Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCNC(=O)Cc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.4 %

Procedure:
2-({4-[2-(Heptylamino)-2-oxoethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (12.0 g) obtained in Example 303-1 was dissolved in tetrahydrofuran (120 mL), 1 M-borane/tetrahydrofuran complex (100 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (400 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (120 mL) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; dichloromethane:methanol=20:1 to 10:1) to give the title compound (5.5 g) as a slightly yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: COc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3nc(C(C)=O)cs3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].F[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[CH2:7]([O:14][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:26])([F:28])[F:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCCCCCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of potassium t-butoxide (20.7 g) in N,N-dimethylformamide (120 ml) was added n-heptanol (15.6 ml), and the mixture was stirred at room temperature for 30 min. A solution of 4-fluoro-3-trifluoromethylbenzoic acid (16.7 g) in N,N-dimethylformamide (60 ml) was added dropwise to the reaction mixture at 0° C., and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was ice-cooled, water (320 ml) was added, and 6M-hydrochloric acid (40 ml) was added at room temperature. The mixture was stirred at room temperature for 30 min and precipitated crystals were collected by filtration. The crystals were dissolved in ethanol (60 ml) at 70° C., water (96 ml) was added dropwise at the same temperature and the mixture was stirred for 30 min. The mixture was allowed to cool to room temperature, and stirred for 30 min under ice-cooling. The precipitated crystals were collected by filtration to give the object product (24.1 g) as pale-brown crystals.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:22])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[NH:19][N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[I:1][C:2]1[C:3](=[O:22])[C:4]2[CH:5]=[CH:6][N:7]3[C:20](=[O:21])[N:19]([CH3:23])[N:18]=[C:8]3[C:9]=2[O:10][C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccn1c(=O)[nH]nc21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To an ice-cooled solution of 7-iodo-8-phenyl-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione in DMF (2 mL) was added cesium carbonate (73 mg, 0.224 mmol) and iodomethane (0.021 mL, 0.336 mmol). The mixture was allowed to warm to RT and stirred for 1.5 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was isolated and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (25.5 mg, 51%, over 2 steps) as a yellow solid. LCMS (Method A): RT=3.98 min, [M+H]+=420.
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C:7]1[C:19]2[CH2:18][CH2:17][C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[NH:9][C:8]=1Br)=[O:6])[CH3:3].[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.[Li+].[Cl-]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:2]([O:4][C:5]([C:7]1[C:19]2[CH2:18][CH2:17][C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[NH:9][C:8]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:30])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(Br)[nH]c2c1CCc1cnccc1-2
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2C)[nH]c2c1CCc1cnccc1-2
Temperature: 150 °C
Yield: 85 %

Procedure:
To a suspension of 2-bromo-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid ethyl ester F1 (0.497 mmol) in toluene (4 mL) and ethanol (4 mL), o -tolylboronic acid (0.75 mmol), LiCl (1.49 mmol), Na2CO3.10H2O (1.74 mmol) and (PPh3)2PdCl2 (3.5 mg) were added. The mixture was heated at 150° C. for 15 min with microwave irradiation then evaporated to dryness. Chromatography on silica gel (eluant: DCM/MeOH 95:5) afforded the title compound (85% yield). ESI (+) MS: m/z 333 (MH+). 1H NMR: 1.03 (d, J=7.07, 3H), 2.18 (s, 3H), 2.93 (t, J=7.40, 2H), 3.03 (t, J=7.30, 2H), 4.00 (q, J=7.07, 2H), 7.22-7.39 (m, 4H), 7.45 (d, J=5.12, 1H), 8.34 (d, J=5.00, 1H), 8.36 (s, 1H), 12.18 (bs, 1H). Employing the same methodology but using phenylboronic acid the following compound was prepared:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1>>[C:7]([OH:12])(=[O:13])/[CH:8]=[CH:9]\[C:10]([OH:4])=[O:11].[C:7]([OH:12])(=[O:13])/[CH:8]=[CH:9]\[C:10]([OH:4])=[O:11].[CH3:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4]
Reactant: O=C1C=CC(=O)O1
Agent: CC(CO)CO
Product: O=C(O)/C=C\C(=O)O

Procedure:
A three-liter glass reactor equipped as described in Example 17 is charged, under a stream of nitrogen, with 2-methyl-1,3-propanediol (216 g, 2.4 mol) and maleic anhydride (471 g, 4.8 mol). The mixture is heated at 195°-210° C. for 1.5 to 2 h with no steam in the reflux column to give 2-methyl-1,3-propanediol bismaleate. The reactor is then charged with 2-methyl-1,3-propanediol (115 g) and 497 g of a glycol ester made from 2-methyl-1,3-propanediol (1442 g) and terephthalic acid (1329 g) (2:1 molar ratio of diol to acid used to make the glycol ester).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10]C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1)[CH3:10]
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Product: CC(=Nc1ccc(C2=NNC(=O)CC2C)cc1)c1ccc(O)cc1O
Temperature: 140 °C

Procedure:
A mixture of 0.167 g (0.0011 mol) of 2',4'-dihydroxypropiophenone and 0.203 g (0,001 mol) of 6-(4-aminophenyl)-4,5-dihydro-5-methylpyridazin-3(2H)one was heated for 1 h at 140° C. The product was triturated with ethanol and filtered. Yield 0.15 g (45%), m.p. 185°-190° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](F)=[O:19].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30])[OH:28])[OH:26].C(=O)(O)[O-].[Na+].Cl>CC(C)=O.O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([O:23][C@@H:24]1[O:32][C@H:31]([C:33]([OH:35])=[O:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]1[OH:26])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)F)C(C)(C)CCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 61.1 %

Procedure:
Retinoyl fluoride (2.4 g, 7.9 mmol) was dissolved in 200 ml of acetone. D-glucuronic acid (6 g, 31 mmol) dissolved in 50 ml of water and sodium bicarbonate (970 mg) dissolved in 50 ml of water were added to the retinoyl fluoride solution. The mixture was stirred at room temperature for 20-24 hrs. The solution was neutralized with 1N HCl, diluted with water, and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness in a rotary evaporator. The residue was dissolved in 2-3 ml of diethyl ether and transferred to a silica gel (for dry column chromatography, wet packed with hexane) column. The column was developed with hexane containing diethyl ether (5-50%) to remove retinoic acid and other products. The major yellow band containing retinoyl glucuronide was next eluted with a mixture of CH2Cl2 /CH3OH (1:1). The solvent was evaporated to dryness to give solid retinoyl β-glucuronide (2.3 g, 60%). This preparation consisted mainly of the all-trans isomer, and can be used as such.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:39][N:38]([CH3:40])[CH2:37][CH2:36][O:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH:13]([C:11]([N:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=1)[C:24]1[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=1)=[O:12])[CH2:14][CH2:15][CH2:16]2
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(O)ccc32)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(OCCN(C)C)ccc32)cc1
Temperature: 50 °C
Yield: 13.1 %

Procedure:
To a solution of N-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) in dimethylformamide (10 mL) were added 2-chloro-N,N-dimethylethylamine hydrochloride (0.26 g) and potassium carbonate (0.62 g), and the mixture was stirred with heating at 50° C. for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 6-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide ⅕ hydrate (0.1 g). melting point: 132.6° C.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]CC)=[O:32])[C:29]2([CH3:37])[CH3:36])=[CH:4][CH:3]=1.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[F:47]>>[F:40][C:41]1[CH:42]=[C:43]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:28]3[C@H:30]([C:31]([OH:33])=[O:32])[C:29]3([CH3:36])[CH3:37])=[CH:38][CH:39]=2)[CH:44]=[CH:45][C:46]=1[F:47]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccc(F)c(F)c3)cc2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 3,4-difluorophenylboronic acid in Step A. MS (ESI): mass calcd. for C36H29F2N3O3, 589.22; m/z found, 590.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=8.5, 1H), 8.11 (d, J=8.6, 1H), 7.85 (d, J=8.2, 1H), 7.79-7.73 (m, 1H), 7.71 (d, J=8.5, 1H), 7.60-7.55 (m, 1H), 7.53-7.49 (m, 2H), 7.39-7.36 (m, 1H), 7.35-7.30 (m, 1H), 7.29-7.28 (m, 1H), 7.27-7.21 (m, 2H), 7.18-7.12 (m, 3H), 5.51-5.38 (m, 4H), 2.35-2.31 (m, 1H), 2.14-2.11 (m, 1H), 1.21 (s, 3H), 1.03 (s, 3H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:32]([OH:34])=[O:33])=[C:19]([CH:22]([S:26][C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH2:23][CH2:24][OH:25])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.C([O-])(=O)C.[Na+].O>O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:32]([OH:34])=[O:33])=[C:19]([CH:22]([S:26][C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH2:23][CH2:24][OH:25])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: O=C(O)C1=C(C(CCO)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)C(=NOC3CCCC3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(C(CCO)Sc4nnn[nH]4)CS[C@H]23)cs1
Yield: 71.5 %

Procedure:
A solution of 7-[2-[2-(2,2,2-trifluoroacetamido)-thiazol-4-yl]-2-cyclopentyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 2.5 g.), sodium acetate 3 hydrate (4.9 g.), water (30 ml.) and tetrahydrofuran (14.0 ml.) was stirred at room temperature for 18 hours. After removing tetrahydrofuran from the resultant solution in vacuo, water (20 ml.) was added to the residue and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-cyclopentyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 1.54 g.), mp. 150°-156° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2cccc(Cl)c2Cl)cc1
Solvent: NC1CCCCC1
Product: O=C(O)CCCc1ccc(-c2cccc(Cl)c2Cl)cc1
Yield: 97 %

Procedure:
Prepared analogous to Example 12 from 4-(2' ,3'-dichloro-4-biphenylyl)-4-oxo-butyric acid. Yield: 97% of theory, m.p. 70°-71° C. (from petroleum ether/cyclohexane); melting point of the cyclohexylamine salt: 163°-165° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](OC)=[O:39])=[CH:33][CH:32]=1>C1COCC1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](=[O:39])[CH2:26][C:25]([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)=[O:27])=[CH:33][CH:32]=1
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 1-(1-trityl-1H-imidazol-4-yl)ethanone (1.5 g, 4.26 mmol) in anhydrous THF (25 mL) was added NaH (0.23 g, 8.52 mmol) at 0° C. The mixture was stirred at RT for 2 hours, and methyl (4-fluorophenyl)acetate (1.43 g, 12.78 mmol) was added at 0° C. The mixture was refluxed overnight. The mixture was evaporated and the residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:5) to yield the title compound (1.018 g, 48.0%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[C:14]([O:15][CH:16]([F:18])[F:17])=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[Br-:21].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[C:14]([O:15][CH:16]([F:18])[F:17])=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][C:9](=[O:10])[C:4]=2[C:3]=1[Br:21]
Reactant: Nc1ccc2c(c1)c(=O)oc1cccc(OC(F)F)c12
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: Nc1ccc2c(c1Br)c(=O)oc1cccc(OC(F)F)c12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of Example 27B (4.03 g, 14.54 mmol) in THF (200 mL) at room temperature was treated over 15 minutes with pyridinium tribromide (5.16 g, 15.26 mmol), stirred for 14 hours, and concentrated. The concentrate was treated with water (200 mL), stirred at room temperature for 15 minutes, and filtered. The resulting solid was washed with water (200 mL), suspended in hot CH3CN, cooled to room temperature, and filtered to provide a first crop of desired product. The filtrate was treated with charcoal, filtered, and concentrated to provide a solid which was suspended in diethyl ether and filtered to provide a second crop of desired product. MS (ESI(−)Q1MS) m/z 355 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[O:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:41][CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and tetrahydro-2H-pyran-4-amine using methods similar to Example 563 to provide a white solid: ES+ MS: 523 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[C:10]([F:25])=[CH:11][C:12]([O:21][CH2:22][O:23][CH3:24])=[C:13]([CH:20]=1)[C:14](OCOC)=[O:15])#[N:8].C(OCC)(=O)C>C(OCC)C.[Cl-].[Na+].O>[C:7]([C:9]1[C:10]([F:25])=[CH:11][C:12]([O:21][CH2:22][O:23][CH3:24])=[C:13]([CH:20]=1)[CH2:14][OH:15])#[N:8]
Reactant: COCOC(=O)c1cc(C#N)c(F)cc1OCOC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCOc1cc(F)c(C#N)cc1CO
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
Lithium aluminum hydride (2.39 g) was added portionwise to a solution of methoxymethyl 5-cyano-4-fluoro-2-methoxymethoxybenzoate (16.6 g) in diethyl ether (500 ml) at -30° C., and the mixture was stirred for 30 minutes. The reaction mixture was poured into a saturated brine, to which was added ethyl acetate, followed by filtration through celite. The organic layer was washed with a saturated brine, dried (anhydrous magnesium sulfate), and concentrated. The residue was chromatographed on silica gel using ethyl 10 acetate/hexane as eluent to give 5-cyano-4-fluoro-2-methoxymethoxybenzyl alcohol (10.0 g) (Compound B-49). The physical properties are shown in Table 8.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:24][CH:25]1[CH2:28][CH2:27][CH2:26]1)[C:20]([NH:22][CH3:23])=[O:21]>>[CH:25]1([CH2:24][CH:19]([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH2:27][CH2:28]1
Reactant: CNC(=O)C(N)CC1CCC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CNC(=O)C(CC1CCC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 2-amino-3-cyclobutyl-N-methyl-propionamide (41.2 mg, 0.32 mmol) as starting materials and isolated (20 mg, 25.16%) as white solid; LC-MS (UV peak area, ESI) 99.32%, 373.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)[CH:2]=C.[O:16]=[O+][O-]>>[O:16]=[CH:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: O=[O+][O-]
Reactant: C=CCOc1ccc(CCC(=O)O)cc1
Product: O=CCOc1ccc(CCC(=O)O)cc1
Yield: 82 %

Procedure:
4-(2-Propenyloxy)benzenepropanoic acid (120 mg, 0.58 mmol) is treated with ozone by the procedure described in Example 2 to give 100 mg (82%) of 4-(2-oxoethoxy)benzenepropanoic acid as a white powder: m.p. 95°-100°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 1740, 1720, 1610 cm-1 ; MS (CI low res) m/e 207, 191, 179, 165, 149.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:17]#[N:18].[C:23]([N:42]1[CH:46]=[C:45]([CH2:47][CH2:48][CH:49]=[O:50])[N:44]=[CH:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCOC(C)=O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[C:21]=1[CH:49]([OH:50])[CH2:48][CH2:47][C:45]1[N:44]=[CH:43][N:42]([C:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:46]=1)[C:17]#[N:18]
Reactant: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: N#Cc1cc(F)c(C(O)CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c(F)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (0.53 mL, 3.75 mmol) is dissolved in 5 mL THF and cooled down to −78° C. To this is added n-BuLi (2.3 mL, 1.6M in hexanes). After 15 min, a solution of 3,5-difluorobenzonitrile (0.52 g, 3.75 mmol) and THF (5 mL) is added and the solution maintained at that temperature for 0.5 h before adding a solution of 3-(1-trityl-1H-imidazol-4-yl)propionaldehyde and THF (20 mL). After 2 h, the solution is diluted with EtOAc and quenched with saturated aqueous NH4Cl. The mixture is then partitioned between EtOAc and saturated aqueous NH4Cl. The organic is dried (Na2SO4) and evaporated. The residue is purified via flash column chromatography (EtOAc/hexanes 2:8→EtOAc) to give 3,5-difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile as a yellow powder. MS (ESI) m/z 506.2 (M+H).