Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl-].[Li+]>CS(C)=O.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]([OH:17])=[O:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 23.3 %

Procedure:
Cyanoester 2 (0.76 g, 3.91 mmol), water (0.14 mL, 7.82 mmol) and lithium chloride (0.66 g, 15.6 mmol) were heated to 150° C. in DMSO (40 mL) for 22 hours. The mixture was allowed to cool, diluted with water (150 mL), and extracted with ether (3×50 mL). The combined ether fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 95:5) to give the cyanide 3 (0.21 g, 44%) as a 60:40 mixture of diastereoisomers; Rf(heptane-ethyl acetate, 9:1) 0.44; νmax(film)/cm−1 2238 (CN); Major diastereoisomer: δH (400 MHz; CDCl3) 2.97 (1H, m), 2.87 (2H, m), 2.32–2.18 (2H, m), 2.10–1.96 (3H, m), 1.92–1.78 (2H, m), 1.48–1.38 (1H, m); Minor diastereoisomer: δH (400 MHz; CDCl3) 3.13 (1H, m), 2.87 (2H, m), 2.32–2.18 (2H, m), 2.10–1.96 (3H, m), 1.92–1.78 (2H, m), 1.48–1.38 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:31]=[CH:30][C:12]3[N:13]=[C:14]([NH:16][C@H:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]4)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH3:32][N:33]1[CH:37]=[C:36]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:31]=[CH:30][C:12]4[N:13]=[C:14]([NH:16][C@H:17]5[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]5)[S:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:35]=[N:34]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc3ccc(Oc4ccnc(Cl)c4)cc3s2)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCN(C(=O)OC(C)(C)C)C5)sc4c3)ccn2)cn1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
To the reaction mixture of (S)-tert-butyl 3-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (68 mg, 148 μmol) in 1.2 m of DME, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg, 192 μmol, Pd(dppf)2Cl2 (18 mg, 22 μmol and aq. 2M Na2CO3 (400 μL, 800 μmol were added. The reaction mixture was stirred at 85° C. for 72 hours or until done by LC. The reaction mixture was poured into 40 ml of saturated NaHCO3 solution and extracted with ethyl acetate (2×80 ml). The combined organic layers were washed with water (2×20 ml) and brine (20 ml), then dried over Na2SO4, filtered and evaporated in vaccuo to give a brown glue (77 mg) that was purified on prep HPLC to give (S)-tert-butyl 3-(6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate as powder (9.6 mg). ES/MS m/z 507.1 (MH+).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][Si:7]([CH3:10])([CH3:9])Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][C:1]([CH3:4])([O:5][Si:7]([CH3:10])([CH3:9])[CH3:6])[CH3:3]
Reactant: CC(C)(C)O
Reactant: C[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC(C)(C)O[Si](C)(C)C

Procedure:
1 mole of tert. butanol, 1.5 moles of trimethylchlorosilane and 0.001 moles of tetra-n-butyl ammonium bromide were reacted at the reflux temperature (54°-67° C.) as in Example 1 and then worked up by distillation.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:17][CH3:18])[C:8]([O:15][CH3:16])=[N:9]2.C(N(CC)CC)C.[Cl-].[CH2:27]([O:29][C:30](=[O:34])[C:31](O)=[O:32])[CH3:28]>C1COCC1>[CH2:27]([O:29][C:30](=[O:34])[C:31]([NH:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:17][CH3:18])[C:8]([O:15][CH3:16])=[N:9]2)=[O:32])[CH3:28]
Reactant: CCOC(=O)C(=O)O
Reactant: COc1nc2cc(Br)cc(CN)c2nc1OC
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NCc1cc(Br)cc2nc(OC)c(OC)nc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
300 mg (1 mmol) of 5-aminomethyl-7-bromo-2,3-dimethoxyquinoxaline hydrochloride are suspended in 10 ml of THF and the suspension is cooled to 0° C. 0.183 ml (1.3 equiv.) of triethylamine is added and then 0.123 ml (1.1 equiv.) of oxalic acid monoethyl ester chloride is added dropwise in the course of 30 minutes. The mixture is stirred at 0° C. for 2 hours, then at 20° C. for 16 hours and is concentrated by evaporation. The residue is stirred in diethyl ether, and the solid is filtered off, washed with water and diethyl ether and dried.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C=C([F:71])C(C2C=NN(CCCO)C=2)=C2C=1C(=O)N(C)C2>>[F:71][C:11]1[C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=2)=[C:18]2[C:14]([C:15](=[O:20])[N:16]([CH3:19])[CH2:17]2)=[C:13]([NH:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:23]=2)[CH:12]=1
Reactant: CN1Cc2c(c(N)cc(F)c2-c2cnn(CCCO)c2)C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cc(F)c(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared analogously to Compound 1B replacing Compound 1C with 7-amino-5-fluoro-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 31C). 1H NMR (CD3OD, 400 MHz): δ 8.39 (d, J=13.9 Hz, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.82 (d, J=1.3 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J=8.3 Hz, 1H), 4.51 (s, 2H), 4.33 (t, J=6.9 Hz, 2H), 4.08 (quin, J=7.3 Hz, 4H), 3.91 (s, 3H), 3.58 (t, J=6.1 Hz, 2H), 3.28 (d, J=21 Hz, 2H, obscured), 3.12 (s, 3H), 2.10 (quin, J=6.5 Hz, 2H), 1.28 (t, J=7.1 Hz, 6H). MS (ESI): m/z=722.23 [M+H]+. UPLC: tR=1.43 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15](=[O:20])[N:16]([CH2:18][CH3:19])[CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([N:16]1[CH:17]=[C:12]([C:4]2[S:3][C:2]([NH:1][C:21]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:28])=[N:6][C:5]=2[C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:13]=[CH:14][C:15]1=[O:20])[CH3:19]
Reactant: CCn1cc(-c2sc(N)nc2-c2ccco2)ccc1=O
Reactant: O=C(O)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1cc(-c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)ccc1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
2-Amino-5-(1-ethyl-2-oxo-1,2-dihydropyridin-5-yl)-4-(2-furyl)thiazole (287 mg, 1.00 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and isonicotinic acid (246 mg, 2.00 mmol), PyBOP (1.14 g, 2.20 mmol) and triethylamine (0.613 mL, 4.40 mmol) were added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:1), followed by reslurrying with a mixed solvent of methanol and diethyl ether to afford the entitled Compound 127 (99.0 mg, 25%) as a pale brown solid.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]4)[CH:17]=[CH:18][C:13]=3[NH:12]/[C:11]/2=[N:30]\[C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[CH3:40][CH:41]([NH2:43])[CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClC(Cl)C>[F:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[C:31](/[N:30]=[C:11]1\[NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:27])[CH3:28])[CH2:22][CH2:21]3)=[CH:15][C:14]=2[N:10]\1[C@H:7]1[CH2:8][CH2:9][C@@H:4]([CH:1]([NH:43][CH:41]([CH3:42])[CH3:40])[CH3:2])[CH2:5][CH2:6]1)=[O:39]
Reactant: CC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(F)c3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)NC(C)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(F)c3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.5 %

Procedure:
(E)-N-(1-(cis-4-acetylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide (0.06 g, 0.112 mmol) was suspended in 0.37 mL of dichloroethane. To this mixture was added propan-2-amine (7.30 mg, 0.123 mmol) followed by sodium triacetoxyborohydride (0.033 g, 0.157 mmol) and AcOH (6.42 pt, 0.112 mmol). The resulting mixture was stirred for 6 hours at RT and quenched with 1N aqueous NaOH (5 mL). DCM (20 mL) was added and the layers were separated. The organic portion was dried over sodium sulfate and concentrated to afford a yellow residue which was purified by silica gel chromatography (5-30% MeOH/DCM) to afford (E)-3-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(1-(isopropylamino)ethyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as an off-white solid (10 mg, 15.42% yield). MS m/z=578.4 [M+H]. Calc'd for C34H48FN5O2: 577.4
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:29][C:28]([C:34]4[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=4)([C:30]([F:33])([F:32])[F:31])[O:27][N:26]=3)=[CH:21][C:20]=2Br)([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:47]=[O:48])C>O.[C-]#N.[C-]#N.[Zn+2].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>[CH:1]([N:14]1[CH2:17][C:16]2([C:19]3[C:20](=[CH:21][C:22]([C:25]4[CH2:29][C:28]([C:34]5[CH:39]=[C:38]([Cl:40])[C:37]([Cl:41])=[C:36]([Cl:42])[CH:35]=5)([C:30]([F:33])([F:32])[F:31])[O:27][N:26]=4)=[CH:23][CH:24]=3)[C:47](=[O:48])[O:18]2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: O=C1OC2(CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 150 °C
Yield: 58 %

Procedure:
To a solution of 1-benzhydryl-3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol (500 mg, 0.7 mmol) in DMF (12 mL) was added Zn(CN)2 (180 mg, 1.5 mmol) and the reaction was degassed with N2 purge. Pd(PPh3)4 (40 mg, 0.04 mmol) was added and the reaction mixture was heated at 150° C. for 15 minutes under microwave irradiation. The reaction mixture was diluted with water, extracted with EtOAc, dried, and concentrated under vacuum. The crude material was chromatographed (40 g Redi-Sep column) eluting from 100% heptane to 50:50 EtOAc:heptane to afford the intermediate (268 mg, 58%) as a glass. 1HNMR (CDCl3) δ ppm: 8.32 (1H), 8.18 (1H), 7.95 (1H), 7.68 (2H), 7.51 (4H), 7.35-7.23 (6H), 4.55 (1H), 4.15 (1H), 3.79-3.69 (3H), 3.60 (2H); m/z (CI) 657 ([M+H]+.
Reaction SMILES: [CH3:1][OH:2].[CH2:3]([N:8]([C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])[C:9](=[O:13])[C:10](Cl)=[O:11])[C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:3]([N:8]([C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])[C:9](=[O:13])[C:10]([O:2][CH3:1])=[O:11])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CO
Reactant: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)OC
Yield: 97.9 %

Procedure:
0.64 g (0.02 mole) of methanol are added to 5.35 g (0.02 mole) of 97% pure N-neopentyl-N-2-propinyloxycarbonyloxamic acid chloride in 50 ml of toluene, and 2.02 g (0.02 mole) of triethylamine are then added dropwise, while cooling with ice. After the precipitate has been filtered off, the filtrate is washed with water, dried over sodium sulphate and freed from the solvent under a high vacuum. 5 g (98% of theory) of methyl N-neopentyl-N-2-propinyloxycarbonyl-oxamate of refractive index nD20 =1.4634 are obtained.
Reaction SMILES: [N+](C1C=CC(C2C3C=C4OCOC4=CC=3CC(C)NN=2)=CC=1)([O-])=[O:2].ClCCl.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCCCC(O)=O>>[CH:37]1([NH:36][C:35]([NH:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[O:2])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Solvent: ClCCl
Solvent: CCCCC(=O)O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of a 2.5 g (7.68 m/mol) portion of the product of Example 26 in 40 ml of anhydrous dichloromethane 4.75 g (23 mmol) of dicyclohexylcarbodiimide and 2.88 g (23 mmol) of n-valeric acid were added and the reaction mixture was maintained at 25° C. under intermittent stirring for 24 hours. Then the N,N'-dicyclohexylurea formed as by-product was filtered, the filtrate was evaporated under reduced pressure, the residue was mixed with 2×40 ml of distilled water, decanted and the wet product was left to solidify under 50 ml of 50% ethanol. The solid compound was filtered, washed with 2×10 ml of 50% ethanol and dried at 80° C. The raw product obtained was recrystallized from 24 ml of ethanol and the crystals were dried at 100° C. to yield 2.20 g (70%) of the aimed product as a yellow powder, m.p.: 145°-147° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O1CCOCC1>[NH:12]([C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(C(=O)O)ccn1
Temperature: 100 °C
Yield: 4.2 %

Procedure:
To a solution of 2-chloropyridine-4-carboxylic acid (1.57 g, 100 mmol) in 1,4-dioxane (30 mL) was added hydrazine hydrate (1.0 g, 200 mmol) dropwise at rt. The reaction mixture was heated at 100° C. overnight. The mixture was concentrated, and the residue was purified by flash column chromatography (CH2Cl2/MeOH=20/1) to afford the title compound (650 mg, 42%) as a white solid. [M+H] Calc'd for C6H7N3O2, 154. Found, 154.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[F:15])[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[F:15])[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:40])([F:42])[F:41])[NH:30][CH2:29]2)=[O:7])[NH:1][C:36]([O:35][CH3:34])=[O:43])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccncc1F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccncc1F

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 from Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=714 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>CCCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: OCCCCCCCCBr
Reactant: C1=COCCC1
Solvent: CCCCCCC
Product: BrCCCCCCCCOC1CCCCO1
Reaction time: 22 h

Procedure:
To a stirred, room temperature suspension of Amberlyst 15 resin (2.37 g) in a solution of 8-bromo-1-octanol (9.50 g, 0.0454 mol) in heptane (95 mL) was added dropwise neat 3,4-dihydro-2H-pyran (5.0 mL, 0.055 mol) under a nitrogen atmosphere, and the mixture was stirred for 22 hours. The resin was filtered off, and the filtrate was rotoevaporated to an oil. The oil was chromatographed on silica gel (400 g, 230-400 mesh) using PET ether-diethyl ether (10:1, 10×500 mL) as eluent. Fractions containing title compound were rotoevaporated and dried in vacuo to give a clear, colorless oil, yield 10.92 g (82%). 1H NMR (CDCl3): δ 4.6 (dd, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.4 (m, 3H), 1.8 (m, 3H), 1.7 (m, 1H), 1.6 (m, 6H), 1.4 (m, 1H), 1.3 (m, 7H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH:11]([S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[CH2:12].C(N(CC)CC)C>CN1C(=O)CCC1>[O:14]=[S:13]1(=[O:15])[CH2:16][CH2:17][N:1]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH2:12][CH2:11]1
Reactant: NCCc1ccc(N)cc1
Reactant: C=CS(=O)(=O)C=C
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1ccc(CCN2CCS(=O)(=O)CC2)cc1

Procedure:
A mixture of 4-(2-amino-ethyl)-phenylamine (1 g) and ethenesulfonyl-ethene (0.74 ml) in NMP (2.5 ml) containing triethylamine (1.02 ml) was heated to 110 C for 30 mins. The mixture was then allowed to cool and the solid produced was collected by filtration, washed with ether, and dried, giving the title compound as a pale yellow solid (1.59 g).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@H:7]([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>>[OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@H:7]([CH3:11])[C:8]([Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](Oc1ccc(O)cc1)C(=O)O
Product: C[C@@H](Oc1ccc(O)cc1)C(=O)Cl

Procedure:
4.0 g (0.022 mol) of (R)-2-(4-hydroxyphenoxy)propionic acid was dissolved in 25 ml of thionyl chloride, the mixture was refluxed for 5 hours, and distilled under a reduced pressure. 3.3 g (0.016 mol) of (R)-2-(4-hydroxyphenoxy)propionic acid chloride thus obtained was dissolved in 60 ml of tetrahydrofuran, and the mixture was cooled to 0° C. 3.04 g (0.018 mol) of 2-amino-5-chlorobenzoxazole and triethylamine dissolved in 15 ml of tetrahydrofuran were sequentially added to the reaction mixture. The mixture was stirred at room temperature for 5 hours, and the solvent was removed therefrom under a reduced pressure. After adding water thereto, the mixture was extracted three times with ethyl acetate three times. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was subjected to column chromatography (ethyl acetate:n-hexane=1:4) to obtain the title compound (4.04 g, 75.9%).
Reaction SMILES: C[O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)N(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-dimethoxy-N,N-dimethylbenzamide (100 mg, 0.48 mmol) in methylene chloride (2.5 mL) is added BBr3 (1.0M in methylene chloride, 1.4 mL) dropwise and the mixture is stirred at RT for 18 h. Water is added and the suspension is extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound: 1H NMR (DMSO-d6) δ 9.35 (s, 2H), 6.93-6.89 (t, J=8.34 Hz, 1H), 6.29-6.27 (d, J=8.09 Hz, 2H), 2.89 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:28]([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][C:12]1[CH:28]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:14][CH:13]=1
Reactant: CC[BH-](CC)CC
Reactant: CCCCCC(=O)/C=C/c1occc(=O)c1OCCCCCC(=O)OCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(O)/C=C/c1occc(=O)c1Oc1cccc(C(=O)OCC)c1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution, cooled under nitrogen to -78°, of 0.200 g (0.53 mmol) of 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-4-pyrone in 2 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70° to -75°, 0.53 ml (0.53 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 0.5 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.131 g (65%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carboethoxypenyloxy)-4-pyrone. NMR (CDCl3, 100 M Hz): δ0.90 (3H, t, J=4.5 Hz), 2.33 (2H, t, J=6 Hz), 4.13 (4H, m), 4.35 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[O:21][C:22]([CH3:28])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[CH3:28])=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: Cc1nc(C(=O)O)c(C)o1
Product: Cc1nc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)c(C)o1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2,5-dimethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=383.2 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[C:8](OC(=O)C)(=[O:10])[CH3:9].CO>O1CCCC1>[C:8]([NH:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1)(=[O:10])[CH3:9]
Reactant: Nn1nnnc1S
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nn1nnnc1S
Reaction time: 0.33 h
Yield: 82.9 %

Procedure:
1-Amino-5-mercapto-1H-tetrazole (4.18 g) was dissolved in tetrahydrofuran (30 ml), and acetic anhydride (4.01 g) was added thereto. The mixture was refluxed for 6 hours and then condensed under reduced pressure to remove solvent. Methanol (4 ml) was added to the residue thus obtained, and the methanol solution was allowed to stand at room temperature for 20 minutes. The mixture was evaporated to remove solvent. Hot isopropanol was added to the residue thus obtained, and the solution was allowed to stand at room temperature. Crystalline precipitates were collected by filtration. 4.71 g of 1-acetamido-5-mercapto-1H-tetrazole were obtained as colorless needles. mp 147°-148° C. (decomp.)