)[N:16]=[C:11]([S:10][CH2:9][C:6]2[CH2:7][S:8][C@@H:3]3[CH:2]([NH:1][C:42](=[O:43])[CH2:41][C:40](=[O:45])[CH2:39][Cl:38])[C:24](=[O:25])[N:4]3[C:5]=2[C:21]([OH:23])=[O:22])[CH:12]=1
Reactant: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)nn2nnnc12
Reactant: O=C(Cl)CC(=O)CCl
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Nc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC(=O)CCl)[C@H]3SC2)nn2nnnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
7-Amino-3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)thiomethyl]-3-cephem-4-carboxylic acid (3.8 g; 0.01 mole) was suspended in anhydrous N,N-dimethylformamide (50 ml) and N,O-bis(trimethylsilyl)acetamide (8.13 g; 0.04 mole) was added. After 2 hours of stirring at room temperature almost all the starting material was dissolved. A solution of 4-chloroacetoacetyl chloride (2.35 g; approximately 0.015 mole) in anhydrous methylene chloride (20 cc) was dropped into the cooled mixture (at -30° C.). The mixture was stirred at -30° C. for 2 hours and allowed to come to room temperature within an additional hour, after which time isopropanol (40 ml) was added, in order to decompose the silylated compounds. The solvents were evaporated under reduced pressure and the oily residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with aqueous sodium chloride solution, concentrated to a small volume under reduced pressure, and diethyl ether was added to complete the precipitation. The solid was collected by filtration, washed with fresh ether and dried under vacuum, thus giving 4.6 g of the title compound, which was used in the following step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:29][C:30](=[O:33])[NH:31][CH3:32])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:61])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([O:29][C:30](=[O:33])[NH:31][CH3:32])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:61])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-methylcarbamoyloxypropan IIIc1 is allowed to react and worked up by the same procedure as described in (5). The summary of the experimental condition and the physical data of the prodcut are listed in the Table 8.
Reaction SMILES: [C:1]([NH:6][NH:7][C:8]([NH2:10])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2].[N:11]([O-])=[O:12].[Na+].Cl>O.CO>[C:1]([N:6]([N:11]=[O:12])[NH:7][C:8]([NH2:10])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CCC(C)(C)NNC(N)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C)(C)N(N=O)NC(N)=O

Procedure:
1-tert-Pentyl semicarbazide (12 g) in a mixture of 50 ml of water and 25 ml of methanol is cooled in an ice bath and 5.6 g of sodium nitrite are added. Conc. hydrochloric acid is added dropwise to this solution until a pH of 4 to 5 is established.
Reaction SMILES: [N:1]([C@H:4]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C@@:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[F:15])([OH:7])[CH3:6])=[N+:2]=[N-:3].BrC1C=NC=C([C@@H]2[C@](C3C=C(F)C=CC=3F)(C)O2)C=1>>[N:1]([C@H:4]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C@:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[F:15])([OH:7])[CH3:6])=[N+:2]=[N-:3]
Reactant: C[C@@](O)(c1cc(F)ccc1F)[C@H](N=[N+]=[N-])c1cncc(Br)c1
Agent: C[C@]1(c2cc(F)ccc2F)O[C@@H]1c1cncc(Br)c1
Product: C[C@](O)(c1cc(F)ccc1F)[C@H](N=[N+]=[N-])c1cncc(Br)c1

Procedure:
Prepared according to the same procedure as (1R,2R)-1-azido-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol, starting with 3-bromo-5-((2R,3R)-3-(2,5-difluorophenyl)-3-methyloxiran-2-yl)pyridine 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=2.3 Hz, 1H), 8.32 (d, J=1.8 Hz, 1H), 7.86 (t, J=2.0 Hz, 1H), 7.20 (ddd, J=11.0, 9.0, 4.6 Hz, 1H), 7.15-7.02 (m, 2H), 6.38 (s, 1H), 5.08 (s, 1H), 1.72 (d, J=1.3 Hz, 3H). Mass spec.: 371.1 (MH)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(#N)C>[NH2:14][C:13]1[CH:15]=[CH:16][C:10]([S:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:6][CH2:5]2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Product: Nc1ccc(S(=O)(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
4-(Piperidin-4-ylsulfonyl)aniline (1.748 mmol, 420 mg), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.748 mmol, 589 mg) and potassium carbonate (3.50 mmol, 483 mg) were combined in acetonitrile (5 mL). Dimethylsulfoxide (0.5 mL) was added and the reaction stirred at room temperature for 1.5 hours. The reaction mixture was filtered and filtrate was concentrated under vacuum. The residue was purified by SCX chromatography to give the title compound (700 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44]O)=[CH:39][CH:38]=1)#[N:36].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:44][CH2:43][C:40]2[CH:41]=[CH:42][C:37]([C:35]#[N:36])=[CH:38][CH:39]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(OCCc2ccc(C#N)cc2)c1
Yield: 44.3 %

Procedure:
To a solution of t-butyloxycarbonylamino-3-hydroxybenzene (418.5 mg; 2 mmol; from step (i) above), triphenylphosphine (629.5 mg; 2.4 mmol) and 2-(4-cyanophenyl)ethanol (353.2 mg; 2.4 mmol) in THF (50 mL), under an atmosphere of nitrogen, was added diethylazodicarboxylate (518 mg; 3 mmol) and the mixture was stirred for one week. Ice cold water was added and the THF was removed by evaporation. The remaining water phase was extracted three times with EtOAc. The combined organic phase was washed twice with 0.2 M NaOH, once with brine, and then dried (Na2SO4). Evaporation followed by flash chromatography using a stepwise gradient of toluene:EtOAc (100:0, 90:10, 80:20 and 60:40) gave 300 mg (44%) of the sub-title compound.