Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:15][NH:16]CC2C=CC=CC=2)([CH2:13][OH:14])[CH2:9]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH2:16][CH2:15][C:10]1([CH2:13][OH:14])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: OCC1(CNCc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: NCC1(CO)CCNC1

Procedure:
1-Benzyl-3-(benzylaminomethyl)-3-hydroxymethylpyrrolidine (2.0 g) was dissolved in ethanol (20 ml), and 10% palladium-carbon (1 g) was added. The mixture was hydrogenated under atmospheric pressure. After the completion of the reaction, the catalyst was removed, and the manure was concentrated to give the object compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]2[NH:17][C:18](=[O:23])[O:19][C:20]([CH3:22])([CH3:21])[C:15]=2[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]([C:31]#[N:30])=[CH:11][CH:10]=[C:9]1[C:13]1[CH:25]=[CH:24][C:16]2[NH:17][C:18](=[O:23])[O:19][C:20]([CH3:22])([CH3:21])[C:15]=2[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.6 %

Procedure:
To a solution of 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester (2.0 g, 5.8 mmol) in THF (anhydrous, 50 mL) at −78° C. was added chlorosulfonyl isocyanate (0.66 mL, 6.7 mmol). After 90 min. DMF (9 mL, 116 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (50 mL) and the product was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography on silica gel (30% ethyl acetate/hexane) gave 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester (1.1 g, 52%) as a white powder, mp 165-167° C., 1H NMR (DMSO-d6) δ1.36 (s, 9H), 1.61 (s, 6H), 6.44 (d, 1H, J=3.7 Hz), 6.92 (d, 1H, J=8.2 Hz), 7.27-7.32 (m, 2H), 7.36 (‘d’, 1H, J=1.5 Hz), 10.36 (s, 1H); MS (EI) m/z 367 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Br
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Bromo-4,5-difluoro-2-nitro-benzene (24 g, 100 mmol) was carefully added dropwise to a solution of sodium methoxide (1.2 eq) in MeOH. After addition was complete, the reaction was stirred at room temperature for 2.5 hours. The solvent was removed in vacuo and the residue diluted with water and extracted 2×250 mL with Et2O. The organic layers were combined, dried over MgSO4, filtered, and the solvent removed in vacuo leaving a yellow solid of 1-bromo-4-fluoro-5-methoxy-2-nitro-benzene: 1H NMR (300 MHz, CDCl3) 3.99 (s, 3H), 7.26 (m,1H) , 7.83 (d, 1H). MS(FD+): m/z 249, 251 (M+). Calculated for C7H5BrFNO3: C, 33.63; H, 2.02; N, 5.60; found: C, 33.79; H, 1.98; N, 5.62. 1-Bromo-4-fluoro-5-methoxy-2-nitro-benzene (20.5 g, 82 mmol) was hydrogenated over Pt on C (sulfided) at 60 psi (413 kPa) in THF (600 mL) for 4 hours. The reaction was filtered through celite to remove the catalyst. Removal of the solvent left a brown solid of 2-bromo-5-fluoro-4-methoxy-phenylamine which was taken on without further purification. 2-Bromo-5-fluoro-4-methoxy-phenylamine (18 g, 81.8 mmol) was dissolved in pyridine (200 mL) in a 500 mL round bottom flask equipped with a stir bar, septum, pressure equalizing dropping funnel, and nitrogen line with bubbler. The solution was cooled in an ice bath and ethyl chloroformate (1.5 eq.,122.7 mmol) was added dropwise from the dropping funnel. After addition was complete, the reaction was allowed to stir overnight gradually warming to room temperature. The pyridine was removed leaving a brown residue. This residue was taken up in Et2O/water and transferred to a separatory funnel. The water was extracted with Et2O (2×300 mL). The organic layers were combined, dried over MgSO4, filtered, concentrated in vacuo to obtain a 23.62 g (99%) of a brown solid: 1H NMR (300 MHz, CDCl3, 1.33 (t, 3H), 3.85 (s, 3H), 4.23 (q, 2H), 7.09 (d, 1H), 7.97 (bd, 1H); MS(FD+): m/z 291, 293 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.[OH-].[NH4+]>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C1=COCCC1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a warmed (60° C.) slurry of 6-chloropurine (20 g, 0.1294 mol) and R-toluenesulfonic acid monohydrate (0.35 g), dihydropyran (13.4 mL, 0.172 mol) was added with stirring over a period of 30 minutes. After an additional 30 minutes of heating, the mixture was allowed to cool to room temperature for 1 hour. Concentrated ammonium hydroxide (12 mL) was added and stirring was continued for 5 minutes. The solution was washed with water (4×70 mL) and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a syrup (about 29 g) which slowly crystallized upon standing. Extraction with boiling hexane gave the product as a solid, 24.36 g in two crops (784), mp 70°-71° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[N:12]=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[CH:9][CH:10]=1
Reactant: O=c1ccc(-c2ccccc2O)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Oc1ccccc1-c1ccc(Cl)nn1

Procedure:
Preferably, in the present process, the 6-(2-hydroxyphenyl)-3(2H)-pyridazinone is added to a cold mixture of phosphorus oxychloride and the disubstituted formamide. The reaction mixture is then heated to about 75°-90° C. for about 4-5 hours. The product is isolated from the reaction mixture by methods known to the art for example by cooling the reaction mixture, quenching in cold water, preferably below 40° C., and filtering to give the 3-chloro-6-(2-hydroxyphenyl)pyridazine.
Reaction SMILES: C([Li])CCC.C1C[O:9][CH2:8]C1.Br[C:12]1[S:13][C:14]([C:18]2[C:19]([CH3:33])=[N:20][N:21]3[C:26]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:25][C:24]([CH3:32])=[N:23][C:22]=23)=[C:15]([Br:17])[N:16]=1.C(N1CCOCC1)=O>CCOCC>[Br:17][C:15]1[N:16]=[C:12]([CH:8]=[O:9])[S:13][C:14]=1[C:18]1[C:19]([CH3:33])=[N:20][N:21]2[C:26]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:25][C:24]([CH3:32])=[N:23][C:22]=12
Reactant: C1CCOC1
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3Br)c(C)nn12
Agent: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCC(CC)c1cc(C)nc2c(-c3sc(C=O)nc3Br)c(C)nn12
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, add n-butyl lithium (1.6 M in hexanes, 0.312 mL, 0.50 mmol) to a THF solution (2.5 mL) of 3-(2,4-dibromo-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (230 mg, 0.50 mmol) at −78° C. and stir for 30 min. Add a THF (0.5 mL) solution of N-formyl morpholine (58 mg, 0.50 mmol). Stir for one hour, then store the reaction at −20° C. overnight. Warm the reaction to room temperature, dilute with ether, and quench by adding 4 N HCl (4 mL). Separate and extract the organic phase with 4 N HCl (2×4 mL). Combine the aqueous portions, treat with solid sodium bicarbonate to pH=8 to 9 and then extract with diethyl ether. Combine all the organic layers, wash with brine, dry over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes/dichloromethane/ethyl acetate (5/5/1) to give the title compound (154 mg). MS (APCI) m/z (81Br) 409.0 (M+1)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[CH:21][C:16]=3[N:15]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]2=[O:31])=[C:10]([O:34][CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:46]=2N=N1.CCN(C(C)C)C(C)C.C(N)(CC)(C)C>C(Cl)Cl>[CH:25]1([N:15]2[C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:17]=3[N:13]([CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH2:3][CH3:46])=[CH:9][C:10]=3[O:34][CH3:35])[C:14]2=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)C)cc1OC
Agent: CCC(C)(C)N
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 0.9 g of the compound obtained in Example 15 Step B, 0.9 g of BOP and 1 ml of DIPEA in 20 ml of DCM is added 1 g of tert-amylamine, and the mixture is left stirring for 3 hours at RT. The reaction mixture is washed with 1N HCl solution, with 1N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with DCM. 0.34 g of the expected product is obtained, mp=164° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=1.N12CCCN=C1CCCCC2.[I-].[NH2:25][N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([CH2:10][CH2:11][CH3:12])=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:5]=[CH:4][N:3]=1
Reactant: N[n+]1ccccc1
Reactant: CCCC#Cc1ccnc(F)c1
Agent: [I-]
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nn2ccccc2c1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 75.3 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-4-pent-1-ynylpyridine (650 mg, 3.98 mmol) in acetonitrile (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.89 mL, 5.97 mmol) and 1-aminopyridinium iodide (974 mg, 4.38 mmol). The resultant dark solution was allowed to warm to room temperature and stirred vigorously. An additional equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene and 1-aminopyridinium iodide were added after 18 and again after 36 hours. Water was added and the mixture concentrated in vacuo. The residue was partitioned between water and ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (4:1 to 3:1 hexane-ethyl acetate) provided 3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (765 mg, 75%) as an off-white solid. 1H NMR (CDCl3) δ 8.48 (d, 1H), 8.30 (d, 1H), 7.64 (d, 1H), 7.32–7.23 (m, 2H), 7.04 (s, 1H), 6.86 (t, 1H), 2.95 (t, 2H), 1.82 (m, 2H), 1.03 (t, 3H); 19F NMR (CDCl3) δ −68.48; MS m/z 256 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[F:41])[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([N:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[N:31]=2)[CH:28]=1>O1CCCC1.CN(C)C=O.O>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:40]([F:41])=[C:19]([NH:18][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:20]=4)=[CH:28][N:27]3[N:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: CCn1nc(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.22 mmol) in tetrahydrofuran (7 mL) were added oxalyl chloride (160 μL, 1.83 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (3 mL). N-[6-(3-Amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (254 mg, 90%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(O)C.O>[C:18]([NH:1][CH2:2][C:3]12[CH2:17][CH:10]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=31)[C:11]1[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: NCC12CC(c3ccccc31)c1ccccc12
Solvent: CCO
Solvent: O
Product: CC(=O)NCC12CC(c3ccccc31)c1ccccc12

Procedure:
A solution of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene (235 mg) and acetic anhydride (217 mg) in ethanol (5.0 ml) was refluxed for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-acetylaminomethyl-9,10-dihydro-9,10-methanoanthracene. M.P. 184°-185.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:9][C:10]=2[C:11]2[CH:27]=[CH:26][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:33][O:34][CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][O:34][CH3:33])=[N:9][C:10]=2[C:11]2[CH:27]=[CH:26][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC/C=C/C(=O)O
Reactant: CCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Product: CCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4C(=O)/C=C/COC)n4ccnc(N)c34)cc2)c1
Yield: 28.8 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-ethylpyridin-2-yl)benzamide (intermediate 13) and (E)-4-methoxybut-2-enoic acid (Intermediate 3), to afford the title compound (10.6 mg, 28.8%). Data: UPLC (C) Rt: 1.60 min; m/z 526.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([NH:30][NH2:31])=[O:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:31][NH:30][C:28]([C:24]3[CH:23]=[C:22]4[C:27](=[CH:26][CH:25]=3)[N:18]=[CH:19][CH:20]=[N:21]4)=[O:29])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=O)c1ccc2nccnc2c1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc2nccnc2c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 10 %

Procedure:
A solution of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (25 mg, 0.087 mmol) and quinoxaline-6-carboxylic acid hydrazide (25 mg, 0.087 mmol) in dimethylsulfoxide (0.5 mL) was stirred at 100° C. for 12 hours and the reaction mixture was concentrated under the reduced pressure. To the residue was added chloroform and the precipitated solid was collected by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (yield 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:36][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Nc1ccccc1N
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccccc5N)cccc4c3)c2cc1OC
Yield: 85.9 %

Procedure:
The title compound (40.0 mg, 86% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid (37.5 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.93 (s, 3H, —OCH3), 3.95 (s, 3H, —OCH3), 4.99 (s, 2H, benzene-NH2), 6.56 (d, J=5.2 Hz, 1H, Ar—H), 6.63 (t, J=7.6 Hz, 1H, Ar—H), 6.81 (d, J=7.6 Hz, 1H, Ar—H), 6.98 (t, J=7.2 Hz, 1H, Ar—H), 7.36 (d, J=7.6 Hz, 1H, Ar—H), 7.43 (s, 1H, Ar—H), 7.56-7.58 (m, 2H, Ar—H), 7.65 (t, J=7.6 Hz, 1H, Ar—H), 7.87-7.90 (m, 2H, Ar—H), 8.08 (d, J=8.0 Hz, 1H, Ar—H), 8.43 (d, J=9.2 Hz, 1H, Ar—H), 8.49 (d, J=5.2 Hz, 1H, Ar—H), 9.87 (s, 1H, benzene-NH). LC-MS (m/z) 466 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+]>CO>[CH2:11]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NCC(O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 2-amino-1-phenyl-ethanol (12.0 g, 87.48 mmol) in methanol (60 mL) was added benzaldehyde (9.3 g, 8.9 mL, 87.48 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then cooled to 0° C. and sodium borohydride (3.3 g, 87.48 mmol) was added. The reaction mixture was gradually allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo, diluted with water, and filtered. The residue was rinsed with cold isopropanol (3×), then dried in vacuo to give 2-(benzylamino)-1-phenylethanol as white crystals (14.0 g, 70%). ESI-MS m/z calc. 227.1. Found 228.2 (M+1)+; Retention time:0.8 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 7.37-7.27 (m, 8H), 7.27-7.19 (m, 2H), 4.78 (dd, J=8.5, 4.5 Hz, 1H), 3.77 (q, J=13.0 Hz, 2H), 2.82-2.68 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19](O)=[O:20])=[CH:14][CH:15]=3)[C:10]([CH:22]=[N:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:9]2)=[CH:5][CH:4]=1.Cl.[O:41]1[CH2:46][CH2:45][CH:44]([CH2:47][NH2:48])[CH2:43][CH2:42]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N1CCOCC1)C>CN(C=O)C>[O:41]1[CH2:46][CH2:45][CH:44]([CH2:47][NH:48][C:19](=[O:20])[CH2:18][O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:36]=[CH:37][C:3]([C:2]([F:38])([F:39])[F:1])=[CH:4][CH:5]=2)[CH:9]=[C:10]3[CH:22]=[N:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH2:43][CH2:42]1
Reactant: NCC1CCOCC1
Reactant: O=C(O)COc1ccc2c(c1)c(C=NOCc1ccc(C(F)(F)F)cc1)cn2Cc1ccc(C(F)(F)F)cc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(COc1ccc2c(c1)c(C=NOCc1ccc(C(F)(F)F)cc1)cn2Cc1ccc(C(F)(F)F)cc1)NCC1CCOCC1
Reaction time: 5 h
Yield: 68 %

Procedure:
To a solution of compound prepared in example 8 (250 mg, 0.454 mmoles) in DMF (2 mL), (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (83 mg, 0.545 mmoles), HOBT (Catalyst), EDC.HCl (130 mg, 0.681 mmoles) and N-ethyl morpholine (0.173 ml, 1.362 mmoles) were added and the reaction mixture was srirred at 25° C. for 5 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography to yield 200 mg (68%) of product as white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([CH:42]([CH2:46][CH2:47][CH2:48][CH3:49])[C:43](O)=[O:44])[CH2:39][CH2:40][CH3:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:43](=[O:44])[CH:42]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:38][CH2:39][CH2:40][CH3:41])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCCC(CCCC)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCCC(CCCC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 62.8 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 627 mg (3.6 mmol) of 2-butylhexanoic acid, to provide 797 mg of the title compound.
Reaction SMILES: C(=O)(O)O.[OH:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH2:7][NH2:8].[CH2:16]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=2[CH3:33])=[CH:23][CH:22]=1)[C:17]([CH3:19])=O>>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH:6]([OH:5])[CH2:7][NH:8][CH:17]([CH3:19])[CH2:16][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH2:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=2[CH3:33])=[CH:25][CH:26]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)COc1ccc(C2=C(C)NC(=O)CC2)cc1
Agent: O=C(O)O
Product: CC1=C(c2ccc(OCC(C)NCC(O)c3cccc(Cl)c3)cc2)CCC(=O)N1

Procedure:
5-[4-[2-[(3-Chloro-β-hydroxyphenethyl)amino]propyloxy]phenyl]-3,4-dihydro-6-methyl-2(1H)-pyridinone was prepared as a 1:1 mixture of diastereoisomers, m.pt. 99°-104° C., from 2-hydroxy-2-(3-chlorophenyl)ethanamine carbonate (0.58 g) and 3,4-dihydro-5-(4-acetonyloxyphenyl) 6-methyl-2(1H)-pyridinone (0.75 g) in an analogous manner to the compound described in Example 38.