Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Sc1ccncc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 100 ml of ethanol were suspended 6.66 g of 4-mercaptopyridine and 16.9 g of N-(4-bromobutyl)phthalimide. To the suspension was added 9.09 g of triethylamine, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure. To the residue was added 300 ml of water, and the mixture was subjected to extraction twice with dichloromethane. The extract solutions were combined, washed with an aqueous saline solution, then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel (500 g) column chromatography, using as the developer a mixture of hexane and ethyl acetate (1:2), followed by elution with ethyl acetate. The eluate was concentrated under reduced pressure. To the concentrate were added ethyl acetate and hexane. Resulting powders were collected by filtration to give N-[4-(4-pyridylthio)butyl]phthalimide as a colorless powdery product, m.p. 106.5°-107.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[CH:3]=1.C1(P(=[CH:31][C:32]([O:34][CH3:35])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Product: COC(=O)Cc1coc2cc(O)ccc12

Procedure:
A mixture of 6-hydroxy-(2H)-benzofuran-3-one (5.0 g, 33.3 mmol), methyl (triphenylphosphoranylidene)acetate (25.0 g, 73 mmol), and xylenes (100 mL) is refluxed 6 hr. The reaction is concentrated and diluted with enough 1M aqueous hydrochloric acid to adjust pH to 2-3. The product is extracted into ethyl acetate (3×100 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified via silica chromatography eluting with 7:3 hexanes:ethyl acetate to afford the product as a orange oil, 1.3 g, 20%. MS M++1 207. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH3:20][CH:21]([CH3:24])[CH:22]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:20][CH:21]([CH3:24])[CH2:22][N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1
Reactant: CC(C)C=O
Reactant: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CN1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 37) (31 mg, 0.12 mmol) in dichloromethane (3 ml) was added 2-methylpropanal (17 mg, 0.24 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirring continued for 2 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E16). MS (ES+) m/e 313 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9]=2[N+]([O-])=O)[N:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:31](OCC)(=[O:33])[CH3:32]>>[C:31]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:14]([F:15])([F:16])[F:17])=[CH:8][CH:9]=2)[N:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2c([N+](=O)[O-])cc(C(F)(F)F)cc21
Reactant: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(C(F)(F)F)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-1-(ethoxycarbonyl)-6-trifluoromethylnitroindole (step 2). tlc: Rf=0.6 (50% ethyl acetate in hexanes)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11]O.S(=O)(=O)(O)O>O>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)cc1

Procedure:
p-Hydroxybenzoic acid (50 g, 0.36 mole), absolute methanol (200 ml), and concentrated sulfuric acid (6 ml) were heated at reflux for 3 hrs. The solution was cooled and poured into water (1000 ml). The precipitate was filtered and dried; mp 122°-5°. Yield: 45 g (82%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:41])([F:39])[F:40])=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Reactant: OC(c1ccc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(S(=O)(=O)c2ccc(-c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cn3)cc2)cn1
Temperature: 100 °C
Yield: 39.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (381 mg, 1.06 mmol, Example 264, step 1), 2-(6-chloro-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (148 mg, 0.53 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (22 mg, 0.03 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (517 mg, 1.59 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.5 mL), and water (0.15 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 30 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3/MeOH in DCM, to provide 2-(6-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (99 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][N:5]([CH:25]2[CH2:26][O:23][CH2:24]2)[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3COC3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 341C (72 mg) in tetrahydrofuran (1.5 mL) and acetic acid (0.5 mL) was added oxetan-3-one (14 mg) and MP-cyanoborohydride (2.38 mmol/g, 162 mg). The mixture was stirred at room temperature overnight. The reaction was then filtered and the filtrate was concentrated under vacuum. The residue was slurried in ether and the product was collected by filtration.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:20][C:21](=[O:31])[CH2:22][C:23]([C:25]1[S:26][CH:27]=[CH:28][C:29]=1[Cl:30])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:29]1[CH:28]=[CH:27][S:26][C:25]=1[C:23]1[CH2:22][C:21](=[O:31])[NH:20][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1sccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2sccc2Cl)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 125.5 %

Procedure:
Prepared from {3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K20) (100 mg, 0.21 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (93 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=2[CH:16]=[CH:15][N:14]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][C:26]=1[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][C:26]=1[C:27]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[CH:15][N:14]=[C:13]2[NH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[F:1])=[O:28]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Nc3ccc(C(F)(F)F)cc3F)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4ccc(C(F)(F)F)cc4F)nccc23)c1
Yield: 18.2 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N1-(2-fluoro-4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (Intermediate-39, 80 mg, 0.24 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 134 mg, 0.49 mmol), oxalyl chloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) in CH2Cl2 (5 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.38 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.21 (t, 1H), 8.00-7.93 (m, 2H), 7.88 (t, J=7.5 Hz, 1H), 7.71 (d, J=9.3 Hz, 2H), 7.60-7.53 (m, 3H), 7.44 (d, J=5.7 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 4.32 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 573.29 (M+H)+.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:9]([O:14]C)([O:12][CH3:13])(=[O:11])=[O:10].O>C(OCC)C>[S:9]([O-:14])([OH:12])(=[O:11])=[O:10].[CH3:8][S+:7]([CH3:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COS(=O)(=O)OC
Reactant: CSc1ccccc1
Solvent: O
Solvent: CCOCC
Product: C[S+](C)c1ccccc1
Product: O=S(=O)([O-])O

Procedure:
6.2 g (0.05 mole) of thioanisole and 6.9 g (0.055 mole) of dimethyl sulfate were stirred for 12 hours at room temperature. 100 g of water and 50 ml of diethyl ether were added to the reaction solution whereupon the mixture separated into two layers. The aqueous layer was taken out, which was an aqueous solution of the target compound, dimethylphenylsulfonium hydrogen sulfate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH2:5]1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:16][C:12]1[CH:11]=[C:10]([N:6]2[CH2:5][CH:4]([CH2:3][CH2:2][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)[O:8][C:7]2=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1OC(CCCl)CN1c1cccc(Cl)c1
Product: O=C1OC(CCN2CCN(c3ccccc3)CC2)CN1c1cccc(Cl)c1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 5-(2-chloroethyl)-3-(3-chlorophenyl)-2-oxazolidinone and 1-phenylpiperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.[CH:14]([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:3]=1)[CH3:14]
Reactant: Cc1ccnc(-c2ccccc2)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccnc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
To 4-methyl-2-phenylpyridine (8 g, 47.3 mmol) in dry THF (150 mL) at −78° C. was added dropwise lithium diisopropylamide (LDA) (30.7 mL, 61.5 mmol). The dark solution was stirred for 3 h at −78° C. and then CH3I was added (4.1 mL, 66.2 mmol) dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight. Ammonium chloride solution and EtOAc were added and the reaction transferred to a reparatory funnel. The layers were separated, washing the aqueous twice with EtOAc and combined organics once with water. After removal of the solvent, the crude product was chromatographed on silica gel with 9/1 (v/v) hexane/EtOAc to give 5.5 g (63.5%) of 4-ethyl-2-phenylpyridine. HPLC purity: 99.0%.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([N+:16]([O-])=O)[C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)([O-])=O.[H][H].C(O)(=O)C(O)=O>[Pt](=O)=O.C(O)C>[NH2:1][C:4]1[CH:15]=[C:14]([NH2:16])[C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3
Reactant: O=C1c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2OC12CC2
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: Nc1cc(N)c2c(c1)C(=O)C1(CC1)O2

Procedure:
250 mg. of 5,7-Dinitrospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one, 50 mg. of platinum dioxide and 20 ml. of ethanol were stirred in a stream of hydrogen for 1.25 hour under atmospheric pressure. To the reaction mixture was added oxalic acid, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure until its volume became above 3 ml. Ether was added to the concentrate, and the resulting powder was collected by filtration. The powder was dissolved in ethanol. To the ethanolic solution was added activated charcoal for decoloration, followed by addition of ether. The precipitating powder was collected by filtration to obtain 5,7-diaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]3-one.1/2 oxalate.monohydrate as yellowish brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[N:8](O)[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2].C(OC(C1C(=O)NC2C(C=1)=CC(F)=C(F)C=2)=O)C.P(Cl)(Cl)[Cl:39].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:39])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2n(O)c1=O
Reactant: ClP(Cl)Cl
Agent: CCOC(=O)c1cc2cc(F)c(F)cc2[nH]c1=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Temperature: 0 °C
Yield: 88 %

Procedure:
A mixture of 3-ethoxycarbonyl-6,7-difluoro-1-hydroxy-2-oxoquinoline (25 g at a concentration of 75 mol %, equivalent to 69.65 mmol), 3-ethoxycarbonyl6,7-difluoro-2-oxoquinoline (25 g at a concentration of 5 mol %, equivalent to 4.9 mmol), phosphorus trichloride (59.6 g, equivalent to 433.5 mmol) and phosphoryl chloride (15.05 g, equivalent to 98.05 mmol) in 1,2-dichloroethane (170 cm3) is heated at reflux for 3 hours. After cooling to 0° C., the reaction mixture is poured onto slushed ice (250 g of ice +250 g of water at 0° C.) and left to separate overnight. The organic phase is washed with saturated NaHCO3 solution (100 cm3), followed by water (100 cm3), and then concentrated to dryness in order to obtain 19.8 g of 3-ethoxycarbonyl-6,7-difluoro-2-chloroquinoline of 90% assay (HPLC), equivalent to a yield of 88%.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8]CC2C=CC([N+]([O-])=O)=CC=2)[CH2:6][CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:3]1.[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[F:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](OCc2ccc([N+](=O)[O-])cc2)[C@H](F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl trans-3-fluoro-4-[(4-nitrobenzyl)oxy]piperidine-1-carboxylate (180 g, 0.45 mol) in THF/H2O (1500 mL) was added LiOH (39 g, 0.9 mol) in portions at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC (EtOAc:petroleum ether=1:2) showed the starting material was consumed completely. The reaction mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (800 mL), dried over anhydrous Na2SO4 and concentrated to a crude residue. The residue was purified by column chromatography (EtOAc:petroleum ether=1:20) to afford benzyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[OH:5].[F:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]=[CH:22][O:21]2)=[CH:16][CH:15]=1>O=P(Cl)(Cl)Cl.C(OCC)C.C(N(CC)CC)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@@H:20]2[O:21][C@@H:22]([O:5][CH:4]([C:6]3[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=3)[CH2:3][CH2:2][Cl:1])[CH2:23][CH2:24][CH2:25]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(OCC2CCC=CO2)cc1
Reactant: OC(CCCl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Fc1ccc(OC[C@H]2CCC[C@H](OC(CCCl)c3ccc(F)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.2 %

Procedure:
One drop of phosphorus oxytrichloride was added to a solution of 222 mg of 3-chloro-1-(4-fluorophenyl)propanol and 233 mg of 2-(4-fluorophenoxymethyl)-3,4-dihydro-2H-pyran in 5 ml of diethyl ether, and the mixture was stirred at room temperature for 2 days. At the end of this time, 2 drops of triethylamine were added, the solvent was evaporated off and the residue was purified by column chromatography through silica gel, to give 245 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:22]=[CH:23][C:24](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[CH:22]=[CH:23]/[C:24]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=S
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CCC)c1=S
Yield: 46.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.00 g (16.5 mmol) of 5,6-diamino-1,3-dipropyl-2-thiouracil and 3.79 g (18.2 mmol) of 3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.16 g (yield 46%) of Compound 71 as yellow needles.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=2)[N:33]=1.[C:45](=[O:48])([OH:47])[O-].[Na+]>>[C:38]([OH:40])(=[O:39])/[CH:37]=[CH:35]/[C:45]([OH:47])=[O:48].[C:38]([OH:40])(=[O:39])/[CH:37]=[CH:35]/[C:45]([OH:47])=[O:48].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]([CH3:43])([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=4)[N:33]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(OC2CCN(CCCN)CC2)c2ccc(C)cc2)cc1
Reactant: O=C([O-])O
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccc(C)cc4)c4ccc(C)cc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O

Procedure:
2.11 g of 4-[bis(4-methylphenyl)methoxy]-1-piperidinepropanamine and 0.803 g of ethyl 2-[6-chloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate were stirred at 190-200° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (95:5:1). The desired fraction was collected, dissolved in 20 ml of ethyl acetate; a solution of 358 mg of fumaric acid in 20 ml of methanol was added, followed by concentration. Acetone was added to the residue; the crystal precipitated was collected by filtration, washed with acetone and dried to yield 0.901 g of the title compound.
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][C:15](=O)[CH2:14]2)=[CH:9][CH:8]=1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33]>>[NH2:1][C:2](=[O:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:17][CH2:16][CH:15]([NH:31][C@@H:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[C:24]([O:32][CH3:33])[CH:25]=3)[CH3:30])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: NC(=O)CCNC(=O)c1ccc([C@H]2CCC(=O)C2)cc1
Reactant: COc1cc([C@@H](C)N)ccc1F
Agent: Cl
Product: COc1cc([C@@H](C)NC2CC[C@H](c3ccc(C(=O)NCCC(N)=O)cc3)C2)ccc1F

Procedure:
General procedure B was followed using N-(3-amino-3-oxo-propyl)-4-[(1S)-3-oxocyclopentyl]benzamide as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)-ethylamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 8.39 (t, J=5.6 Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.37-7.31 (m, 3H), 7.16 (dd, J=8.6, 1.8 Hz, 1H), 7.10 (dd, J=11.5, 8.2 Hz, 1H), 6.91-6.87 (m, 1H), 6.82 (br s, 1H), 3.83 (s, 3H), 3.77-3.71 (m, 1H), 3.46-3.37 (m, 2H), 2.99-2.87 (m, 2H), 2.34 (t, J=7.3 Hz, 2H), 2.26-2.19 (m, 1H), 1.96-1.85 (m, 1H), 1.78-1.58 (m, 2H), 1.53-1.34 (m, 2H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[CH:32]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[S:30][CH:29]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>CO.C1COCC1>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[CH:32]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[S:30][CH:29]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cs1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxamide (74 mg, 0.14 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (86 μL, 2.75 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.