Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([O:19]CC)=[O:18])[C:6]=2[CH:22]=1.[Li+].[OH-]>O1CCOCC1.O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([OH:19])=[O:18])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of ethyl 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylate (2.5 g, 5.8 mmol) and LiOH (0.5 g, 21.0 mmol) in dioxane (30 mL) and water (10 mL) was allowed to stir at 90° C. for 1 hour. The mixture was cooled to room temperature and extracted with dichloromethane, the organic extract was washed with brine, dried over Na2SO4 and concentrated to provide 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylic acid (2.2 g, yield: 91%). 1H-NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.81˜7.84 (m, 2H), 7.34 (s, 1H), 6.89˜6.93 (m, 2H), 3.79˜3.82 (m, 2H), 2.66˜2.70 (m, 2H), 2.26˜2.31 (m, 2H). MS (M+H)+: 418/420.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 78.3 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 286 mg of 5-[4-{2(S)-[5(S)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propoxy}benzyl]-3-triphenylmethylthiazolidine -2,4-dione (prepared as described in Preparation 41), 1 ml of trifluoroacetic acid and 1 ml of methylene chloride were used, to give 150 mg of the title compound, melting at 54° C. to 56° C. and having [α]D =+41.8° (methanol, c=0.975).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:14]([OH:20])([C:16]([F:19])([F:18])[F:17])=[O:15]>O=[Pt]=O.O>[C:14]([OH:20])([C:16]([F:19])([F:18])[F:17])=[O:15].[NH2:1][C@@H:2]([CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH2:12]1)[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(C[C@H](N)C(=O)O)cc1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1CCC(C[C@H](N)C(=O)O)CC1
Reaction time: 48 h

Procedure:
A 250 mL Parr shaker vessel was charged with 1.0 g (5.6 mmol) of (S)-2-amino-3-p-tolylpropanoic acid, 63 mg (0.28 mmol, 5 mol %) of PtO2, and 10 mL of 1:1 TFA:water. The vessel was placed in a Parr hydrogenation shaker, pressurized to 50 psi, and shaken for 2 d. Analysis of the mixture by LC/MS indicated a ca 1:1 mixture of cis:trans isomers. The contents were filtered through a pad of Celite and the spent catalyst washed with additional water. The clear filtrate was evaporated to afford crude TFA salt of (S)-2-amino-3-(4-methylcyclohexyl)propanoic acid which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34](O)=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:38][CH:39]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccc(C)cc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccc(C)cc2)c1

Procedure:
425 mg of compound 33 was obtained in a similar manner to those described in the Examples 1 and 2 using 777 mg of ethyl 4-(2-aminophenoxy)butyrate and 531 mg of 3-[1-(4-methylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.CN(C=O)C>O>[Si:18]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2ncc(O)cc2c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(O[Si](C)(C)C(C)(C)C)cc2c1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A 500 mL flask, equipped with magnetic stirrer and septum, was charged with 16.6 g crude 16 (0.095 mole), 22.1 g TBDMS-Cl (97%, 0.142 mole), 13.1 g imidazole (99%, 0.19 mole) and 240 mL DMF (distilled, added by syringe). The mixture was stirred under argon for 8 hours and then poured into 1.0 L of water and extracted with ether (3×450 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give 36.4 g of crude (orange solid). Crystallization from Et2O-pentane (1:9) and chromatography of the mother liquor concentrate on silica gel (Et2O-pentane 1:2) gave 25.0 g of 17, 91% yield.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[CH2:30][C@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (171 mg, 0.77 mmol) [prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (270 mg, 0.77 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (436 mg, 0.93 mmol) in chloroform (7.5 mL). DIEA (680 μL, 3.89 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (246 mg, 0.44 mmol, 52%): LC-MS (ES) m/z=521 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1.[CH2:25](N(CC)CC)[CH3:26].C(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH2:25]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:6]1[CH:5]=[CH:4][C:3]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=3[N:14]=2)=[C:2]([F:1])[CH:7]=1)[CH3:26]
Reactant: CCN(CC)CC
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 50F (150 mg) in methanol (6 mL) was added triethylamine (125 mL) and 32 wt/v % acetaldehyde in water (210 mL). The solution was stirred for 1 hour, treated with sodium cyanoborohydride (95 mg), stirred for 3 hours at ambient temperature and at 50° C. for 18 hours and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 1.31-1.36 (m, 3H), 2.30-2.42 (m, 2H), 2.61-2.70 (m, 1H), 3.17-3.29 (m, 2H), 3.34-3.41 (m, 1H), 3.52-3.62 (m, 1H), 3.94-4.01 (m, 1H), 4.64-4.73 (m, 1H), 7.75 (t, J=7.98 Hz, 1H), 7.87 (d, J=7.67 Hz, 1H), 7.93 (d, J=11.35 Hz, 1H), 8.07 (d, J=7.98 Hz, 1H), 8.13 (d, J=7.67 Hz, 1H), 8.28 (t, J=7.52 Hz, 1H).
Reaction SMILES: CO[C:3]1[NH:4][CH2:5][CH2:6][CH:7]=1.[C:8]1([C:14]2[CH:22]=[CH:21][C:17]([CH2:18][C:19]#[N:20])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N12CCCCC1C=NCCC2>C(OCC)C>[C:14]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:15]=[CH:16][C:17]([C:18]([C:19]#[N:20])=[C:3]2[CH2:7][CH2:6][CH2:5][NH:4]2)=[CH:21][CH:22]=1
Reactant: COC1=CCCN1
Reactant: N#CCc1ccc(-c2ccccc2)cc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOCC
Product: N#CC(=C1CCCN1)c1ccc(-c2ccccc2)cc1

Procedure:
Stir 32.7 g of 2-methoxypyrroline, 63.8 g of 4-phenylbenzylcyanide and 5 g of 1,5-diazabicyclo[5,4,0]undec-5-ene for 26 hours at 110°. After cooling, take up the mixture with 500 ml of diethyl ether. Filter the formed precipitate and recrystallize it from 400 ml of ethanol with activated charcoal to obtain 12.2 g (14% of theory) of the title compound (m.p. 168° to 170°).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30]>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Clc1ccccc1Br
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromoclorobenzene. Light yellow solid. MS (ESI): 425.1 (MH+)
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]([C:12](O)=[O:13])=[N:10][CH:11]=1.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH3:15])[C:9]([C:12]([Cl:3])=[O:13])=[N:10][CH:11]=1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cnc1C(=O)Cl
Temperature: 60 °C

Procedure:
Thionyl chloride (71 μl, 962 μmol) is added to a mixture of 5-chloro-3-methyl-pyridine-2-carboxylic acid (150 mg, 874 μmol), toluene (1 ml) and DMF (20 μl). The mixture is heated to 60° C. for 1 hour. The mixture is concentrated in vacuo and the crude product used directly without further purification.
Reaction SMILES: CO.[O:3]1CCO[CH:4]1[C:8]1[CH:21]=[CH:20][C:11]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[C:14]1([NH:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([CH:4]=[O:3])=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(NCc2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To a mixture solution of methanol and tetrahydrofuran (1:1, 20 mL) of (4-[1,3]dioxolane-2-yl-benzyl)-phenyl-amine (4.16 g, 16.3 mmol) described in Manufacturing Example 73-1-2 was added 5N hydrochloric acid (20 mL). This mixture was stirred for 1 hour at room temperature. This mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.5 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: [K].[CH3:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[CH3:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:7][C:6](=[O:8])[N:5]([S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])[C:4]1=[O:9]
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [K]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)NC(=O)N(S(=O)(=O)c2ccc3ccccc3c2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
5-Methyl-5-phenylimidazolidine-2,4-dione potassium salt (1.00 g) was suspended in tetrahydrofuran (10 mL), 2-naphthalenesulfonyl chloride (1.02 g) was added slowly, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 242 mg of white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][C:5]([CH3:15])([CH3:14])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:22][OH:23].Cl>O>[CH3:1][C:2]([CH3:16])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][C:5]([CH3:15])([CH3:14])[NH2:4])[CH:3]=[N:22][OH:23]
Reactant: NO
Reactant: CC1(C)C=NC(C)(C)CC=CCCC=CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 134.8 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 110 g (0.5 mol) of 3,3,12,12-tetramethyl-1-aza-1,5,9-cyclododecatriene, 41 g (0.25 mol) of hydroxylamine sulfate, 50 ml of concentrated hydrochloric acid and 250 ml of water are used. Distillation yields 85 g (0.337 mol) of 2,2,11,11-tetramethyl-11-amino-undeca-4,8-dienal oxime; yield 67.4% of theory; boiling point 130° C./7 Pa.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].C(N(C(C)C)C(C)C)C>O1CCCC1>[CH2:28]([N:30]([CH2:31][CH3:32])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])[CH3:29]
Reactant: CCNCC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 81.3 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), diethylamine (250 ul, 2.42 mmole), N-ethyldiisopropylamine (282 ul, 1.62 mmole) and propylphosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (5 ml) is stirred for 22 h at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4,N4-diethyl-1-methyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (140 mg, 81.3%) as a white solid. Mp.: 165-7° C. MS: m/z=427.4 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:16][CH3:17])[C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7][C:6]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[S:30][CH:31]=[CH:32][N:33]=1>CN(C=O)C>[CH2:16]([N:4]1[C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7][C:6]=2[N:15]=[C:3]1[CH2:2][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[CH3:17]
Reactant: CCn1c(CCl)nc2cnc(C(F)(F)F)cc21
Reactant: c1c[nH]c(-c2nccs2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-Chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine (1 g, 3.8 mmol) in anhydrous DMF (15 mL) were added K2CO3 (2.68 g, 19 mmol), and 2-(1H-imidazol-2-yl)-thiazole (555 mg, 3.8 mmol) and stirred at room temperature for 48 h. The crude residue after usual work up was purified eluting with 5% MeOH-CH2Cl2 containing few drops of NH4OH to afford1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (800 mg, 80 %); 1H NMR (CD3OD): δ 8.83 (s, 1H), 8.14 (s, 1H), 7.71 (d, J=2.7 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.19 (d, J=0.9 Hz, 1H), 6.30 (s, 2H), 4.54 (q, J=5.4 Hz, 2H), 1.46 (t, J=5.4 Hz, 3H); m/z 379 [M+1]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:33])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].[CH3:38]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[N:20]([CH3:38])[CH:21]=[C:22]([CH2:26][C:27]4[CH:32]=[N:31][CH:30]=[N:29][CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:33])=[CH:4][C:3]=1[C:34]([F:35])([F:36])[F:37]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6108108 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (80 mg, 0.148 mmol) and DIPEA (0.078 mL, 0.445 mmol) in DCM (3.0 mL) was added MeI (0.019 mL, 0.297 mmol) dropwise. The reaction mixture was stirred at room 25° C. for 3 h. Purification via MDAP then afforded the title compound (5 mg, 9.04 mol, 6.0% yield). LCMS: rt=3.46 min, [M+H]=553
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16]O)[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc2ccc(OCc3ccccc3)cc2o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran (300 mL) solution of (6-benzyloxy-benzofuran-2-yl)-methanol (14.2 g, 55.8 mmol) described in Production Example 1-2-2 were added phthalimide (9.03 g, 61.4 mmol), triphenylphosphine (17.6 g, 67 mmol) and diethylazodicarboxylate (29.2 g, 67 mmol) at 0° C., which was stirred at room temperature for 7 hours 30 minutes. To the reaction mixture was added water at room temperature followed by extraction with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain a mixture of the title compound and a by-product (14.3 g) as a white solid. This was then used in the next reaction without additional purification.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[C:22]1([C:28]2[N:32]=[C:31]([SH:33])[NH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:28]2[N:32]=[C:31]([S:33][CH2:2][C:3]3[O:4][C:5]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)=[CH:6][C:7]=3[CH2:8][OH:10])[NH:30][N:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Reactant: Sc1nc(-c2ccccc2)n[nH]1
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)oc1CSc1nc(-c2ccccc2)n[nH]1

Procedure:
The title compound was prepared using methyl 2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 44) and 3-phenyl-1,2,4-triazole-5-thiol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (58.6 mg), 2-hydroxy-5-methylbenzophenone (276 mg), and 4-dimethylaminopyridine (156 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 5 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (98.9 mg, yield 95%).
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][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1.O.[NH2:38][NH2:39].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:21][C:19]([F:20])([F:22])[O:18][C:14]1[CH:13]=[C:12]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:38][N:39]=[C:24]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=4)[C:3]=3[C:4]2=[O:23])[CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(C(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethoxyphenyl)-3-(4-trifluoromethylphenylacetyl)-1,8-naphthyridine-2(1H)-one (508 mg, 1.0 mmol) produced in Synthesis Example 22 in DMF (8 mL) was added hydrazine monohydrate (purity of 80%, 194 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 5-(3-trifluoromethoxyphenyl)-3-(4-trifluoromethylbenzyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (162 mg, yield 32%).