Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Cl-].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][Zn+].C1COCC1>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>[Br:7][C:6]1[C:2]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:4][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Br
Reactant: Clc1ccc(C[Zn+])cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCOCC2)c(Br)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A sealable reaction vessel containing a suspension of ethyl 3,4-dibromo-5-(morpholin-4-yl)thiophene-2-carboxylate (0.560 g, 1.40 mmol), 0.500 M 3,4-dichlorobenzylzinc chloride in THF (3.368 mL, 1.684 mmol) and THF (2.06 mL, 25.4 mmol) was purged via vacuum/backfilling with argon. To this suspension was added tetrakis(triphenylphosphine)palladium(0) (81.07 mg, 0.07016 mmol), the vial was capped, and the resulting black suspension was stirred at 95° C. overnight. The reaction mixture was adsorbed to celite in vacuo, and the solid thus obtained was purified via column chromatography (eluent: 0-15% EtOAc:hexane) to afford ethyl 4-bromo-3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)thiophene-2-carboxylate (323 mg, 50%). LCMS: (FA) ES+ 478, 480, 482; 1H NMR (400 MHz, DMSO) δ 7.53 (d, J=8.3 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.3, 2.1 Hz, 1H), 4.36 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 3.75-3.70 (m, 4H), 3.17-3.12 (m, 4H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH3:26])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.N1C=CC=CC=1>[ClH:1].[CH3:26][O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)c1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (111 g, 0.5 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and methyl anthranilate (75.6 g, 0.5 mole) are dissolved in a mixture of dimethylformamide and pyridine (1:1, 1250 ml), and thereto is added dicyclohexylcarbodiimide (103 g, 0.5 mole), and the mixture is stirred at room temperature for 40 hours. After the undissolved materials are filtered off, the solvent is evaporated under reduced pressure. To the residue are added methanol (500 ml) and water (80 ml), and the mixture is stirred, and the undissolved materials are again filtered off and the solvent is evaporated under reduced pressure. The resulting residue is washed with acetone (2000 ml) and recrystallized from water to give the title compound (143 g) as white crystals. The physical data of this compound are identical with those of N-(o-methoxycarbonylphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride prepared in Example 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)c3ccccc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 15 μL (0.11 mmol) benzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:44]([NH:46][CH2:47][C:48]([CH2:54][NH:55][C:56]1[CH:64]=[C:63]([CH3:65])[CH:62]=[C:61]2[C:57]=1[CH:58]=[N:59][N:60]2[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([OH:53])[C:49]([F:52])([F:51])[F:50])[CH3:45]>CN(C)C=O>[CH2:44]([N:46]([CH2:47][C:48]([OH:53])([CH2:54][NH:55][C:56]1[CH:64]=[C:63]([CH3:65])[CH:62]=[C:61]2[C:57]=1[CH:58]=[N:59][N:60]2[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:49]([F:52])([F:51])[F:50])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:45]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: Cc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of 2-methylbenzoic acid (12.7 mg, 0.09 mmol) in N,N-dimethylformamide (100 μl) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol) in dimethylformamide (150 μl) followed by N,N-diisopropylethylamine (36 μl, 0.21 mmol). The mixture was shaken for 5 minutes and then a solution of 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol (27 mg, 0.07 mmol) in N,N-dimethylformamide (150 μl) was added. The mixture was again shaken for 5 minutes and then left to stand at room temperature for 18 hours. The crude reaction was purified by mass-directed autopreparation (System A) to give the title compound (21.1 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20]Cl)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:22][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
A solution of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (1.00 g, 3.28 mmol) in DMF (3.0 mL) was added to a solution of N-hydroxyphthalimide (642 mg, 3.94 mmol) and triethylamine (0.915 mL, 6.56 mmol) in DMF (3.0 mL). The flask containing the solution of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was rinsed with DMF (3.0 mL), which was added to the reaction solution. The solution was stirred at room temperature for 3 hours and a solid formed. The solid was isolated by filtration, washed with dichloromethane, and dried. The off-white solid was dissolved in hot DMF (20 mL). Acetonitrile (50 mL) was added to the solution, which was then placed in a freezer. Crystals formed and were isolated by filtration, washed with acetonitrile, and dried to provide 288 mg of 2-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione as orange crystals, mp 270.0-272.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: C1CCNC1
Product: O=Cc1ccc(Cl)cc1N1CCCC1

Procedure:
The title compound was prepared from 4-chloro-2-fluorobenzaldehyde and pyrroldine according to the representative procedures of Example 56, Step 1: 1H NMR 400 MHz (CDCl3) δ 10.04 (s, 1H), 7.64 (d, J=8.1 Hz, 1H), 6.82 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 3.41-3.33 (m, 4H), 2.06-1.96 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH2:22])([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH3:3].CCN(C(C)C)C(C)C.[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:34]=1[C:35](Cl)=[O:36]>CN(C=O)C>[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]([F:43])[C:34]=1[C:35]([NH:22][C:2]([CH3:3])([C:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH3:1])=[O:36]
Reactant: CCCS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)N)CC1
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(c2ccccn2)(C(C)(C)NC(=O)c2c(F)ccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of {1-Methyl-1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine (II-1, 43 mg, 0.13 mmol) in DMF (0.7 mL) was treated with i-Pr2NEt (0.066 mL, 0.38 mmol) and 2-chloro-3,6,-difluorobenzoyl chloride (0.2 mL, 0.8 mmol) and stirred at room temperature for 1.5 h. The reaction mixture was purified directly by reverse phase HPLC to afford 2-chloro-3,6-difluoro-N-{1-methyl-1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (II-2). Analytical LCMS: single peak (214 nm), 2.803 min. 1H NMR (CD3OD, 300 M ) δ 8.67 (d, J=3.9 Hz, 1H), 8.51 (s, 1H), 8.15 (ddd, J=1.8, 7.8, 8.1 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.60 (dd, J=5.5, 6.9 Hz, 1H), 7.34 (ddd, J=4.8, 9.3, 14.1 Hz, 1H), 7.21 (ddd, J=4.2, 8.4, 12.3 Hz), 1H), 3.76-3.65 (m, 2H), 2.86-2.78 (m, 4H), 2.69-2.54 (m, 2H), 2.25-2.15 (m, 2H), 1.76-1.63 (m, 2H), 1.43 (s, 6H), 0.98 (t, J=7.2 Hz, 3H); RMS m/z 500.1572 (C22H28ClF2N3O3S+H+ requires 500.1581).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:13]=[CH:12][C:11]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:39])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=2)=[CH:6][CH:5]=1>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][C:11]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:39])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=2)=[CH:40][CH:41]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCc2ccc(F)cc2)c1
Yield: 64 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 10 eq) of sodium hydroxide and methyl 3-[2-(4-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 310 mg of 3-[2-(4-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=79° C.). Yield=64% over the two steps.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]=[C:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.CCOCC>[Cl:1][C:2]1([Cl:7])[C:3](=[O:4])[CH2:8][C:9]21[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
28.42 mL (254.65 mmol) of trichloroacetyl chloride dissolved in 70 mL of dimethoxyethane are added dropwise, at 0° C., to a mixture containing 7.98 g (47.16 mol) of tert-butyl 3-methyleneazetidine-1-carboxylate (WO 2008/124 085) and 36.48 g (282.94 mmol) of zinc-copper amalgam suspended in 200 mL of ether. The reaction medium is stirred at room temperature for 12 hours. The mixture is then poured portionwise into a sodium carbonate solution at 0° C. The solution obtained is filtered through Celite and rinsed thoroughly with water and ether. The aqueous phase is then separated out and extracted several times with ether. The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the product obtained, in the form of a brown oil, is used without further purification in the following step.
Reaction SMILES: C(O)(=O)C.Cl.[C:6]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][C:29](=O)[CH2:28]1)=[O:26])[CH3:23]>O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][C:30]2[NH:20][C:17]3[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:19][C:18]=3[C:29]=2[CH2:28]1)=[O:26])[CH3:23]
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C1CCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To 250 ml of 80% acetic acid in water, were added 4-phenylmethoxyphenylhydrazine hydrochloride (30 g, 0.12 mole) and 3-oxocyclopentane carboxylic acid ethyl ester (20 g, 0.13 mole). After stirring at ambient temperature for one hour and then at 100° C. for four hours, the mixture was cooled and poured into one liter of water. After stirring for five minutes, the mixture was extracted with ethyl acetate (3×). The organic layer was washed successively with water (2×) and saturated sodium chloride solution, and thereafter dried over anhydrous MgSO4. After filtering, the solution was concentrated to a dark oil (~48 g), which was eluted on a silica gel column with 5% ethyl acetate/dichloromethane via HPLC. The desired fractions were combined and concentrated to give the product as a thick brown oil (24.1 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]N1C(=O)CCC1=O>[N+]([O-])(O)=O.C(O)(=O)C>[Br:16][C:8]1[C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2ccccc2)on1
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1noc(-c2ccccc2)c1Br
Yield: 77.8 %

Procedure:
A solution of methyl 5-phenylisoxazole-3-carboxylate (100 mg, 0.492 mmol) and N-bromosuccinimide (119 mg, 0.669 mmol) in 5% fuming nitric acid in acetic acid (2 mL) was heated to 150° C. for 10 minutes via microwave. The reaction mixture was concentrated and purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to afford methyl 4-bromo-5-phenylisoxazole-3-carboxylate (108 mg). The compound had an HPLC ret. time=3.21 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=284+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:5]([CH3:18])[C:4]=1[CH3:19].C([O-])(=O)C.[Na+].[Br:25]Br.O>C(O)(=O)C>[Br:25][C:8]1[C:7]([CH3:9])=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:5]([CH3:18])=[C:4]([CH3:19])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)c(NC(=O)OC(C)(C)C)c(C)c1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1Br
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamate synthesized in Reference Example 128 (12.7 g, 47.9 mmol) and sodium acetate (4.72 g, 57.5 mmol) in acetic acid (50 mL) was added bromine (8.42 g, 52.7 mmol) at room temperature and the mixture was stirred at the same temperature for 1 hour. Water (80 mL) was poured into the reaction mixture, and the precipitated crystals were collected by filtration and then dissolved in ethyl acetate. The solution was washed with a saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from methanol to obtain 15.0 g (yield 91%) of the title compound. Melting point: 159-161° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32]C)=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:14]1([C:11]2[S:12][CH:13]=[C:9]([CH2:8][O:7][C:6]3[CH:20]=[CH:21][C:3]([CH2:2][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([OH:32])=[O:31])=[CH:4][CH:5]=3)[N:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccccc1OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole (1.95 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (0.85 g) and N,N-dimethylformamide (15 mL) was stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueous sodium hydroxide solution (10 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.76 g, 29%) of 2-[2-[4-[(2-phenyl-4-thiazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1ccccc1Oc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4OC)nc3n2)cc1
Temperature: 4 °C
Yield: 69.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (10.2 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-(2-methoxyphenoxy)-1,8-naphthyridine (13.4 g). The product produced by precipitation in water (18 g; m.p. 167° C.) is dissolved in boiling ethanol (400 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-[7-(2-methoxyphenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (14 g) is produced, m.p. 168°-170° C.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][N:7]=CC1C2C(=CC=CC=2)C=CC=1O)=[O:5].[C:24](C1C=CC(C(O)=O)=CC=1)([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C1C=CC=CC=1.NN>>[C:24]([C:22]1[CH:23]=[CH:2][C:3]([C:4]([NH:6][NH2:7])=[O:5])=[CH:20][CH:21]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1C(=O)NN=Cc1c(O)ccc2ccccc12
Agent: NN
Agent: O=C(O)c1ccccc1
Product: CC(C)(C)c1ccc(C(=O)NN)cc1

Procedure:
The particularly preferred substituted aromatic hydrazone 2-hydroxy-1-naphthaldehyde-p-(t-butyl)-benzoyl hydrazone is prepared in a manner similar to the preparation of 2-hydroxy-1-naphthaldehyde-o-aminobenzoyl hydrazone, Equations (1) through (3) above. Since the ester of p-(t-butyl)-benzoic acid is not available the preparation of this hydrazone requires the additional step of esterification of the benzoic acid. The ester of p-(t-butyl)-benzoic acid is reacted with hydrazine to produce p-(t-butyl)-benzhydrazide. This hydrazide is then reacted with 2-hydroxy-1-naphthaldehyde to yield 2-hydroxy-1-naphthaldehyde-p-(t-butyl)-benzoyl hydrazone.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@H:8]([OH:10])[CH2:9][C@@H:2]12.C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>ClCCl>[OH:10][C@H:8]1[CH2:7][N:3]2[CH2:4][CH2:5][N:6]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)=[O:24])[CH2:1][C@@H:2]2[CH2:9]1
Reactant: O[C@@H]1C[C@H]2CNCCN2C1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](O)C[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 1 g, 4.30 mmol) and ethanol (10 mL) were added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of crude (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.422 g, 10 mmol) and triethylamine (1.62 g, 16 mmol) in dichloromethane (50 mL) was slowly added a solution of 3-(trifluoromethyl)benzoyl chloride (2.09 g, 10 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, and filtered. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.63 (m, 2H), 2.10-2.27 (m, 3H), 2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.50 (m, 2H), 4.22 (m, 1H), 4.42-4.60 (m, 1H), 4.80 (m, 1H), 7.70 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCCCCC.C(Cl)Cl>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccccc1O
Reactant: OCCCCCCCCCCCCCCCCBr
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCOc1ccccc1CCCCCCCCCCCCCCCCBr
Yield: 83.4 %

Procedure:
12.8 g (66 mmol) of 2-hexyloxyphenol, 23.3 g (73 mmol) of 16-bromohexadecan-1-ol and 20.0 g (99 mmol) of tri-n-butylphosphine were added to 350 mL of dehydrated methylene chloride followed by cooling with ice in the presence of argon. After adding 25.0 g (99 mmol) of 1,1′-(azodicarbonyl) dipiperidine a little at a time while stirring, 150 mL of methylene chloride were added. After stirring for 30 minutes at room temperature in the presence of argon, the reaction solution was refluxed for 6 hours. After cooling, the reaction solution was dropped into 100 mL of hexane and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain 26.5 g of a clear liquid.