Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:11][Cl:12])[C:5]([O:7]CC)=[O:6].[OH-].[Na+].S(=O)(=O)(O)O.O>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:13][CH2:14][CH2:15][O:16]1)[CH2:11][Cl:12])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)C1(CCl)OCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)O)C1(CCl)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of ethyl 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 10.4 g) in ethanol (30 ml) was added an aqueous solution (10 ml) of sodium hydroxide (3.3 g) under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was adjusted to pH 7 with 20% sulfuric acid under ice-cooling and stirring, and water (30 ml) was added thereto, and then the solvents are distilled off. To the residue was added water (30 ml), and the resultant solution was washed with diisopropyl ether (50 ml). To the aqueous solution was added diisopropyl ether (100 ml), adjusted to pH 2 with 20 % sulfuric acid under ice-cooling and stirring and then saturated with sodium chloride. The diisopropyl ether layer was separated, and the remaining aqueous layer was further extracted with diisopropyl ether. The diisopropyl ether layer and extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with an activated carbon and then filtered. The filtrate was concentrated and the remaining oil was allowed to stand for 1 hour under reduced pressure to give crystals of 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyric acid (syn isomer), mp 80°-81° C. in yield of 99.6%.
Reaction SMILES: [CH2:1]([C:3]1[C:8](/[CH:9]=[CH:10]/[O:11]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)=[N:16][N:17]=1)[CH3:2].Cl.O.O.CC(=O)OCC>O1CCOCC1>[CH2:1]([C:3]1[C:4]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]([F:30])([F:29])[F:31])[CH:19]=3)=[N:16][N:17]=2)=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]=[O:11])[CH3:2]
Reactant: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 20 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
To a solution of 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D18) (42 mg) in 1,4-dioxane (15 mL) stirred under nitrogen at room temperature was added 6 M HCl/water (15 mL). The reaction mixture was stirred at 20° C. for 5 h. Water was added. EA was used to extracted the aqueous layer for 3 times. The combined organic phases were washed with brine, dried over sodium sulphate and evaporated in vacuo to give the crude product (2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)acetaldehyde (D19) (40 mg), which was used directly for the next step. MS (ES): C22H21F3N2O2S requires 434. found 435.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]([S:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[C:5]3[CH:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:6]3[C:7]=2[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1.[N:29]([Sn](CCCC)(CCCC)CCCC)=[N+:30]=[N-:31].CC(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[C:4]([S:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[C:5]3[CH:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:6]3[C:7]=2[CH:8]=[C:9]([C:11]2[N:29]=[N:30][NH:31][N:12]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(C#N)cc12
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(-c3nn[nH]n3)cc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of (+/−)-methyl {8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate (example 31, Step 1, 200 mg, 0.42 mmol) in toluene (3 mL) was added azidotributyltin (279 mg, 0.84 mmol). The reaction mixture was stirred at 90° C. for 16 hours, AcOH (1 mL) was added and the reaction was stirred for 2 hours and concentrated. The residue was swished in acetone/hexane 1:2 to give 160 mg of the title compound as a white solid used as such for next reaction.
Reaction SMILES: C([O:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1=[O:22])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][C@H:11]1[C@H:12]([CH3:13])[N:9]([OH:8])[C:10]1=[O:22])=[O:16])([CH3:20])([CH3:19])[CH3:21]
Reactant: [H][H]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Yield: 79 %

Procedure:
A solution of 9.18 g of (3S-trans)-N-benzyloxy-3-t-butoxycarbonylamino-4-methylazetidinone in 300 ml of 95% ethanol was stirred in an atmosphere of hydrogen with 1.85 g of 10% palladium on charcoal. After 141 minutes the slurry was filtered and evaporated in vacuo. The residue was recrystallized from ether-hexane to yield 5.12 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][OH:21].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: OCCCBr
Solvent: O
Solvent: CC#N
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 63.9 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol) K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140°-142° C. ANALYSIS: Calculated for C13H19FN2O2: 64.73%C 6.88%H 10.06%N Found:. 64.79%C 6.97%H 10.03%N
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9](=[O:17])[NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:29]([OH:31])[CH3:30]>>[CH2:29]([O:31][N:2]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9](=[O:17])[NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][CH:27]=1)[CH3:30]
Reactant: CCOC(=O)CNC(=O)N(Cc1ccc(C#N)cc1)OCc1ccccc1
Reactant: CCO
Agent: Cl
Product: CCON=Cc1ccc(CN(OCc2ccccc2)C(=O)NCC(=O)OCC)cc1
Temperature: -30 °C
Reaction time: 24 h

Procedure:
2.99 g (8.14 mmol) of ethyl (3-(4-cyanobenzyl)-3-benzyloxyureido)acetate are dissolved in 250 ml of ethanol and cooled to -30° C. Dry HCl gas is introduced into the solution. After 24 h, excess HCl gas is driven out by nitrogen and the solvent is removed in vacuo. The residue crystallizes from ethyl acetate/ether.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[BH4-].[Na+].Cl>CO>[OH:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][I:1]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCI)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCI)cc1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 50 mg of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 3, in 3 mL of methanol was added 50 mg of NaBH4. The mixture was stirred for 30 minutes, acidified with 2N HCl, and the methanol removed in vacuo. The concentrate was extracted with EtOAc. The organics were dried over Na2SO4, filtered, and concentrated to afford 40 mg of 4-(1-hydroxy-4-iodobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=2[O:31][CH3:32])[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:36]1C=C(S(Cl)(=O)=O)C=C[C:41]=1Cl>>[CH2:36]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:41]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(3,4-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=523.1 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,4-dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=1[C:13]([F:16])([F:15])[F:14])=[O:5])[CH3:2].[Br:17]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:17])[C:9](=[O:12])[NH:8][C:7]=1[C:13]([F:16])([F:14])[F:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (157.6 g, 0.60 mol) in tetrahydrofuran (1500 mL) was added with stirring N-bromosuccinimide (124.3 g, 0.66 mol). The mixture was stirred for 1 h at room temperature. Two thirds of the solvent were removed in vacuo and the remaining material was poured portionwise (15 min) with stirring into cold water (20 L). The product precipitated and the suspension was stirred for 1 h at room temperature, filtered and the filter cake was washed extensively with water (6×200 mL). The filter cake was redissolved in ethyl acetate (2000 mL), dried with MgSO4 and concentrated to a volume of ˜300 mL. This solution was added dropwise into n-heptane (800 mL) to precipitate the product. Filtration and washing with n-heptane/ethyl acetate (4:1, 4×50 mL) and drying (in vacuo, 40° C.) yielded the title compound (93 g) as a white solid. Concentration of the mother liquor and addition of n-heptane/ethyl acetate (3:1, 150 mL) yielded a second crop of 16.4 g.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].[CH:8]1([O:14][C:15](Cl)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([O:14][C:15]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(=O)OC1CCCCC1

Procedure:
From 24.8 g (0.20 mole) of trimethylphosphite and 32.1 g (0.20 mole) of cyclohexylchloroformate. (Y. Iwakura and A. Nabeya, J. Org. Chem. 25 (1960) 1118; M. E. Fourneau et al. Chem. Abstr. 16 (1922) 240; J. H. Saunders et al. J. Am. Chem. Soc. 73 (1951) 3797). (100° C., 2 hours). Yield 30 g (64%). Bp1.4-1.8 148°-151° C. nD21 1.4543.
Reaction SMILES: [OH:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[S:13](Cl)([CH3:16])(=[O:15])=[O:14].Cl>C(Cl)Cl>[CH3:16][S:13]([O:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](OS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of (S)-methyl 2-hydroxy-2-phenylacetate (20.0 g, 120 mmol) in DCM (240 mL) maintained at 0° C. under N2 flowstream, are added mesylchloride (11.2 mL, 144 mmol) and TEA (20.1 mL, 144 mmol) and the mixture is stirred at RT for 1 hour (UPLC-MS monitoring: complete conversion). The mixture is cooled to 0° C., 0.1N HCl (240 mL) is added and the desired compound is extracted with DCM (2×200 mL). The combined DCM phases are dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by filtration through a silica bed eluting with DCM, obtaining 22.4 g of the title compound as white solid (76% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11](B(O)O)=[CH:12][C:3]1=2.Br[C:18]1[CH:22]=[C:21]([CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[O:20][CH:19]=1>O>[CH2:28]([O:27][CH:23]([O:24][CH2:25][CH3:26])[C:21]1[O:20][CH:19]=[C:18]([C:11]2[CH:10]=[CH:9][C:4]3[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:16])([CH3:1])[C:3]=3[CH:12]=2)[CH:22]=1)[CH3:29]
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: CCOC(OCC)c1cc(Br)co1
Solvent: O
Product: CCOC(OCC)c1cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)co1

Procedure:
Prepared according to procedure B from 4,4-dimethyl 2 oxo-1,4-dihydro 2 H-benzo [d][1,3]oxazine -6-boronic acid and 3-bromo-5-diethoxymethyl furan. A brown gum: 1H NMR (DMSO-d6) δ10.2 (s, 1H), 8.12(s, 1H), 7.54-7.49 (m, 2H), 6.93-6.88(m, 2H), 5.56(s, 1H), 3.60-3.38(m, 4H), 1.67(s ,6H), 1.2-1.14 (m, 6H). MS (ESI) m/z 344 [M−H]−. Anal. Calcd. For C19H23NO5.½ H2O: C, 64.39; H, 6.77; N, 3.95. Found C, 64.90; H, 6.79; N, 3.78.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17](=O)([O:20]C)[O:18][CH3:19].[Li+].CC([N-]C(C)C)C.CC(O)=O>C1COCC1>[CH3:19][O:18][C:17]([CH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)=[O:20]
Reactant: Cc1nc(-c2ccccc2)ncc1C(=O)O
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)Cc1nc(-c2ccccc2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
A solution of 3.00 g (14.0 mmol) of 4-Methyl-2-phenyl-pyrimidine-5-carboxylic Acid and 2.53 g (28.0 mmol) of dimethyl carbonate in 75 mL of THF is added dropwise with rapid overhead stirring to a slurry of 6.00 g (56.1 mmol) of LDA in 24 mL of THF at −78° C. The mixture is stirred at 25° C. for 5 h and then chilled to −78° C. The reaction is added all at once and rapidly (overhead stirring) to 81 mL (1.40 mol) of glacial HOAc in 210 mL of THF, also held at −78° C. The mixture is warmed to 25° C. and the THF and some HOAc is removed. Water (180 mL) is added and the product is extracted into EtOAc. The extract is washed with H2O (5×), dried (MgSO4) and evaporated. The residue is dissolved in excess aqueous NaHCO3 and extracted with Et2O (5×). These washes were discarded. The aqueous solution is acidified with 2M HCl and extracted with Et2O. The ethereal extracts were backwashed with H2O (6×), dried (MgSO4) and evaporated to give 3.4 g (89%) of orange crystals: mp 173-175° C. (dec); 1H NMR (DMSO-d6) δ 9.29 (s, 1H), 8.44 (m, 2H), 7.60 (m, 3H), 4.45 (s, 2H), 3.65 (s, 3H); MS (ESI) m/z 271.0 (M−H). Analysis for C14H12N2O: Calcd: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.90; H, 4.73; N, 10.11.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])=[N:4][NH:3]1.[NH:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28]CC)=[O:27])[CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>O1CCCC1.O.CC(N(C)C)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([N:22]2[CH2:23][CH2:24][CH:25]([C:26]([OH:28])=[O:27])[CH2:31][CH2:32]2)=[O:17])=[N:4][NH:3]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Reaction time: 18 h
Yield: 7.2 %

Procedure:
3-(4-Oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (A)(7.0 g, 0.25 mol), ethyl isonipecotate (5 ml, 0.32 mol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (12.3 g, 0.32 mol) and N,N,-diisopropylethylamine (10.0 ml, 0.55 mol) were added to dimethylacetamide (40 ml) and stirred for 18 h. Water (100 ml) was added to the reaction mixture and the product was extracted into dichloromethane (4×50 ml). The combined organic layers were washed with water (3×100 ml), dried over MgSO4, filtered and evaporated in vacuo to yield an oil. To a solution of the oil in tetrahydrofuran (100 ml) was added 10% aqueous sodium hydroxide solution (20 ml) and the reaction was stirred for 18 hours. The reaction was concentrated, washed with ethyl acetate (2×30 ml) and acidified with 2M HCl to pH 2. The aqueous layer was extracted with dichloromethane (2×100 ml), then the extracts were dried over MgSO4, filtered and evaporated to yield 1-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoyl]piperidine-4-carboxylic acid (C) as a yellow solid (7.0 g, 65%), m/z [M+1]+ 392 (96% purity), δH 1.3-1.8 (5H, m), 2.8-3.1 (4H, m), 4.4 (2H, s), 7.2-7.3 (1H, m), 7.3-7.4 (1H, m), 7.7-8.0 (5H, m), 8.2-8.3 (1H, m), 12.6 (1H, s).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:24][Si](CC)(CC)CC)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40].[NH4+].[Cl-]>C(Cl)Cl.CCOCC>[CH2:1]([N:8]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:24])([C:20]([F:23])([F:21])[F:22])[C:16]([F:19])([F:17])[F:18])[CH2:11][CH2:10]1)[C:39](=[O:41])[CH3:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NCc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)N(Cc1ccccc1)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 50 mg (0.11 mmol) of trans benzyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine (example 3.1) in 1 mL of CH2Cl2 was treated with 0.1 mL of NEt3, cooled to 0° C. and treated with 0.14 mL (1.97 mmol) of acetylchloride. The mixture was stirred for 30 min and distributed between a saturated aqueous solution of NH4Cl and Et2O. The crude material obtained after drying of the combined organic phases over Na2SO4 and evaporation of the solvent was redissolved in 1 mL of THF, treated with an excess of TBAF and left to stir for 1 hr. Distribution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4, evaporation of the solvent and chromatography on silica gel with EtOAc/heptane 1:1 gave 50 mg (95%) of trans N-benzyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-acetamide as a colorless viscous oil, MS: 398 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:27][NH:26][C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: Cc1ccc(NN)cc1
Product: Cc1ccc(NNC(=O)c2ccncc2Nc2ccc(I)cc2F)cc1

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N′-(4-methylphenyl)isonicotinohydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.4 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.6 mmol of 4-methyl-phenylhydrazine. LC/MS [5.07 min; 463 (M+1)]
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[F-].[K+].O>CS(C)=O>[CH3:16][N:15]1[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]1
Reactant: O=C1CCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)CC1
Yield: 109.8 %

Procedure:
Three identical solutions of piperidin-4-one hydrochloride hydrate (1.84 g, 12.0 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.3 g, 8.0 mmol) and potassium fluoride (1.86 g, 32 mmol) in dry DMSO (20 mL) were heated in a microwave at 100° C. for 12 hr. The mixtures were combined, poured into water (700 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.97 g, 36%). To a solution of this ketone in DMF (40 mL) was added NEt3 (3.05 mL, 21.9 mmol) and chlorotrimethylsilane (1.55 mL, 12.3 mmol). The reaction vessel was sealed and the mixture heated at 90° C. for 16 hr. The mixture was cooled and the product extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine as a yellow gum (1.53 g, 59%). This gum was dissolved in MeCN (130 mL) and cooled to 0° C. A solution of SelectFluor® (1.99 g, 5.61 mmol) in 2:1 MeCN:DMF (10 mL) was added dropwise over 20 min and the mixture stirred at between −5° C. and 0° C. for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (40 mL). The product was extracted into EtOAc (50 mL) and DCM (50 mL), and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a pale yellow solid (1.23 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.04 (ddd, J=48.3, 8.2, 5.7 Hz, 1H), 3.89 (s, 3H), 3.77-3.64 (m, 2H), 3.64-3.51 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.72 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([NH:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:25][NH2:26]>O1CCOCC1.CCOC(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:15]2[CH2:16][C@@H:14]2[CH2:13][NH:12][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:25][NH2:26])[C:7]=2[C:8]([F:11])([F:10])[F:9])=[CH:18][CH:19]=1
Reactant: NN
Reactant: Fc1ccc([C@H]2C[C@@H]2CNc2ccnc(Cl)c2C(F)(F)F)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Yield: 101.3 %

Procedure:
A mixture of 2-chloro-N-(((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)-3-(trifluoromethyl)pyridin-4-amine (0.7 g, 2.031 mmol) and hydrazine monohydrate (2.033 g, 40.6 mmol) in dioxane (8 mL) was heated to reflux under nitrogen for 16 h. The reaction mixture was diluted with EtOAc and extracted with aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were washed with aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to give N-(((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-3-(trifluoromethyl)pyridin-4-amine (0.7 g, 65%) which was used for the next step without purification.