Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1.[C:20](O)(=[O:22])[CH3:21].CN(C)C=O.O>C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1.CO>[C:20]([O:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc2cc(O)c(C(=O)OC)cc2c1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc2cc(OC(C)=O)c(C(=O)OC)cc2c1
Temperature: 50 °C
Yield: 84.4 %

Procedure:
2-Hydroxy-3,6-di-methoxycarbonylnaphthalene (2.6 g) obtained in Example 26 was suspended in acetic anhydride (10.0 g), acetic acid (12.0 g) and N,N-dimethylformamide (20.0 g) and 4-dimethylaminopyridine (0.1 g) was added, followed by heating to 50° C. After heating for about 6 hours, the reaction solution was poured into a mixed solution of water (300 g) and methanol (100 g). The deposit was filtered and then washed with water to obtain 2.55 g of 2-acetoxy-3,6-di-methoxycarbonylnaphthalene as pale yellow powder (DSC analysis value: 130.6° C.).
Reaction SMILES: O1CCCC1.[CH3:6][O:7]/[N:8]=[C:9](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:10][O:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH2:30][CH2:31][CH3:32])[CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.CO.[OH-].[Na+]>O>[CH3:6][O:7]/[N:8]=[C:9](/[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)\[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH2:30][CH2:31][CH3:32])[CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:33][CH:34]=1
Reactant: CCCC(CC(=O)OC)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(CC(=O)O)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with 3 mL of tetrahydrofuran. To the stirred solvent were added methyl 3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}hexanoate (0.017 g, 0.03 mmol), methanol (0.5 mL) and sodium hydroxide (0.013 g, 0.32 mmol) in water (0.5 mL). After addition, the reaction mixture was stirred at room temperature 30 minutes. The reaction mixture was concentrated to distill off the solvent; the crude was washed with diethyl ether (5 mL). The salt was dissolved in water (1 mL) and the aqueous layer was acidified with saturated citric acid to solution to make pH 6. The aqueous layer was extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by preparative TLC using methanol and chloroform as eluents. The product was obtained as white semi solid (0.012 g, yield: 24.73%). MS (ESI, 120 ev): m/z=462.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.C(OC(C1C(C2C=CC=CN=2)=NOC=1)=O)C>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)=[N:12][CH:13]=1
Reactant: CCOC(=O)c1conc1-c1ccc(F)cn1
Agent: CCOC(=O)c1conc1-c1ccccn1
Product: O=C(O)c1conc1-c1ccc(F)cn1
Yield: 66.7 %

Procedure:
As described for example 358b, 3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid ethyl ester (1.0 g, 4.23 mmol) was converted, instead of 3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (587 mg, 67%) which was obtained as a dark brown solid. MS: m/e=207.1 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccccc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 59.1 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-phenoxyphenyl)ethanone (5.18 g, 16.2 mmol) and thiourea (1.24 g, 16.3 mmol) in 95% EtOH (23.2 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-phenoxyphenyl)thiazol-2-amine (2.84 g) as yellow solids in 59% yield: 1H NMR (500 MHz, CDCl3) δ 7.33 (t, J=7.5 Hz, 2 H), 7.26 (t, J=7.5 Hz, 1 H), 7.10 (d, J=7.3, 2 H), 6.72 (s, 2 H), 6.30 (s, 1 H), 5.18 (bs, 2 H), 2.14 (s, 6 H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[C:14]([F:16])[CH:15]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:55]1[CH:56]=[C:57]([F:62])[C:58]([F:61])=[N:59][CH:60]=1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:9][C:10]1[CH:11]=[C:12]([C:55]2[CH:56]=[C:57]([F:62])[C:58]([F:61])=[N:59][CH:60]=2)[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(F)cc(-c2cnc(F)c(F)c2)c1
Temperature: 100 °C

Procedure:
A mixture of palladium (II) acetate (0.0375 g, 0.167 mmol), potassium phosphate (2.13 g, 10.0 mmol), 3,5-difluorophenylboronic acid (1.58 g, 10.0 mmol), X-Phos (0.159 g, 0.334 mmol) and 5-chloro-2,3-difluoropyridine (0.347 ml, 3.34 mmol) was diluted with 1,4-dioxane (0.1M, 33.4 mL) and water (0.3M, 11.0 mL) and was heated under nitrogen at 100° C. for 45 minutes. The reaction was concentrated in vacuo. The concentrated material was triturated with water, filtered and rinsed with MeCN. The crude solid was taken up in dichloromethane and filtered over a plug of Celite to eliminate residual palladium. The material was dissolved in minimal DCM, and purified via MPLC (eluting with 0-10% EtOAc in hexanes) to yield 5-(3,5-difluorophenyl)-2,3-difluoropyridine. The material was converted to the hydrazine in a method similar to that in the synthesis of (S)-6-(1-(8-fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)quinoline. The following compounds were prepared using a similar method as 1-(5-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)hydrazine:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:14]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22](=[O:33])/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:16][CH2:15]1)[CH2:5][C:6](=[O:13])[N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Li+].[BH4-].OS([O-])(=O)=O.[K+]>CCO>[Cl:32][C:27]1[CH:26]=[C:25](/[CH:24]=[CH:23]/[C:22]([N:17]2[CH2:18][CH2:19][C:20](=[O:21])[N:14]([CH:4]([CH2:3][OH:2])[CH2:5][C:6](=[O:13])[N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)[CH2:15][CH2:16]2)=[O:33])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: COC(=O)C(CC(=O)N1CCCCC1)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(C(CO)CC(=O)N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
A cooled (0° C.) solution of 0.150 g (0.29 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-oxo-4-piperidin-1-yl-butyric acid methyl ester in 3.7 ml of EtOH was treated with 0.013 g (0.59 mmol) of LiBH4 (in 3 portions during 48 h until to the end of the reaction). The mixture was stirred at RT for 48 h, cooled to 0° C. and aqueous 10% KHSO4 solution was slowly added. The mixture was partitioned between aqueous saturated NaHCO3/EtOAc (3×). The organic phases were dried (Na2SO4) and evaporated to give 0.136 g (96%) of the titled compound as white foam. MS: 482.2 (MH+, 2Cl).
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[N:49]=[C:48]([C@@:50]2([CH:69]([F:71])[F:70])[CH2:55][C@@H:54]([C:56]([F:59])([F:58])[F:57])[O:53][C:52]([NH:60][C:61](=[O:68])[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[N:51]2)[C:47]([F:72])=[CH:46][CH:45]=1.[Cl:73][C:74]1[CH:75]=[CH:76][C:77]([C:80]([NH2:82])=[O:81])=[N:78][CH:79]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:61]([NH:60][C:52]1[O:53][C@H:54]([C:56]([F:59])([F:58])[F:57])[CH2:55][C@@:50]([C:48]2[N:49]=[C:44]([NH:82][C:80](=[O:81])[C:77]3[CH:76]=[CH:75][C:74]([Cl:73])=[CH:79][N:78]=3)[CH:45]=[CH:46][C:47]=2[F:72])([CH:69]([F:71])[F:70])[N:51]=1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: O=C(NC1=N[C@](c2nc(Br)ccc2F)(C(F)F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Reactant: NC(=O)c1ccc(Cl)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(NC1=N[C@](c2nc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 71.4 %

Procedure:
A round-bottomed flask was charged with Pd2(dba)3 (2.91 mg, 3.17 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.35 mg, 0.013 mmol), N-((4R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (21 mg, 0.042 mmol), 5-chloropicolinamide (9.61 mg, 0.061 mmol), and cesium carbonate (34.5 mg, 0.106 mmol). The flask was evacuated under vacuum and then flushed with nitrogen. Dioxane (0.5 mL) was then added and the reaction was stirred in a 90° C. oil bath for 10 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc. The filtrate was concentrated and the residue was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 30% EtOAc in hexane, to provide N-(6-((4R,6S)-2-benzamido-4-(difluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-chloropicolinamide (17 mg, 0.030 mmol, 70.2% yield) as white solid. MS m/z=572, 574 M+, Calculated for C24H16ClF6N5O3: 571.86.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:17]2[C:18]3[C:9]([CH2:10][NH:11][C:12](=O)[C:13]=3[CH:14]=[CH:15][CH:16]=2)=[CH:8]1.N1C2C3[C:22](CNCC=3C=CC=2)=[CH:21]1.C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CO>[CH2:21]([N:11]1[CH2:10][C:9]2=[CH:8][NH:7][C:17]3[C:18]2=[C:13]([CH:14]=[CH:15][CH:16]=3)[CH2:12]1)[CH3:22]
Reactant: O=C1NCc2c[nH]c3cccc1c23
Reactant: c1cc2c3c(c[nH]c3c1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CO
Product: CCN1Cc2cccc3[nH]cc(c23)C1
Reaction time: 1 h

Procedure:
LiAlH4 (0.440 g, 11.6 mmol) was added in portions to a solution of 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5(1H)-one, Intermediate 1 (0.4 g, 2.32 mmol) in dry THF (20 ml). The mixture was brought to reflux for 3 hours, cooled, diluted with aqueous THF and filtered. The solid cake was washed with THF (2×) and the residue was evaporated to give a light brown solid. This brown solid was dissolved in MeOH (20 ml) and acetaldehyde (0.334 g, 7.6 mmol) and sodium triacetoxy borohydride (0.482 g, 2.3 mmol) were added. The mixture was stirred for 1 hour and evaporated to half its volume and partitioned between 1N Na2CO3 and dichloromethane. The organic phase was washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using 10% MeOH to 50% MeOH in dichloromethane with 1% NEt3. Yield: 142 mg. Grey solid. MS m/z 187 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH3:14])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[NH2:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][C:18]=2[C:17]=1[C:24]#[N:25]>>[C:24]([C:17]1[C:18]2[CH2:23][CH2:22][CH2:21][C:19]=2[S:20][C:16]=1[NH:15][C:4](=[O:5])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]([CH3:1])[CH2:13][CH3:14])#[N:25]
Reactant: N#Cc1c(N)sc2c1CCC2
Reactant: CCC(C)C(C(=O)Cl)c1ccccc1
Product: CCC(C)C(C(=O)Nc1sc2c(c1C#N)CCC2)c1ccccc1
Reaction time: 20 h

Procedure:
Reaction of 3-methyl-2-phenylvaleryl chloride (Prepared in Example 7, Step1) and 2-Amino-3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene (164 mg; 1.0 mmol) according to the procedure outlined in Example 5 for 20 h at room temperature provided after workup, crude which triturated with diethylether to give 94 mg of crude 3-Methyl-2-phenyl-pentanoic acid (3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-amide which was further purified by dissolving in methylene chloride and passing through a short plug of Merck Silica gel 60 to provide 82 mg (24%) of 3-Methyl-2-phenyl-pentanoic acid (3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-amide as a mixture of diastereomers. ES-HRMS m/e calcd for C26H38N2O2 (M+Ht) 411.3006, found 411.3011.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:34][NH:35][O:36][CH3:37].CN1CCOCC1>CC(N(C)C)=O.O>[C:1]([C:4]1[S:8][C:7]([C:9]([N:35]([O:36][CH3:37])[CH3:34])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNOC
Reactant: CC(=O)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Solvent: O
Product: CON(C)C(=O)c1ccc(C(C)=O)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
A solution of 5-acetylthiophene-2-carboxylic acid (5 g, 0.0294 mol) in DMA (80 mL) was treated with EDCI (8.47 g, 0.044 mol), HOBt (3.97 g, 0.044 mol), N,O-dimethylhydroxylamine hydrochloride (5.7 g, 0.059 mol) and 4-methylmorpholine (16.14 mL, 0.147 mol). The resulting thick mixture was stirred at 25° C. for 16 h. Water (250 mL) was added and the mixture was extracted with 1:1 EtOAc/ether (2×200 mL). The combined extracts were washed with 1N HCl (150 mL), water (3×200 mL), saturated NaHCO3 (150 mL), and brine (150 mL); dried (Na2SO4); filtered; and evaporated to afford 5.4 g (86%) of the desired product. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.58 (s, 3H) 3.31 (s, 3H) 3.78 (s, 3H) 7.85 (d, J=4.04 Hz, 1H) 7.92 (d, J=4.04 Hz, 1H); MS (DCI) 214 m/z (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.Cl.[C:25]1([S:31]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CN(C)C=O.O>[C:25]1([S:31]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([CH2:2][C:3]3[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]4[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=4)=[CH:5][CH:4]=3)[CH2:38][CH2:37]2)(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: O=S(=O)(CCN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1ccc(OCc2ccc(CN3CCN(CCS(=O)(=O)c4ccccc4)CC3)cc2)cc1
Temperature: 70 °C
Reaction time: 66 h
Yield: 61.6 %

Procedure:
To a solution of methyl 3-(4-([4-(chloromethyl)benzyl]oxy}phenyl)propanoate (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added a suspension of 1-(2-benzenesulfonylethyl)piperazine dihydrochloride (62 mg, 0.19 mmol) in N,N-dimethylformamide (0.5 mL) and potassium carbonate (80 mg, 0.58 mmol) and the mixture was stirred at 70° C. for 66 hr. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 mL). The organic layer was concentrated by a GeneVac centrifugation concentration apparatus under reduced pressure. The obtained product was dissolved in methanol (2 mL), 1 N aqueous sodium hydroxide solution (0.32 mL, 0.32 mmol) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was acidified with 1 N Hydrochloric acid, and the precipitated crystals were collected by filtration, and washed with diethyl ether to give the title compound (51.5 mg, yield 63%). MS (ESI+, m/e) 523 (M+1).
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[O:20]1[CH2:22][CH:21]1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=1>CO.O>[ClH:1].[OH:20][CH:21]([CH2:22][NH:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:9][CH:10]=1)[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][CH:30]=1
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(OCC(O)CNCCOc2ccc(-n3ccnc3)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2.3 g (0.008 mol) of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanamine dihydrochloride in 100 ml of methanol add a solution of 0.66 g of sodium hydroxide in 5 mL of water. Stir for 15 minutes. Add 2.0 g (0.008 mol) of N-[4-(oxiranylmethoxy)phenyl]methanesulfonamide and reflux for 16 h. Monitor the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride, methanol, triethylamine, 84:15:1). Remove the solvent in vacuo. Chromatograph the oil on 350 g of silica gel using amixture of methylene chloride:methanol:triethylamine (94:5:1). Combine the fractions containing residue and remove the solvent in vacuo. Dissolve theresidue in methanol and add a solution of hydrogen chloride in methanol. Remove the solvent in vacuo. Recrystallize the salt from acetonitrile:methanol to obtain the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1)[CH2:8]2.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:13]1[N:14]=[C:15]([N:24]3[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]3)[CH:16]=[CH:17][CH:18]=1)=[O:20])[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(Br)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
N-(adamantan-2-yl)-6-bromopicolinamide (80 mg, 0.239 mmol), tert-butyl piperazine-1-carboxylate (49 mg, 0.263 mmol), Pd2(dba)3 (4.4 mg, 0.005 mmol), xantphos (8.3 mg, 0.014 mmol), and sodium-tert-butoxide (34 mg, 0.359 mmol) were suspended in toluene (3 ml), and then stirred at 100° C. under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (40% EtOAc/Hexanes), to obtain 86.8 mg of pale yellow oil (83%).
Reaction SMILES: [O:1]=[C:2]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:11]=2[O:10][C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:3]1.S(Cl)([Cl:27])(=O)=O>ClCCl>[Cl:27][C:14]1[C:15]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:11]2[O:10][C:4]3([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:3][C:2](=[O:1])[C:12]=2[CH:13]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)COc1ccc2c(c1)OC1(CCCCC1)CC2=O
Solvent: ClCCl
Product: CCOC(=O)COc1cc2c(cc1Cl)C(=O)CC1(CCCCC1)O2
Yield: 75 %

Procedure:
Ethyl 2-{(3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]7-yl)oxy}acetate prepared in Preparation 28) (0.72 g, 2.26 mmol) is dissolved in dry dichloromethane (7.2 ml). To the solution is added dropwise 1M sulfuryl chloride solution in dichloromethane (2.3 ml, 2.3 mmol) at -40° C. with stirring. After 2 hours stirring at -40° to -10° C., the solvent is removed by distillation. The residue is dissolved in dichloromethane, and the solution is washed with water, dried, and concentrated. The residue is applied to a Lober column and eluted with a mixture of ethyl acetate and hexane (1:2). The resulting crude product is recrystallized from a mixture of diethyl ether and hexane to yield the title compound (0.6 g, yield 75%, m.p.=116°-117° C.).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[CH:16]=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=2)[S:9][CH:10]=1)C.[Li+].[OH-].Cl>O1CCCC1>[CH2:20]([O:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([O:22][CH2:23][CH3:24])[CH:16]=1)[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:26])=[O:3])[N:7]=1)=[O:25])[CH3:21]
Reactant: CCOC(=O)Cc1csc(NC(=O)c2cc(OCC)cc(OCC)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(OCC)cc(C(=O)Nc2nc(CC(=O)O)cs2)c1
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of [2-(3,5-diethoxy-benzoylamino)-thiazol-4-yl]acetic acid ethyl ester (38 mg, 0.1 mmol) in tetrahydrofuran (2 mL) was added 2 N aqueous LiOH (2 mL) and the contents were stirred for 2 h. Then acidified with conc HCl and extracted with ethyl acetate. The extracts were dried (Na2SO4) and concentrated to afford colorless 3,5-diethoxy-N-(4-carboxymethyl-thiazol-2-yl)-benzamide (30 mg, 90%).
Reaction SMILES: N1CCOCC1.[CH3:7][C:8]1([O:11][CH2:10]1)[CH3:9].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:25]#[N:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.C(=O)(O)[O-].[Na+]>O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:25]#[N:26])[CH2:20][CH2:21][N:22]([CH2:10][C:8]([OH:11])([CH3:9])[CH3:7])[CH2:23][CH2:24]2)=[N:17][CH:18]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCNCC1
Reactant: CC1(C)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCN1
Solvent: O
Product: CC(C)(O)CN1CCC(C#N)(c2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 91.4 %

Procedure:
Morpholine (catalytic amount) and isobutylene oxide (2.84 g) were added to 4-(5-bromopyridin-2-yl)piperidine-4-carbonitrile (3.4 g) of Reference Example 88(2) and water (35 ml), and the mixture was stirred at 100° C. for 4.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated brine dried over anhydrous sodium sulfate and concentrated in vacuo. Water was added to the residue and the precipitated solid was washed with water to give 4-(5-bromopyridin-2-yl)-1-(2-hydroxy-2-methylpropyl)piperidine-4-carbonitrile (3.95 g) as a light brown solid.