Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.Cl.[Cl:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:13]=2[C:14]#[N:15])=[C:8]([CH3:25])[CH:7]=1.[OH-].[K+]>>[NH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([CH2:11][O:10][C:9]2[CH:23]=[CH:24][C:6]([Cl:5])=[CH:7][C:8]=2[CH3:25])[C:13]=1[C:14]#[N:15]
Reactant: Cc1cc(Cl)ccc1OCc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: Cc1cc(Cl)ccc1OCc1cccc(N)c1C#N
Temperature: 15 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a cooled (15° C.) and stirred solution of tin (II) chloride (0.56 g, 2.48 mmol) and con. hydrochloric acid (2.0 mL) was added a solution of 2-(4-chloro-2-methylphenoxymethyl)-6-nitrobenzonitrile (150.0 mg, 0.5 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was poured on to crushed-ice and potassium hydroxide solution, stirred, extracted with dichloromethane, filtered and dried to yield 120 mg of 2-amino-6-(4-chloro-2-methylphenoxymethyl)benzonitrile.
Reaction SMILES: CN.[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:36])=[C:9]([C@:11]23[CH2:20][O:19][C@@H:18]([C:21]4[O:22][CH:23]=[C:24]([CH3:26])[N:25]=4)[CH2:17][C@H:16]2[CH2:15][S:14][C:13]([NH:27]C(=O)C2C=CC=CC=2)=[N:12]3)[CH:10]=1)#[N:4]>C(O)C>[NH2:27][C:13]1[S:14][CH2:15][C@@H:16]2[CH2:17][C@H:18]([C:21]3[O:22][CH:23]=[C:24]([CH3:26])[N:25]=3)[O:19][CH2:20][C@:11]2([C:9]2[CH:10]=[C:5]([CH:6]=[CH:7][C:8]=2[F:36])[C:3]#[N:4])[N:12]=1
Reactant: Cc1coc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)n1
Agent: CN
Solvent: CCO
Product: Cc1coc([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3cc(C#N)ccc3F)CO2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methylamine (8 M in ethanol, 7.1 mL, 57.1 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(4-methyl-1,3-oxazol-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C41) (0.227 g, 0.48 mmol) in ethanol (12 mL). The resulting solution was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a yellow oily residue. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as an off-white solid. Yield: 144 mg, 81%. LCMS m/z 374.1 [M+H+]. 1H NMR (400 MHz, CD3OH) δ 7.77 (ddd, J=8.5, 4.5, 2.2 Hz, 1H), 7.68 (dd, J=7.2, 2.3 Hz, 1H), 7.61 (q, J=2.3 Hz, 1H), 7.35 (dd, J=12.1, 8.6 Hz, 1H), 4.82 (dd, J=11.9, 2.5 Hz, 1H), 4.25 (dd, J=11.2, 2.2 Hz, 1H), 3.79 (d, J=11.2 Hz, 1H), 3.06-3.13 (m, 1H), 2.89 (dd, J=12.7, 4.1 Hz, 1H), 2.78 (dd, J=12.7, 2.9 Hz, 1H), 2.33-2.43 (m, 1H), 2.15 (d, J=1.4 Hz, 3H), 1.87-1.91 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]([CH2:49][CH3:50])[C:46]([NH2:48])=[O:47])#[CH:38].CCN(CC)CC>CN(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.[Cu]I>[NH2:48][C:46](=[O:47])[CH:45]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37]#[C:38][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1)[CH2:49][CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1C(CC)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 68.2 %

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K3) (193 mg, 0.422 mmol), PdCl2(PPh3)2 (15 mg, 0.021 mmol), t-Bu3PH.BF4 (6 mg, 0.021 mmol), CuI (4 mg, 0.021 mmol) and 2-(2-ethynylphenyl)butanamide (K1) (87 mg, 0.47 mmol) in DMF (3.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed under reduced pressure and the residue was adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A1 as a yellow solid (175 mg, 68%); 1H NMR (400 MHz, d6-DMSO) δ 10.39 (s, 1H), 8.88-8.76 (m, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.63-7.47 (m, 3H), 7.37 (td, J=7.4, 1.6 Hz, 1H), 7.27-7.17 (m, 3H), 7.01 (s, 1H), 4.07 (s, 2H), 3.89 (dd, J=8.6, 6.4 Hz, 1H), 2.80 (br, 2H), 2.64 (J m, 1H), 1.98-1.90 (m, 1H), 1.74 (d, J=12.7 Hz, 2H), 1.70-1.60 (m, 1H), 1.55-1.44 (m, 2H), 1.42 (s, 9H), 0.87 (t, J=7.3 Hz, 3H). LCMS-A: rt 6.726 min; m/z 606 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[F:23][CH:24]([F:35])[O:25][C:26]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].O>CN(C)C=O>[F:23][CH:24]([F:35])[O:25][C:26]1[CH:33]=[C:32]([O:10][CH:7]([C:6]2[S:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][CH3:9])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: N#Cc1ccc(F)cc1OC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1ccc(C#N)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
To a solution of 1.7 g of 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in 4.7 mL of dimethylformamide at 5° C. was added 250 mg of a 55% suspension of sodium hydride in mineral oil. The reaction volume was completed with dimethylformamide to about 8.5 mL. The reaction mixture was stirred for 30 minutes at 5° C. 4.3 mL of the resulting mixture was slowly added to a solution of 450 mg of 2-difluoromethoxy-4-fluoro-benzonitrile in 2 mL of dimethylformamide at 5° C. The resulting mixture was stirred at 5° C. allowing the temperature to warm up to room temperature. It was then heated in a sealed tube to 60° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 50/ethyl acetate 50) to give 490 mg of 2-difluoromethoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[N:32]2[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OCC3C=CC=CC=3)[CH2:33]2)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1[C:13]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[N:32]2[CH2:37][CH2:36][CH2:35][C@H:34]([NH2:38])[CH2:33]2)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cc2ccccc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.4 %

Procedure:
To a solution of benzyl [(3S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate (from step 5 in Example 1, 51.3 mg, 0.0723 mmol) in MeOH (2.0 mL), 10 wt % Pd on carbon (8.3 mg, 0.0078 mmol) was added. The mixture was stirred at room temperature under hydrogen (1 atm.) for 15 h. The reaction mixture was then filtered through a pad of diatomaceous earth, eluted with MeOH and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound as a yellow solid (4.3 mg, 16%). LCMS calc. for C20H23N6O (M+H)+: m/z=363.2. found 363.2.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19](OC(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18][CH2:17]2)=[O:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].CC(C(O)=O)(C1C=CC(C(CCCN2CCC([O:56][CH:57]([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)CC2)=O)=CC=1)C>CS(C)=O>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:12])[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:57]([OH:56])([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:18][CH2:17]2)=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
To prepare the 10 mM stock solution of PS1, 1 mg of PS1 having a molecular weight of 618.8 was added to 162 μl of DMSO. For preparing the 50 mM stock solution of ebastine, 10 mg of ebastine having a molecular weight of 469.66 was added to 426 μl of DMSO. In preparing the 25 mM solution of carebastine, 1 mg of carebastine having a molecular weight of 499.65 was added to 80μ of DMSO. To obtain the 50 mM terfenadine stock solution 1.5 mg of terfenadine having a molecular weight of 471.7 was added to 64 μl of ETOH. To prepare the 50 mM stock solution of fexofenadine, 10 mg of fexofenadine chloride having a molecular weight of 538.12 was added to 372 μl of DMSO. Further, to prepare the 50 mM stock solution of astemizole, 10 mg of astemizole having a molecular weight of 458.57 was added to 436 μl of DMSO. Table 10 then lists the preparation of the solutions for use in the tests above.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=1[CH3:26])=O.Cl(O)(=O)(=O)=O.[C:32](O)(=[O:34])[CH3:33]>[C].[Pd]>[C:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=1[CH3:26])(=[O:34])[CH3:33]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCCO)c(O)c1OC
Reactant: CC(=O)O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cc(C)c(CCCCCCCCCCCCOC(C)=O)c(O)c1OC

Procedure:
To a solution of 6-(12-hydroxy-1-oxododecyl)-2,3-dimethoxy-5-methylphenol (6.4 g) in acetic acid (150 ml) are added 5% palladium-carbon (50% hydrous) (1.1 g) and 70% perchloric acid (0.1 ml) and the mixture is subjected to the catalytic reduction at atmospheric temperature and pressure. After the absorption of hydrogen has been completed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane and the dichloromethane layer is washed with a 5% aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent is distilled off to give 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methylphenol (6.8 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(Cl)(=[O:29])C.O>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An alternative procedure to prepare compound B from compound A is as follows: Compound A (1.0 g) in 25 ml dry methylene chloride and 10 ml of 2.5 N NaOH was cooled to 0° C. and treated with 0.25 ml of acetyl chloride dropwise. After 2 hours the solution was allowed to warm up to room temperature and stirring was continued overnight. The solution was treated with distilled water and extracted with methylene chloride. The methylene chloride layer was separated, dried over anhydrous sodium sulfate, filtered and evapotated to give 1.33 g of crude amide reaction product, which was purified by flash column (silica, methylene chloride:methanol:25% NH4OH 90:9:1) to yield 0.7 g of 2-(4-fluorophenyl)-5-(N-acetylpiperidin-4-yl)-3-(4-pyridyl)pyrrole. This amide was dissolved in 15 ml of tetrahydrofuran and treated with 3 ml of 1M lithium aluminum hydride (LAH) in THF under an atmosphere of nitrogen at room temperature. After completion of addition of LAH, the solution was refluxed for two hours, cooled to 0° C., quenched with water (0.19 ml) and 2.5 N NaOH (0.19 ml) and filtered. The filtrate was dried over sodium sulfate, filtered, evaporated and purified by flash column as shown above to give compound B (0.65 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][CH:10]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CCN(S(=O)(=O)c2ccc(C)cc2)C1c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc[nH]c1-c1ccccc1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
2-Phenyl-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester (0.42 g, 1.13 mmol) (prepared according to the method disclosed in reference 1) and 1.0 M potassium tert-butoxide in THF (1.42 mL, 1.42 mmol) were stirred in THF at 0° C. for 30 min, then warmed to rt for 30 min. The reaction was diluted with diethyl ether, washed 1× with satd. NH4Cl, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using hexanes/ethyl acetate (9:1) gave 0.195 g of title compound. (80% yield). 1H NMR (CDCl13) δ 9.14 (bs, 1H), 7.50-7.46 (m, 2H), 7.32-7.27 (m, 3H), 6.68-6.66 (t, J=2.90 Hz, 1H), 6.56-6.55 (t, J=2.90 Hz, 1H), 4.12-4.06 (q, J=7.25 Hz, 2H), 1.20-1.16 (t, J=7.25 Hz, 3H). 13C NMR (CDCl3) δ 165.8, 137.4, 132.4, 129.3, 128.8, 128.3, 128.2, 118.3, 112.1, 60.0, 14.4; MS APCI: [M+H]+=216.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][O:6][C@@H:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@@H:3]1[OH:21].[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O)(=O)C.C([C@@H]1CC=CCO1)(C1C=CC=CC=1)C1C=CC=CC=1>CC(C)=O>[CH:8]([C@H:5]1[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][CH2:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][CH:23]=[CH:24]3)[CH2:7][O:6]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O
Agent: C1=CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCc1ccc2[nH]ccc2c1

Procedure:
(2R,4S,5S)-5-amino-2-benzhydryl-tetrahydropyran-4-ol 31b (0.05 g, 0.18 mmol) was reacted with 1H-indol-5-carbaldehyde (0.03 g, 0.18 mmol), glacial acetic acid (0.01 g, 0.18 mmol) and NaCNBH3 (0.02 g, 0.35 mmol) (Procedure C) to give (2R,4S,5S)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol, (+)32b, 0.05 g (69%, [α]D=(+) 70.9, c=1, Acetone).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[N:11]=[CH:10]N[C:7]=2[CH:8]=1.[C:12](O)(=O)C>[Pd]>[CH3:1][O:2][CH:3]1[CH2:4][N:5]2[CH:12]=[CH:10][N:11]=[C:6]2[CH2:7][CH2:8]1
Reactant: COc1cnc2nc[nH]c2c1
Reactant: CC(=O)O
Agent: [Pd]
Product: COC1CCc2nccn2C1
Yield: 97 %

Procedure:
Add acetic acid (40 mL) to a heterogeneous solution of 6-methoxyimidazopyridine (1.0 g; 1.0 equiv; 6.75 mmoles) and 10% palladium on carbon (1.0 g; 1.4 equiv; 9.40 mmoles). Evacuate and backfill the reaction vessel with nitrogen (3×) then hydrogen (3×). Vigorously stir the reaction under hydrogen at ambient temperature for 3 hours. Filter the reaction mixture through celite, and wash the filter cake with a 1:1 mixture of dichloromethane and methanol. Concentrate the filtrate and dissolve the crude product mixture in 20 mL methanol, then load onto a scx ion-exchange column. Elute with methanol followed by 2M ammonia in methanol to give 6-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.00 g; 97%) as a colorless oil. 1H NMR (DMSO): δ 1.84-1.94 (m, 1H), 2.00-2.09 (m, 1H), 2.63-2.68 (m, 2H), 3.27 (s, 3H), 3.77-3.82 (m, 1H), 3.92-4.03 (m, 2 H), 6.74 (d, 1H), 6.91 (d, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]([C:53]([NH:55][C@H:56]([CH2:67][OH:68])[C:57]([O:59]CC2C=CC=CC=2)=[O:58])=[O:54])=[N:18][C:19]([NH:38][CH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:20]([C:22]([NH:24][C@H:25]([CH2:36][OH:37])[C:26](=[O:35])[O:27]CC2C=CC=CC=2)=[O:23])[N:21]=1>C(O)C.O.O.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]([C:53]([NH:55][C@@H:56]([C:57]([OH:59])=[O:58])[CH2:67][OH:68])=[O:54])=[N:18][C:19]([NH:38][CH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:20]([C:22]([NH:24][C@@H:25]([C:26]([OH:35])=[O:27])[CH2:36][OH:37])=[O:23])[N:21]=1
Reactant: COCCOCCOCCOCCCNc1nc(C(=O)N[C@H](CO)C(=O)OCc2ccccc2)c(NCCCOCCOCCOCCOC)nc1C(=O)N[C@H](CO)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COCCOCCOCCOCCCNc1nc(C(=O)N[C@H](CO)C(=O)O)c(NCCCOCCOCCOCCOC)nc1C(=O)N[C@H](CO)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A 50 mL round-bottom flask equipped with magnetic stir bar was charged with bis-benzyl ester 12 (0.501 g, 0.521 mmol), dissolved in EtOH—H2O (20 mL; 3:1, v/v), and 10% Pd—C (100 mg) was added as slurry in water (1-2 mL). The reaction mixture was purged thoroughly with argon and then with H2 and stirred at room temperature for 2 h in an atmosphere of H2. The catalyst was removed by filtration, solvents were removed in vacuo, and the crude product subjected to purification by preparative RP-HPLC to give 11 (0.108 g, 26%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=4)=[C:33]([Cl:45])[CH:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])[CH3:2].[F:47][C:48]([F:53])([F:52])[C:49](O)=[O:50].C(=O)([O-])O.[Na+]>ClCCl>[Cl:45][C:33]1[CH:32]=[C:31]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][C:11]3[N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:46])=[O:8])[C:14]([OH:15])=[C:13]([CH3:23])[N:12]=3)[CH2:26][CH2:27]2)[CH:36]=[CH:35][C:34]=1[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][O:44][C:49](=[O:50])[C:48]([F:53])([F:52])[F:47])=[CH:39][CH:38]=1
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)c(Cl)c3)CC2)nc(C)c1OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(COC(=O)C(F)(F)F)cc4)c(Cl)c3)CC2)nc(C)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
Ethyl({[5-(benzyloxy)-2-({1-[2-chloro-4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (0.96 g, 1.5 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (20 mL) was added under a nitrogen atmosphere, followed by stirring at room temperature for 7 hours. An aqueous sodium hydrogencarbonate solution was added to the reaction solution for neutralization, followed by extraction with dichloromethane, and subsequently the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: dichloromethane/ethyl acetate), and a fraction corresponding to the Rf value=0.80 (dichloromethane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.74 g, 1.3 mmol) as a yellow oil (yield 90%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:14])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.O=S(Cl)Cl.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:19][N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH3:14])[C:2]=1[Cl:1])=[O:13]
Reactant: Cn1c(Cl)c(C(=O)O)c2ccccc21
Reactant: CNc1ccccc1
Solvent: O=S(Cl)Cl
Product: CN(C(=O)c1c(Cl)n(C)c2ccccc12)c1ccccc1
Yield: 67 %

Procedure:
Similar reaction of 2-chloro-1-methylindole-3-carboxylic acid [XXI] with SOCl2 and N-methylaniline gave N-methyl-N-phenyl 2-chloro-1-methylindole-3-carboxamide [XXII: R6 =Me; R7 =Ph] (67% yield); mp (Me2CO/water) 163° C.
Reaction SMILES: [C:1]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15]OC(=O)C)[CH2:13][S:14][C@H:9]12)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(=O)([O-])O.[Na+].[CH3:30][C:31]1[S:35][C:34]([SH:36])=[N:33][N:32]=1.P([O-])([O-])([O-])=O>>[C:1]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][S:36][C:34]3[S:35][C:31]([CH3:30])=[N:32][N:33]=3)[CH2:13][S:14][C@H:9]12)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12

Procedure:
A mixture of 0.356 g. of 7-acetoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid, 0.84 g. of sodium hydrogen carbonate, 0.246 g. of 5-methyl-1,3,4-thiadiazol-2-thiol and 20 ml. of a phosphate buffer of pH 6.4 is heated at 60° C for 7.5 hours. After cooling, it is washed with ethyl acetate, adjusted to pH 2 with 50 % phosphoric acid, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure, followed by cooling with ice. The resultant crystals are recovered by suction-filtration, washed with hexane and dried. The described procedure gives 7-acetoacetamido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid as crystals melting at 177°-180° C (decomp.). Yield 0.274 g. (64 %).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH3:19][C:20](CCC=C(C)COC(=O)C1C=CC=CC=1)=CCCC(=O)C>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:19]#[CH:20]
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC(C)=O
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC(=O)c1ccccc1
Product: C#CC(C)(O)CCC=C(C)CCC=C(C)COC(C)=O

Procedure:
The procedure described in Example 9 was repeated except that 6,10-dimethyl-11-acetoxy-5,9-undecadien-2-on or 6,10-dimethyl-11-(benzoyl)oxy-5,9-undecadien-2-one was employed as a starting material to give 3,7,11-trimethyl-12-acetoxy-6,10-dodecadien-1-in-3-ol and 3,7,11-trimethyl-12-(benzoyl)oxy-6,10-dodecadien-l-in-3-ol.