Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([CH2:16][CH2:17][CH:18]=C)[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]([F:20])([CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17][CH:18]=[O:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCC(F)(F)CCOCCCCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCCC(F)(F)CCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
Intermediate 16 (110 mg, 0.39 mmol) was dissolved in a mixture of THF (3 mL) and water (1 mL). To this solution was added sodium metaperiodate (272 mg, 1.27 mmol) and osmium tetroxide (4% water solution, 0.15 ml). The suspension was stirred 12 hours at room temperature, filtered and concentrated. The residue was purified by column chromatography on silica gel using methylene chloride/acetone (10:1) as eluent, to afford the title compound (89 mg, 81%) as oil.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10]([N:12]2[C:20]3[C:15](=[C:16]([O:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26])[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:29][CH3:30]>C1COCC1.CCO>[CH3:30][NH:29][S:25]([CH2:24][CH2:23][CH2:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]2[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=1)(=[O:27])=[O:26]
Reactant: CCCCSc1nccc(-n2ccc3c(OCCCS(=O)(=O)Cl)cccc32)n1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCSc1nccc(-n2ccc3c(OCCCS(=O)(=O)NC)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[1-(2-Butylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonyl chloride (10.97 mmol) was dissolved in THF (25 mL) and added dropwise to H2NMe (30 mL) in EtOH at 0° C. and stirred for 30 min, and then allowed to warm to RT The reaction mixture was then poured into ice water, extracted with EtOAc, washed with water and brine, dried with sodium sulfate, filtered, and the solvent removed in vacuo to yield 3-[1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonic acid methylamide.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Br[CH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>C1COCC1>[C:9]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[C:23]3=[O:28])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C1CCc2c1cccc2-c1cccc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2Cc3c(cccc3-c3cccc4ccccc34)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 0.50 mL, 1.0 mmol) was added to a solution of 4-(naphthalen-1-yl)-2,3-dihydro-1H-inden-1-one (254 mg, 0.98 mmol) in THF (3.4 mL) at −78° C. After 1 h at −78° C., a solution of methyl 4-(bromomethyl)benzoate (230 mg, 1.0 mmol) in THF (1.7 mL) was added via cannula. After 1 h at −78° C., the mixture was allowed to slowly warm to 0° C. After 30 min at 0° C., the reaction was quenched with saturated aqueous NH4Cl (25 mL), diluted with water (10 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→30% EtOAc/hexanes, gradient) to afford 53 mg (13%) of methyl 4-((4-(naphthalen-1-yl)-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)benzoate.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1.[CH2:29]([OH:31])[CH3:30]>>[CH2:29]([O:31][C:4]1[N:9]=[C:8]([C:10]2[C:18]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:30]
Reactant: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Add sodium hydride (25.5 mg, 0.64 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (50 mg, 0.14 mmol) in ethanol (2.5 mL) at 0° C. Stir the reaction mixture at 0° C. for 10 minutes, room temperature for 10 minutes more, and reflux overnight. Cool the reaction mixture to room temperature, quench with saturated aqueous ammonium chloride (3 mL). Add water (20 mL) and extract the aqueous solution with methylene chloride (3×20 mL). Dry the combined organic layers with sodium sulfate and purify by flash column chromatography (SiO2, 50% ethyl acetate/hexanes) to give the title compound 48 mg (94%) as an off-white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([C:10]1[N:11]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2)[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:29]([CH:31]1[CH2:33][CH2:32]1)=O)=[O:9])[CH3:6]>ClCCl>[CH2:5]([O:7][C:8]([C:10]1[N:11]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2)[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:29][CH:31]1[CH2:32][CH2:33]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cccc(C(=O)C3CC3)c2n1Cc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cccc(CC3CC3)c2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (0.24 g, 2 eq.) was suspended in dichloromethane (20 mL) and cooled to 0° C. Borane-t-butylamine complex (0.14 g, 1.8 eq.) was added slowly, and the mixture was stirred for 30 minutes. A solution of ethyl-3-(4-t-butylphenyl)-7-(cyclopropyl)carbonyl-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 201, 0.405 g, 0.9 mmol.) in dichloromethane (5 mL) was added, and the reaction was stirred for two hours. The mixture was quenched with water and diluted with dichloromethane. The organic layer was washed with 1N HCl and saturated sodium bicarbonate, dried over sodium sulfate, then purified by flash chromatography over silica to give 0.26 g (62%.) The desired product had: 1H NMR (300 MHz, CDCl3) 7.21-7.4 (m, 5 H), 7.11 (d, 1 H), 7.02 (t, 1 H), 6.95 (t, 1 H), 6.59 (d, 1H), 6.35 (m, 2 H), 5.9 (s, 2 H), 3.9 (q, 2 H), 3.58 (s, 3 H), 2.75 (d, 2 H), 1.26 (s, 9 H), 0.85 (t, 3 H), 0.4 (m, 2 H), 0.02 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[N:18]1.[C:30]([CH:32]1[CH2:34][CH2:33]1)#[CH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:31]#[C:30][CH:32]3[CH2:34][CH2:33]3)=[CH:25][CH:24]=2)=[N:18]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1F
Reactant: C#CC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1F
Yield: 41 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-68, 0.050 g, 0.094 mmol), ethynylcyclopropane (0.009 g, 0.142 mmol), TBAF (0.074 g, 0.283 mmol), bis(triphenylphosphine)palladium(11) chloride (0.003 g, 0.003 mmol) and DMSO (3.0 mL) to afford 0.018 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 0.75 (m, 2H), 0.77-0.91 (m, 2H), 1.36 (s, 9H), 1.53-1.59 (m, 2H), 7.38 (t, J=5.9 Hz, 1H), 7.46-7.52 (m, 3H), 8.79 (d, J=4.4 Hz, 2H), 8.19 (t, J=4.3 Hz, 1H); MS (m/z): 467.15 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:32])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:14]=2[CH:31]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:32][S:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)(=[O:43])=[O:42])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:14]=2[CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(C)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(C)cc1

Procedure:
6-[(5-Amino-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=O)[S:24][CH:25]=1>[OH-].[K+].CCO>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])[S:24][CH:25]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cc(Br)cs2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 43 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.252 g, 0.98 mmol) was reacted with 4-bromothiophene-2-carboxaldehyde (0.282 g, 1.5 mmol) in 5 mL of 4% KOH in EtOH to afford 0.181 g (43%) of the title compound as a light tan powder, mp 164-166° C.: CI-MS m/e 428, 430 (M+); 429, 431 (M+ +1); 1H-NMR (CDCl3): δ 8.03 (1H, d, J=8.8 Hz), 7.82 (1H, s), 7.58 (1H, s), 7.33 (1H, s), 7.20 (1H, s), 7.05 (1H, s), 7.01 (1H, s), 6.80 (1H, dd, J=8.8 Hz, J=2.4 Hz), 6.66 (1H, d, J=2.2 Hz), 4.34 (2H, m), 4.25 (2H, m), 3.10 (2H, m), 2.93 (2H, m).
Reaction SMILES: [N:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[OH-:21].[Li+]>CO>[C:2]([CH2:3][O:4][CH2:5][CH2:6][NH:1][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])([OH:21])=[O:7]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1
Agent: [Li+]
Solvent: CO
Product: O=C(O)COCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
400 mg (1.43 mmol) methyl 4-(morpholin-3-on-4-yl)-3-nitro-benzoate are dissolved in 15 ml of methanol and combined with 4.5 ml (4.5 mmol) 1-molar lithium hydroxide solution. The mixture is stirred for 2 hours at ambient temperature. Then it is evaporated down i. vac., the residue is diluted with water, cooled in the ice bath and acidified with 2-molar hydrochloric acid. After 10 minutes cooling in the ice bath the precipitate formed is filtered off, washed with water until neutral and dried at 50° C. in the drying cupboard.
Reaction SMILES: [S:1]1[C:5]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[C:5]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:8])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1cc2ccccc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
A mixture of 2-(benzo[b]thiophen-2-yl)-2-(phenylamino)acetic acid (I30) (796 mg, 2.81 mmol), (R)-quinuclidin-3-ol (429 mg, 3.37 mmol), HOBT (516 mg, 3.37 mmol), and DCC (696 mg, 3.37 mmol) in THF (30 ml) was stirred at r.t. overnight. THF was evaporated, and the crude product was partitioned between EtOAc and 1M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH=98/2) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-2-yl)-2-(phenylamino)acetate (361 mg, 32.7% yield).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:16]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[O:15][C@:8]([O:13][CH3:14])([C:9]([O:11]C)=[O:10])[CH2:7][C@@H:6]1[OH:23])(=[O:3])[CH3:2].[OH-].[Na+:25]>>[C:1]([NH:4][C@H:5]1[C@H:16]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[O:15][C@:8]([O:13][CH3:14])([C:9]([O-:11])=[O:10])[CH2:7][C@@H:6]1[OH:23])(=[O:3])[CH3:2].[Na+:25]
Reactant: COC(=O)[C@]1(OC)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@]1(C(=O)[O-])C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To methyl 5-acetamido-3, 5-dideoxy-2-O-methyl-β-D-glycero-D-galacto-2-nonulopyranosonate (3.06 g, 9.07 mmol) was added 0.1N aqueous solution of sodium hydroxide (100 ml, 10.0 mmol) under ice cooling and then the mixture was stirred at room temperature for 22 hours. The reaction mixture was neutralized by addition of Dowex (50W×8, H+) resin. The resin was filtered off and the filtrate was concentrated to obtain sodium 5-acetamido-3, 5-dideoxy-2-O-methyl-β-D-glycero-D-galacto-2-nonulopyranosonate as an oil.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[C:16](=[C:33]([OH:36])[CH2:34]Cl)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[OH:40]>O1CCCC1>[O:1]([CH2:8][C:9]([NH:10][CH:11]1[C:12](=[O:37])[N:13]2[C:16]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:33]([OH:36])[CH2:34][S:15][C@H:14]12)=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(=C(O)CCl)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: CO
Agent: Cl
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled solution of diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate (36 mg) in a mixture of methanol and tetrahydrofuran (1:1) (1.1 ml) is added 1N-hydrochloric acid (0.39 ml), warmed to the room temperature, and the mixture is stirred for 1.5 hours. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with 5% aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate, and evaporated. Purification of the obtained residue by thin-layer chromatography using a mixture of benzene and ethyl acetate (3:2) gives diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (6 mg). m.p. 125°-126° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCO)ccc(C(C)=O)c1O
Reaction time: 64 h
Yield: 28 %

Procedure:
A mixture of 5.80 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 3.6 ml of 3-bromo-1-propanol and 8.3 g of anhydrous potassium carbonate in 50 ml of anhydrous dimethyl formamide was stirred at 75° for 64 hours. The reaction mixture was concentrated in vacuo, the residue was acidified and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo to 8.7 g of an oil which was chroma,ographed on 150 g of silica gel. Elution with 40% ethyl acetate-toluene gave 2.84 g which was crystallized from ether-hexane to yield 2.14 g, mp 57-59°, (28% yield) of 1-[2-hydroxy-4-(3-hydroxypropoxy)-3-propyl-phenyl]ethanone, the titled compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH2:37]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN(C)CCCN
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCN(C)C)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N1,N1-dimethylpropane-1,3-diamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-2.01 (m, 2H) 2.44 (s, 3H) 2.80 (d, J=4.04 Hz, 6H) 3.13 (dt, J=10.36, 4.93 Hz, 2H) 3.37 (q, J=6.40 Hz, 2H) 7.67 (d, J=7.83 Hz, 1H) 7.74 (s, 1H) 7.79 (br. s., 1H) 8.22 (d, J=16.93 Hz, 1H) 8.43 (br. s., 1H) 8.86 (br. s., 1H) 8.93 (dd, J=2.15, 0.88 Hz, 1H) 9.38 (br. s., 1H) 13.25 (br. s., 1H). MS m/z [M+H]+ 405.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[F:56][C:57]([F:61])([F:60])[CH2:58][NH:59][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:31]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (32 mg, 1.2 eq.), EDAC.HCl (45 mg, 1.2 eq.), TEA (0.068 mL, 2.5 eq.) and 2,2,2-trifluoro-ethylamine (48 mg, 2.5 eq.) in DMF (2 mL) was stirred at rt for 7 days. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, dried, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:51])[CH2:7][N:8]([CH2:45][C:46]([O:48]CC)=[O:47])[C:9](=[O:44])[C:10]1[CH:15]=[C:14]([O: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][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=[CH:12][C:11]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)C>>[C:46]([CH2:45][N:8]([C:9](=[O:44])[C:10]1[CH:15]=[C:14]([O: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][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=[CH:12][C:11]=1[O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:7][C:6]([OH:51])=[O:5])([OH:48])=[O:47]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN(CC(=O)O)C(=O)c1cc(OCCCCCCCCCCCCOc2ccccc2)ccc1OCc1ccccc1
Yield: 65 %

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy)benzoyl]glycine ethyl ester using conditions described in Example 81 gave N-(carboxymethyl)-N-[5-[(12-phenoxydodecyl)oxy]-2-(phenylmethoxy)benzoyl]glycine (65% yield, mp 70°-75°).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[F:23])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 80 °C

Procedure:
A stirred mixture of 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidin-4-ol (Step A; 300 mg; 0.952 mmol) and p-toluenesulfonic acid monohydrate (18 mg; 0.0952 mmol) in benzene (20 mL) was heated at 80° C. for 14 h. An additional 100 mg of p-toluenesulfonic acid monohydrate was added and the reaction heated at 80° C. for 1 h. The reaction was partitioned between EtOAc (50 mL) and H2O (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined extracts were washed with H2O (3×50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford 1-benzyl-4-(2-fluoro-4-methoxyphenyl)1,2,3,6-tetrahydropyridine as a yellow oil. LCMS=297.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 9.56 (br s, 1 H), 7.42-7.38 (m, 2 H), 7.34 (t, J=7.3 Hz, 2 H), 7.28 (d, J=7.3 Hz, 1 H), 7.17 (t, J=8.7 Hz, 1 H), 6.64 (dd, J=8.7, 2.5 Hz, 1 H), 6.59 (dd, J=13.0, 2.5 Hz, 1 H), 5.91-5.89 (m, 1 H), 3.78 (s, 3 H), 3.66 (br s, 2 H), 3.18 (br s, 2 H), 2.71 (br s, 2 H), 2.54 (br s, 2 H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[C:12]=2[F:15])[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO.O>[F:15][C:12]1[C:11]([F:16])=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][C:6]([NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[CH:26]=[C:27]([CH3:28])[CH3:29])([C:4]([OH:5])=[O:3])[CH2:7]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccc(F)c(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)c(F)c2C1
Temperature: 25 °C

Procedure:
4,5-Difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (387) (650 mg, 1.57 mmol) is dissolved in EtOH (50 mL) and set to stir at RT. To this solution is added 5M KOH (4 mL). The reaction mixture is stirred at RT overnight. After concentration in vacuo, the residue obtained is dissolved in water (20 mL) and washed with EtOAc (20 mL). The phases are separated and the aqueous phase is acidified with concentrated HCl to pH 2. The solid precipitate is collected via filtration, dried under vacuum, and then purified on an HPLC. The desired product (388) is obtained as white solid (440.0 mg, 73%).