Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31][CH:30]=1>>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:8](=[O:10])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:31][CH:30]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2F)cc1=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3F)cc2=O)nc1
Yield: 30 %

Procedure:
Using the method described in Example 66, 3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 43) and 6-amino-nicotinic acid methyl ester afforded 6-{3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester as a yellow solid (200 mg, 30%); ESI-LRMS m/e calcd for C25H25F N4O5 [M+] 481, found 481 [M+H+]. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.21 (m, 1H) 1.26-1.84 (m, 8H) 1.87-2.05 (m, 1H) 2.22-2.40 (m, 1H) 3.86 (s, 3H) 5.58 (dd, J=10.9, 4.2 Hz, 1H) 5.82 (d, J=2.8 Hz, 1H) 7.29-7.56 (m, 4H) 8.10 (d, J=9.0 Hz, 1H) 8.24 (d, J=2.8 Hz, 1H) 8.28 (dd, J=9.0, 2.3 Hz, 1H) 8.87 (d, J=2.3 Hz, 1H) 11.42 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.[F:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1>>[F:23][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]=2[CH:13]=[C:12]([C:38]2[CH:37]=[CH:36][N:35]=[C:34]([F:33])[CH:39]=2)[N:11]=1)=[CH:3][C:2]([C:26]1[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1ccnc(F)c1
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3)ccc1Oc1c2cc(-c2ccnc(F)c2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 15B, 3-pyridylboronic acid and 2-fluoropyridine-4-boronic acid. MS m/z=458.0 [M+H]+. Calculated for C25H17F2N5O2: 457.14
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.[C-]#[N:14].[Na+].C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32](=O)[CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH2:28][CH2:27]1)=O)C1C=CC=CC=1>CN(C=O)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([C:6]2[NH:14][C:32]([CH:29]3[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]3)=[CH:33][C:34]=2[C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: O=C(C=Cc1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2[nH]c(C3CCNCC3)cc2-c2ccncc2)c1
Reaction time: 1 h

Procedure:
To m-trifluoromethylbenzaldehyde (2.44 g, 0.014 mol) in 5 mL of DMF was added NaCN (0.147 g, 0.003 mol) and the mixture was stirred under argon for 1 hour. This solution was added to 1-(1-benzyloxycarbonyl-4-piperidinyl)-3-(4-pyridyl)-2-propen-1-one in 10 mL of DMF. The mixture was stirred at 65°-75° C. for 20 hours. The volatile components were removed in vacuo. The residual oil was taken up in EtOAc and sat'd NaCl. The EtOAc extract was separated, dried, filtered and concentrated in vacuo to form an oil. The crude oil was chromatographed on silica gel eluting with ethyl acetate, producing 3.45 g of the title compound as a yellow foam.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25]>>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[S:22][C:23]1[C:24](=[O:25])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:27]=1[OH:28]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: Cc1cccc(C)c1SC(C(=O)O)C(=O)O
Product: Cc1cccc(C)c1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2,6dimethylphenyl)thio]propanedioic acid (2.0 g, 6.8 mmol) . m.p. 248-249° C.; 1H NMR (400 MHz, DMSO-d6) δ2.47 (s, 6H), 6.75 (s, 1H), 7.08 (m, 3H), 7.39 (m, 3H), 7.78 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[CH2:9][CH2:10]I)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH:21]2[CH2:24][NH:23][CH2:22]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[CH2:9][CH2:10][N:23]1[CH2:24][CH:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:26][CH:25]=2)[CH2:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CCI)NC(=O)OC(C)(C)C
Reactant: Clc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C

Procedure:
A solution of ((R)-3-iodo-1-methyl-propyl)-carbamic acid tert-butyl ester (0.038 mg, 0.13 mmol), 3-(4-chloro-phenoxy)-azetidine hydrochloride (0.030 g, 0.13 mmol) and triethylamine (0.073 ml, 0.52 mmol) in DMF (1 ml) is stirred at room temperature for 18 hours. The reaction mixture is partitioned between ethylacetate and a saturated solution of sodium bicarbonate. The organic phase is washed with water and brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 1:1 ethylacetate:hexane as eluent to afford {(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamic acid tert-butyl ester. [M+H] 355.33
Reaction SMILES: [C:1]([C@@H:3]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([O-:7])=[O:6])#[N:2].[K+].O.[OH-].[K+].[H][H]>[Ni].C(O)(C)C>[NH2:2][CH2:1][C@@H:3]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@H](C#N)CC(=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of potassium (S)-3-cyano-5-methylhexanoate (20 g, 103.5 mmol), water (50 mL), 45% KOH (12 g), isopropanol (12 g), and Raney Nickel were shaken overnight in a Parr Shaker under 50 psi of hydrogen. The mixture was filtered, heated to approximately 50° C., treated with acetic acid (6.5 mL) and stirred overnight at room temperature. The mixture was then adjusted to slightly above pH 7 with 45% KOH and concentrated under vacuum to remove most of the isopropanol. Isopropanol (20 mL) was added to the mixture, which was then acidified with acetic acid, stirred overnight at room temperature, and filtered to give 4.3 g of (S)-3-aminomethyl-5-methylhexanoic acid as a white crystalline solid. The enantiomeric purity was determined to be 100% e.e. by preparing a derivative of (S)-3-aminomethyl-5-methylhexanoic acid using Marfey's reagent (Na-(2,4-dinitro-5-fluorophenyl)-L-alaninamide) and analyzing by HPLC on a BDS Hypersil C18 column (250×4.6 mm, 5μ) eluted with acetonitrile:1% triethylamine (pH 3) (38:62, v/v).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[C:12]([CH:15]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16](OCC)=[O:17])(=O)[CH3:13]>CC1C=CC=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:15]1[C:12]([CH3:13])=[N:1][C:2]2[N:6]([N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=2)[C:16]=1[OH:17])[CH3:26]
Reactant: CCOC(=O)c1cc(N)[nH]n1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1O
Yield: 75.3 %

Procedure:
A suspension of ethyl 5-amino-1H-pyrazole-3-carboxylate (35.5 g, 229 mmol, prepared according to WO 2008015271), diethyl 2-acetylsuccinate (51.2 mL, 275 mmol) and TsOH.H2O (0.218 g, 1.144 mmol) in o-xylene (500 mL) was refluxed using a Dean-Stork condenser for 5 h. (Note: The suspension turned into a clear homogeneous solution and then in about 15 min a yellow solid started precipitated out of solution). Then, the reaction mixture was cooled, diluted with hexanes (250 mL), filtered, washed with hexanes and dried to afford ethyl 6-(2-ethoxy-2-oxoethyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (53 g, 75% yield) as light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.61 (br. s., 1H), 6.49 (s, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.34 (s, 3H), 1.33 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H). LCMS (M+1)=308.04.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.C([Cl:26])(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[Cl:26]
Reactant: OC(c1ccccc1)(c1ccc(F)cc1)c1ccccc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(c2ccccc2)c2ccccc2F)cc1
Reaction time: 12 h

Procedure:
(2-Fluorophenyl)-(4-fluorophenyl)phenylmethanol (1.47 g, 5.0 mmol) was added to a 20% solution of acetyl chloride in dichloromethane (10 mL) at rt. The resulting solution was stirred for 12 h after which the solvent was removed by evaporation. Toluene (2×20 mL) was added to the residue and evaporated to afford crude 2-fluorophenyl-(4-fluorophenyl)phenylchloromethane which was used without purification in the next step.
Reaction SMILES: CO.[Cl-].[NH4+].[CH3:5][NH:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:8]>[Fe].O>[CH3:5][NH:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:8]
Reactant: CNC(=O)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CNC(=O)n1ccc2cc(N)ccc21
Yield: 76 %

Procedure:
Methanol (6 ml), water (2 ml), iron (0.32 g) and ammonium chloride (0.64 g) were added to N1-methyl-5-nitro-1H-1-indolecarboxamide (0.32 g, 1.46 mmol) synthesized in Production example 218-1; and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue was filtrated with celite, and concentrated under reduced pressure to yield the title compound (210 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[I:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl-4-iodobenzoate ( 10.0 g, 36.2 mmol) in H2SO4 (20 ml) at 0° C. was added dropwise HNO3 ( 4.7 ml, 72.4 mmol). Reaction was stirred at room temperature for 1 h, cooled to 0° C., quenched with ice, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo to yield the crude title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1CC1OC(N)=NC=1.ClC(CC1C=CC=CC=1OC)C=O.[NH2:29]C(N)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[NH2:29]
Reactant: NC(N)=O
Reactant: COc1ccccc1Cc1cnc(N)o1
Agent: COc1ccccc1CC(Cl)C=O
Solvent: CCO
Product: COc1ccccc1N

Procedure:
5-(2-Methoxy-benzyl)-oxazol-2-ylamine A mixture of 2-chloro-3-(2-methoxylphenyl)-propionaldehyde (10 g, crude from above) and urea (9.6 g, 0.16 mol) was dissolved in ethanol (250 mL) and then heated at reflux overnight. The solvent was evaporated to dryness. The residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were adjusted to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was separated, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by silica gel column chromatography to yield the yellow-red solid product (0.72 g, 0.35% from 2-methoxyaniline). ESI-MS m/z calc. 204.1, found 205.1 (M+1)+; 1H NMR (CDCl3) δ 7.26-7.20 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.91-6.86 (m, 2H), 6.35 (s, 1H), 4.49 (bs, 2H), 3.85 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]2[CH:8]=[CH:9][CH:4]([C:5]([CH2:10][CH2:11][OH:12])=[CH:6]2)[C:3]1=[O:13].[H][H]>[Pd].C(O)(C)C>[CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11][OH:12])[CH2:6]2)[C:3]1=[O:13]
Reactant: CC1(C)C(=O)C2C=CC1C=C2CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC1(C)C(=O)C2CCC1CC2CCO
Temperature: 100 °C
Yield: 89.8 %

Procedure:
A mixture of 60 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octa-5,7-diene-2-one produced according to Example I, 300 ml of isopropyl alcohol and 5 g of 5% palladium on charcoal catalyst is placed in an autoclave. The autoclave is pressurized with hydrogen and heated to 100° C. for six hours. The resulting reaction mixture is filtered and the solvent is removed by vacuum stripping. Distillation of the residue through a 3" microvigreaux column yields 55 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octanone having the structure: ##STR27##
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:27])[CH2:12][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)(O)[C:14]([F:17])([F:16])[F:15])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.N1C=CC=CC=1>C(Cl)Cl.[NH4+].[Cl-]>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:27])[CH:12]=[C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:14]([F:15])([F:16])[F:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1cc2c(Cl)cccc2s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1cc2c(Cl)cccc2s1
Yield: 99.2 %

Procedure:
Stir a mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one (1.1 g, crude, 2.43 mmol), SOCl2 (1.16 g, 0.7 mL, 9.43 mmol) and pyridine (384 mg, 0.4 mL, 4.86 mmol) in anhydrous DCM (10 mL) at ambient temperature for overnight. Dilute the mixture with saturated NH4Cl solution and extract the aqueous mixture with DCM (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford crude 1-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one as brown solid (1.05 g, 100%). 1H NMR (400 MHz, CDCl3) 68.12-8.10 (s, 1H), 7.69-7.64 (m, 1H), 7.47-7.44 (m, 2H), 7.38-7.35 (m, 2H), 7.27-7.24 (m, 1H), 6.96-6.92 (s, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27]>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCCBr
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Product: CC(=O)CCCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
4-(5-dibenzo[a,d]cycloheptenylidene)piperidine is reacted in a manner analogous to that described in Example 7 with 5-bromo-2-pentanone. M.P. of the hydrochloride of the title compound 206°-207° after crystallization from isopropanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:17]([NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(=O)n(C(=O)Nc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol* (0.25 g, 1.94 mmol) in dry N,N-dimethylformamide (DMF; 5 mL) was added phenyl isocyanate (0.231 mL, 2.13 mmol), and the mixture was stirred at room temperature for 1 h. The suspension was suction filtered, and washed with diethyl ether (Et2O; 3×10 mL). The resulting solid was air-dried overnight to yield 4-amino-5-fluoro-2-oxo-N-phenylpyrimidine-1(2H)-carboxamide (0.32 g, 66%) as a white solid: mp 275-277° C. dec; 1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.63 (s, 1H), 8.43 (d, J=7.25 Hz, 1H), 8.35 (s, 1H), 7.55 (d, J=7.58 Hz, 2H), 7.37 (t, J=7.58 Hz, 2H), 7.13 (t, J=7.25 Hz, 1H); ESIMS m/z 247.1 ([M−H]−). 4-Amino-5-fluoropyrimidin-2-ol can be purchased commercially.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=2)[OH:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=2)=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(O)c2ccc(OC)c(OCc3ccccc3)c2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc(OC)c(OCc3ccccc3)c2)ccc1OC
Yield: 100.8 %

Procedure:
To a stirred solution of (3-benzyloxy-4-methoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol (7.22 g, 18.3 mmol) in CH2Cl2 (40 mL) at room temperature was added activated MnO2 powder (4.6 g, 53 mmol) and kept adding 2˜3 equivalents of MnO2 every 35 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (3-benzyloxy-4-methoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone as a brown solid (7.24 g, 100% yield): 1H NMR (CDCl3) δ 1.49 (t, J=7 Hz, 3H, CH2CH3), 3.95 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 4.14 (q, J=7 Hz, 2H, CH2CH3), 5.20 (s, 2H, CH2), 6.83 (d, J=8 Hz, 1H, Ar), 6.94 (d, J=8 Hz, 1H, Ar), 7.23-7.47 (m, 9H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [Cl-].[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[C:27]([N:33]2[C:42]3[C:37](=[CH:38][C:39]([F:45])=[C:40](F)[C:41]=3[CH3:43])[C:36](=[O:46])[C:35]([C:47]([OH:49])=[O:48])=[CH:34]2)[C:28]([CH3:32])=[CH:29][C:30]=1[F:31]>C(OCC)C>[NH2:24][C:25]1[CH:26]=[C:27]([N:33]2[C:42]3[C:37](=[CH:38][C:39]([F:45])=[C:40]([N:5]4[CH2:6][CH:3]([OH:2])[CH2:4]4)[C:41]=3[CH3:43])[C:36](=[O:46])[C:35]([C:47]([OH:49])=[O:48])=[CH:34]2)[C:28]([CH3:32])=[CH:29][C:30]=1[F:31]
Reactant: Cc1cc(F)c(N)cc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C)c21
Reactant: OC1CNC1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1cc(F)c(N)cc1-n1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(O)C3)c(C)c21
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
70 mg of 3-hydroxyazetidine monochloride, 200 mg of 1,8-diazabicyclo[5.4.0]-7-undecene, and 200 mg of pyridine were stirred at 80° C., and to this mixture was added 150 mg of 1-(3-amino-4-fluoro-6-methylphenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. The mixture was stirred at 90° C. for 20 minutes. Diethylether was added to the reaction solution, and the solution was decanted. 1 ml of ethanol was added to the residue and the solid precipitate was collected by filtration and dried to obtain 70 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[Cl:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25]=CC(O)=O)=[CH:23][CH:22]=1.[C:32](=[O:35])([O-])[O-:33].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:33][C:32](=[O:35])[CH2:25][C:24]1[CH:30]=[CH:31][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
In a reaction vessel were placed 0.20 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.11 g of 4-chlorocinnamic acid, 0.08 g of potassium carbonate and 5 ml of N,N-dimethylformamide, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water, and extracted twice with 30 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.24 g of 3,5-dichloro-4-(3-(4-chlorophenylacetyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy) benzene (96% yield), m.p. 62.2° C.
Reaction SMILES: [C:1]([C:3]1([N:11]([OH:23])[C:12](=[O:22])[CH2:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1)#N.S(=O)(=O)(O)[OH:25].[C:29](=O)([O-])[OH:30].[Na+]>CO>[CH3:29][O:30][C:1]([C:3]1([N:11]([C:12](=[O:22])[CH2:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[OH:23])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1)=[O:25]
Reactant: CON1CCC(C#N)(N(O)C(=O)Cc2cc(C)ccc2C)CC1
Reactant: O=C([O-])O
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(N(O)C(=O)Cc2cc(C)ccc2C)CCN(OC)CC1

Procedure:
To a solution of N-(4-cyano-1-methoxy-piperidin-4-yl)-2-(2,5-dimethyl-phenyl)-N-hydroxy-acetamide (1.5 g, 4.73 mmol) in methanol (15 ml) at 0° C. was added concentrated sulfuric acid (1.26 ml, 2.3 g, 23.64 mmol) slowly dropwise and the reaction mixture was stirred at reflux for 40 hours. The mixture was poured on ice (50 g), neutralized carefully with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (5×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 2:1) to afford 136 mg of an off-white solid. This material was triturated with a tert-butyl methyl ether/hexane 1:4 solution (2-3 ml), filtered and dried. Yield: 82 mg of 4-{[2-(2,5-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (title compound P3ii.1) as a white solid, mp 140-142° C.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6](N(CC)CC)C.[CH:13]1([N:19]=[C:20]=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CI>CN(C=O)C>[CH:13]1([NH:19][C:20](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[S:21][CH3:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#CCC#N
Reactant: CCN(CC)CC
Reactant: S=C=NC1CCCCC1
Solvent: CI
Solvent: CN(C)C=O
Product: CSC(NC1CCCCC1)=C(C#N)C#N
Reaction time: 0.08 h

Procedure:
Dissolved malononitrile (5.0 g) in DMF (50 mL), added triethylamine (1 eq), and stirred for 5 minutes before adding Cyclohexyl isothiocyanate (1 eq) dropwise, then stirred until complete by TLC (absence of Cyclohexyl isothiocyanate, 3 hrs). Added methyl iodide (1 eq) dropwise, then stirred until intermediate was fully consumed (absent on TLC, 18 hrs); poured into 100 mL ice water, then filtered resulting solution to obtain 2-((cyclohexylamino)(methylthio)methylene)malononitrile as a white powder.