Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1.Cl[C:34]1[N:39]=[CH:38][C:37]([CH2:40][CH2:41][CH3:42])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:31][C:2]([F:32])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]([C:34]1[N:39]=[CH:38][C:37]([CH2:40][CH2:41][CH3:42])=[CH:36][N:35]=1)[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCCc1cnc(Cl)nc1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCc1cnc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2C(F)(F)F)nc1

Procedure:
Condensation of methyl 2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (250 mg; 0.54 mmol) with 2-chloro-5-propyl-pyrimidine (85 mg; 0.54 mmol) as per general procedure E (1.25 eq. K2CO3, dioxane, 220C, 15 hr) was accompanied by partial ester hydrolysis and afforded the title compound in low yield. For ease of purification, the carboxylic acid was converted to its methyl ester derivative (using a standard trimethylsilyldiazomethane/MeOH protocol), chromatographed and subjected to the base-mediated hydrolysis procedure H to afford the title compound in 17% yield (29 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C(O)C1

Procedure:
1.50 g (5.65 mmol) 4,6-Dihydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XLII), 840 mg (6.22 mmol) (bromomethyl)cyclopropane and 1.60 g (11.3 mmol) K2CO3 in 10 mL DMF are stirred at 80° C. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is concentrated by evaporation and the residue is purified by HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:16]=2)[N:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>C1COCC1.C(Cl)Cl>[C:42]([O:41][C:40]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:16]=2)[N:3]=1)=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1OCCCCl
Reactant: CC(C)(C)OC(=O)NCCCCCCCCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2nc(NCCCCCCCCNC(=O)OC(C)(C)C)nc(OCC(F)(F)F)n2)cc1OCCCCl
Reaction time: 16 h
Yield: 71.4 %

Procedure:
To a solution of methyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-(3-chloropropoxy)benzoate (200 mg, 0.439 mmol) in THF (2 mL) was added tert-butyl (8-aminooctyl)carbamate (118 mg, 0.483 mmol) and Hunig'sBase (230 μl, 1.318 mmol). The resulting mixture was stirred for 16 h. The mixture was diluted with DCM and washed with water, then brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography using a gradient of 20-40% EtOAc/hexanes. The product fractions were collected and the solvent removed under vacuum to give 208 mg (96%) methyl 4-(4-(8-(tert-butoxycarbonylamino)octylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-2-(3-chloropropoxy)benzoate.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:12])[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][CH2:18][Cl:19])=[O:15]>>[C:14](=[O:15])([O:12][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][Cl:11])[O:16][CH2:17][CH2:18][Cl:19]
Reactant: O=C(Cl)OCCCl
Reactant: OC(CCl)COc1ccccc1
Product: O=C(OCCCl)OC(CCl)COc1ccccc1

Procedure:
By reacting 3-phenoxy-1-chloro-2-propanol with 2-chloroethyl chloroformate according to conventional chloroformate ester reaction procedures, 2-chloroethyl 3-phenoxy-1-chloro-2-propyl carbonate is obtained. When the latter compound is heated in the presence of a phosphonium or ammonium salt catalyst as shown in the foregoing examples, phenyl glycidyl ether is produced as the principal epoxide product.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O:3]C)=[O:2].[OH-].[Na+]>CC(C)=O.O>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]1[C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([OH:3])=[O:2]
Reactant: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)O)N2C(=O)c1ccccc1
Yield: 93.1 %

Procedure:
To a solution of 7.02 g of benzyl α-(3ξ-carbomethoxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 85 ml of acetone and 26.5 ml of water is added 20 ml of 1.012 N aqueous solution of sodium hydroxide at -3° to -4° C. over a period of an hour and the mixture diluted with water and washed with ethyl acetate. The aqueous layer is separated, adjusted to pH 2.0 with 4 N hydrochloric acid, and then extracted with ethyl acetate. The extract is washed with water, dried on sodium sulfate, and concentrated under reduced pressure to yield 6.34 g of benzyl α-(3ξ-carboxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as foamy material.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([O:17]C)[CH:11]=2)[CH:3]=1.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([F:16])=[CH:14][NH:13][C:12](=[O:17])[CH:11]=2)[CH:3]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C#N)c(F)cn1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1F

Procedure:
210 mg (0.77 mmol) of 4-chloro-2-(5-fluoro-2-methoxypyridin-4-yl)benzonitrile and pyridinium hydrochloride were reacted according to General Method 3A. Yield: 126 mg (66% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:21])[C:7]3[C:8]([CH:19]=[CH:20][C:4]=2[CH:3]=1)=[N:9][CH:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:12]=3.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:21]=[C:6]1[C:7]2[C:8](=[N:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=2)[CH:19]=[CH:20][C:4]2[CH:3]=[C:2]([NH:1][C:25](=[O:26])[O:27][CH2:28][CH3:29])[CH:23]=[CH:22][C:5]1=2
Reactant: Nc1ccc2c(=O)c3cc(-c4ccccc4)cnc3ccc2c1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(=O)c3cc(-c4ccccc4)cnc3ccc2c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a 0° C. solution of 8-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.4 mg, 0.021 mmol) in pyridine (0.3 mL) was added a catalytic amount of 4-dimethylaminopyridine (tip of the spatula) and ethyl chloroformate (0.1 mL, 0.31 M in CH2Cl2) The mixture was then stirred at room temperature. After 7 hours, more ethyl chloroformate (3 μL, 0.032 mmol) was added. After stirring for 14 hours, a new addition of ethyl chloroformate (6 μL, 0.064 mmol) was followed by stirring for 2 more hours.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C@@H:13]2[C@@H:20]3[C@@H:16]([CH2:17][NH:18][CH2:19]3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30](=O)([O:38]C1C=CC([N+]([O-])=O)=CC=1)[O:31][CH2:32][C:33]1[N:34]=[CH:35][S:36][CH:37]=1.C1CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C@@H:13]2[C@@H:20]3[C@@H:16]([CH2:17][N:18]([C:30]([O:31][CH2:32][C:33]4[N:34]=[CH:35][S:36][CH:37]=4)=[O:38])[CH2:19]3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(O[C@H]2CC[C@@H]3CNC[C@@H]32)c2ccccc12
Reactant: O=C(OCc1cscn1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1cscn1)N1C[C@H]2CC[C@H](Oc3ccc(Cl)c4ccccc34)[C@H]2C1
Yield: 18.9 %

Procedure:
The process is performed according to the procedure described in Example 1, step 1.3. Starting with 0.059 g (0.21 mmol) of (3aR,4S,6aS)-4-[(4-chloro-1-naphthyl)oxy]-octahydrocyclopenta[c]pyrrole, obtained in step 13.3., 0.04 mL (0.25 mmol) of N,N-diisopropylethylamine and 0.066 g (0.23 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate (WO 2008/013 834), and after chromatography on silica gel, eluting with a 95/5 and then 90/10 mixture of cyclohexane and ethyl acetate, 0.017 g (19%) of expected product is obtained in the form of an oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:29]1[C:30]([CH:38]([CH3:40])[CH3:39])=[CH:31][C:32]2[N:33]([N:35]=[CH:36][N:37]=2)[N:34]=1>O1CCCC1>[C:22]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:29]3[C:30]([CH:38]([CH3:40])[CH3:39])=[CH:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[N:34]=3)[CH2:14][CH2:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)c1cc2ncnn2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2ncnn2nc1OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 50.9 %

Procedure:
160 mg of 60% sodium hydride in oil was suspended in 20 ml of tetrahydrofuran; 1.20 g of 4-(diphenylmethyl)-1-[2-(2-hydroxyethoxy)ethyl]piperazine was added, followed by heating and refluxing for 1 hour. After cooling, 610 mg of 6-chloro-7-isopropyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 1 hour. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 790 mg of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:12][C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2].ClC1C=C(C(OO)=[O:37])C=CC=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]([S:12]([C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:37])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-[3-(3-formyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.0034 mol) and 3-Chloro-benzenecarboperoxoic acid (also known as MCPBA or meta-chloroperbenzoic acid) (0.7 g; 75%) in CHCl3 (q.s.) was stirred for 4 hours at room temperature. Then a NaHCO3 solution was added, and the reaction mixture was stirred. The organic layer was separated, dried, and filtered, and the solvent was evaporated. The residue was purified by column chromatography over Biotage (gradient eluent: CH2Cl2:CH3OH). The purest product fractions were collected, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[C@H:22]([NH:30][C:31]2[C:36]([NH2:37])=[CH:35][N:34]=[C:33]([N:38]3[C:42]4[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:41]=4[N:40]=[CH:39]3)[N:32]=2)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:53](N2C=NC=C2)=[O:54])C=1>C1COCC1>[Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[C@H:22]([N:30]2[C:53](=[O:54])[NH:37][C:36]3[C:31]2=[N:32][C:33]([N:38]2[C:42]4[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:41]=4[N:40]=[CH:39]2)=[N:34][CH:35]=3)[CH2:21][CH2:20]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2N)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
N4-((1R,4R)-4-(tert-butyldiphenylsilyloxy)-7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)pyrimidine-4,5-diamine (490 mg, 0.751 mmol, 1 equiv) was dissolved in anhydrous THF (15 mL) and CDI (737 mg, 4.54 mmol, 7 equiv) was added. The reaction was stirred at RT under argon overnight. The solvent was removed by evaporation. The residue was dissolved in EtOAc (30 mL) and washed with saturated NaHCO3, water and brine, dried (Na2SO4). The organic layer was evaporated to dryness. The residue was applied to ISCO (12 g column, MeOH—CH2Cl2 0-2%) to give a white solid product (420 mg, 82%). MS (ESI): 673.3
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:33][CH:30]1[CH2:32][CH2:31]1)=[O:6]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: NC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: Nc1c(Br)cccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a heterogenous mixture of 2-amino-3-bromobenzoic acid (Sigma-Aldrich; 8.00 g, 37.0 mmol) in EtOAc (80 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride (T3P) (Alfa-Aesar; 50 wt. % solution in EtOAc, 24.00 mL, 40.7 mmol) followed by cyclopropylamine (2.57 mL, 37.0 mmol). The ice bath was removed and the reaction was stirred at RT for 1 h. Saturated NaHCO3 (aq.) was added and the mixture was stirred for 5 minutes. The layers were separated and the organic layer was washed with saturated NaHCO3 (aq.) and brine. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford 2-amino-3-bromo-N-cyclopropylbenzamide (723a; 6.00 g, 23.52 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (dd, J=7.82, 1.37 Hz, 1H), 7.20 (dd, J=7.92, 1.27 Hz, 1H), 6.50 (t, J=7.82 Hz, 1H), 6.13 (br. s., 2H), 2.85 (tq, J=7.02, 3.54 Hz, 1H), 0.83-0.91 (m, 2H), 0.57-0.64 (m, 2H). m/z (ES, +ve) 255.1, 257.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCOC3)c2n1
Yield: 66.5 %

Procedure:
A solution of 2-butyloxy-8-methoxy-9-[2-(tetrahydro-3-furanyl)ethyl]-9H-purin-6-amine (102 mg) in methanol (1 mL) was treated with 4N HCl in 1,4-dioxane (0.5 mL) for 1.5 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried to give the title compound (65 mg).
Reaction SMILES: N1C=CC=CC=1.C(N(CC)CC)C.[C:14]([O:18][C:19]([N:21]1[CH2:29][C:28]2[C:27]([O:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[N:36]([C:40](=[O:52])[NH:41][C:42]3[CH:46]=[C:45]([C:47]5([CH2:50][OH:51])[CH2:49][CH2:48]5)[O:44][N:43]=3)[CH:35]=[CH:34]4)=[N:26][CH:25]=[N:24][C:23]=2[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.CS(C)=O>[C:14]([O:18][C:19]([N:21]1[CH2:29][C:28]2[C:27]([O:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[N:36]([C:40](=[O:52])[NH:41][C:42]3[CH:46]=[C:45]([C:47]5([CH:50]=[O:51])[CH2:48][CH2:49]5)[O:44][N:43]=3)[CH:35]=[CH:34]4)=[N:26][CH:25]=[N:24][C:23]=2[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cc(C5(CO)CC5)on4)c3)c2C1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cc(C5(C=O)CC5)on4)c3)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of SO3.pyridine (0.992 g, 6.23 mmol), triethylamine (1.086 mL, 7.79 mmol) and DMSO (1.11 mL, 15.6 mmol) at 0° C., 4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (0.83 g, 1.559 mmol) in DCM (5 mL) and DMSO (1 mL) is added. The reaction is stirred at 0° C. for 2 h. After the reaction is complete, it is quenched with NH4CL, extracted, and evaporated. 4-{1-[5-(1-Formyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester is then obtained using FCC and eluting with 100:0 heptane:EtOAc to 0:100 Heptane:EtOAc. MS (ESI) m/z 531.0 (M+1).
Reaction SMILES: FC(F)(F)S(O[C@@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CCOC(C)=O>[N:17]([C@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])=[N+:18]=[N-:19]
Reactant: CC1(C)COC(=O)[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)COC(=O)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (10 g) in DCM (10 mL) was added tetra-n-butylammonium azide (11.1 g). The reaction mixture was stirred at rt for 16 hr. The reaction was diluted with EtOAc, washed with water, sat. NaHCO3, citric acid, water, and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 3.87-4.02 (3H, m), 1.17 (3H, s), 1.02 (3H, s).
Reaction SMILES: C(OCC[N:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:12]1)C1C=CC=CC=1.[C:22](O)(=[O:24])[CH3:23]>C1COCC1.[Pd]>[C:16]1([C:13]2[CH:14]=[C:15]([CH2:23][CH2:22][OH:24])[NH:11][N:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)O
Reactant: c1ccc(COCCn2ccc(-c3ccccc3)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCCc1cc(-c2ccccc2)n[nH]1
Reaction time: 96 h

Procedure:
5-(2-(Benzyloxy)ethyl-3-phenyl-1H-pyrazole (2.1 g, 7.54 mmol) was dissolved in acetic acid (10 mL) and THF (10 mL). Palladium on carbon (0.080 g, 0.754 mmol) was added and the reaction was stirred for 4 days under hydrogen atmosphere on the Parr shaker at 55 psi. After this time, the reaction was filtered through celite and washed with EtOAc. The solvents were evaporated. The reaction progress was checked by TLC and shown to be ˜50-60% complete. The reaction was set up on the Parr shaker again. After three more days on the Parr shaker, the reaction was stopped. The reaction was filtered through celite and the solvents removed. The reaction was extracted (70 mL each of H2O and EtOAc). The aqueous layer was extracted again with EtOAc (70 mL). The combined organic layer was dried and concentrated, and the residue was purified by column chromatography to give the title compound (665 mg) as a white solid. LCMS m/z=189.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.68-2.82 (m, 2H), 3.60-3.71 (m, 2H), 4.73-4.81 (m, 1H), 6.48 (s, 1H), 7.20-7.49 (m, 3H), 7.55-7.96 (m, 2H), 12.53 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([OH:27])=O)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:63][CH2:64][CH2:65][OH:66]>CN(C=O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:30])([F:31])[F:29])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:63][CH2:64][CH2:65][OH:66])=[O:27])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NCCO
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCO)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1-naphthoic acid (Preparation 7, 1 g, 2.1 mmol) in DMF (35 mL) was added HATU (970 mg, 2.5 mmol) and triethylamine (1.0 mL, 7.0 mmol). The reaction was stirred at room temperature for 15 minutes then treated with 2-amino-ethanol (145 mg, 2.4 mmol). The reaction was stirred at room temperature for 2 hours. Next, the reaction was diluted with 0.1N NaOH and extracted with EtOAc (2×150 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (80 g Redi-Sep column) eluting from 100% heptane to 40:60 EtOAc:heptane to afford the intermediate (734 mg, 67%) as a solid. 1HNMR (CDCl3) δ ppm: 8.82 (1H), 8.33 (1H), 7.76-7.60 (5H), 7.50 (1H), 6.51 (1H) 4.28 (1H), 3.94-3.83 (3H), 3.76 (2H), 2.35 (1H); m/z (Cl) 515 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([OH:7])=O.[NH2:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][O:24][C:25](=[O:33])[NH:26]C(=O)C(Cl)(Cl)Cl)[CH2:21][S:22][C@H:17]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([NH:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][O:24][C:25](=[O:33])[NH2:26])[CH2:21][S:22][C@H:17]12)=[O:7]
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Reactant: NC1C(=O)N2C(C(=O)O)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1cccc(O)c1
Yield: 19.8 %

Procedure:
2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.1 g.) and 7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (2.35 g.) were reacted and post-treated according to a similar manner to that of Example 3 to give 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g.). This compound is identified with the compound obtained in Example 2 by I.R. and N.M.R. spectra.