Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][CH2:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([O:17]CC)=O)[CH:13]=2)=[N:6][CH:7]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>Cl>[CH:31]1([NH:34][C:15](=[O:17])[CH2:14][N:12]2[CH:13]=[C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:20][CH2:21][C:22]4[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=4[F:30])[C:2]([F:1])=[CH:7][N:6]=3)[CH:10]=[N:11]2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)Cn1cc(Nc2ncc(F)c(NCc3c(F)cc(F)cc3F)n2)cn1
Reactant: NC1CC1
Agent: Cl
Product: O=C(Cn1cc(Nc2ncc(F)c(NCc3c(F)cc(F)cc3F)n2)cn1)NC1CC1
Temperature: 140 °C

Procedure:
Ethyl 2-(4-((5-fluoro-4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetate I-54 (97 mg, 0.23 mmol, prepared by Procedure B), cyclopropylamine (0.5 mL, 7.2 mmol) and conc. hydrochloric acid (2 drops) were mixed in a vessel and then heated in a microwave reactor at 140° C. for 30 min. The resulting precipitate was collected, triturated in ethyl acetate, filtered, washed with ether and methanol to afford N-cyclopropyl-2-(4-((5-fluoro-4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide I-4 (24 mg, 0.05 mmol) as a white solid. LC-MS (Method B), RT=5.88 min. (ES+) 436.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: O=C1NCc2ccccc21
Reactant: Fc1ccc(CBr)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-2,4-difluoro-benzene (0.248 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.11 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2,4-difluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.199 g, 77%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.34 (s, 2H), 4.84 (s, 2H), 6.85 (m, 2H), 7.35-7.54 (m, 4H), 7.86 (d, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:11]([C:12]#[N:13])=[C:10]([CH2:18][CH3:19])[CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH2:18][CH3:19])[C:11]([CH2:12][NH2:13])=[C:14]([CH2:16][CH3:17])[CH:15]=1
Reactant: CCc1cc(Br)cc(CC)c1C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(Br)cc(CC)c1CN
Temperature: 0 °C
Reaction time: 20 h
Yield: 5.4 %

Procedure:
Under an inert atmosphere, lithium aluminum hydride (359 mg, 9.4 mmol) was suspended in anhydrous THF (9 mL) was cooled to 0° C. and then a solution of 4-bromo-2,6-diethylbenzonitrile (1.73 g, 7.36 mmol) in anhydrous THF (3 mL) was added dropwise. The reaction mixture was then allowed to warm to ambient temperature and stirring was continued for 20 h. Sodium sulfate decahydrate (6 g) was then added to quench the reaction and the resultant reaction mixture was filtered then the filtrate was then evaporated under reduced pressure. The resultant oil was purified by flash chromatography (silica, 50 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as an orange oil (96 mg, 5%). 1H NMR (DMSO-D6, 400 MHz): 7.18 (s, 2H), 3.68 (s, 2H), 2.73-2.64 (m, 4H), 2.52-2.48 (m, 2H), 1.19-1.11 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH:12]([CH3:14])[CH3:13].[H][H]>[Ni].CO>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:11][CH:12]([CH3:14])[CH3:13]
Reactant: [H][H]
Reactant: CC(C)Sc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)Sc1c(N)cccc1Cl
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
40 g of 2-chloro-6-nitrophenyl-isopropylsulfane, 160 g of methanol and 2.4 g of Raney nickel 37-1 (methanol-moist) were initially introduced into a 0.7 l steel autoclave. After rinsing with nitrogen, 70 bar of hydrogen were forced in and the contents of the autoclave were heated to 100° C., while stirring. The hydrogen pressure was increased to 80 bar. After 50 minutes, the uptake of hydrogen had ended. The mixture was kept under the reaction conditions for a further 30 minutes. After cooling, letting down the hydrogen and removing the catalyst, the solvent was distilled off. Crude 2-amino-6-chlorophenyl-isopropylsulfane was already obtained as a 99% pure product (GC) which contained only 0.2% of 2-aminophenyl-isopropylsulfane (formed by dechlorination) and only 0.3% of m-chloroaniline (formed by desulfurization). The yield was 34.5 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2CCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
To methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in DMF (6 ml) were added potassium carbonate (415 mg, 3.00 mmol) and 4-fluorobenzyl bromide (0.206 ml, 1.65 mmol), and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 ml) was added to the residue and the resulting mixture was washed with water (5 ml×3) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 15 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure to obtain methyl 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (485 mg, 1.49 mmol, 99%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1.Br[C:40]1[CH:41]=[N:42][C:43]([CH3:46])=[N:44][CH:45]=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([C:40]4[CH:41]=[N:42][C:43]([CH3:46])=[N:44][CH:45]=4)=[CH:22][CH:23]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1
Reactant: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)C(=O)O2)o1
Reactant: Cc1ncc(Br)cn1
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CCc4nnc(C)o4)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-2-methylpyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.035 min, m/z=484.1; 1H NMR (CD3OD) 1.57 (m, 3H), 2.29 (m, 2H), 2.38 (m, 1H), 2.41 (s, 3H), 2.47 (m, 1H), 2.50 (m, 1H), 2.63 (m, 1H), 2.72 (s, 3H), 2.96 (m, 1H), 3.15 (m, 1H), 5.58 (m, 1H), 7.12 (m, 2H), 7.33 (m, 3H), 7.38 (m, 2H), 7.47 (m, 2H), 8.88 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[C:29]([F:30])=[CH:28][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH3:27])=[O:8])=[C:5]([F:31])[C:4]=1[N+:32]([O-])=O)#[N:2].[H][H]>CO.[Pd]>[NH2:32][C:4]1[C:5]([F:31])=[C:6]([CH:28]=[C:29]([F:30])[C:3]=1[C:1]#[N:2])[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])=[CH:12][C:11]=1[CH3:27])=[O:8]
Reactant: [H][H]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(C#N)c([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(C#N)c(N)c1F
Yield: 16.9 %

Procedure:
A solution of 4-cyano-2,5-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (5.99 g, 12 mmol) (Example I16) in methanol was reacted with hydrogen for 16 hours in the presence of 10% palladium on carbon (40 bar, 40° C.). The reaction mixture was filtered to remove the catalyst and the filtrate concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give 3-amino-4-cyano-2,5-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.953 g, 17% yield). 1H-NMR (400 MHz, CDCl3): 2.36 (6H, s), 4.82 (2H, bs), 7.12 (1H, m), 7.38 (2H, s), 7.78 (1H, d) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:12])[C:4]=2[N:3]=1.[I:13]N1C(=O)CCC1=O>C(#N)C>[I:13][C:8]1[C:9]2[CH:10]=[CH:11][C:2]([CH3:1])=[N:3][C:4]=2[C:5](=[O:12])[NH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc2cc[nH]c(=O)c2n1
Solvent: CC#N
Product: Cc1ccc2c(I)c[nH]c(=O)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
2-Methyl-7H-[1,7]naphthyridin-8-one (10.0 g, 62.4 mmol) was suspended in 300 ml acetonitrile and N-iodosuccinimide (16.9 g, 74.9 mmol) was added. The suspension was stirred for 3 hours at reflux. The reaction mixture was cooled to room temperature and filtered. The solid was washed with acetonitrile and dried for 30 minutes at 50° C. and <20 mbar, to get the desired compound as a brown solid (14.3 g, 80%), MS: m/e=287.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=1)[CH2:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=1)[CH2:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CO)cc1)Cc1ncccc1O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc(C=O)cc1)Cc1ncccc1O
Yield: 82.4 %

Procedure:
A solution of (4-hydroxymethyl-benzyl)-(3-hydroxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (0.99 g, 2.9 mmol) in CH2Cl2 (14 mL) was stirred at room temperature with a suspension of 85% MnO2 (3.0 g, 29 mmol) for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give orange crystals (818 mg, 83%). 1H NMR (CDCl3) □ 1.44 (s, 9H), 4.54 (s, 2H), 4.61 (s, 2H), 7.17 (dd, 1H, J=8.1, 4.5 Hz), 7.26 (dd, 1H, J=8.1, 1.5 Hz), 7.37 (d, 2H, J=8.1 Hz), 7.84 (d, 2H, J=8.1 Hz), 8.03 (dd, 1H, J=4.5, 1.2 Hz), 9.55 (s, 1H), 10.00 (s, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].C(=O)=O.CC(C)=O>C(OCC)C.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([F:14])[CH:9]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cc(Br)ccc1Br
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: C[Si](C)(C)c1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A solution of n-butyllithium (n-BuLi, 2.5 Molar (M) in hexanes; 900 microliters (μL), 2.2 millimoles (mmol), 1.1 equivalents (equiv)) was added to a stirred solution of 1,4-dibromo-2-fluorobenzene (500 milligrams (mg), 2.0 mmol, 1.0 equiv) in diethyl ether (Et2O; 10 milliliters (mL)) at −78° C. The resulting pale yellow solution was stirred at −78° C. for 2 hours (h). Chlorotrimethylsilane (TMSCl; 300 μL, 2.4 mmol, 1.2 equiv) was added, and the resulting pale yellow solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and was stirred for 72 h. The reaction mixture was diluted with water (H2O; 50 mL) and was extracted with dichloromethane (CH2Cl2; 3×50 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a pale yellow oil (350 mg, 71%): IR (thin film) 3068 (w), 2955 (m), 2927 (m), 2855 (w), 1598 (w), 1567 (w) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.38-7.49 (m, 3H), 0.30 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.Cl.[C:18]([NH2:26])(=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]1[N:25]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:26][CH:2]=1
Reactant: N=C(N)c1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1-c1c[nH]c(-c2ccccc2)n1
Yield: 92 %

Procedure:
As described for Example 57, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (1.0 g, 4 mmol) using benzamidine HCl instead of acetamidine HCl was converted to the title compound (992 mg, 92%) which was obtained as a white solid. MS: m/e=302.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:22]COC)=[C:6]([O:20][CH3:21])[CH:7]=[C:8]2/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2].Cl.O>C(O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:22])=[C:6]([O:20][CH3:21])[CH:7]=[C:8]2/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C=C/c1cc(OC)c(O)c2c(CC)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 1.3 g of ethyl (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)propenoate in ethanol (10 ml) was added 1 ml of concentrated hydrochloric acid and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation, hexane was added for crystallization to obtain 0.76 g of the titled compound as pale yellow crystals.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CBr
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC(C)C)c2)n1

Procedure:
Using the compound obtained in Example 97 and isobutyl bromide, colorless oily N-[2-(4-difluoromethoxy-3-isobutoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([Mg]Br)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:2].BrC1C=CC(C2C=CC=CC=2)=C(C=C)C=1.[Mg].[O:33]=[C:34]1[CH2:38][N:37]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[C@H:36]([C:48]([O:50][CH3:51])=[O:49])[CH2:35]1>C1COCC1.C1(C)C=CC=CC=1>[OH:33][C@:34]1([C:7]2[CH:6]=[CH:5][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:3]([CH:1]=[CH2:2])[CH:8]=2)[CH2:38][N:37]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:47])[CH3:45])=[O:40])[C@H:36]([C:48]([O:50][CH3:51])=[O:49])[CH2:35]1
Reactant: C=Cc1cc([Mg]Br)ccc1-c1ccccc1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Agent: C=Cc1cc(Br)ccc1-c1ccccc1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1cc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 18.2 %

Procedure:
(2-vinylbiphenyl-4-yl)magnesium bromide (2.66 g, 9.38 mmol) solution, made by refluxing Intermediate 7 with 1 eq. of magnesium turnings in THF, was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (2.7 g, 9.38 mmol) in toluene (75 mL) at 0° C. and stirred for 1 hr and then quenched with sat. NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (20-33% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (800 mg, 1.711 mmol, 18% yield). LCMS: rt=1.85 min. [M+Na]+=490; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][CH2:25][O:24]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][CH2:25][O:24]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 78 %

Procedure:
To a solution of tert-butyl 2-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}-1,4-oxazepane-4-carboxylate 132 (0.32 g, 0.63 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 15 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}-1,4-oxazepane-4-carboxylate 133 (0.205 g, 78%) as a colorless foam.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:25]2[CH:26]=[C:21]([Cl:20])[N:22]=[CH:23][N:24]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a solution of 2a (0.76 g, 4.06 mmol) in 10 mL of THF at room temperature, was added potassium tert-butoxide (0.65 g, 1.4 eq). The resulting mixture was stirred at room temperature for 30 minutes then 4,6-dichloropyrimidine (0.8 g, 1.3 eq) was added. The reaction mixture was stirred at room temperature for 16 h then the solvent was removed under a stream of nitrogen. The residue was taken up with DCM and purified by flash chromatography (elution with 0-40% ethyl acetate and 0.1% TEA in hexanes) to give 0.51 g of 2b (42% yield).
Reaction SMILES: OS(O)(=O)=O.O.[C:7]1([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I:18]I>CC(O)=O.CCOC(C)=O>[I:18][C:10]1[CH:11]=[CH:12][C:7]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)CCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of H2SO4 (1.25 mL), water (12.5 mL) and AcOH (25 mL) in a 250 mL flask and 3-phenylpropanoic acid (3.00 g, 20.0 mmol), iodine (1.40 g, 5.5 mmol) and KIO3 (0.98 g, 4.6 mmol) was added. The reaction was heated to reflux and a solution of iodine (1.40 g, 5.5 mmol) in AcOH (25 mL) was added in portions of 5 mL as the colour of the reaction faded from purple to orange. After 3 hours when no further colour changes appeared the reaction was cooled to room temperature. before quenching with 1M NaHSO3. The reaction was added water and extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4 and concentrated under vacuum. The product (4.15 g, 75%), containing minor impurites of starting material and the ortho-iodinated product, was recrystallised from PE to provide 1.83 g (33%) of the pure and white crystalline product. Rf: 0.10 (EtOAc:hexanes, 1:4); 1HNMR (CDCl3) δ 7.62-7.59 (m, 2H), 6.97-6.95 (m, 2H), 2.92-2.87 (t, 2H, J=7.5 Hz), 2.68-2.63 (t, 2H, J=7.5 Hz); 13CNMR (CDCl3) δ 178.5, 139.7, 137.6, 130.4, 91.6, 35.2, 30.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](Br)[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].[CH2:16]([O:18]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:17].Cl.O>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:16](=[O:18])[CH3:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc2c(Br)cccc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccnc2c(C(C)=O)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8-Bromo4-quinoline carboxylic acid methyl ester, D16 (E. R. Buchman et al., J. Amer. Chem. Soc., 1946, 68, 2692), (0.712 g), (1-ethoxyvinyl)tributyltin (1.60 g) and tetrakis(triphenylphosphine)palladium (O) in 1,4-dioxane (50 ml) were heated at reflux for 16 h. The reaction mixture was cooled to ambient temperature, HCl (5M, 1 ml) and water (15 ml) added and the resulting mixture stirred for 3 h. The solvent was removed at reduced pressure, the residue suspended in EtOAc and the solid removed by filtration. The organic phase was washed with saturated sodium bicarbonate, dried (Na2SO4), removal of the solvent under reduced pressure gave a dark oil which was chromatographed (silica gel, hexane diethyl ether) to give the title compound (0.500 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[O:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:22][CH:21]=[CH2:20])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[O:7]2
Reactant: Cc1cc(O)cc2oc(=O)ccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(C)c2ccc(=O)oc2c1

Procedure:
A Me2CO (250 ml) solution of 5-methyl-7-hydroxycoumarin (I; 15.0 g) was reacted with allyl bromide (20 ml) in the presence of K2CO3 (5.0 g) by refluxing the mixture for 5 hours. After chilling the K2CO3 is filtered off and washed with fresh Me2CO. The pooled filtrate and acetonic washings were concentrated to dryness and the residue crystallized from cyclohexane giving 5-methyl-7-allyloxycoumarin (IV; 13.8 g; m.p. 83° ). ##STR7##