Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[C@@H:10]1[CH2:14]CC[N:11]1[C:15](=[O:36])[CH2:16][CH2:17][C:18](=[O:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.[C:38]1(C[C@H](NC(OC(C)(C)C)=O)C(=O)CCC(O)=O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][O:8][C:9](=[O:37])[C@H:10]([CH2:14][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:11][C:15](=[O:36])[CH2:16][CH2:17][C:18](=[O:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 95 %

Procedure:
The experimental procedure employed for the synthesis of (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-proline benzyl ester was followed using the free acid compound 9 (98 mg, 0.3054 mmol, 1.0 eq.), L-phenylalanine methyl ester hydrochloride (55 mg, 0.3054 mmol, 1.0 eq.), 1-Hydroxybenzotriazole hydrate (HOBt) (42 mg, 0.3054 mmol, 1.0 eq.), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl) (59 mg, 0.3054 mmol, 1.0 eq.), iPr2NEt (0.11 mL, 0.6110 mmol, 2.0 eq.) and dry DMF/CH2Cl2 (2:8 ratio)(5 mL). Work-up as usual and column chromatography on silica gel elution with 33% EtOAc-hexane afforded the (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-phenylalanine methyl ester (NACE 119) as a pale viscous oil (0.140 g, 95%); Rf 0.35 (40% EtOAc-hexane); IR (liquid film) ν 1645 (CO) and 3170 (broad, NH) cm−1; 1H NMR (400 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 2.44 (2H, t, J=6.2 Hz, —CH2CO), 2.77 (2H, m, —CH2CO), 2.91 (1H, dd, J=6.6 and 13.2 Hz, —CHαPh), 3.00-3.15 (3H, m, —CHβPh and —CH2Ph), 3.71 (3H, s, OCH3), 4.49 (1H, m, —CH—), 4.84 (1H, m, —CH—), 5.07 (1H, d, J=7.0 Hz, —NH), 6.03 (1H, d, J=7.7 Hz, —NH) and 7.08-7.58 (10H, m, Ar—H); 13C NMR (100 MHz, CDCl3) δC 28.2, 29.3, 29.4, 37.8 (2C), 52.2, 53.2, 60.3, 64.8, 126.9 (2C), 127.0, 127.1, 128.4, 128.5, 128.6, 129.2, 129.3, 129.5, 135.8, 136.4, 158.3, 171.9, 172.0 and 206.7; EI-MS m/z calcd for C27H34N2O6 (M+) 482.2417, found 482 (M+).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][C@@H:18]([OH:28])[C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5](OC)=[O:6].O>C1COCC1>[OH:26][C@@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:20]([CH2:19][C@@H:18]([OH:28])[C@@H:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:29])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][OH:6])[CH2:25]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A suspension of LiA1H4 (0.15 g, 3 mols. equiv.) in dry THF (25 ml) was stirred under nitrogen whilst standing in an ice/methanol bath. Methyl chenodeoxycholate (5c) (0.5 g, 1.2 mmol) in dry THF (30 ml) was then added dropwise and the resultant mixture stirred at ambient temperature overnight. Water was then introduced carefully to the mixture until all the excess LiA1H4 had been destroyed. The resultant mixture was acidified with 2M HCl and extracted into EtOAc (3×). The combined organic extracts were washed with water (2×), dried and evaporated to give a white foam (0.47 g. 100%). Recrystallisation of 0.27 g from dichloromethane afforded pure 3α,7α,24-trihydroxy-50-cholane (7c)3 (0.16 g, 59%): m.p. 116°-118° C. [Lit. 9a 150° C.; also reported as an amorphous solid9b ]; 1H nmr (90 MHz; CDCl3 /DMSO d 6) δ0.64 (3H, s, 18-CH3), 0.88 (3H, s, 19-CH3), 2.9-3.2 (2H, s (exchanges on adding D2O], OH's, 3.1-3.6 (1H, m, 3β-H), 3.4-3.6 (2H, t[broadened), 24-CH2), 3.6-4.0 (1H, m[exchanges on adding D2O], OH), 3.7-3.9 (1H, m, 7β-H); IR (KBr) 3420 (OH's) cm-1 ; MS: Found m/z 378.3130; C24H42O3 (M) requires m/z 378.3134.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[CH2:7][NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([NH:16]C(=O)C(F)(F)F)[CH:12]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.[NH2:38][OH:39]>C(O)C.O.C(OCC)(=O)C>[NH2:16][C:13]1[CH:12]=[C:11]([C:9](=[N:38][OH:39])[NH:8][CH2:7][C:6]2[CH:23]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:24])[O:15][N:14]=1
Reactant: Cc1ccc(Cl)cc1CNC(=O)c1cc(NC(=O)C(F)(F)F)no1
Reactant: NO
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(Cl)cc1CNC(=NO)c1cc(N)no1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
N-(5-chloro-2-methylbenzyl)-3-[(trifluoroacetyl)amino]isoxazole-5-carboxamide (550 mg, 1.5 mmol) and phosphorus pentachloride (620 mg, 3.0 mmol) were weighed into a vial. Toluene (18 mL) was added and the vial was heated at 90° C. for 1.5 h. The solution was stripped to dryness and residue was dissolved in ethanol (14 mL) and 50% hydroxylamine in water (3.1 mL) was added. After stirring for 0.5 h, reaction was diluted with ethyl acetate and water. Aqueous layer was extracted with ethyl acetate once. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product (570 mg, 100%). LCMS calculated for C14H13ClF3N4O3(M+H)+: m/z=377.1.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16](=O)[CH2:17]Br)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.C(OCC)(=O)C>C1COCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[N:3]=[CH:1][S:2][CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Reactant: NC=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(-c2cscn2)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Freshly prepared thioformamide (Helv. Chim. Acta, 31, 2065, 1948) (160 mg) was added to a solution of α-bromoketone from Step 2 (200 mg) in THF (5 mL) and the reaction mixture was stirred at r.t. for 2 h. Ethyl acetate was then added and the organic phase was washed with saturated aqueous NH4Cl, H2O and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (65:35) afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]23[CH2:14][CH:13]2[CH2:12][O:11][C:10]3=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClCCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:10][OH:15])[CH2:14][CH:13]2[CH2:12][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1OCC2C[C@@]12c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC1C[C@]1(CO)c1ccc(Cl)c(Cl)c1
Yield: 917.2 %

Procedure:
BMS (17.16 mL, 18 mmol) was added to (1R)-1-(3,4-dichlorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (22 g, 9 mmol) in dry tetrahydrofuran (200 mL), under nitrogen atmosphere. The reaction mass was refluxed for 5 hours and monitored by TLC (dichloromethane (100%)). The reaction mass was quenched with 10% potassium carbonate solution. The aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 20.4 g (92%) of desired product. 1H NMR δ(300 MHz,CDCl3): 0.9-1.25 (1H,m), 1.35-1.52 (1H,m), 1.75-1.79 (1H,m), 3.32-3.42 (2H,m) 3.97-4.12 (2H,m) 7.26-7.30 (1H,dd,J=8.4,2.1 Hz), 7.40-7.43 (1H,d,J=8.4 Hz), 7.52-7.53 (1H,d,J=2 Hz).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[O:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:37][NH2:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:38][CH2:37][C:33]1[O:32][CH:36]=[CH:35][N:34]=1)=[O:4]
Reactant: NCc1ncco1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ncco1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 15.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), oxazol-2-ylmethanamine (6.82 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 35-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(oxazol-2-ylmethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (3.7 mg, 7.23 μmol, 15.60% yield): LCMS=512.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.28 Hz), 7.50-7.83 (9 H, m), 7.09 (1 H, s), 5.20 (1 H, s), 4.45-4.67 (2 H, m); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[C:24]([CH2:30][OH:31])[C:25]=2[O:26][CH2:27][O:28][CH3:29])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[C:24]([CH:30]=[O:31])[C:25]=2[O:26][CH2:27][O:28][CH3:29])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COCOc1c(CO)csc1-c1ccc(C(C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1c(C=O)csc1-c1ccc(C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Dimethyl sulfoxide (0.050 mL, 0.70 mmol) in dichloromethane (0.28 mL) was added to oxalyl chloride (0.049 mL, 0.56 mmol) in dichloromethane (2.8 mL) at −78° C., and after 10 minutes of stirring at −78° C., 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-hydroxymethylthiophene (87 mg, 0.28 mmol) in dichloromethane (0.93 mL) was added dropwise. After the addition, the reaction solution was stirred at −78° C. for 20 minutes and at −40 to −50° C. for 1 hour. Triethylamine (0.28 mL, 2.0 mmol) was added dropwise, and the reaction solution was stirred for another 20 minutes under cooling with ice. After addition of saturated aqueous ammonium chloride, the reaction solution was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the desired product as a brown oil (58 mg, yield 68%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH2:15][CH:16]1[CH2:18][CH2:17]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N(CC1CC1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from cyclopropylmethyl-(4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (85%). MS (ESI): m/z=359.152 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16](=O)[CH2:17][C:18](=O)[CH3:19])[C:10]2[CH:37]=[C:38]([CH3:45])[C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:47][OH:48].C([O-])(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([C:33]([F:35])([F:36])[F:34])[CH:24]=2)[C:16]2[O:48][N:47]=[C:18]([CH3:19])[CH:17]=2)[C:10]2[CH:37]=[C:38]([CH3:45])[C:39]([C:41]([F:44])([F:42])[F:43])=[CH:40][C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN(C(=O)OC(C)(C)C)c2cc(C(F)(F)F)c(C)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc(C(F)(F)F)c(C)cc32)on1
Yield: 16.8 %

Procedure:
To a solution of compound (S)-5-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (600 mg, 0.916 mmol) in methanol (5 mL) at 0° C., add hydroxylamine hydrochloride (96 mg, 1.37 mmol) and sodium acetate (3 mg, 0.046 mmol). Heat the reaction mixture under reflux for 4 h. Cool and remove the solvents under reduced pressure. Dilute the residue with ethyl acetate and brine. Separate the layers and dry the organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate (20:1 to 3:1) to afford the title compound as an off-white solid (100 mg, 17%). 1H NMR (CDCl3, 300 MHz) δ 1.10-2.10 (m, 16H), 2.21 (s, 3H), 2.54 (s, 3H), 4.22-4.83 (m, 3H), 6.89-6.92 (m, 1H), 7.36-7.89 (m, 4H); ESI MS m/z 652 [C30H30F9N3O3+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH:37]([F:39])[F:38])[C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:27][CH2:28][OH:29])[C:21]([NH:24]C=O)=[CH:22][CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.Cl.C(OCC)(=O)C>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH:37]([F:38])[F:39])[C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][N+:19]4[N:20]([CH2:27][CH2:28][OH:29])[C:21]([NH2:24])=[CH:22][CH:23]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=NOC(F)F)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccc(NC=O)n4CCO)CS[C@H]23)cs1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc(C(=NOC(F)F)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccc(N)n4CCO)CS[C@H]23)cs1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a suspension of 7β-[2-(2-aminothiazol-4-yl)-2(difluoromethoxyimino)acetamido]-3-[3-formamido-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (0.7 g) in methanol (3.5 ml) was added concentrated hydrochloric acid (0.42 ml) at ambient temperature. After being stirred at the same temperature for 2 hours, the mixture was poured into ethyl acetate. The resulting precipitate was collected by filtration. The precipitate was dissolved in water, and adjusted to pH 2 with 5% aqueous sodium bicarbonate solution. This solution was subjected to a column chromatography on macroporous non-ionic adsorption resin "Diaion HP20". The object compound was eluted with 10% diisopropyl alcohol, and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(difluoromethoxyimino)acetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (0.41 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](C#N)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrCC1C=C([N:42]2[CH:46]=[CH:45][CH:44]=[CH:43]2)C=CC=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:42]4[CH:46]=[CH:45][CH:44]=[CH:43]4)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Reactant: BrCc1cccc(-n2cccc2)c1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2cccc(-n3cccc3)c2)c1=O

Procedure:
Title compound 22 was prepared by the methods used in the preparation of compound 17, except that 1-(3-bromomethyl-phenyl)-1H-pyrrole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.59 (d, J=7.3 Hz, 1 H), 7.48 (t, J=7.7 Hz, 1 H), 7.24-7.36 (m, 4 H), 7.21 (t, J=7.6 Hz, 2 H), 7.02 (t, J=2.1 Hz, 2 H), 6.32 (t, J=2.0 Hz, 2 H), 5.42 (s, 1H), 5.11-5.20 (ABq, J=44.7, 15.9 Hz, 2 H), 5.06 (s, 2 H), 3.36 (m, 2 H), 2.98 (m, 1 H), 2.89 (m, 1 H), 2.70 (m, 1 H), 2.10 (m, 1 H), 1.88 (m, 1 H), 1.73-1.58 (m, 2H). MS (ES) [m+H] calc'd for C28H29N6O2, 481.2; found 481.2.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)nc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cn1
Temperature: 60 °C
Yield: 20.6 %

Procedure:
To a solution of methyl 2-[2-methyl-4-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.035 g; 0.080 mmol) in methanol (1 mL) was added a solution of sodium hydroxide 10 N (0.100 mL; 1 mmol) and the mixture was heated at 60° C. for 18 h. The volatiles were removed under reduced pressure and the residue was dissolved in water. The mixture was then acidified by adding 1N HCl until a precipitate was formed. The solid was filtered, washed with water and dried under reduced pressure. The crude product was suspended in a mixture of acetonitrile and methanol, filtered, washed with acetonitrile and dried under reduced pressure to furnish 0.007 g (20%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([NH2:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:12][C:8]([CH3:13])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([NH2:11])=[O:10]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C(N)=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C(N)=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-hydroxy-α,α-dimethyl-benzeneacetamide (Example 198b, 15.34 g) dissolved in DMF (150 mL) was treated with potassium carbonate (11.83 g) and benzyl bromide (10.18 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water (500 mL) and stirred for 30 min. The solid was filtered off and washed with water and dried in vacuo to afford the subtitle compound (19.45 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([NH2:23])([C:20]([NH2:22])=[O:21])[CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(OC)OC>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]1([C:20](=[O:21])[NH:22][C:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:23]1)[CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: NC(=O)C1(N)Cc2ccc(NC(=O)OCc3ccccc3)cc2C1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2c(c1)CC1(C2)N=C(c2ccccc2)NC1=O)OCc1ccccc1

Procedure:
A solution of (±)-benzyl[2-amino-2-(aminocarbonyl)-2,3-dihydro-1H-inden-5-yl]carbamate (described in Intermediate 1, 35.0 mg, 0.108 mmol) and (trimethoxymethyl)benzene (0.022 mL, 0.129 mmol) in toluene (5 mL) was heated at reflux for 7.5 h. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in DMSO (1 mL) and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=412 (M+1).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:4]=1)[NH2:2].[C:19](OC(OCC)OCC)(=O)C>>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([C:5]2[N:4]3[CH:19]=[N:2][N:1]=[C:3]3[CH:8]=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: NNc1ccnc(-c2cccc(C(F)(F)F)c2)n1
Product: FC(F)(F)c1cccc(-c2nccc3nncn23)c1

Procedure:
The general procedure of Example 1 is repeated: A solution of 0.300 g. of 4-hydrazino-2-[3-(trifluoromethyl)phenyl]pyrimidine and 1 ml. of diethoxymethyl acetate is stirred at room temperature for 24 hours. The mixture is diluted with an excess of petroleum ether and the precipitate which forms is collected after 20-30 minutes to give 0.182 g. of the product of the example; m.p. 145°-146° C. when recrystallized from chloroform/hexane.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3c(F)cccc3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [Li]CCCC.[Br-].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:12]=[CH:11]2.[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][CH2:47][C@@H:48]([S:57][CH2:58][C:59]1([CH2:62][C:63]([O:65][CH3:66])=[O:64])[CH2:61][CH2:60]1)[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=O)[CH:50]=1>CCCCCC.C1COCC1>[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][CH2:47][C@@H:48]([S:57][CH2:58][C:59]1([CH2:62][C:63]([O:65][CH3:66])=[O:64])[CH2:60][CH2:61]1)[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[CH:19][C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][C:17]([F:18])=[C:8]([F:7])[CH:9]=3)[N:14]=2)[CH:50]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(C=O)c2)CC1
Reactant: Fc1cc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2cc1F
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(C=Cc3ccc4cc(F)c(F)cc4n3)c2)CC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
At -78° C., 1.6M BuLi in hexane (700 μL) was added to a suspension of the phosphonium salt of Step 9 (646 mg, 1.1 equiv.) in 6 mL of anh. THF and the mixture was stirred at -10° C. for 10 min. At -78° C., a solution of the aldehyde of Step 8 (515 mg, 1.12 mmol) in 4 mL of THF was then added dropwise. The mixture was stirred at -78° C. for 30 min. and at -10° C. for 30 min. and was quenched with 25% aq. NH4OAc. The product was extracted in EtOAc, dried over Na2SO4, is and purified by flash chromotography on silica with EtOAc:toluene 2.5:97.5 and 5:95.