Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].O=[C:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O.C(O)C>[OH:9]/[N:8]=[C:11](\[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)/[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CC/C(=N/O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
Sodium carbonate (0.80 g, 5.76 mmol) was added to hydroxylamine hydrochloride (0.80 g, 11.5 mmol) in water (3 mL), and the mixture stirred for 15 minutes with ice cooling. The resulting mixture was added to 4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (2.99 g, 8.86 mmol) (Example 1) in ethanol (50 mL) and the resulting mixture refluxed for 6 hours, concentrated to one-third volume, and allowed to cool. The resulting precipitate was dissolved in hot sodium bicarbonate solution, filtered, and the filtrate acidified with 1M HCl to yield a slurry which was filtered, washed with water, and dried in vacuo to give the title compound as a white solid (1.17 g, %C,H,N found: 71.77, 6.79, 7.88).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>CO.O>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C=O)cc1
Reactant: c1ccc(C2=NCCN=C2c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(Cc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1

Procedure:
The same procedures as in Example 3 were repeated using 2,3-diphenyl-5,6-dihydropyrazine and p-anisaldehyde. 2,3-Diphenyl-5-(p-methoxybenzyl)pyrazine was obtained as colorless prisms, m.p. 102°-103° C. (recrystallized from methanol-water). Physical properties of the product support a chemical structure of the below formula (VIII).
Reaction SMILES: CS(OC[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:19]([NH:20][C:21](=[O:50])[NH:22][C@@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C@H:26]([O:33][C:34]4[CH:35]=[CH:36][C:37]5[N:38]([C:40]([N:43]6[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]6[CH3:49])=[N:41][N:42]=5)[CH:39]=4)[CH2:25][CH2:24]3)=[CH:18][C:17]([C:51]([CH3:72])([CH3:71])[CH2:52][O:53][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:16]2)[CH:10]=1)(=O)=O.[CH3:73][NH:74][CH3:75].[CH2:76]1C[O:79]CC1>>[CH:52]([OH:53])=[O:79].[CH3:73][N:74]([CH3:76])[CH2:75][CH2:7][O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([NH:20][C:21]([NH:22][C@@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C@H:26]([O:33][C:34]4[CH:35]=[CH:36][C:37]5[N:38]([C:40]([N:43]6[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]6[CH3:49])=[N:41][N:42]=5)[CH:39]=4)[CH2:25][CH2:24]3)=[O:50])=[CH:18][C:17]([C:51]([CH3:71])([CH3:72])[CH2:52][OH:53])=[N:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: C1CCOC1
Reactant: CNC
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 60 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A solution of Intermediate 153i (131 mg, 0.13 mmol) in THF (0.8 mL) was treated with a 2M solution of dimethylamine in THF (1.3 mL, 2.6 mmol) and the mixture was stirred at 60° C. for 18 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-8% (2N NH3/MeOH) in DCM, to give the title compound as a white foam (93 mg, 75%). LCMS (Method 3): Rt 3.91 min, m/z 960.6 [MH+].
Reaction SMILES: BrC1C=CC(C2C3C=CC(O)=CC=3ON=2)=CC=1.BrCCCCCCBr.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:49]=[CH:48][C:37]2[C:38]([C:41]3[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=3)=[N:39][O:40][C:36]=2[CH:35]=1.[CH2:50]([NH:53][CH3:54])[CH:51]=[CH2:52]>>[CH2:50]([N:53]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:49]=[CH:48][C:37]2[C:38]([C:41]3[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=3)=[N:39][O:40][C:36]=2[CH:35]=1)[CH3:54])[CH:51]=[CH2:52]
Reactant: C=CCNC
Reactant: BrCCCCCCOc1ccc2c(-c3ccc(Br)cc3)noc2c1
Agent: BrCCCCCCBr
Agent: Oc1ccc2c(-c3ccc(Br)cc3)noc2c1
Product: C=CCN(C)CCCCCCOc1ccc2c(-c3ccc(Br)cc3)noc2c1

Procedure:
Analogously to Example 12b, from 3-(4-bromo-phenyl)-benzo[d]isoxazol-6-ol and 1,6-dibromohexane via 6-(6-bromo-hexyloxy)-3-(4-bromo-phenyl)-benzo[d]isoxazole and by reaction with N-allyl-methyl-amine there is obtained allyl-[6-[3-(4-bromo-phenyl)-benzo[d]isoxazol-6-yloxy]-hexyl]-methyl-amine which is converted into the fumarate, MS: m/e 443 (M+H+, 1 Br).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]#[C:15][Si](C)(C)C.[C:20]([O:24][C:25](=[O:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1Br)([CH3:23])([CH3:22])[CH3:21].C(C1C=CC=C(S(CCC)(=O)=O)C=1)#C>>[C:20]([O:24][C:25](=[O:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:15]#[C:14][C:3]1[CH:2]=[CH:7][CH:6]=[C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:4]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Br
Reactant: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Agent: C#Cc1cccc(S(=O)(=O)CCC)c1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(F)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from tert-butyl(2-bromo-4-fluorophenoxy)acetate (Intermediate 119) and 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: O[CH:2]([CH3:8])[C:3]#[C:4][C:5](=[O:7])[CH3:6].Br.[CH2:10]([S:16][C:17](=[NH:19])[NH2:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[CH2:10]([S:16][C:17]1[N:19]=[C:4]([CH:5]([OH:7])[CH3:6])[CH:3]=[C:2]([CH3:8])[N:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)C#CC(C)O
Reactant: CCCCCCSC(=N)N
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCSc1nc(C)cc(C(C)O)n1
Reaction time: 3 h
Yield: 61.1 %

Procedure:
5-Hydroxy-hex-3-yn-2-one (2 g, 18 mmol) and 2-hexyl-isothiourea hydrobromide (5.2 g, 21 mmol) were dissolved in THF (10 mL). Then the triethylamine (5.5 mL, 40 mmol) was added and stirring continued for 3 h. The reaction was slightly exothermic. The mixture was extracted with AcOEt and sat. NH4Cl solution. The crude product was purified by chromatography on silica gel with a heptane/AcOEt gradient. One obtained 2.8 g (61%) of a light yellow oil. MS: m/z=254 (M)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20]CC)=[O:19])=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CO.O.[OH-].[Li+]>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:18]([OH:20])=[O:19])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C2CCC3(CC2)OCCO3)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(C2CCC3(CC2)OCCO3)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-amino-6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridine-2-carboxylate (Compound 232E, 228 mg, 0.744 mmol) was taken up in THF (1.0 mL) and MeOH (1.0 mL, 25 mmol). This was treated with a solution of Lithium hydroxide, monohydrate (156 mg, 3.72 mmol) in H2O (1.0 mL) and allowed to stir at rt for 4 hours. The THF was removed in vacuo and treated, dropwise with 1N HCl until a pH of ˜5 was achieved. This aqueous solution was extracted with EtOAc (3×50 mL) and saturated with salt and stirred with ˜100 mL DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to a crude yellow oil which was used without further purification. MS (ES+): m/z=278.86 [MH+]. HPLC: tR=2.39 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.CO.O[Li].O.Cl>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of ethyl 2-(4-methoxyphenyl)acetate (5.0 g, 0.025 mol) in 2:2:1 MeOH:THF:H2O (50 mL) was added LiOH.H2O (5.14 g, 0.128 mol). The reaction mixture was stirred at RT for 16 h and concentrated in vacuo to obtain the crude product. The crude material was acidified with HCl (1N) to pH 2 and then the product was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-(4-methoxyphenyl)acetic acid (4.05 g, 94%) as a solid.
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCCCCCCBr
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)CCCCCCCOc1ccc(C(=O)Cc2ccccc2)c(O)c1

Procedure:
A mixture of 22.8 parts of 2,4-dihydroxyphenyl benzyl ketone, 22.1 parts of isodecyl bromide, 27.6 g. anhydrous potassium carbonate and 250 parts of dry acetone was stirred under reflux for 3 days. After cooling and filtering the filtrates were evaporated to dryness, the residue dissolved in petrol ether and the solution filtered. The filtrates well washed with 4 × 50 parts of N sodium hydroxide solution followed by 5 × 100 parts of water. The dried petrol solution was evaporated to give 26.2 parts of 2-hydroxy-4-isodecyloxyphenyl benzyl ketone as a dark, viscous oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[O:15][C:14](=[O:23])[CH:13]=1)[CH3:10].N(CCCC#N)=NCCCC#N>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][CH2:9][CH3:10])=[CH:13][C:14](=[O:23])[O:15]2)=[CH:20][CH:19]=1
Reactant: CCOc1cc(=O)oc2cc(C)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(=O)oc2cc(CBr)ccc12
Yield: 76.7 %

Procedure:
N-Bromosuccinimide (9.59 g; 0.054 mole) was added to stirred solution of 4-ethoxy-7-methylcoumarin (11 g; 0.054 mole) in carbontetrachloride (600 ml) followed by a catalytic quantity of azo bisbutyronitrile. After refluxing the mixture for 1 hr the solvent was removed in vacuo and the residue recrystallized from ethanol to give 11.73 g (77%) of product of m.p. 150°-3° C. Further recrystallization gave material of m.p. 152°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].C([O-])(=O)C.[NH4+:23].O>C1(C)C=CC=CC=1>[NH2:23]/[C:10](/[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[CH:11]/[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13]
Reactant: [NH4+]
Reactant: C=CCOC(=O)CC(=O)Cc1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)/C=C(/N)Cc1ccc(F)cc1F
Yield: 100.4 %

Procedure:
Allyl 4-(2,4-difluorophenyl)-3-oxobutanoate (5.0 g, 19.67 mmol) and ammonium acetate (7.58 g, 98.33 mmol) were refluxed in toluene (20 mL) for 2 h with azeotropic removal of H2O and then cooled and concentrated. The residue was redissolved in Et2O and the organics washed with 1N HCl (2×), H2O, brine, and then dried (Na2SO4), filtered and concentrated to give 5.0 g (100% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.25–7.14 (m, 1H), 6.63 (dd, J=16.1, 7.9 Hz, 2H), 5.97–5.88 (m, 1H), 5.28 (dd, J=17.2, 1.5 Hz, 1H), 5.19 (dd, J=10.2, 1.1 Hz, 1H), 4.60 (s, 1H), 4.55 (d, J=5.7 Hz, 2H), 3.43 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[S:25]1[CH:29]=[C:28]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[N:27]=[N:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([C:28]4[N:27]=[N:26][S:25][CH:29]=4)=[CH:31][CH:32]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=Cc1ccc(-c2csnn2)cc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ccc(-c4csnn4)cc3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by coupling the 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione to 4-[1,2,3]thiadiazol-4-yl-benzaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (DMSO-d6): d 1.36-1.71 (br m, 8H), 1.92 (m, 2H), 2.37 (m, 1H), 2.56 (m, 3H), 2.84 (d, 1H, J=17.5 Hz), 3.60 (d, 1H, J=14.3 Hz), 3.71 (d, 1H, J=14.3 Hz), 3.79 (s, 3H), 6.96 (s, 2H), 7.19 (s, 1H), 7.41 (d, 2H, J=8.1 Hz), 8.08 (d, 2H, J=8.3 Hz), 9.59 (s, 1H), 11.01 (s, 1H) Anal. Calcd. For C28H29N2O4ClS.0.75H2O: C, 62.44; H, 5.71; N, 5.20. Found: C, 62.43; H, 5.58; N, 5.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:14][C:15]1[C:29]([F:30])=[CH:28][C:18]([C:19]([NH:21][S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[O:20])=[C:17]([F:31])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH2:14][C:15]2[C:29]([F:30])=[CH:28][C:18]([C:19]([NH:21][S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[O:20])=[C:17]([F:31])[CH:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(O)cc1Cl
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ncc(OCc2cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc2F)cc1Cl
Yield: 30 %

Procedure:
A solution of 5-chloro-6-isopropoxypyridin-3-ol (Preparation 6, 44 mg, 0.232 mmol), 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 83 mg, 0.23 mmol) and potassium carbonate (64 mg, 0.47 mmol) in dimethyl sulfoxide (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and acidified to ˜pH 4 using acetic acid (2 mL). The resulting precipitate was filtered, washed with water (20 mL) and dried to afford the title compound as a white solid (32 mg).
Reaction SMILES: N(C(OC(C)C)=O)=N[C:3](OC(C)C)=O.[F:15][C:16]([F:58])([F:57])[C:17]1[CH:18]=[C:19]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[CH2:20][N:21]([C:45]1[N:46]=[N:47][NH:48][N:49]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:24]2[CH:36]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:38]([CH3:40])=[CH:39][C:23]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C1(C)C=CC=CC=1>[F:54][C:53]([F:56])([F:55])[C:51]1[CH:50]=[C:19]([CH:18]=[C:17]([C:16]([F:57])([F:15])[F:58])[CH:52]=1)[CH2:20][N:21]([C:45]1[N:46]=[N:47][N:48]([CH3:3])[N:49]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[C:24]2[CH:36]=[C:37]([C:41]([F:42])([F:43])[F:44])[C:38]([CH3:40])=[CH:39][C:23]1=2
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Add diisopropyl azodicarboxylate (0.56 mL, 3.94 mmol) to a solution of (S)-tert-butyl 5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.10 g, 3.29 mmol) and triphenylphosphine (1.03 g, 3.94 mmol) in methanol (0.20 mL, 4.94 mmol) and toluene (30 mL) at 0° C. under nitrogen. Warm the mixture to room temperature and stir for 12 h. Add silica gel, remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:3), to provide the title compound as a colorless oil (2.04 g, 95%). APCI MS m/z 653 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH2:11])[N:3]=1.Br[CH2:13][CH:14](OC)OC>CCO.C(Cl)Cl.[Fe]>[CH3:1][C:2]1[N:3]2[CH:13]=[CH:14][N:11]=[C:4]2[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Reactant: COC(CBr)OC
Agent: [Fe]
Solvent: CCO
Solvent: ClCCl
Product: Cc1c(N)ccc2nccn12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
2-Methyl-3-nitro-6-amino pyridine (63 mg, 0.41 mmol) was suspended in 1.3 mL EtOH containing 0.3 mL conc. HCl. 2-Bromo-1,1-dimethoxy-ethane (73 μL, 0.62 mmol) was added and the resulting mixture was refluxed for 8 h, at which point additional 2-bromo-1,1-dimethoxy-ethane (0.1 mL, 0.85 mmol) was added. The mixture was stirred at reflux overnight, cooled and diluted with CH2Cl2. The organics were washed with sat. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in 4 mL AcOH/EtOAc (1:1) and the resulting solution was heated to 75° C. Iron powder (46 mg, 0.82 mmol, 325 Mesh) was added and the mixture was stirred for 20 min. Additional iron powder (46 mg, 0.82 mmol, 325 Mesh) was added and stirring was continued for 30 min. The mixture was cooled to room tempearture and concentrated. The resulting residue was purified by silica gel silica gel flash chomatography with 20% MeOH in CH2Cl2 to give compound 843A (51 mg, 85%) as a yellow-brown solid. HPLC: 72% at 0.18 min and 28% at 0.27 min (retention time) (YMC S5 ODS-A column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 mincontaining 0.2% H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 147.85 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12]>C(O)C.Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:9][C:2](=[O:1])[CH:3]=[CH:4][C:5]2[CH:8]=[CH:13][C:11]([OH:12])=[CH:10][CH:6]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: CCO
Product: O=C(C=Cc1ccc(O)cc1)C=Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 150 g (1.23 mole) of 4-hydroxybenzaldehyde and 30 g (0.52 mole) of acetone in 600 ml of absolute ethanol was cooled while passing in hydrogen chloride for 45 minutes. After two hours of stirring, ice water was added and the resulting dark solid was filtered off. It was crystallized from absolute ethanol to give 90 g of brown, crystalline product.
Reaction SMILES: [CH2:1]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H][H]>C(O)C>[C:12]1([CH2:11][N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:7][CH2:8][CH2:9][NH2:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: [H][H]
Reactant: NCCCCCCCCN
Solvent: CCO
Product: NCCCCCCCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
Combine 14.4 gm of diaminooctane, 20.3 ml of benzaldehyde and 0.66 gm of Pt2O in 100 ml of ethanol. Treat the resulting mixture with hydrogen at 45 lbs./sq.in. until no further hydrogen is taken up. Filter, evaporate the solvent (in vacuo), and distill the rendered material to obtain 25.5 gm of the desired product, bp 185°-190° C. at 0.1 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:22][CH2:23][C:24](O)=[O:25])[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([Cl:39])(=O)OCC.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.[ClH:47]>C1COCC1>[ClH:39].[ClH:47].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:22][CH2:23][C:24]([N:44]2[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]2)=[O:25])[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1csc(Nc2ncc(CCC(=O)O)cc2OCc2ccccc2)n1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncc(CCC(=O)N3CCN(C)CC3)cc2OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
A 10 mL round-bottomed flask was charged with 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)propanoic acid (60 mg, 0.16 mmol), triethylamine (0.091 ml, 0.65 mmol), and THF (3 mL). The reaction was cooled to 0° C., ethyl carbonochloridate (0.017 ml, 0.17 mmol) was added, and the reaction was stirred at 0° C. for 20 minutes. 1-Methylpiperazine (0.036 ml, 0.32 mmol) was added and stirred at 0° C. for 1.5 hours. The reaction was partitioned between EtOAc and water. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica gel column (15% methanol in EtOAc with NH4OH) to afford the title compound (59.8 mg, 70.2% yield) as a white solid after HCl salt formation. 1H NMR (DMSO-d6) δ 11.25 (bs, 1H), 11.05 (bs, 1H), 7.89 (s, 1H), 7.62 (m, 3H), 7.45-7.33 (m, 3H), 6.83 (s, 1H), 5.32 (s, 2H), 4.43 (d, 1H), 4.06 (d, 1H), 3.47 (t, 1H), 3.38 (d, 2H), 3.01 (m, 2H), 2.84 (m, 3H), 2.74 (m, 5H), 2.32 (s, 3H). Mass spectrum (apci) m/z=452.2 (M+H-2HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH2:12]([O:14][C:15]([C@:17]1([F:37])[C@@H:22]2[C@H:18]1[CH2:19][C@@H:20]([OH:36])[C@@:21]2([N:33]=[N+:34]=[N-:35])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:16])[CH3:13].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:12]([O:14][C:15]([C@:17]1([F:37])[C@@H:22]2[C@H:18]1[CH2:19][C@@H:20]([O:36][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)[C@@:21]2([N:33]=[N+:34]=[N-:35])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:16])[CH3:13]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OC(=O)c3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Temperature: 25 °C
Reaction time: 28 h
Yield: 99.9 %

Procedure:
234 mg of 3,4-dichlorobenzoyl chloride was added to 202 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester dissolved in 3.7 mL of pyridine, and the mixture was stirred for 28 hours at room temperature, under a nitrogen atmosphere. After 100 mL of ethyl acetate was added to the reaction solution, this ethyl acetate solution was washed with a saturated aqueous solution of copper sulfate and with water, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=10:1), thereby yielding 298 mg of (1R,2R,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzoyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.