Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:18]1([CH:25]=[CH:24][C:22]([OH:23])=[CH:21][CH:20]=1)[OH:19]>CN(C=O)C>[OH:19][C:18]1[CH:25]=[CH:24][C:22]([O:23][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[CH:21][CH:20]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COc1ccc(O)cc1)Nc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 31 %

Procedure:
A mixture of compound 1a (338 mg, 2 mmol), K2CO3 (553 mg, 4 mmol), and KI (66 mg, 0.4 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (440 mg, 4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography on silica gel to provide the compound (150 mg, 0.62 mmol, 31% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.32 (br s, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.38 (t, J=7.8 Hz, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.90 (d, J=9.2 Hz, 2H), 6.84 (d, J=9.2 Hz, 2H), 5.07 (br s, 1H), 4.58 (s, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:30])[CH2:26][N:27]=[N+]=[N-])[N:17]=[CH:16]2)[C@@H:6]1[F:31])(=O)C.[H][H]>CO.[Pd]>[NH2:27][CH2:26][C:25]([C:18]1[N:17]=[CH:16][N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][OH:11])[C@@H:5]([OH:4])[C@H:6]2[F:31])[C:19]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[O:30]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F

Procedure:
In step 17, compound (22) is subjected to catalytic reduction with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium black in methanol at room temperature for converting the azido group of compound (22) into amino group. Thereby, 4-aminoacetyl-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-5-(dimethylaminomethyleneamino)imidazole [compound (24)] is produced.
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].C(O[CH:14]=[C:15]([C:21](=O)[CH:22]([CH3:24])[CH3:23])[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])C>CO>[CH:17]([C:16]([C:15]1[C:21]([CH:22]([CH3:24])[CH3:23])=[N:9][CH:8]=[N:10][CH:14]=1)=[O:20])([CH3:19])[CH3:18]
Reactant: CCOC=C(C(=O)C(C)C)C(=O)C(C)C
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C(=O)c1cncnc1C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
11.5 g (60 mmol) of a 28% sodium methoxide solution was dissolved in 100 ml of methanol, and 5.6 g (54 mmol) of formamidine acetate was added, followed by stirring at room temperature for 15 minutes. Then, 11.5 g (54 mmol) of 4-ethoxymethylene-2,6-dimethyl-3,5-heptanedione was added under cooling with ice. The reaction mixture was further reacted at 50° C. for one hour. The solvent was distilled off under reduced pressure, and 200 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=4:1) to obtain 9.2 g (yield: 89%) of 5-isopropylcarbonyl-4-isopropylpyrimidine as slightly yellow liquid.
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[C:10]2[C:11](=[N:21][N:22]([CH3:24])[CH:23]=2)[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29]>CCOCC.O>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[CH3:24][N:22]1[CH:23]=[C:10]2[C:11]([N:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=[C:9]2[O:6][CH2:5][CH2:4][CH:3]([CH3:7])[CH3:2])=[N:21]1
Reactant: CC(C)CCO
Reactant: Cn1cc2c(Cl)cc(-c3ccccc3)nc2n1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CC(C)CCOc1cc(-c2ccccc2)nc2nn(C)cc12
Reaction time: 8 h

Procedure:
To a solution of 1.61 g. of sodium (0.07 mol.) in 200 ml. of 3-methyl butanol, 17.1 g. of 4-chloro-2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridine (0.07 mol.) are added and the mixture is refluxed for six hours while stirring. The cooled solution is agitated with water, the organic layer dried and then evaporated in vacuo to give 20 g. (97%) of oil. To 18.5 g. of the oil (0.063 mol.), dissolved in 50 ml. of ether, a solution of 14.6 g. of maleic acid (0.126 mol.) in 500 ml. of ether is added. The precipitated maleate of 2-methyl-4-(3-methylbutoxy)-6-phenyl-2H-pyrazolo [3,4-b]pyridine, at first oily, crystallizes on standing overnight, yield: 24.6 g. (83%); m.p. 114°-116°. Recrystallization from ethyl acetate gives a product which melts at 119°-120°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2)CC1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)C1(c2ccc(S(=O)(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
Chlorosulfonic acid (10 mL) was cooled to 0° C. Then compound 36A (6.80 g, 38.6 mmol) was added over 30 min. The mixture was stirred at RT for 3 h and was poured into ice (−500 g). The cloudy solution was extracted with ether (2×200 mL). The extracts were dried with magnesium sulfate and concentrated to give a brown oil which was passed through a short pad of silica gel to afford the desired product 36B (6.05 g, 57%) as white plates. MS: 239 (M−Cl)+. Step 3. Preparation of 1-(4-Mercapto-phenyl)cyclopropanecarboxylic acid methyl ester (Compound 36C)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH:14]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc(NC(=O)c2cccc(N)c2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(3-amino-benzoylamino)-benzoic acid ethyl ester (50.0 mg, 0.18 mmol) in pyridine (0.40 ml) was treated with a solution of benzensulfonyl chloride (31.0 mg, 0.18 mmol) in pyridine (0.10 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated, yielding crude 4-(3-benzenesulfonylamino-benzoylamino)-benzoic acid ethyl ester, MS (ISP): m/e=425.1 (M+H+), which was used as such in the next step.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:59]1[CH2:64][CH2:63][CH:62]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:61][CH2:60]1>CN(C=O)C.C(OCC)(=O)C>[N:1]1[N:2]=[C:3]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:59]3[CH2:60][CH2:61][CH:62]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:69])([CH3:71])[CH3:70])[CH2:63][CH2:64]3)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: O=C(O)c1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(-c3nnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoic acid (0.5 g, 1.4 mmol) in DMF (5 mL) was added HBTU (0.56 g, 1.4 mmol) follwed by triethylamine (0.392 mL, 2.8 mmol). The reaction mixture was stirred at room temperature for 15 minutes then tert-butyl piperidin-4-ylcarbamate (0.31 g, 1.5 mmol) was added and the mixture stirred at room temperature for an additional 3 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, gradient: 50% ethyl acetate in hexanes to 100% ethyl acetate). The tert-butyl (1-(4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoyl)piperidin-4-yl)carbamate was obtained as a white solid (0.478 g, 63%). M.p.=196-202° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.81 (br.s, 1H), 8.22 (dd, J=4.4, 1.6 Hz, 1H), 7.97 (dd, J=7.6, 1.6 Hz, 1H), 7.52-7.4 (m, 5H), 7.35 (d, J=8.0 Hz, 1H), 7.19 (dd, J=8.0, 1.2 Hz, 1H), 7.14 (dd, J=7.6, 1.2 Hz, 1H), 6.93 (dd, J=8.0, 1.6 Hz, 1H), 6.89 (br.s, 1H), 4.35-4.25 (m, 1H), 3.6-3.45 (m, 2H), 3.2-3.05 (m, 1H), 3.02-2.9 (m, 1H), 1.9-1.65 (m, 2H), 1.38 (s, 9H), 1.35-1.15 (m, 2H); LCMS [M+H]: 538.
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C4CC4)=CN=3)CC2)=O)=C(F)C=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.[CH:43]1([C:46]2[CH:47]=[C:48]([CH3:83])[C:49]([N:52]3[CH2:57][CH2:56][N:55]([C:58]([C:60]4[CH:65]=[CH:64][C:63]([N:66]5[CH:70]([CH3:71])[CH2:69][N:68](CC6C=CC(OC)=CC=6)[C:67]5=[O:81])=[CH:62][C:61]=4[F:82])=[O:59])[CH2:54][CH2:53]3)=[N:50][CH:51]=2)[CH2:45][CH2:44]1>>[CH:43]1([C:46]2[CH:47]=[C:48]([CH3:83])[C:49]([N:52]3[CH2:53][CH2:54][N:55]([C:58]([C:60]4[CH:65]=[CH:64][C:63]([N:66]5[CH:70]([CH3:71])[CH2:69][NH:68][C:67]5=[O:81])=[CH:62][C:61]=4[F:82])=[O:59])[CH2:56][CH2:57]3)=[N:50][CH:51]=2)[CH2:44][CH2:45]1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C6CC6)cc5C)CC4)c(F)c3)C2=O)cc1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Agent: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)NCC3C)cc2F)CC1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (167 mg) described in Preparation Example 121 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 506, the title compound (109 mg) was obtained via 3-{4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[N:40]=[C:5]2[N:6]([CH2:33][C:34](=O)[C:35]([F:38])([F:37])[F:36])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:42][O:43][CH2:44][CH3:45].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH2:44]([O:43]/[N:42]=[C:34](/[C:35]([F:37])([F:36])[F:38])\[CH2:33][N:6]1[C:7](=[O:32])[C:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][C:29](=[O:31])[O:28][N:27]=3)=[CH:18][CH:19]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:40]=[C:5]12)[CH3:45]
Reactant: CCON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(F)(F)F)c2nc(C)nn12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N\OCC)C(F)(F)F)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(3,3,3-trifluoro-2-oxopropyl) [1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.14 g), 2-(aminooxy)ethane hydrochloride (0.37 g) and pyridine (5 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.041 g, 28%).
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]5)[C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>ClCCl>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH:37][C:47](=[O:49])[CH3:48])[CH2:33]5)[C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Yield: 53.7 %

Procedure:
A solution of (3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine (Example 5; 0.15 g, 0.27 mmol), DIEA (0.14 mL, 0.81 mmol) and acetic anhydride (0.038 mL, 0.41 mmol) in dichloromethane (4 mL) was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated and washed with aqueous 1N HCl (5 mL), water and brine, then dried (MgSO4), filtered and concentrated under reduced pressure to afford N-((3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl)acetamide (0.076 g, 54%). LCMS APCI (+) m/z 525 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[C:9](=[O:13])[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>C1(C)C=CC=CC=1>[CH3:14][N:15](/[CH:17]=[C:8]1/[C:9](=[O:13])[C:10]2[CH:11]=[N:12][C:3]([S:2][CH3:1])=[N:4][C:5]=2[CH2:6][CH2:7]/1)[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: CSc1ncc2c(n1)CCCC2=O
Solvent: Cc1ccccc1
Product: CSc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a solution of 2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (0.2 g, 1.0 mmol) in toluene (3 mL) was added DMFDMA (0.2 mL, 1.5 mmol). The reaction mixture was then refluxed for 16 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, gradient from 100% dichloromethane to 2% methanol in dichloromethane) to give the pure desired product (0.15 g, 60%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 9.0 (s, 1H), 7.72 (s, 1H), 3.18 (s, 6H), 2.98 (t, J=6.0 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 2.60 (s, 3H); LCMS [M+H]: 250.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29]Cl)=[O:27])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:31].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][I:31])=[O:27])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CC(=O)OCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(CC(=O)OCI)cc1
Yield: 80.1 %

Procedure:
Chloromethyl 4-(N-CBZ-L-valyloxy)phenylacetate (0.83 g, 1.9 mmol) and sodium iodide (1.15 g, 7.6 mmol) were heated in acetonitril (45 ml) for 5 h. The mixture was filtrated, the solvent removed, taken up in dichloromethane and filtrated again. Evaporation and purification by chromatography (ether-hexane, 2:3) yielded the title product (0.8 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([CH3:9])[O:3]1
Reactant: Cc1cc(=O)cc(C)o1
Agent: [Pd]
Solvent: CCO
Product: CC1CC(=O)CC(C)O1
Reaction time: 25 h

Procedure:
2,6-Dimethyl-4H-pyran-4-one (4 g) was dissolved in ethanol (20 mL) and 10% Pd/C (400 mg) was added. The mixture was hydrogenated under H2 (1 atm) at room temperature for 25 hrs.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[NH2:3].[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH:24][C:25](=[O:38])/[C:26](/[C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=O)=[CH:27]\N(C)C)[CH2:21]2>C(O)C.C(O)(=O)C>[CH:16]12[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:14]([CH2:23]3)[CH:15]1[NH:24][C:25]([C:26]1[CH:27]=[N:3][N:2]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)[C:31]=1[CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:38])[CH2:22]2
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: CN(C)/C=C(\C(=O)NC1C2CC3CC(C2)CC1C3)C(=O)C1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C2CCCC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
Methyl 4-hydrazinylbenzoate hydrochloride (Intermediate#123) (0.712 g, 3.51 mmol) was added in one portion to (Z)—N-(2-adamantyl)-2-(cyclopentanecarbonyl)-3-dimethylamino-prop-2-enamide (Intermediate#67), 1.21 g, 3.51 mmol) in ethanol (30 mL). 5 drops of acetic acid were added and the resulting solution was stirred at 80° C. for 2 hours and then cooled to ambient giving a precipitate. The reaction mixture was filtered and the product recovered, washed with ethanol (10 mL) and water (10 mL) before being dried under vacuum to give methyl 4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoate (0.620 g, 39.4%) as a white solid.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([C:34](=[O:36])[CH3:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH:18]=[CH:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([C:34](=[O:36])[CH3:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)[C@@H]1CN(C(C)=O)C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)N1C[C@@H]2CC=CC[C@H](NC(=O)c3ccccc3)C(=O)N2[C@H](C(=O)NC2CC(=O)OC2O)C1
Reaction time: 0.5 h

Procedure:
A solution of (4S,6S,10aS)-2-acetyl-6-benzoylamino-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide, 19, (70 mg, 0.14 mmol) in acetonitrile/water is treated with trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford the desired product as a white solid.
Reaction SMILES: [N:1]([CH:4]([C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][CH2:17][CH3:18])=[CH:11][CH:10]=1)[C:5]([CH3:8])([CH3:7])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>C1COCC1.CO>[CH3:6][C:5]([CH3:7])([CH3:8])[CH:4]([C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=1)[NH2:1]
Reactant: CCCSc1ccc(C(N=[N+]=[N-])C(C)(C)C)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCSc1ccc(C(N)C(C)(C)C)cc1
Temperature: 50 °C
Yield: 90.9 %

Procedure:
To a stirred solution of 1-(1-azido-2,2-dimethylpropyl)-4-(propylthio)benzene (282 mg, 1.07 mmol) in THF (8 ml) were added triphenylphosphine (842 mg, 3.21 mmol) and water (2 ml). The mixture was heated at 50° C. for 18 hours then allowed to cool to room temperature. Methanol (10 ml) was added and the mixture was passed through an SCX cartridge, which had been pre-treated with HCl in MeOH, eluting first with several column lengths of methanol to remove the triphenylphosphine oxide, then with 2M solution of ammonia in methanol to elute the product. The appropriate fractions were evaporated to give the title product as a pale yellow oil (231 mg). 1H NMR 3 (CDCl3) 7.27-7.19 (4H, m), 3.67 (1H, s), 2.89 (2H, t, J=7.3 Hz), 1.72-1.62 (2H, m), 1.02 (3H, t, J=7.3 Hz), 0.89 (9H, s).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Li+].CC([N-]C(C)C)C.[F:27][C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1.[B:41](OC(C)C)([O:46]C(C)C)[O:42]C(C)C>O1CCCC1>[F:27][C:28]1[C:29]([B:41]([OH:46])[OH:42])=[CH:30][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:32][N:33]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(CN2CCOCC2)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(CN2CCOCC2)cnc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of diisopropylamine (13.51 mL, 96 mmol) in tetrahydrofuran (66 mL) was treated with 2.0 M n-butyl lithium in hexane (48.2 mL, 96 mmol) at −40° C. and stirred for 1 h. The resulting LDA solution was cooled to −78° C. and a solution of 4-((6-fluoropyridin-3-yl)methyl)morpholine (15.767 g, 80 mmol) in THF (50 mL) was added via cannula over 20 min. The deep-red mixture was stirred at −78° C. for 1.5 h. A solution of triisopropyl borate (27.7 mL, 121 mmol) in THF (22 mL) was added slowly. The resulting mixture was stirred at −78° C. for 30 min and then the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The mixture was quenched with 1 N NaOH(aq) (50 mL) and stirred. The aqueous layer was separated and the organic layer was extracted with 1 N NaOH (2×20 mL). The combined aqueous layers were carefully acidified with 5N HCl until acidic (pH 5 to about 6) and the resulting cloudy mixture was extracted with EtOAc (3×100 mL). The aqueous layer was lyophilized. The resulting residue was diluted with 1:1 MeOH/DCM and placed into a sonicator for 5 min. The mixture was filtered through a fine-fritted funnel. The filtrate was concentrated to give 2-fluoro-5-(morpholinomethyl)pyridin-3-ylboronic acid (19.000 g, 79 mmol, 99% yield) as a tan oil. 1H NMR (400 MHz, d4-MeOH) δ 8.46 (s, 1H); 8.32 (d, J=6.06 Hz, 1H); 4.42 (s, 2H); 3.82-4.00 (m, 4H); 3.23-3.36 (m, 4H); 2.01 (s, 1H). m/z (ESI, +ve ion) 241.1 (M+H)+.