Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]([CH2:13][NH2:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][C:16]1[C:17]([CH:23]=O)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:15][C:16]1[C:17]([CH2:23][NH:14][CH2:13][C:8]2[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: NCc1ncccc1N1CCCCC1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cnc(CNCc2ncccc2N2CCCCC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of C-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl)-methylamine, 3,5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-ylmethyl)-amine. 1H NMR (CDCl3) δ 1.50-1.57 (m, 2H), 1.63-1.72 (m, 4H), 2.24 (s, 3H), 2.28 (s, 3H), 2.82 (t, 4H, J=5.1 Hz), 3.91 (s, 2H), 4.01 (s, 2H), 7.07 (dd, 1H, J=4.5, 8.1 Hz), 7.20 (s, 1H), 7.28 (dd, 1H, J=1.2, 8.1 Hz), 8.20 (s, 1H), 8.23 (dd, 1H, J=1.2, 4.5 Hz). Further reaction of (3,5-dimethyl-pyridin-2-ylmethyl)-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-ylmethyl)-amine, 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde and NaBH(OAc)3 following General Procedure B gave a colorless oil. Deprotection with NH2NH2.H2O following General Procedure E, and subsequent conversion to the HBr salt, gave COMPOUND 202 as a yellow solid. 1H NMR (CD3OD) δ 1.55-1.83 (m, 10H), 2.51 (s, br. 6H), 2.71-2.76 (m, 2H), 2.922 (t, 2H, J=7.5 Hz), 3.00-3.04 (m, 4H), 4.32 (s, 2H), 4.33 (s, 2H), 7.89 (dd, 1H, J=5.7, 8.4 Hz), 8.20 (d, 1H, J=8.4 Hz), 8.23 (s, 1H), 8.56 (d, 1H, J=5.7 Hz), 8.62 (s, 1H); 13C NMR (D2O) δ 17.20, 17.45, 23.08, 23.45, 25.04, 25.73, 39.68, 52.55, 53.42, 54.35, 56.32, 126.47, 133.78, 135.55, 137.45, 137.74, 147.08, 147.50, 148.70, 150.86. ES-MS m/z 382 (M+H). Anal. Calcd. for C23H35N5O.3.8HBr.0.9H2O.0.3C4H10O: C, 39.96; H, 6.04; N, 9.63; Br, 41.74. Found: C, 39.93; H, 6.08; N, 9.64; Br, 41.68.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH4-].[Na+].O>C1COCC1.C(Cl)Cl>[CH2:29]([N:21]1[CH2:22][CH2:23][C:24]2[N:16]3[N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]=2[CH2:20]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c1cnccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CN(Cc1ccccc1)CC3
Temperature: 65 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a suspension of 2-(4-phenoxyphenyl)-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carbox-amide (2.46 g, 0.0067 mol) in 150 mL of THF was added benzyl bromide (1.14 g, 0.0067 mol) dropwise, then the mixture was stirred at 65° C. overnight. After cooling down to RT, the mixture was concentrated, the residue was suspended in 150 mL of MeOH, NaBH4 (10 g, 0.26 mol) was added portionwise. The mixture was stirred at RT overnight. To the reaction was added 200 mL of water followed by 200 mL of DCM. The aqueous phase was further extracted with 100 mL of DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to get the crude product which was chromatographed on 10 g of silica gel using DCM/MeOH (200/1 to 80/1) as eluant to afford 0.786 g (26%) of 6-benzyl-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]pyridine-3-carboxamide as a tan foam. MS (ESI) m/e [M+1]+ 463.9.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[C:6]([CH:8]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9](OCC)=[O:10])#[N:7]>C(O)C>[NH2:7][C:6]1[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[C:9]([OH:10])[C:8]=1[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(C#N)c1ccc(C)cc1
Reactant: NNCCO
Solvent: CCO
Product: Cc1ccc(-c2c(O)nn(CCO)c2N)cc1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
2-Hydroxyethylhydrazine (5.87 g) was added dropwise over 5 minutes to a stirred solution of ethyl cyano-(4-methylphenyl)acetate (Synthesis, 1985, 5, 506) (10.14 g) in absolute ethanol (200 ml) and the resulting mixture was then heated under reflux overnight. The reaction mixture was cooled to room temperature and the ethanol was evaporated under reduced pressure. The resulting yellow/orange oil was triturated with methanol and the solid was isolated by filtration to give the title compound as a white solid (3.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.CCN=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O.C1(N)CC1>CN(C=O)C>[CH:18]1([NH:19][C:8](=[O:10])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:16][CH2:17]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CC1)c1ccc(O)cc1

Procedure:
4-Hydroxybenzenecarboxylic acid was stirred with WSC hydrochloride, HOBt hydrate and cyclopropylamine in DMF at room temperature to obtain N-cyclopropyl-4-hydroxybenzamide.
Reaction SMILES: CC(C)C[OH:4].CN(C1C=CC=CN=1)C.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCOCC>O1CCCC1.CCCCCC>[C:22]([NH:21][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)([NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:4]
Reactant: CC(C)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
Compound 63 (0.45 g., 0.83 mmole) is dissolved in tetrahydrofuran (5 ml.) and 2-methylpropan-1-ol (0.07 g., 0.99 mmole), dimethylaminopyridine (50 mg. ), and dicyclohexylcarbodiimide (0.205 g., 0.99 mmole) are added. The mixture is stirred for three hours. Ether (1 5 ml.) and hexane (5 ml.) are added, the dicylohexylurea formed is filtered off and the solvent is evaporated. The residual oil is purified by chromatography on silica using 2% methanol in ethyl acetate as eluant, to give Compound 64.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][C:6]2[S:7][C:8]([C:10](N3CCOCC3)([CH:13]([CH3:17])[CH2:14][C:15]#[N:16])C#N)=[CH:9][C:5]=2[CH:4]=1.C(O)(=[O:30])C>O>[CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][C:6]2[S:7][C:8]([C:10](=[O:30])[CH:13]([CH3:17])[CH2:14][C:15]#[N:16])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(C#N)(C(C)CC#N)N3CCOCC3)sc2cc1OC
Reactant: CC(=O)O
Solvent: O
Product: COc1cc2cc(C(=O)C(C)CC#N)sc2cc1OC
Temperature: 0 °C

Procedure:
A mixture of 2-(5,6-dimethoxy-benzo[b]thien-2-yl)-3-methyl-2-(4-morpholinyl)-pentanedinitrile (7.4 g), glacial acetic acid (37.5 ml) and water (12.5 ml) was stirred and heated at reflux under an atmosphere of nitrogen. After 45 min. the reaction mixture was cooled and poured into crushed ice (200 g). The ice was allowed to melt and the resultant precipitate was filtered and dried at 65° C. under vacuum to give 4-(5,6-dimethoxybenzo[b]thien-2-yl)-3-methyl-4-oxo-butane nitrile as a pale yellow solid (5.2 g). A portion crystallized from dichloromethane/diethyl ether had m.p. 148°-150° C.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:31]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1>>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:31])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(c3ccc(/C=C/C(=O)OC)cc3)=C1c1ccc(OC)cc1C2
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC12CCC(=O)C(c3ccc(/C=C/C(=O)O)cc3)=C1c1ccc(O)cc1C2
Temperature: 190 °C
Reaction time: 2 h

Procedure:
A mixture of methyl (2E)-3-[4-(9a-butyl-7-methoxy-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-4-yl)phenyl]-2-propenoate (60 mg, 92% weight pure, 0.128 mmol) and pyridine hydrochloride (741 mg, 6.41 mmol) was placed under a nitrogen atmosphere, heated in an oil bath at 190° C., and stirred. The reaction flask was periodically dipped deeper into the heating bath in order to melt the pyridine hydrochloride that condensed on the sides of the flask. After 2 hours at 190° C., the reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and water (10 mL). The aqueous phase was extracted with more EtOAc (2×5 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to a yellow solid (55 mg). The crude product was suspended in EtOAc (10 mL) and extracted with 5% NaHCO3 (5 mL). The NaHCO3 solution was acidified with 2N HCl (2.5 mL) and extracted with EtOAc (2×5 mL). The latter EtOAc extracts were combined, washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to a yellow solid (39.4 mg). This material was triturated with diethyl ether and dried under vacuum to afford (2E)-3-[4-(9a-butyl-7-hydroxy-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-4-yl)phenyl]-2-propenoic acid as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]([N+:20]([O-])=O)[CH:17]([CH3:19])[CH3:18])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Fe]>[NH2:20][CH:16]([C:13]1([OH:15])[CH2:12][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[O:10])[CH2:14]1)[CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)C([N+](=O)[O-])C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(N)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol (189 mg, 0.34 mmol) was taken into 4:1 THF:water (5 mL) followed by addition of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) and the mixture was heated to reflux. After four hours additional aliquots of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) were added and the mixture was allowed to reflux an additional 12 hours. The mixture was cooled to room temperature and diluted with ethyl acetate then filtered. The filtrate was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate then the organic layer washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a residue that was further purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents to give a residue (36.5 mg) that was further purified by preparative reverse phase HPLC to give 3-(1-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol trifluoroacetate salt (7.9 mg) as a colorless amorphous solid after lyophilization of the combined pure fractions. 1H-NMR (400 MHz, D6-DMSO): 8.63 (s, 1H), 7.58 (dd, 1H), 7.37 (d, 1H), 7.35-7.31 (m, 1H), 7.17 (q, 1H), 6.71-6.66 (m, 1H), 4.23 (dd, 1H), 4.03 (dd, 1H), 3.80 (dd, 1H), 3.66 (dd, 1H), 2.34 (dd, 1H), 1.79-1.70 (m, 1H), 0.84-0.77 (m, 6H). MS (EI) for C20H21F3IN3O2: 520 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:18][OH:19]>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([CH:16]=[N:18][OH:19])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: NO
Reactant: CCc1cc(-c2ccc(C=O)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C=NO)o2)c(C)[nH]c1=O

Procedure:
Example 198 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]furan-2-carbaldehyde and hydroxylamine to afford the title compound. MS: m/e=247 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[OH:6][C@:7]1([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[CH:19]=2)[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.[Cl-].[Na+].O>[OH:6][C@:7]1([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:4][CH2:3][O:2][CH3:1])=[CH:31][CH:32]=3)[CH:19]=2)[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9]
Reactant: N#Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(O)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1

Procedure:
2-Bromoethyl methyl ether (85 μl) is added to a mixture of 4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzonitrile (0.30 g) and cesium carbonate (0.39 g) in 3 mL of dimethylformamide. The mixture is stirred at 80° C. for 16 h, before water and brine are added. The resulting mixture is extracted with ethyl acetate, the combined extracts are dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[C:10]([NH2:25])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.C(Cl)Cl.CCOC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([NH2:25])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(N)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 3-amino-6-(tert-butyl-dimethyl-silanyloxy)-indazole-1-carboxylic acid tert-butyl ester 672 mg (1.85 mmol) in dry THF (10 ml) was treated with 1M TBAF in THF (1.85 ml, 1.85 mmol) and stirred at r.t. for 30 min. Water (20 ml) was then added and the mixture extracted with EtOAc (3×50 ml). The separated organic layers were combined, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography over silica gel eluting with DCM/EtOAc 6:4 affording 429 mg (yield: 93%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][C@@H:32]([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][C@@H:32]([CH3:35])[CH2:33][OH:34])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 85 %

Procedure:
In a manner similar to that described in 321, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (38 mg, 0.089 mmol) and (2S)-2-amino-1-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1 S)-2-hydroxy-1-methylethyl]-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (34 mg, 85% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.07 (d, J=8 Hz, 1 H), 8.58 (s, 1 H), 8.19 (s, 1 H), 7.37-7.33 (m, 2 H), 7.14-7.09 (m, 2 H), 5.19 (m, 2 H), 5.01 (m, 1 H), 4.12 (s, 2 H), 4.03 (m, 1 H), 3.43 (m, 2 H), 1.16 (d, J=6.8 Hz, 3 H); HRMS m/z calcd for C21H20F4N3O4: 454.1385. Found: 454.1391.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.Cl.O1CCOCC1>CO>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=3)[O:5][CH2:4]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)OCC(=Cc1ccc(F)cc1)C2=O

Procedure:
The title compound was prepared from methyl 4-oxochroman-7-carboxylate (Koch, K., and Biggers, M. S. J. Org. Chem. 1994, 59, 1216-1218) and 4-fluorobenzaldehyde according to Method A2 using methanol and 4 N Hydrogen chloride/dioxane. Off-white solid (76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 5.48 (s, 1H), 7.35 (t, J=8.59 Hz, 2H), 7.50-7.61 (m, 3H), 7.66 (d, J=7.25 Hz, 1H), 7.80 (s, 1H), 8.01 (d, J=8.06 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[N:12]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[N:13]1.S(Cl)([Cl:22])(=O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[N:12]1[C:16]([CH3:17])=[C:15]([Cl:22])[C:14]([CH3:18])=[N:13]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1cc(-n2nc(C)cc2C)c(F)cc1Cl
Solvent: ClC(Cl)Cl
Product: CCOc1cc(-n2nc(C)c(Cl)c2C)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 1-(2-fluoro-4-chloro-5-ethoxyphenyl)-3,5-dimethylpyrazole (26.9 g) in chloroform (200 ml) was added dropwise sulfuryl chloride (13.5 g) for 10 minutes under water-cooling, and the reaction mixture was stirred for further 30 minutes to effect the chlorination reaction. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (30.0 g) as a pale yellow crystalline solid. After recrystallization of the solid from a mixture of n-hexane/ethyl acetate, the resulting white crystalline product showed the melting point of 106°-107.5° C.
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O.[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])[O-:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:6]([P+:7]([CH2:1][CH2:6][CH2:5][CH3:4])([CH2:10][CH2:15][CH2:14][CH3:13])[CH2:15][CH2:10][CH2:11][CH3:12])[CH2:1][CH2:2][CH3:3]
Reactant: O=P(O)(c1ccccc1)c1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])(c1ccccc1)c1ccccc1

Procedure:
To a suspension of 43.6 grams of diphenylphosphinic acid in 300 milliliters of distilled water is added a solution of 8.0 grams of sodium hydroxide in 200 milliliters of water and the mixture stirred. The acid dissolves slowly. To the resulting solution is added a solution of 59 grams of tetra-n-butylphosphonium chloride in about 200 milliliters of distilled water. The reaction mixture is stirred for half an hour and is then extracted with two 250-milliliter portions of chloroform. The extract is dried over anhydrous Na2SO4 and the chloroform is then distilled. A light-brown viscous liquid remains. It is dried overnight at 80° C. On cooling, tetra-n-butylphosphonium diphenylphosphinate separates as white crystals. It is collected by filtration and is washed with anhydrous ether; the crystals melt at 83° to 84° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:34][C:35]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)[CH:38]=[CH:37][C:36]=1[C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.O[CH:58]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[CH3:74])[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]>O1CCCC1>[C:49]([C:36]1[CH:37]=[CH:38][C:39]([O:41][CH2:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[CH:40][C:35]=1[O:34][CH:58]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[CH3:74])[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])(=[O:56])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Cc1ccccc1C(O)CCC(=O)OC(C)(C)C
Reactant: O=C(c1ccccc1)c1ccc(OCc2cccnc2)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCC(=O)OC(C)(C)C)Oc1cc(OCc2cccnc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl azodicarboxylate (6.45 mL) is added dropwise to a stirred, cooled (0° C.) solution of triphenylphosphine (8.6 g) in dry tetrahydrofuran (60 mL). After a further 30 minutes, a solution of 2′-hydroxy-4′-(pyridin-3-ylmethoxy)benzophenone (5 g) and tert-butyl 4-hydroxy-4-(2-methylphenyl)butanoate, thought to be the (S)-enantiomer, (5.13 g) in dry tetrahydrofuran (60 mL) is added dropwise over 25 minutes and stirring continued for a further 3 hours at °C. The reaction is allowed to warm to ambient temperature overnight before being concentrated under vacuo. The resultant oil is purified by flash chromatography on silica eluting with a mixture of dichloromethane and ethyl acetate (9:1 v/v). Fractions homogeneous in the required product are combined and concentrated under reduced pressure to give t-butyl 4-[2-benzoyl-5-(pyridin-3-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, as a colourless oil (8.66 g).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:32][NH2:33]>O1CCCC1.ClCCl.CO>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Reactant: CN
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.4.). Starting with 2.77 g (6.33 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{5-[4-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazine-carboxylate, obtained in step 4.1., and 15.80 ml (31.67 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, followed by recrystallization from ethyl acetate, 1.69 g of product are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14]([OH:16])=O)=[N:7]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH2:46][CH2:47][C:48]1[N:52]=[CH:51][NH:50][CH:49]=1>C(N(CC)CC)C>[NH:50]1[CH:49]=[C:48]([CH2:47][CH2:46][NH:45][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[C:9]([OH:13])[C:10]([Cl:12])=[CH:11][C:2]=3[Cl:1])[N:7]=2)=[O:16])[N:52]=[CH:51]1
Reactant: O=C(O)c1ccc2c(Cl)cc(Cl)c(O)c2n1
Reactant: NCCc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCc1c[nH]cn1)c1ccc2c(Cl)cc(Cl)c(O)c2n1

Procedure:
According to the procedure described in Example 1,5,7-dichloro-8-hydroxyquinoline-2-carboxylic acid 19 (597 mg, 2.31 mmol), dicyclohexylcarbodiimide (483 mg, 2.31 mmol), 1-hydroxybenzotriazole hydrate (316 mg, 2.31 mmol), histamine dihydrochloride (425 mg, 2.31 mmol) and triethylamine (0.5 mL) gave, after column purification (silica gel, ethyl acetate/isopropanol/water (12:4:1)), 5,7-dichloro-8-hydroxyquinoline-2-carboxylic acid [2-(1H-imidazol-4-yl)-ethyl]-amide (PBT 1038) as a pale straw-coloured solid (276 mg, 34%). 1H NMR (DMSO-d6, 400 MHz): δ 11.40 (br, 2H), 9.74 (m, 1H), 8.64 (d, J=8.6, 1H), 8.28 (d, J=8.6, 1H), 7.92 (s, 1H), 7.53 (s, 1H), 6.83 (s, 1H), 3.59 (m, 2H), 2.81 (m, 2H).