Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[O:7]1CCO[CH2:9][CH2:8]1.[Br:13]CCO>CC(C)=O>[Br-:13].[OH:7][CH2:8][CH2:9][N+:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1
Reactant: C1COCCO1
Reactant: Cc1cscn1
Reactant: OCCBr
Solvent: CC(C)=O
Product: Cc1csc[n+]1CCO
Product: [Br-]
Reaction time: 0.5 h

Procedure:
To the mixture of 4-methylthiazole (24 g) and dioxane (30 ml) was added 2-bromoethanol (40 g), and the resulting mixture was heated under reflux for 4 hours. To the reaction left standing at room temperature for about 0.5 hour was added acetone (100 ml) with stirring to give white to pale yellow solids, which were collected by filtration, washed with acetone and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].N1C=CC=C(C)C=1.[CH2:26]([NH:28][CH2:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:27]>[OH-].[NH4+]>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:32]3[CH2:33][CH2:34][CH:30]([CH2:29][NH:28][CH2:26][CH3:27])[CH2:31]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1cccnc1
Product: CCNCC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)C1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 2.70 g (10.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 60 ml of β-picoline and 3.85 g (30.0 mmole) of N-ethyl-3-pyrrolidinemethanamine were refluxed overnight. Reaction mixture was cooled to room temperature, 100 ml concentrated ammonium hydroxide added, and the solvents removed at reduced pressure. A solution of 200 ml dichloromethane/ether (1:3) was added. The resulting precipitate was filtered, washed with ethanol/ether (1:3) and finally with ether until dry to give 1.87 g of 1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 248°-252° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]([O:13][CH2:14][C:15]#[N:16])=[C:11]([CH3:20])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].CC[O:25]CC>>[F:1][C:2]([F:21])([F:22])[C:3]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]([O:13][CH2:14][C:15]([NH2:16])=[O:25])=[C:11]([CH3:20])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: CCOCC
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC#N
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(N)=O

Procedure:
Stir a sample of crude 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetonitrile, prepared as described in Example 8a, with ether for 30 minutes. Filter the solid and recrystallize from ether to obtain as a white solid, 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetamide, m.p. 180°-182° C.
Reaction SMILES: I[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].C([N-]C(C)C)(C)C.[Li+]>CN1C(=O)N(C)CCC1>[CH2:23]([O:22][C:19](=[O:21])[CH2:20][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1)[CH3:24]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CI
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)CCc1cc(-c2ccc(C(F)(F)F)cc2)nn1C

Procedure:
In analogy to the procedure described in example 20 b], 5-iodomethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole was reacted with ethyl acetate in the presence of lithium diisopropylamide and DMPU to obtain 3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propionic acid ethyl ester as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]([I:17])=[C:11]([CH3:16])[C:12]=1[CH2:13][CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[NH:9][C:10]([I:17])=[C:11]([CH3:16])[C:12]=1[CH2:13][CH:14]=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(I)[nH]c(C(=O)OC(C)(C)C)c1CCO
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(I)[nH]c(C(=O)OC(C)(C)C)c1CC=O
Reaction time: 3 h
Yield: 70.8 %

Procedure:
3-(2-Hydroxy-ethyl)-5-iodo-4-methyl-1H-pyrrole-2-carboxylic acid tert-butyl ester (0.34 mmol, 114 mg) in DMSO (2 mL) was treated with o-iodoxybenzoic acid (IBX, 0.51 mmol, 148 mg), then held at room temperature for 3h. The mixture was diluted with ethyl acetate (50 mL), washed with brine (10 mL), then concentrated under reduced pressure to provide 84 mg (75%) of 5-iodo-4-methyl-3-(2-oxo-ethyl)-1H-pyrrole-2-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) δ 9.63 (1H, s), 8.91 (1H, br s), 4.09 (2H, s), 2.62 (3H, s), 1.52 (9H, s).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCC[CH2:35]1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:34][CH2:35][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CCCc3cccc(C(F)(F)F)c3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3-(3-(trifluoromethyl)phenyl)propanal for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61 (d, J=6.4, 1H), 7.69-7.62 (m, 3H), 7.53 (d, J=6.5, 1H), 7.46 (t, J=7.8, 1H), 7.42 (d, J=5.5, 1H), 7.34 (t, J=7.5, 2H), 7.26 (t, J=7.3, 1H), 4.37 (tt, J=6.4, 12.7, 1H), 3.24 (d, J=10.5, 1H), 3.00 (dd, J=1.9, 8.9, 0.5H), 2.78-2.63 (m, 3H), 2.61 (dd, J=2.3, 9.1, 0.5H), 2.57-2.45 (m, 1H), 2.40 (dd, J=7.1, 14.3, 0.5H), 2.37-2.26 (m, 3H), 2.24-2.07 (m, 3H), 1.93-1.83 (m, 1H), 1.83-1.71 (m, 2H), 1.71-1.63 (m, 1H), 1.48-1.37 (m, 1H), 1.37-1.30 (m, 0.5H), 1.23 (dd, J=6.5, 13.6, 3H), 0.72 (dd, J=4.4, 6.6, 3H); MS (ESI+) m/z 473 (M+H)+.
Reaction SMILES: [Br-].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[CH:17]O[N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1.[Br:20]C[C:22]([NH:24]C1C=CN=CN=1)=O>>[Br-:20].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[CH:17][N:24]=[CH:22][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Reactant: O=C(CBr)Nc1ccncn1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccncn1

Procedure:
This compound was prepared by an analogous method to (R)-3-Hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) by replacing 2-bromo-N-isoxazol-3-yl-acetamide (Ai) with 2-bromo-N-pyrimidin-4-yl-acetamide (Qi).
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH2:6]([O:13][C:14]([NH:5][C:3](=[NH:4])[S:2][CH3:1])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSC(=N)N
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSC(=N)NC(=O)OCc1ccccc1

Procedure:
13.9 g (0.1 mole) of S-methyl-isothiourea are dissolved in 50 ml of water, cooled to a temperature of 0° to 5° C., and at this temperature and with constant stirring 15 ml (0.1 mole) of chloroformic acid benzyl ester and 50 ml of 4 N sodium hydroxide are added in about 20 minutes. The precipitate formed is filtered, washed three times with 50 ml of cold water, then three times with 50 ml of n-hexane, and finally dried over phosphorpentoxide in vacuo. Yield 15.7 g (70 percent) of the named compound. M.p.: 74° to 75° C.; RF1 0.70 to 0.75.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([NH2:23])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([Cl:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.N1C=CC=CC=1>ClCCl>[ClH:33].[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:23][C:16]2[CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)cc3ccoc23)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cc(N3CCNCC3)c3occc3c2)cc1
Product: Cl
Yield: 17.6 %

Procedure:
4-(5-Amino-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (44 mg, 0.139 mmol) in 3 ml dichloromethane was added to a tube containing p-toluenesulfonyl chloride (32 mg, 0.167 mmol) together with pyridine (100 μl, 1.25 mmol) and left on a shaker over weekend. After purification by preparative HPLC, the resulting Boc-material was treated with HCl in ether and left on a shaker until the salt had formed. The solution was centrifugated and the supernatant was removed. Ether was added, then centrifugated and decanted (repeated three times) to remove the excess HCl. The remaining ether was finally evaporated in a SpeedVAc concentrator to yield 10 mg of title product. HPLC purity=94%, m/z=372.3 (M+H). 1H NMR (270 MHz, methanol-d4) δ ppm 2.35 (s, 3 H) 3.45 (m, 8 H) 6.63 (d, J=1.85 Hz, 1 H) 6.71 (d, J=2.11 Hz, 1 H) 6.88 (d, J=1.85 Hz, 1 H) 7.25 (m, 2 H) 7.58 (m, 2 H) 7.71 (d, J=2.11 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(C2=NOC(COc3ccon3)C2)cc1F
Product: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1-n1cncn1

Procedure:
(5RS)-3-(3,4-Difluorophenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (140 mg, 0.5 mM) was treated with 1,2,4-triazole using essentially the conditions of Example 5. Crude product was chromatographed on a 5 g silica Mega Bond Elut® column, eluting with a gradient from 0–25% ethyl acetate in dichloromethane. Relevant fractions were combined to give the desired product (45 mg). MS (ESP): 330 (MH+) for C15H12FN5O3
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:2].C(N(CC)CC)C.[C:38]([C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[O:49][CH:50]([CH3:52])[CH3:51])[C:43](Cl)=O)#[N:39]>CN(C)C=O>[C:38]([C:40]1[CH:41]=[C:42]([C:43]2[O:21][N:20]=[C:18]([C:14]3[C:13]([CH3:22])=[C:12]4[C:17](=[CH:16][CH:15]=3)[CH:8]([CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10][CH2:11]4)[N:19]=2)[CH:46]=[CH:47][C:48]=1[O:49][CH:50]([CH3:51])[CH3:52])#[N:39]
Reactant: CCOC(=O)CCCC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[4-(ethyloxy)-4-oxobutyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 27; 240 mg, 0.572 mmol) in N,N-dimethylformamide (DMF) (4 ml) was added triethylamine (0.119 ml, 0.858 mmol) followed by 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (WO 2008128951; 141 mg, 0.629 mmol) in DMF (2 ml) dropwise over one minute at room temperature under nitrogen. The resulting mixture was stirred for 1 h at room temperature, then warmed up to 120° C. After 2 h at 120° C., most of the solvent was removed, and the residue diluted with ethyl acetate. The solution was washed with sodium bicarbonate then brine, dried over MgSO4 and concentrated in vacuo to give the crude product (ca. 300 mg). Purification by flash chromatography on silica gel, eluting with 8-38% ethyl acetate in cyclohexane, gave the title compound (120 mg) as a white foam.
Reaction SMILES: [N:1]1([C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[C@H:43]12[CH2:56][C@H:47]([N:48]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46][NH:45][CH2:44]2.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:33][O:32][C:30]([C:29]1[CH:28]=[CH:27][C:26]([C:13]2[C:14]([CH3:24])([CH3:25])[C@H:15]3[C@:10]([CH3:36])([CH2:11][CH:12]=2)[C@@H:9]2[C@:18]([CH3:23])([C@@:19]4([CH3:22])[C@H:6]([CH2:7][CH2:8]2)[C@H:5]2[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:4]2([NH:1][CH2:2][CH2:3][N:45]2[CH2:44][C@@H:43]5[CH2:56][C@@H:47]([N:48]5[C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:46]2)[CH2:21][CH2:20]4)[CH2:17][CH2:16]3)=[CH:35][CH:34]=1)=[O:31]
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CNC[C@H]1C2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4C[C@@H](C3)N4C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Reaction time: 112 h
Yield: 28.9 %

Procedure:
Methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (250 mg, 0.439 mmol) and (1R,5S)-tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (435 mg, 2.194 mmol) were combined in a 20 mL scintillation vial, dissolved in THF (5 mL) and treated with N,N-di-iso-propylethylamine (0.764 mL, 4.39 mmol). The reaction mixture was heated to 100° C. After 112 h, the reaction mixture was cooled to rt, purified by reverse phase HPLC using prep-HPLC method 13 and dried under vacuum to give the title compound (126.6 mg, 0.127 mmol, 29.0% yield) as a white solid. LC/MS: m/e 768.5 (M+H)+, 2.41 min (method 7). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.30 (d, J=4.4 Hz, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.17 (d, J=5.9 Hz, 2H), 3.92 (s, 3H), 3.62 (d, J=11.7 Hz, 1H), 3.56-3.44 (m, 3H), 3.43-3.31 (m, 5H), 2.85-2.72 (m, 1H), 2.66-2.56 (m, 1H), 2.12 (dd, J=17.0, 6.5 Hz, 2H), 2.07-1.89 (m, 5H), 1.75 (d, J=11.5 Hz, 1H), 1.70 (s, 3H), 1.65 (br. s., 1H), 1.60-1.50 (m, 5H), 1.48 (s, 9H), 1.46-1.34 (m, 5H), 1.26-1.19 (m, 1H), 1.13 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.94 (br. s., 3H). 13C NMR (101 MHz, CHLOROFORM-d) δ 167.2, 154.9, 148.6, 146.9, 146.3, 130.0, 128.5, 128.0, 123.9, 111.8, 81.7, 77.2, 72.4, 58.3, 53.9, 52.8, 52.0, 49.4, 49.0, 45.3, 42.1, 41.8, 40.7, 37.9, 37.5, 37.2, 36.2, 33.5, 32.6, 29.4, 28.3, 28.3, 27.8, 26.3, 25.4, 25.1, 21.0, 20.9, 19.6, 19.1, 16.5, 15.8, 14.6.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]([F:23])([F:22])[CH:14]([C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1)[OH:15]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:15][CH:14]([C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)[C:13]([F:12])([F:23])[F:22])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cc1cc(C(O)C(F)(F)F)on1
Product: Cc1cc(C(Oc2cc(F)ccc2N)C(F)(F)F)on1

Procedure:
Intermediate III.8 is prepared in a similar manner as intermediate III.4 from 2,4-difluoro-1-nitro-benzene and 2,2,2-trifluoro-1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[O:5][C:4]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]([C:17]3[CH:24]=[CH:23]C(C#N)=[CH:19][N:18]=3)[N:9]=2)=[N:3]1.CS(O)(=O)=O.[C:30]([O:33]CC)(=[O:32])[CH3:31].[OH2:36]>>[CH3:1][N:2]1[C:6](=[O:5])[O:36][C:4]([C:8]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[N:10]([C:17]3[CH:24]=[CH:23][C:31]([C:30]([OH:33])=[O:32])=[CH:19][N:18]=3)[N:9]=2)=[N:3]1
Reactant: Cn1nc(-c2cc(C(F)(F)F)n(-c3ccc(C#N)cn3)n2)oc1=O
Reactant: CCOC(C)=O
Reactant: O
Agent: CS(=O)(=O)O
Product: Cn1nc(-c2cc(C(F)(F)F)n(-c3ccc(C(=O)O)cn3)n2)oc1=O
Temperature: 70 °C
Yield: 60 %

Procedure:
Step-2: 5-6-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinic acid: In a sealed tube containing a solution of 6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinonitrile (0.80 g, 2.37 mmol) in methanesulfonic acid (5 mL, 77 mmol) and water (4 mL) was heated at 70° C. for 6 h. The reaction mixture was then cooled to room temperature and water (10 mL) was added to the above mixture followed by ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 500 mg (60%) of the title compound as white solid. 1HNMR (400 MHz, DMSO-d6) δ 13.71 (s, 1H, D2O exchangeable), 9.01 (d, J=2.5 Hz, 1H), 8.55 (dd, J=2.5 & 8.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.80 (s, 1H), 3.40 (s, 3H); ESI-MS (m/z) 356 (MH)+.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH2:27]([N:29]1[CH2:34][N:33]([CH3:35])[CH2:32][N:31]([C:36]2[S:37][C:38]3[C:44]([CH2:45]O)=[CH:43][C:42]([C:47]4[CH:48]=[N:49][C:50]([N:53]5[CH2:58][CH2:57][C:56]([CH3:64])([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]5)=[N:51][CH:52]=4)=[CH:41][C:39]=3[N:40]=2)[C:30]1=[O:65])[CH3:28]>C(Cl)Cl>[CH2:27]([N:29]1[CH2:34][N:33]([CH3:35])[CH2:32][N:31]([C:36]2[S:37][C:38]3[C:44]([CH2:45][I:25])=[CH:43][C:42]([C:47]4[CH:48]=[N:49][C:50]([N:53]5[CH2:58][CH2:57][C:56]([CH3:64])([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]5)=[N:51][CH:52]=4)=[CH:41][C:39]=3[N:40]=2)[C:30]1=[O:65])[CH3:28]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(CO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(CI)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
Imidazole (75 mg, 1.09 mmol), triphenylphosphine (276 mg, 1.05 mmol) and iodine (267 mg, 1.05 mmol) were dissolved in CH2Cl2 (15 mL) and stirred at rt for 5 mins. A solution of ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-(hydroxymethyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (485 mg, 0.88 mmol) in CH2Cl2 (10 mL) was then added and the mixture stirred at rt for 2 h. The mixture was pre-adsorbed onto silica gel and purified by flash column chromatography (80 g GraceResolv silica cartridge—dry loaded) eluting with 25-100% EtOAc/heptane to afford the desired compound (323 mg, 56%) as a pale yellow foam. MS: 664.02 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17](CO)([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O-])(O)=[O:25].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:19][CH2:18][C:17]([CH:16]=[O:15])([CH2:20][CH2:21]2)[O:25][CH2:24]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: O=C([O-])O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a mixture of (4-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-1-yl)methanol (5A; 182 mg, 0.586 mmol) and NaHCO3 (59 mg, 0.704 mmol) in CH2Cl2 (5 mL) at 0° C. was added Dess-Martin periodinane (298 mg, 0.70 mmol). The solution was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc, washed successively with sat'd aq NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 100% EtOAc:hexanes) to afford the title compound (123 mg, 68% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H), 7.41-7.28 (m, 3H), 7.12-7.16 (m, 1H), 7.06-6.89 (m, 4H), 6.88 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 4.12-4.09 (m, 2H), 2.17-1.90 (m, 8H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](Cl)=[O:33]>>[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])=[O:33]
Reactant: O=C(Cl)c1ccco1
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Product: O=C(CCNC(=O)c1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylcarbonyl)amino]-1-oxopropyl]hydrazide (31) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared in the manner described above in Example 9, and 2-furoyl chloride in the same manner as described in Example 10 on a 1.9 mmol scale to yield 0.37 g (43%) of product. Analysis calculated for C22H19N4O5Cl (M.W. 454.87): C, 49.26; H, 4.36; N, I2.77; Cl, 7.79. Found: C, 49.05; H, 4.40; N, 12.66; cl, 7.58.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:3]1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>ClCCl>[CH3:1][N:2]1[C:6]([C:7]([Cl:29])=[O:8])=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:3]1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.0 g (12.8 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid are suspended in 50 ml of dichloromethane. 0.02 ml of N,N-dimethylformamide and 3.54 ml (38.4 mmol) of oxalyl chloride are then added in succession. The reaction mixture is then stirred first at room temperature for 30 minutes and then under reflux for 30 minutes. The solvent is removed under reduced pressure on a rotary evaporator. The 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride formed is used for the subsequent synthesis step without further purification.