Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A slurry of 10% Pd/C (0.500 g) in EtOAc (10 mL) was added to a solution of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (I4) (3.24 g, 10.5 mmol) in EtOAc (90 mL) and the resulting suspension was stirred under a hydrogen atmosphere for 42 hours at room temperature. The catalyst was removed by filtration through Celite, washing with EtOAc (7×10 mL), then the filtrate was evaporated to dryness to give the title compound K3 as a pale pink solid (2.92 g, 99%); 1H NMR (400 MHz, d6-DMSO) δ 6.72-6.66 (m, 2H), 6.52-6.45 (m, 2H), 4.60 (s, 2H), 3.44-3.39 (m, 4H), 2.87-2.79 (m, 4H), 1.41 (s, 9H). LCMS-A: rt 4.40 min; m/z 278.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.I[CH:10]([CH3:12])[CH3:11]>CN(C=O)C>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH:10]([CH3:12])[CH3:11])[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a slurry of sodium hydride (95%, 0.58 g, 23 mmol) in DMF (20 mL) was added a solution of 4-Iodo-1H-pyrazole (2023A) (4.07 g, 21 mmol) in DMF (20 mL) and the resulting mixture was stirred at rt for 10 min. Then 2-iodopropane (2.52 mL, 25.2 mmol) was added dropwise and the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water (4 times), brine, dried and concentrated to give an oily residue which was chromatographed (SiO2, 10%-20% ethyl acetate/hexane) to give 4-Iodo-1-isopropyl-1H-pyrazole 2023B (3.27 g, 66%). HPLC-MS tR=1.66 min (UV254 nm); mass calculated for formula C6H9IN2 235.98, observed LCMS m/z 237.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40](O)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:50][CH2:49][CH:48]([OH:51])[CH2:47]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][C@@H:36]4[C@@H:38]([CH:37]4[C:40]([N:46]4[CH2:50][CH2:49][CH:48]([OH:51])[CH2:47]4)=[O:41])[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Reactant: OC1CCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)N3CCC(O)C3)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with pyrrolidin-3-ol (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C39H46Cl2N5O4 [(M+H)+] 718.2922, observed 718.2921.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:35])=[CH:22][CH:21]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1

Procedure:
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-phenylurea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding phenylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 476.5.
Reaction SMILES: ClC1C([C@@H](N2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)C2=O)C)=CC2C(=CC(F)=CC=2)N=1.FC1C=C(B(O)[OH:34])C=CC=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>CC#N.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([OH:23])(=[O:34])[C:21]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: C[C@@H](c1cc2ccc(F)cc2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 232.3 %

Procedure:
To a solution of (S)-2-(1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (150 mg, 423 μmol), 3-fluorophenylboronic acid (65 mg, 465 μmol) and sodium carbonate (90 mg, 846 μmol) in MeCN (8 mL) and water (2 mL) was purged with N2 followed by the addition of Pd(PPh3)4 (24 mg, 21 μmol) and the resulting mixture was stirred at 90° C. overnight. The reaction mixture was diluted with EtOAc washed with water, brine and dried over Na2SO4. Purification using preparatory TLC eluted with 100% EtOAc afforded 2-4(S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)carbamoyl)benzoic acid (120 mg, 66%). Mass Spectrum (ESI) m/e=433 (M+1). 24(S)-1-(7-Fluoro-2-(3-fluorophenyl)-quinolin-3-yl)ethyl)carbamoyl)benzoic acid was dissolved in EtOH (2 mL) and cond HCl (0.1 mL) was added. The resulting solution was heated to 80° C. for 4 h. Solvent was removed and satd NaHCO3 was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified via preparatory TLC using 3% MeOH/DCM saturated with NH3 gas to afford a white solid of 2-((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (85 mg, 49%). Mass Spectrum (ESI) m/e=415 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[OH:59][C@@H:60]([CH3:65])[CH2:61][C:62](O)=[O:63]>CN(C)C=O>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:62](=[O:63])[CH2:61][C@@H:60]([OH:59])[CH3:65])[C@@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@H](C)O)[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
5-{9-Isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (230 mg, 0.5 mmol), dicyclohexylcarbodiimide (160 mg, 0.77 mmol), 1-hydroxybenzotriazole (70 mg, 0.51 mmol), and (S)-3-hydroxybutyric acid (107 mg, 1.0 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred at 40° C. for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (131 mg, 48%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[N:7][CH:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:6]2[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][C@H:8]([CH3:16])[NH:7]2)=[CH:17][CH:18]=1
Reactant: CC(Cc1ccccc1)N=Cc1ccc(I)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(I)cc2)N1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a flask with the crude N-(4-iodobenzylidene)-1-phenylpropan-2-amine (1.17 g) was added trifluoromethanesulfonic acid (6.00 mL, 67805 μmol) and the reaction was heated to 120° C. and stirred 5 h under N2. The reaction was cooled to RT, poured into ice water (20 mL), and basisified with 5 N NaOH (15 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with saturated NaCl (20 mL), dried (MgSO4), and concentrated to give a yellow/brown oil. The residue was purified by ISCO (40 g SiO2, 0-100% EtOAc/hexane) to give (1R,3S)-1-(4-iodophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline as a brown oil.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=3)=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester Example 283, Step 2) and 4′-tert-butyl-biphenyl-4-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C([Sn](CCCC)(CCCC)[CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:30]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=Cc1cc(Br)cs1
Reactant: CCCCCCCCCCC=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC=Cc1csc(C=O)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxaldehyde (35.0), tetrakis(triphenylphosphine)palladium(0) (4.23 g), 2,6-di-t-butyl-4-methylphenol (a few milligrams) and dry toluene (150 ml) was added tri-n-butyl-1-dodecenylstannane (92.0 g), dropwise at room temperature, under nitrogen. The solution was heated under reflux for four hrs, with stirring. After cooling to room temperature, the solution was filtered through a bed of celite, and the filter cake was washed with ether. The filtrate was evaporated and the residue purified by flash chromatography (silica; 5% ethyl acetate-hexane). The appropriate fractions were collected and concentrated. The residue was distilled in a kugclrohr oven (170° C./0.3 mm mercury) to give 46.7 g (92%) of product, as an oil (ca. 4:1-trans:cis).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: OB(O)c1ccc(Cl)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(Cl)nc2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 6-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[C:8]([CH3:15])[C:7]([CH3:16])=[C:6]2O.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:6]1[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([CH3:15])[C:7]=1[CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2nc(C)c(C)c(O)c2c1
Product: COc1cc(OC)c2nc(C)c(C)c(Cl)c2c1

Procedure:
Prepared according to procedure S using 6,8-dimethoxy-2,3-dimethylquinolin-4-ol (1.0 g, 7.0 mmol) and POCl3 (5.0 mL, 53.6 mmol) to afford 4-chloro-6,8-dimethoxy-2,3-dimethylquinoline. Mass Spectrum (ESI) m/e=252.1 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:32])[C:7]([C:30]#[N:31])=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH2:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[N:20]([CH3:28])[N:19]=2)=[C:12]([Cl:29])[CH:11]=1)C.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:29][C:12]1[CH:11]=[C:10]([N:9]2[C:4](=[O:3])[NH:5][C:6](=[O:32])[C:7]([C:30]#[N:31])=[N:8]2)[CH:15]=[C:14]([Cl:16])[C:13]=1[CH2:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[N:20]([CH3:28])[N:19]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Cc2cc(C(C)C)c(=O)n(C)n2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Cc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(C)c1=O
Temperature: 120 °C
Yield: 51.3 %

Procedure:
A solution of (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (95) (190 mg, 0.38 mmol) in glacial acetic acid (4 mL) was treated with sodium acetate (158 mg, 1.15 mmol). The resulting mixture was heated to 120° C. for 3.5 h. The reaction was cooled to 25° C. and was then poured onto water (125 mL). The resulting orange mixture was extracted with ethyl acetate (150 mL). The combined organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, treated with Norite neutral decolorizing carbon, filtered through celite and washed with ethyl acetate. The filtrate was concentrated under vacuum. Purification by HPLC (10-90 acetonitrile/water with 0.1% trifluoroacetic acid over 30 min) afforded 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (96) (87.2 mg, 44%) as an off-white solid; ES-HRMS m/e calcd for C19H16Cl2N6O3 (M+H)+ 447.0734, found 447.0735. Exact Mass=446.0661; Molecular Weight=447.2838.
Reaction SMILES: [C:1]1([CH:11]([CH2:16][C:17](O)=[O:18])[CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>C(OC(C)C)(C)C>[C:1]1([CH:11]2[CH2:16][C:17](=[O:18])[O:14][C:13](=[O:15])[CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(CC(=O)O)c1cccc2ccccc12
Solvent: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2cccc3ccccc23)CC(=O)O1
Temperature: 25 °C

Procedure:
20 g of 3-(1-naphthyl) glutaric acid (0.0774 moles) prepared by the method described by Hey et al [J. Chem. Soc. 1949, 3177-81] were suspended in 400 mL of isopropyl ether. 36.5 mL of acetic anhydride (0.387 moles) were added and the suspension, well agitated, was heated under reflux for three hours. At the end of this time, the mixture was cooled to ambient temperature and the precipitate filtered off and washed well with isopropyl ether. After drying at 60° C. under vacuum, 13.9 g of the product were recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([OH:38])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].[CH3:39]OC>>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: COC
Reactant: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(O)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Product: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(OC)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Yield: 82 %

Procedure:
The product of step C was converted to the methyl ether derivative following the procedure of Example 54, step B. Purification by flash column chromatography (SiO2, 75:25 hexane/ethyl acetate) provided tert-butyl 8-((1-(ethoxycarbonyl)-1H-indol-5-yl)sulfonyl)-6-methoxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (25 mg, 82%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.30 (d, J=8.7 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.88 (dd, J=8.7, 1.8 Hz, 1H), 7.73 (d, J=3.6 Hz, 2H), 7.35 (s, 1H), 6.69 (d, J=3.6 Hz, 1H), 4.60-4.45 (m, 4H), 4.03 (s, 3H), 3.88-3.74 (m, 2H), 2.95-2.75 (m, 2H), 1.50 (s, 9H), 1.47 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[C:13]=3[CH2:12][C:11]2=[O:21])=[CH:7][CH:6]=1.Br[CH:25](Br)[CH3:26]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[C:13]=3[C:12]3([CH2:26][CH2:25]3)[C:11]2=[O:21])=[CH:22][CH:23]=1
Reactant: COc1ccc(CN2C(=O)Cc3c(C#N)cccc32)cc1
Reactant: CC(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C3(CC3)c3c(C#N)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
NaH (0.457 g, 19.0 mmol) was added to a solution of 1-(4-methoxybenzyl)-2-oxoindoline-4-carbonitrile (5.30 g, 19.0 mmol) in DMF (38 mL), and the resulting slurry was stirred at ambient temperature for 1 hour. Dibromoethane (3.94 g, 21.0 mmol) was then added to this mixture, and the mixture was stirred at room temperature for 1 hour. An additional equivalent of NaH (0.457 g, 19.0 mmol) was then added to the reaction mixture, and the reaction was stirred at 80° C. for 3 hours. The reaction mixture was concentrated and purified by column chromatography with a hexanes/ethyl acetate gradient +15% DCM. The mixed product fractions were recrystallized with DCM/hexanes to give 1′-(4-methoxybenzyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-4′-carbonitrile (5.00 g, 16.4 mmol, 86%). LCMS (APCI+) M+H+ 305 (100%); Rt=3.65 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[N+](C)=CCl.[Cl-].[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[O:24])[C:21]([OH:23])=O)[N:19]=1)=[O:13].[NH2:25][CH:26]1[C:47](=[O:48])[N:28]2[C:29]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:35])=[C:30]([Cl:33])[CH2:31][S:32][C@H:27]12>O1CCCC1.C[Si](CC(N)=O)(C)C.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[O:24])[C:21]([NH:25][CH:26]2[C:47](=[O:48])[N:28]3[C:29]([C:34]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=4)=[O:35])=[C:30]([Cl:33])[CH2:31][S:32][C@H:27]23)=[O:23])[N:19]=1)=[O:13]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=CNc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=C(Cl)CS[C@H]23)cs1
Yield: 18.1 %

Procedure:
N,N-Dimethylformamide (88 mg) and phosphorus oxychloride (184 mg) were mixed to prepare Vilsmeier reagent in a conventional manner, and the resultant Vilsmeier reagent was suspended in dry tetrahydrofuran (10 ml). To the suspension was added 2-(2-formamidothiazol-4-yl)glyoxylic acid (0.2 g) under ice-cooling with stirring, and the solution was stirred at the same temperature for 30 minutes to prepare the activated acid solution. 4-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (0.4 g) was dissolved in a solution of trimethylsilylacetamide (1.0 g) in ethyl acetate (100 ml). To the solution was added the activated acid solution obtained above all at once at -20° C., and the solution was stirred at -20° to -5° C. for 1.5 hours. After water and ethyl acetate (50 ml) were added to the resultant solution at -20° C., the insoluble substance was separated by filtration, washed with water and acetone in turn and then dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)glyoxyloylamino]-3-chloro-3-cephem-4-carboxylate (0.1 g).
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](Br)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
D-Leucine (9.9 g, 75.2 mmol) was dissolved in 3.0 M of HBr in water (120 mL) and cooled to 0° C. A solution of NaNO2 (8.3 g, 120 mmol) in water (20 mL, 100 mmol) was added. The reaction was stirred at 0° C. for 2.5 hours and then extracted twice with EtOAc, washed twice with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to afford 12.6 g of intermediate (5a) as a pale yellow oil. This was taken on to the next step without further purification. 1H-NMR (DMSO): 4.31 (1H, t), 1.75 (2H, m) 1.65 (1H, m) 0.82 (6H, dd).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:12]1[C:13]2[N:14]([N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)[C:15]([CH2:18][O:19][CH3:20])=[CH:16][CH:17]=1)[CH2:10][CH3:11].O>CS(C)=O>[CH3:20][O:19][CH2:18][C:15]1[N:14]2[N:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=[C:13]2[C:12]([C:9](=[O:8])[CH2:10][CH3:11])=[CH:17][CH:16]=1
Reactant: CCC(O)c1ccc(COC)n2nc(C(F)(F)F)cc12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)c1ccc(COC)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Yield: 96.8 %

Procedure:
Triethylamine (7.56 mL) was added to a solution of the compound of Example 328 (1.55 g) in dimethylsulfoxide (60 mL). While the solution was stirred at room temperature, sulfur trioxide-pyridine complex (4.28 g) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, water (300 mL) was added. The resulting crystals were collected by filtration and thoroughly dried to afford the title compound as a colorless powder (1.49 g).