Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[C:16]4[C:21]([CH:22]=[C:23]5[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:29]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:29][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:13]2[C:14]3[C:5]([CH:6]=[C:7]4[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]4)=[CH:4][CH:3]=[CH:2][CH:1]=3)=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[CH:27]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-c3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2ccccc2c(-c2c3ccccc3cc3ccccc23)c2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
9,9′-bianthracene (10 g, 28.2 mmol) was dissolved in DMF (200 mL), protected from light and N-bromosuccinimide (5.5 g, 31 mmol) diluted in DMF (20 ml) was added to the solution at 0° C. The reaction mixture was maintained at 0° C. for 1 hour. The solution was then warmed slowly to room temperature and stirred for 4 h. After the reaction completion, water was added to the mixture to terminate the reaction. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product 4.5 g (37%) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:39]=1)C1C=CC=CC=1.Br[CH2:41][CH2:42][CH2:43][C:44]#[N:45].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:23]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][CH2:43][C:44]#[N:45])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:39]=1
Reactant: Oc1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 80 °C
Yield: 98 %

Procedure:
A mixture of 6-benzyloxy-2-(4-hydroxyphenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Part D), 4-bromobutyronitrile (1.2 mol/mol of phenol), and Cs2CO3 (2 mol/mol of phenol) in DMF (about 10 mL/mmol of phenol) was heated to 80° C. for 3 h, poured into 4 volumes of water and extracted with EtOAc. After drying (K2CO3) and evaporation, the title compound was obtained as a foam in 98% yield following MPLC (SiO2; 0.5% in CHCl3 sat'd with NH4OH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=1[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH:23]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]1=[O:25]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]2[C:10]=1[C:18](=[O:20])[N:22]([CH:23]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]1=[O:25])[C:12]2=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccccc4)c3C2=O)C(=O)N1
Yield: 113.9 %

Procedure:
A mixture of 3-benzyloxy-phthalic acid (1.08 g, 4.00 mmol) and rac-α-aminoglutarimide hydrochloride (0.65 g, 4.0 mmol) in pyridine (10 mL) was heated to reflux for 4 h. The reaction mixture was cooled and the solvent was evaporated under vacuum. The residue was suspended in ethyl acetate (200 mL) and washed with dilute aqueous HCl (100 mL). The organic phase was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered, washed with additional ethyl acetate (50 mL), and dried to give the title compound (1.66 g, 86% yield); mp 238-240° C.: HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min. 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.23 (96.71%); 1H NMR (DMSO-d6) δ 1.99-2.08 (m, 1H), 2.45-2.62 (m, 2H), 2.81-2.94 (m, 1H), 5.10 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 5.38 (s, 2H), 7.32-7.53 (m, 6H), 7.60 (d, J=8.5 Hz, 1H), 7.83 (t, J=8.2 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 48.8, 70.0, 115.6, 116.6, 120.2, 127.3, 128.0, 128.5, 133.3, 136.2, 137.0, 155.5, 165.3, 166.8, 169.9, 172.8; Anal. Calcd for C20H16N2O5: C, 65.93; H, 4.43; N, 7.69. Found: C, 65.54; H, 4.35; N, 7.63.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:40]1[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Yield: 54.7 %

Procedure:
A mixed solution of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (10.27 g, 20 mmol), 4-chlorophenylboronic acid (3.75 g, 24 mmol) and sodium carbonate (5.30 g, 50 mmol) in toluene (50 ml)-methanol (10 ml)-water (10 ml) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (1.15 g, 1 mmol) and the mixture was refluxed under heating under an argon atmosphere for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.21 g, 54.8%) as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>[Ni](Cl)Cl>[CH2:16]([O:15][P:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2)([O:18][CH2:19][CH3:20])=[O:21])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Agent: Cl[Ni]Cl
Product: CCOP(=O)(OCC)c1ccc2c(c1)C=CC(C)(C)O2
Temperature: 180 °C

Procedure:
16 g of 6-bromo-2,2-dimethyl-2H-chromene are dissolved in 100 ml of triethyl phosphite. 2 g of nickel chloride are added and the mixture is heated at 180° C. for 24 hours in an autoclave. After the remaining triethyl phosphite has been concentrated, the expected product distils at 130°-140° C. under 133.322 Pa. 11.5 g are collected.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].[O:7]1[CH2:9][CH:8]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]=3[C:32]([F:35])([F:34])[F:33])[O:18][N:17]=2)=[CH:12][CH:11]=1.[CH3:36][CH:37](O)[CH3:38]>CS(C)=O>[OH:7][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]=[C:19]([C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]=3[C:32]([F:34])([F:33])[F:35])[O:18][N:17]=2)=[CH:14][CH:15]=1)[CH2:9][N:17]1[CH2:16][CH2:13][CH2:12][C:37]([CH3:38])([C:1]([OH:2])=[O:4])[CH2:36]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)O
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1(C(=O)O)CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a mixture of ethyl 3-methylpiperidine-3-carboxylate, HCl (62.4 mg, 0.301 mmol), and cesium carbonate (98 mg, 0.301 mmol) in 2-propanol (2 mL) and DMSO (1 mL) was added 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna 5 micron C18 column (30×100 mm); 10% MeOH/water (0.1% TFA)/90% MeOH/water (0.1% TFA); 10%-100% gradient over 15 minutes; 20 mL/min. Fraction with the correct mass were isolated and concentrated in vacuo. The residue was treated with 6N HCl/MeCN for 3 days and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 1 mg of 1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)-3-methylpiperidine-3-carboxylic acid as a TFA salt. MS (m+1)=543. HPLC Peak RT=3.29 minutes (Analytical Method A). Purity=95%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH3:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[ClH:1].[CH3:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[N:5]=[CH:4][C:3]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:28][CH:27]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)c1cnc2ccc(Oc3ccccc3)nc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2ccc(Oc3ccccc3)nc2c1Nc1ccc(OC)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 4-chloro-6-phenoxy-1,5-naphthyridine-3-carboxylate (3.0 g), 4-methoxyaniline (1.16 g), potassium carbonate (2.65 g) and THF (60 ml) was stirred at ambient temperature for 24 hours. The reaction mixture was worked up as described in Example 2 to give ethyl 4-(4-methoxyanilino)-6-phenoxy-1,5-naphthyridine-3-carboxylate hydrochloride, m.p. 191°-193° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=O)=O)(C)(C)C.C[N:25](C=O)C.S(Cl)(Cl)=O>C1COCC1.N1C=CC=CC=1>[C:21]([CH:9]1[NH:8][CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1)(=[O:23])[NH2:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Temperature: 40 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
1,4-Bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.0 g, 3.03 mmol) was suspended in THF (5 mL) and pyridine (0.36 mL), DMF (0.1 mL) was added, followed by thionyl chloride (0.23 mL, 3.03 mmol). The reaction mixture was stirred at 40° C. for 4 h and then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 and transferred to a sealed tube. A saturated solution of ammonia in dioxane (10 mL) was added to the compound and the resulting reaction mixture was stirred at 40° C. for 2 h followed by room temperature stirring for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1.5 N HCl. The aqueous layer was washed with diethyl ether and then basified with 1N sodium hydroxide solution. The organic product was extracted with CH2Cl2. The combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to get tert-butyl 3-carbamoylpiperazine-1-carboxylate (340 mg, yield 49%), which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 6.70 (br s, 1H), 5.51 (br s, 1H), 4.06-4.03 (m, 1H), 3.77 (m, 1H), 3.37-3.33 (m, 1H), 3.11-2.95 (m, 3H), 2.81-2.76 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: C(C1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)C=CC=1CCCCCC)#C.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Br[CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30]>>[C:21]([C:22]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:25]=[CH:24][C:23]=1[CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])#[CH:20]
Reactant: CCCCCCBr
Reactant: C#Cc1c(CCCCCC)ccc2ccccc12
Reactant: CC[C@H](C)CBr
Product: C#Cc1c(C[C@@H](C)CC)ccc2ccccc12

Procedure:
1-Ethynyl-2-(2-(S)-methylbutyl)naphthalene was prepared in a similar manner to 1-ethynyl-2-hexylnaphthalene, except that bromohexane was replaced by 1-bromo-2-(S)-methylbutane.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11](F)=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]#[N:18])=[CH:7]2)[CH2:5][CH2:4][CH2:3]C1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.[Li+].[CH3:33][CH:34]([N-]C(C)C)C>C1COCC1>[C:17]([C:8]1[C:9]2[C:14](=[CH:13][C:12]([CH:15]3[CH2:34][CH2:33]3)=[CH:11][CH:10]=2)[N:6]([CH:1]2[CH2:3][CH2:4][CH2:5]2)[C:7]=1[B:19]([OH:24])[OH:20])#[N:18]
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc2c(cc1F)c(C#N)cn2C1CCCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(B(O)O)n(C2CCC2)c2cc(C3CC3)ccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 1-cyclopentyl-5-fluoro-6-methyl-1H-indole-3-carbonitrile (4.4 g, 18.2 mmol) and triisopropyl borate (7.6 mL, 33 mmol) in THF (75 mL) at −78° C. was added LDA (1.5 M in cyclohexane, 15.8 mL, 23.7 mmol). The mixture was stirred at −78° C. for 30 min, quenched with ice water (200 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with aq. 2 N HCl to pH 5 and then extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-cyano-1-cyclobutyl-6-cyclopropyl-1H-indol-2-ylboronic acid as a solid (6.2 g, 90% pure by LCMS) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]3[OH:28])=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30].[CH2:33]1COCC1.[H-].[Na+].IC>CO.O>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]3[O:28][CH3:33])=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30]
Reactant: CN1c2nc(C3CCN(C(=O)OC(C)(C)C)CC3O)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CI
Product: COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 25 °C

Procedure:
To a flask was added tert-butyl 4-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-3-hydroxypiperidine-1-carboxylate (27-1) (54 mg, 0.114 mmol), & anhydrous THF (2.5 mL). The reaction mixture was cooled to 0 C while stirring under an atmosphere of nitrogen, then added sodium hydride (60% by wt in mineral oil) (5.92 mg, 0.148 mmol) in one portion. Reaction mixture was continued to stir at 0 C for 10 minutes, then added iodomethane (8.54 μl, 0.137 mmol) and permitted to warm to room temperature. After 1 hour reaction mixture was diluted with MeOH & drops of water, then purified by reverse-phase chromatography (10-100% CH3CN:0.1% TFA in H2O) to yield tert-Butyl 4-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazole-[3,4-b]pyridin-5-yl}-3-methoxypiperidine-1-carboxylate (28-1). HRMS (M+H)+: observed=489.1983, calculated=489.1978.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:20][CH:21]3[CH2:38][CH:37]4[N:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([OH:42])=O)([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH:56]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57]1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:20][CH:21]3[CH2:38][CH:37]4[N:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:62][S:59]([CH:56]6[CH2:58][CH2:57]6)(=[O:61])=[O:60])=[O:42])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccncc3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccncc3)nc2c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
The acid 178 (67 mg, 0.11 mmol) and EDAC (26 mg, 0.13 mmol) were dissolved in dichloromethane (3 ml). After stirring at room temperature for 5 h the mixture was diluted with dichloromethane (10 ml) and the organic phase were washed with water and dried (sodium sulphate). The volume was then reduced to 2 ml and cyclopropyl sulphonamide (20 mg, 0.17 mmol) and DBU (36 mg, 2.3 mmol) were added. The mixture was allowed to stir over-night at room temperature and then washed using 5% aqueous citric acid. Purification by chromatography (0 to 2% methanol in dichloromethane gave the title compound (57 mg, 73%), MS (M+H)+ 704.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:36][N:35]=1
Reactant: Cc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methylphenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (521 mg, 1.1 mmol) produced in Synthesis Example 30 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 183 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methylbenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (496 mg, yield 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[S:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[S:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(CO)ccc1OCc1nc(N2CCOCC2)sc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde (7.00 g) in tetrahydrofuran (100 mL)-ethanol (30 mL) was gradually added sodium borohydride (0.76 g) at room temperature. After stirring the reaction mixture at room temperature for 2 hrs, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give {3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as colorless crystals (6.29 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[OH:39][CH:37]([CH3:38])[CH2:36][NH:35][C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: CC(O)CN
Product: CC(O)CNC(=O)C(C)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 1-amino-2-propanol. LCMS (M+H)+: m/z=531.2.
Reaction SMILES: [CH2:1]([NH:18][C:19]([O:21][CH2:22][C@H:23]([OH:26])[CH2:24][OH:25])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:27]1([C:33](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH2:1]([NH:18][C:19]([O:21][CH2:22][C@H:23]([OH:26])[CH2:24][O:25][C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OC[C@H](O)CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCNC(=O)OC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of 12.03 g of 3 -O-(N-heptadecylcarbamoyl)-sn-glycerol (prepared as described in Preparation 15), 10.77 g of triphenylmethyl chloride and 10.8 ml of triethylamine dissolved in 240 ml of toluene was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into water (0.5 liter) and then extracted twice with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 240 ml of tetrahydrofuran. To the resulting solution was added 120 ml of a saturated aqueous solution of sodium bicarbonate, and the mixture was stirred at room temperature for 1 hour. After pouring the reaction mixture into water followed by extracting twice with ethyl acetate, the combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 400 g of silica gel and to medium pressure liquid chromatography using an NQ-3 Packed Column (Wako pure Chemical Industry Co.). 15.89 g of the title compound were obtained from the fractions eluted with mixtures of hexane and diethyl ether ranging from 3:2 to 2:3 by volume as a viscous liquid.