Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[CH:11]1([C:14]([CH3:16])=[O:15])[CH2:13][CH2:12]1.C[O-].[Na+].C1C=CC=CC=1>O>[CH:11]1([C:14](=[O:15])[CH2:16][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:13][CH2:12]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1cnccn1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(CC(=O)C1CC1)c1cnccn1

Procedure:
A stirred mixture of 14.0 g. of methyl pyrazinoate, 16.8 g. of cyclopropylmethyl ketone, 6.0 g. of sodium methoxide and 200 ml. of benzene is heated under reflux for 5 hours. A 400 ml. volume of water is added to the mixture. The benzene phase is separated and the aqueous solution is made weakly acidic with dilute hydrochloric acid. A yellow solid precipitates, which is collected and recrystallized from hexane to give white crystals, m.p. 111°-112° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([F:16])[C:7]1=2)C.[OH-].[Li+].Cl>C1COCC1.O>[F:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(F)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1OB(O)c2cc(Oc3cnccn3)cc(F)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 13.8 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (166 mg, 0.50 mmol) in THF (2 mL) was added dropwise an aqueous solution of lithium hydroxide (102 mg, 2.5 mmol) in water (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified to pH=2 at 0° C. with a diluted HCl solution. The resulting mixture was extracted with ethyl acetate (2×15 mL), the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (21 mg, Yield: 13.8%). 1H NMR (400 MHz, DMSO-d) δ 12.50 (s, 1H), 9.50 (s, 1H), 8.61-8.62 (d, J=2.8 Hz, 1H), 8.42-8.43 (d, J=2.8 Hz, 1H), 8.24-8.25 (m, 1H), 7.31-7.33 (m, 1H), 5.61-5.64 (m, 1H), 2.97-3.02 (m, 1H), 2.37-2.43 (m, 1H). MS (ESI) m/z=305 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C@H:34]([OH:36])C)N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[C:4]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:3][N:2]([CH2:1][C@H:34]([OH:36])[CH3:33])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: C[C@@H](O)CNN
Product: C[C@@H](O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (R)-1-Hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.42 (m, 2 H), 8.18 (d, J=8.3 Hz, 1 H), 8.06 (d, J=8.4 Hz, 1 H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.61 (s, 1 H), 7.54 (m, 1H), 7.36 (d, J=9.1 Hz, 2 H), 7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H), 4.21 (dd, J=13.6, 2.5 Hz, 1H), 4.03 (dd, J=13.6, 7.9 Hz, 1H), 1.26 (d, J=6.2 Hz, 3H); MS: (M+H m/z=437.2).
Reaction SMILES: [CH3:1][C@:2]([N+:8]([O-])=O)([C@H:5]([OH:7])[CH3:6])[CH2:3][OH:4].[C:11]([OH:14])(=[O:13])[CH3:12]>CCO.[Pd]>[C:11]([OH:14])(=[O:13])[CH3:12].[NH2:8][C@@:2]([CH3:1])([C@H:5]([OH:7])[CH3:6])[CH2:3][OH:4]
Reactant: C[C@@H](O)[C@@](C)(CO)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H](O)[C@](C)(N)CO
Reaction time: 48 h

Procedure:
To a solution of (±)-(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (32B, 13.93 g, 0.093 mol) in 95% EtOH (120 mL) was added glacial acetic acid (17 mL) and 10% Pd/C (MCB, 1.0 g). The mixture was reduced in a Parr apparatus at 50 psi of H2 for 48 h. The catalyst was then removed by filtration on a Celite® pad and the solvent removed to give the crude amine salt. Three portions of PhCH3 (50 mL) were added to the flask and removed by rotary evaporation to remove final traces of H2O and acetic acid. The residue, a viscous oil gradually solidified under high vacuum. The solie was triturated with Et2O, filtered and the resulting solid further washed with Et2O to give after drying, 16.23 g (97%) of (±)-(2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate, mp 117°-121°, (C,H,N).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH2:6][C:5]1([CH2:9][CH2:10][NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH2:4][CH2:3][CH2:2]2.S(=O)(=O)(O)[OH:21].N>O>[N:1]12[CH2:2][CH2:3][CH2:4][C:5]1([CH2:9][CH2:10][NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]([NH2:15])=[O:21])[CH2:6][CH2:7][CH2:8]2
Reactant: N#Cc1ccccc1NCCC12CCCN1CCC2
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O
Product: NC(=O)c1ccccc1NCCC12CCCN1CCC2
Temperature: -78 °C
Yield: 67 %

Procedure:
2-[(1-Azabicyclo[3.3.0]octan-5-yl)ethylamino]benzonitrile (1.34 g, 5.25 mmol) obtained by Example 27 was mixed with concentrated sulfuric acid (48.2 ml) and water 7.5 ml to react the mixture for 2 hours at 110° C. The reaction mixture was cooled to -78° C., neutralized by 25% ammonia solution, extracted by ethyl acetate, washed by water, dried over anhydrous sodium sulfate, concentrated in vacuo, and crystallized from ethyl acetate to afford the desired compound (961 mg, 67.0%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1Cl
Yield: 73.3 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (500 mg, 1.72 mmol), morpholine (150 mg, 1.72 mmol) and triethylamine(479 μL, 3.44 mmol) were reacted to form the desired product (430 mg, 73%). LC-MS (m/z) 341.0 (M−).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:18]=[C:17]2[N:8]([C:9](SC)=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1.[NH3:21]>[OH-].[NH4+]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:18]=[C:17]2[N:8]([C:9](=[NH:21])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CSc1nc2ccccc2c2nc(-c3ccco3)nn12
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Product: N=c1[nH]c2ccccc2c2nc(-c3ccco3)nn12

Procedure:
As in Example 37, 2-(2-furyl)-5-methylthio-[1,2,4]triazolo[1,5-c]quinazoline is reacted with ammonium hydroxide (200 ml) saturated with ammonia at 0° in the stainless steel pressure vessel at 150° and 220 p.s.i. over six hours to afford 2-(2-furyl)-5-imino-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazoline, mp 282°-285° after methanol recrystallization.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15](O)=[O:16])=O)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].O.[NH2:21][NH2:22]>C(O)C>[C:1]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]2[CH:12]3[CH:13]([C:15](=[O:16])[NH:21][N:22]=2)[CH2:14]3)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: NN
Reactant: CCC(=O)Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 81.8 %

Procedure:
1.0 g (3.8 millimoles) of cis-2-(p-propionylaminobenzoyl)-cyclopropanecarboxylic acid, 0.22 g (4.4 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 5 hours. After filtering off the product at 25° C. and drying it under reduced pressure at 50° C., 0.8 g (81% of theory) of 2-(p-propionylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 268°-270° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([N:18]1[CH2:43][CH2:42][CH2:41][C@H:19]1[C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:25])=[O:21])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:9]([C:16]([N:18]2[CH2:43][CH2:42][CH2:41][C@H:19]2[C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:25])=[O:21])=[O:17])[NH2:8])[N:12]=[CH:13]1
Reactant: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1cscn1
Reaction time: 2 h

Procedure:
To a solution of the compound (13) (1.2 g, 1.92 mmol) in ethyl acetate (20 ml) was added the solution of 4N-hydrogen chloride in ethyl acetate (20 ml) under ice-cooling and the resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was concentrated in vacuo to give the compound (16) (1.27 g, quantitative). This compound used in the next, reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH:19](I)([CH3:21])[CH3:20].O>CN(C)C=O>[CH:19]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[Br:1])([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
Then, 100 g (0.42 mol) of 2-bromo-4-fluoro-5-nitrophenol was dissolved in 400 ml of dimethylformamide, to which 70 g (0.50 mol) of potassium carbonate was added and after warming to 50° C., 94 g (0.55 mol) of isopropyl iodide was added dropwise, and the mixture was stirred at 45° to 50° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with diluted hydrochloric acid, dried, and concentrated. The residue was subjected to column chromatography, which afforded 99.8 g (0.36 mol) of 2-bromo-4-fluoro-5-nitrophenyl isopropyl ether.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([SH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].I[CH3:14].O>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9][CH3:14])=[C:4]([F:10])[CH:3]=1
Reactant: CI
Reactant: Cc1cc(S)c(F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(C)c(Br)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of 4-bromo-2-fluoro-5-methylbenzenethiol (2.28 g, 10.3 mmol) in 25 mL of DMF at RT was treated with NaH (0.284 g, 12.4 mmol). After 15 minutes the solution was cooled to 0° C. and iodomethane (0.772 mL, 12.4 mmol) was added. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.40 g, 99% yield) as an orange oil. The crude material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[NH:7][CH:8]([CH3:10])[CH3:9].[Cl-].[NH4+].C1C[O:20][CH2:19]C1>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:19](=[O:20])[N:7]([CH:8]([CH3:10])[CH3:9])[C:6]=2[CH:11]=1
Reactant: CC(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)n1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
A mixture of 5-chloro-N-isopropyl-2-nitroaniline (Step 1 of Example 12, 0.76 g, 3.54 mmol), iron (0.99 g, 17.7 mmol) and ammonium chloride (0.38 g, 7.08 mmol) was suspended in ethanol (27 mL) and H2O (9 mL). Then, the mixture was heated at 80° C. for 3 h. After cooling, the insoluble materials was filtered off on a pad of Celite, and the filtrate was evaporated under reduced pressure. To the residue was added N,N′-carbonyldiimidazole (CDI, 0.57 g, 3.50 mmol) and THF (10 mL) and then stirred at 100° C. for 10 h. After cooling, the volatile materials were removed under reduced pressure and the residue was partitioned between ethylacetate and H2O. After extraction with ethylacetate (3 times), the combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (2:1) to give 0.30 g (40%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([Cl:21])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Product: Cc1ccc(C(=O)Cl)cc1OCc1ccccc1
Temperature: 79 °C
Reaction time: 4 h

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=[O:14].[Na+].OOS([O-])=O.[K+].O>C(#N)C.O>[C:1]1([C:7]23[O:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: c1ccc(C23CCCCC2O3)cc1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of phenyl cyclohexene (79 mg, 0.5 mmol) in a mixture of acetonitrile (4.5 ml) and water (2 drops) were added first finely crushed NaHCO3 (168 mg, 2 mmol) and oxone (307 mg, 0.5 mmol) then the catalyst (0.05 mmol). The resulting yellow suspension was allowed to react at RT, under good stirring. TLC was used to follow the reaction which indicated that the reaction was finished in 2 h. Water (3 ml) was added to the reaction mixture followed by extraction into methylene dichloride. The organic extracts were combined and dried over anhydrous sodium sulphate. Concentration on a rotary evaporator gave a material which was purified on a column using 2% ethyl acetate:petrol mixture as eluent to give the desired compound as a colourless oil. (72 mg, 83% yield, 70% e.e).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.8 %

Procedure:
3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). Benzyl bromide (3.21 mL, 27.1 mmol) was added to this suspension, and stirred for 14 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (5.16 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([O:15][P:16]([CH2:21][PH:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>C(#N)C.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.CN1CCOCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([P:22]([CH2:21][P:16]([O:15][CH2:13][CH3:14])([O:17][CH2:18][CH3:19])=[O:20])([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CCO[PH](=O)CP(=O)(OCC)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(P(=O)(CP(=O)(OCC)OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 58.6 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of 4-bromo-benzoic acid ethyl ester (3a) (5 g, 0.0218 mol), ethoxyphosphinoylmethyl-phosphonic acid diethyl ester (3b), (5.86 g, 0.024 mol), NMM (2.88 mL, 0.0262 mmol) and Pd(PPh3)4 (2.017 g, 0.00175 mol) in acetonitrile (20 mL) was stirred at ambient temperature for 5-10 min, then heated at 90° C. for 18 hours. The reaction mixture was filtered through celite, and the celite was washed with EtOAc (3×30 mL) until the filtrate showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on rotary evaporator. The desired product (ix) was purified by silica gel flash chromatography to give a pale yellow oil (5.01 g). 1H NMR (300 MHz, CDCl3) δ (ppm)): 0.96 (t, J=7.07 Hz, 3H), 1.13 (m, 9H), 2.41 (t, J=18.2 Hz, 2H), 3.84 (m, 6H), 4.17 (q, J=7.11 Hz, 2H), 7.71 (m, 2H), 7.92 (m, 2H)., 31P NMR (121 MHz, CDCl3) δ 32.8 and 19.7.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:17]=[C:18]([CH2:22][OH:23])[CH:19]=[CH:20][CH:21]=1>>[OH:23][CH2:22][C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: OCc1cccc(I)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(CO)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (90 mg, 0.48 mmol) and (3-iodophenyl)methanol (0.07 mL, 0.55 mmol) according to the general procedure IB to give 40 mg (32%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:30→1:10). Rf: 0.24 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.53 (s, 1H), 7.46-7.43 (m, 3H), 7.34-7.32 (m, 2H), 7.19-7.16 (m, 2H), 4.69 (s, 2H), 3.66 (s, 3H), 2.98-2.93 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz), 1.83 (s, 1H); 13CNMR (CDCl3) δ 173.1, 141.1, 140.9, 131.7, 130.7, 130.0, 128.6, 128.3, 126.7, 123.6, 121.1, 89.4, 88.9, 64.9, 51.6, 35.4, 30.8; ESI-MS m/z 317.1 (MNa+).
Reaction SMILES: C([O:5][C:6](=[O:51])[CH2:7][N:8]([C:18](=[O:50])[C@H:19]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39]C(OCC1C=CC=CC=1)=O)[NH:20][C@@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:52].CCOCC>C(O)(=O)C>[BrH:52].[BrH:52].[CH2:33]([O:32][C:30]([C@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)[CH2:7][C:6]([OH:51])=[O:5])=[O:50])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](CCCCN)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 0.5 h

Procedure:
Nα -[1-(R)-Ethoxycarbonyl-3-phenylpropyl]-Nε -carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester (1 g) is dissolved in 2 ml of acetic acid. To the solution, 8 ml of 25% hydrobromic acid solution in acetic acid is added, and the mixture is allowed to stand at room temperature for 30 minutes. On adding 200 ml of ether and 100 ml of petroleum forms. This is collected by filtration and recrystallized from a mixture of methanol and ethyl ether to give 0.8 g of Nα -[1-(R)-ethoxycarbonyl-3-phenylpropyl]L-lysyl-N-(indan-2-yl)glycine dihydrobromide melting at [α]D24 =-11.6° (c=1, methanol)
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH2:27][O:26][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:5](=[O:8])[N:4]=1)[CH3:13]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(=O)n(COC(=O)C(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To DMF (3 mL) were added N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.6 mmol), and chloromethyl pivalate (90 mg, 0.6 mmol), and the mixture was shaken at room temperature for 16 h. The mixture was partitioned between EtOAc and H2O. The organic phase was dried over MgSO4, filtered, and evaporated. To the resultant crude oil Et2O (3.5 mL) was added and a precipitate formed which was collected by filtration. The title compound was isolated as a white solid (37 mg, 23%): mp 193-194° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.07 (d, J=6.3 Hz, 1H), 5.60 (s, 2H), 3.22 (s, 3H), 3.09 (s, 3H), 1.11 (s, 9H); ESIMS m/z 299 ([M+H]+).