Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH2:32]([O:39][CH2:40][C@H:41]1[CH2:43][C@@H:42]1[C:44]1[CH:45]=[C:46]([OH:50])[CH:47]=[N:48][CH:49]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:51]([O:55][C:56]([N:58]1[CH2:61][CH2:60][C@H:59]1[CH2:62]O)=[O:57])([CH3:54])([CH3:53])[CH3:52]>C1(C)C=CC=CC=1>[C:51]([O:55][C:56]([N:58]1[CH2:61][CH2:60][C@H:59]1[CH2:62][O:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([C@H:42]2[CH2:43][C@@H:41]2[CH2:40][O:39][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:45]=1)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: Oc1cncc([C@H]2C[C@@H]2COCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.5 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (207 mg, 0.82 mmol, 1.6 equiv.) was dissolved in 2.0 mL of toluene (dried with molecular sieve 3 Å) in a 10 mL round-bottom flask with a side neck. The flask was equipped with rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar (3 times), and the flask was cooled with an ice bath. Tributylphosphine (203 μL, 0.82 mmol, 1.6 equiv.) was added dropwise. The mixture was warmed to room temperature and stirred for 10 min. The resulting colorless solution was then added dropwise (via syringe) with ice cooling to a solution of 5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]-3-pyridinol (131 mg, 0.51 mmol) and 1-(tert-butoxycarbonyl)-2(S)-azetidinylmethanol (154 mg, 0.82 mmol, 1.6 equiv.) in a 25 mL round-bottom flask (equipped with a magnetic stirrer and an Ar balloon). The resulting mixture was warmed to room temperature and stirred overnight. Air was bubbled through the mixture for 2 h. The solvent was evaporated, and the residue was purified by CC on SiO2 (15×1.0 cm, EtOAc) to give the crude product, which was further purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 28.5-30.9 min) to give a colorless oil (170 mg, 79%). MS (EI) m/z 424 (M+, 0.5%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[CH3:25][CH:26]([CH3:33])[C:27]([O:29][CH:30](Cl)[CH3:31])=[O:28]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:31][CH2:30][O:29][C:27](=[O:28])[CH:26]([CH3:33])[CH3:25])=[O:13])(=[O:6])=[O:7]
Reactant: CC(Cl)OC(=O)C(C)C
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 65 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (13.0 g, 34.3 mmol) dissolved in 300 mL of anhydrous toluene was reacted with 15.4 g (103 mmol) of 1-chloroethyl 2-methylpropanoate (22) in the presence of 23 g (86 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 11 g (65% yield) of the title compound (29a) as a colorless oil. Rf=0.63 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.23 (m, 12H), 1.53 (d, J=5.6 Hz, 3H), 2.24-2.32 (m, 2H), 2.51-2.65 (m, 1H), 3.21-3.26 (m, 2H), 3.63-3.66 (m, 2H), 3.83-3.85 (2s, 1H), 3.96 (d, J=9.6 Hz, 1H), 4.20-4.24 (2d, J=8.8, 9.2 Hz, 1H), 4.33-4.37 (2d, J=11.2, 11.6 Hz, 1H), 4.60-4.66 (2d, J=11.6, 11.6 Hz, 1H), 6.91-6.95 (m, 1H), 7.30-7.37 (m, 5H) ppm. MS (ESI) m/z 514.90 (M+Na)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)#[CH:4].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>CN(C=O)C>[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:18][CH:19]=3)[N:12]=2)[N:7]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:6]=1)#[CH:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#Cc1c[nH]c2ncc(-c3ccc(S(=O)(=O)C(C)C)cc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(S(=O)(=O)C(C)C)cc3)nc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 60% dispersion of sodium hydride in mineral oil (19.79 mg, 0.5164 mmol) was added slowly to a stirred solution of 7-ethynyl-2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (140 mg, 0.4303 mmol) in DMF (1.2 mL) at 0° C. The reaction mixture was stirred at this temperature for 20 minutes then tosyl chloride (82.04 mg, 0.4303 mmol) was added and reaction mixture allowed to warm to ambient temperature over 16 hours. The reaction mixture was quenched by the slow addition of water (30 mL) and the mixture stirred for 20 minutes. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated form DCM/diethyl ether and the resultant precipitate isolated by filtration to give the sub-tile compound as an off-white solid (112.6 mg, 59% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.19 (d, 6H), 2.37 (s, 3H), 3.45-3.50 (m, 1H), 4.55 (s, 1H), 7.49 (d, 2H), 8.01 (d, 2H), 8.08 (d, 2H), 8.41 (d, 2H), 8.75 (s, 1H) and 9.22 (s, 1H) ppm; MS (ES+) 480.0.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH:15][CH:16]=[O:17])[S:13][CH:14]=1)[C:7]([OH:9])=O)[CH2:2][CH3:3].[NH2:18][CH:19]1[C:40](=[O:41])[N:21]2[C:22]([C:37]([OH:39])=[O:38])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH2:33][C:34]([OH:36])=[O:35])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12>>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH:15][CH:16]=[O:17])[S:13][CH:14]=1)[C:7]([NH:18][CH:19]1[C:40](=[O:41])[N:21]2[C:22]([C:37]([OH:39])=[O:38])=[C:23]([CH2:26][S:27][C:28]3[N:32]([CH2:33][C:34]([OH:36])=[O:35])[N:31]=[N:30][N:29]=3)[CH2:24][S:25][C@H:20]12)=[O:9])[CH2:2][CH3:3]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12
Reactant: CCCON=C(C(=O)O)c1csc(NC=O)n1
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Yield: 70.6 %

Procedure:
2-n-Propoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.73 g.) and 7-amino-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.0 g.) were reacted according to similar manners to those of Examples 1(b), 2(b), 3(b) and 6(b) to give white powder of 7-[2-n-propoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.32 g.).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[N:5]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:4]1.[OH:30][C:31]([CH3:46])([C:35]([NH:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])=[O:36])[C:32](O)=[O:33].ON1C2C=CC=CC=2N=N1>>[CH2:14]([O:13][CH2:12][CH2:11][N:8]1[C:9](=[O:10])[CH:3]([NH:2][C:32](=[O:33])[C:31]([OH:30])([CH3:46])[C:35]([NH:37][CH2:38][C:39]([F:44])([F:45])[C:40]([F:41])([F:43])[F:42])=[O:36])[CH2:4][N:5]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]1=2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CN(CC(F)(F)F)c2ccccc2N(CCOCc2ccccc2)C1=O
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)NC1CN(CC(F)(F)F)c2ccccc2N(CCOCc2ccccc2)C1=O

Procedure:
In an analogous manner to that described in Example 1e), the condensation of 3-amino-1-(2-benzyloxy-ethyl)-5-(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride and (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid with 1-hydroxy-benzotriazole and N-(3-dimethylaminpropyl)-N′-ethyl-carbodiimide hydrochloride as the condensating agents yielded a mixture of the four epimeric title compounds as a white foam; MS (m/e): 641 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3[F:23])=[N+:2]=[N-:3].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]#[CH:34])=[CH:28][CH:27]=1.C([Si](C)(C)C)#C.C([Mg]Br)C.FC1C=CC(CBr)=CC=1>C1COCC1.[Cu](Br)Br>[F:23][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]1[CH2:24][CH:4]([N:1]3[C:33]([CH2:32][C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:34][N:3]=[N:2]3)[CH2:5][CH2:6][C:7]1=[C:15]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CCc1ccc(F)cc1
Agent: Br[Cu]Br
Agent: C#C[Si](C)(C)C
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: O=C(O)Cc1c2n(c3c(F)cccc13)CC(n1nncc1Cc1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate (EXAMPLE 7, Step 6) and 1-fluoro-4-prop-2-yn-1-ylbenzene obtained according to the following procedure (Gazz. Chim. Ital. 1990, 120, 783). To a mixture of ethynyltrimethylsilane (1 eq) in THF (0.6M) at room temperature was added ethylmagnesium bromide (1 eq). The mixture was stirred at room temperature for 30 min then copper bromide (I) (0.1 eq) was added. After stirring for 30 min, a 1M solution of 4-fluorobenzyl bromide (1 eq) in THF was added and the mixture was heated to reflux overnight. The reaction mixture was quenched by addition to a cold solution of NH4Cl sat, stirred for 30 min then extracted with Et2O, washed with brine, dried and evaporated. Purification by Combi-flash using a gradient of 0-100% EA/Hex afforded the desired TMS alkyne. The TMS alkyne was directly mixed with potassium fluoride (1.2 eq) in DMF (0.2M containing 1% water). The mixture was stirred at room temperature overnight then quenched by addition of HCl 3N, stirred for 1 h then extracted with pentanes, washed with NaHCO3 sat, brine, dried and evaporated. Crude alkyne compound was used directly for click chemistry described in EXAMPLE 3. The resulting racemic esters were resolved by HPLC using a 4.6×250 mm Chiralpak AS column eluting with 60% EtOH, 39.75% Hexanes and 0.25% Et3N at 0.8 mL/min and 254 nm. The resulting chiral esters (retention times=10.3 and 13.3 min) were hydrolyzed to afford EXAMPLE 8.1 and 8.2 respectively. 11-1 NMR of EXAMPLE 8.1: 1H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1 H), 7.55 (s, 1 H), 7.33 (dd, 2 H), 7.27 (d, 1 H), 7.17 (t, 2 H), 6.96 (td, 1 H), 6.85 (dd, 1 H), 5.23-5.09 (m, 1 H), 4.58 (dd, 1 H), 4.44 (dd, 1 H), 4.25 (s, 2 H), 3.65-3.52 (m, 2 H), 3.12-3.02 (m, 1 H), 2.89 (ddd, 1 H), 2.32-2.19 (m, 1 H), 2.14-2.02 (m, 1 H). MS (+ESI) m/z: 423.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1>CC(=O)CC>[Cl:22][C:21]1[C:16]([O:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[N:17][CH:18]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: Oc1ccc(O)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
p-dihydroxybenzene 12.1 g (0.11 mol), anhydrous potassium carbonate 15.2 g (0.11 mol) were added to 500 mL of three-necked flask with 2-butanone (200 mL) in sequence, the reaction mixture was then heated to reflux, forming milky white turbid liquid, a solution of 2,3-dichloro-5-(trifluoromethyl)pyridine 21.6 g (0.1 mol) in 2-butanone (50 mL) was added dropwise to the above solution, after completion of addition for 15 min, then the mixture was refluxed for another 3 h. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure and the residue was purified via silica gel column chromatography (Fluent: ethyl acetate/petroleum ether-1:8) to give the product (24.9 g) as a white solid in 86% yield.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1
Reactant: Oc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2)cn1
Temperature: 60 °C
Yield: 32.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) was mixed with 3-5 ml of dry dimethylformamide and 3-fluorophenol (0.244 ml, 2.7 mmol) was added to the stirred suspension. When the gas evolution was ceased the reaction mixture was heated at stirring at 60° C. and 5-bromo-2-nitropyridine (0.5 g, 2.5 mmol) was added to the reaction mixture in one portion. The reaction-mixture was stirred at 60° C. for about 12 hours. The reaction mixture was then mixed with 50 ml of water and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting mixture was purified by column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 190 mg (33% yield) of desired product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9]CC(O)=O.C([O-])([O-])=O.[K+].[K+].[C:20]([O:24]C(OC(OC(C)(C)C)=O)=O)(C)(C)[CH3:21]>C(OC(=O)C)C.O.O1CCOCC1>[CH2:7]([NH:2][CH:20]([OH:24])[CH3:21])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(O)CCCC1CCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 179.8 %

Procedure:
4-Piperidin-2-ylbutanoic acid Hydrochloride (10.0 g, 48.3 mmol), and K2CO3 (26.6 g, 193.1 mmol) was dissolved in dest. water (70 ml) and Dioxane (124 ml). The reaction mixture was cooled to 0° C. and at this temperature Di-tert-butyldicarbonate (11.4 g, 53.1 mmol) was added slowly. The reaction mixture was stirred for 24 h at room temperature. After completion of the reaction water and Ethylacetate were added, the two phases were separated. The aqueous Phase was extracted once with Ethylacetate. Afterwards the aqueous Phase was triturated with 2 M HCL (aqueous) to reach pH=2. At this pH the aqueous phase was extracted 4× with Dichloromethane. The combined organic layers were dried over Magnesium sulfate, filtered out and evaporated to complete dryness to give (2) (13.13 g, 100%).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:49])[N:17]([CH3:48])[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[O:36][C:37]=3[C:38]([F:41])([F:40])[F:39])=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:10])C1C=CC=CC=1.[OH-].[Li+]>CO.O>[CH3:48][N:17]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[O:36][C:37]=3[C:38]([F:39])([F:40])[F:41])=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:49]
Reactant: CN(C(=O)[C@@H]1CCC[C@H]1C(=O)OCc1ccccc1)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C(=O)[C@@H]1CCC[C@H]1C(=O)O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1

Procedure:
Trans-2-[methyl-(1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-4-yl)-carbamoyl]-cyclopentanecarboxylic acid benzyl ester was hydrolyzed with lithium hydroxide in methanol and water. The resulted crude mixture was concentrated and the residue was dissolved in ethyl acetate and water with citric acid as acidifying agent. The organic layer then was concentrated and purified by reverse phase HPLC. The mixture of isomers was obtained as a yellow solid. LCMS calcd for C30H31F3N4O5 (m/e) 584, obsd 585 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[C:18]([C:26]([S:29]([CH3:32])(=[O:31])=[O:30])([CH3:28])[CH3:27])[CH:19]=[C:20]4[C:25]=3[N:24]=[CH:23][CH:22]=[CH:21]4)[CH:11]=2)=[CH:4][CH:3]=1.[CH3:34][S:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:32][S:29]([C:26]([C:18]1[CH:19]=[C:20]2[C:25](=[C:16]([C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=3)[C:9]([NH:8][C:5]3[CH:6]=[N:7][C:2]([C:39]4[CH:40]=[CH:41][C:36]([S:35][CH3:34])=[CH:37][CH:38]=4)=[CH:3][CH:4]=3)=[O:33])[CH:17]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)([CH3:28])[CH3:27])(=[O:31])=[O:30]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)(c1cc(-c2cccc(C(=O)Nc3ccc(Cl)nc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(-c2ccc(NC(=O)c3cccc(-c4cc(C(C)(C)S(C)(=O)=O)cc5cccnc45)c3)cn2)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of N-(6-Chloro-pyridin-3-yl)-3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzamide, 4-methylsulfanyl-phenyl boronic acid (2 eq), PdCl2(dppf)2 (0.05 eq) and aqueous Na2CO3 (4 eq) in DME (0.04M from benzamide) was stirred at 100° C. for 12 h. The resulting mixture was poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. Flash chromatography (EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([OH:12])[CH2:11][CH:2]1[CH3:1])=[O:19]
Reactant: CC1CC(O)c2ccccc2N1
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(C(=O)N2c3ccccc3C(O)CC2C)c1
Yield: 26.6 %

Procedure:
Starting with 2-methyl-1,2,3,4-tetrahydro-4-quinolinol (3.00 g, 18.3 mmol) synthesized in the published manner and 3-methoxybenzoic acid (3.34 g, 22.0 mmol), the same procedure as shown in Reference Example 19 was repeated to give the titled compound (1.45 g, yield: 27%) as a white crystal. (cis:trans=1:1)
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])(O)=[O:2].S(Cl)([Cl:23])=O>ClCCl.CN(C=O)C>[N:8]1([C:9]2[CH:17]=[CH:16][C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:7][CH2:6][O:5][CH2:4][C:1]1=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1

Procedure:
290 mg (1.02 mmol) 4-(2-carboxymethoxy-ethylamino)-3-nitro-benzoic acid in 100 ml dichloromethane are combined with 0.186 ml (2.55 mmol) thionyl chloride and 2 drops of DMF and refluxed for one day. After evaporation of the solution i. vac. it is evaporated with toluene and the residue is further reacted without any more purification.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[O:28][C:29]=1[CH3:30]>>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:27]1[O:28][C:29]([CH3:30])=[C:25]([CH2:24][N:11]2[C:12]3[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:3]([OH:2])=[O:22])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)[N:26]=1
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)Oc1ccccc1
Product: Cc1oc(-c2ccccc2Cl)nc1Cn1ccc2cc(CC(Oc3ccccc3)C(=O)O)ccc21

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-phenoxy-propionic acid methyl ester (preparation 7) was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxy-propionic acid as off-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]#N)=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.OS(O)(=O)=O.[C:30](=O)(O)[O-:31].[Na+].C(=O)(O)[O-:36].[Na+].ClCCl>ClCCl.CO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:31][CH3:30])=[O:36])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Temperature: 20 °C
Yield: 97.7 %

Procedure:
Nitrile 6 (101 g) and methanol (1.01 L, 10 vol.) were charged to a 3-L flask equipped with stir bar and thermocouple. Concentrated H2SO4 (175 mL, 10.0 equiv.) was added drop wise to the solution over 15 minutes while maintaining a temperature below 60° C. Followed by 30% fuming sulfuric acid (124 mL) was added drop wise to the solution while maintaining a temperature below 60° C. The solution was then heated to reflux with a heating mantle and stirred overnight. When the reaction was deemed complete, it was cooled to 20° C. In a second flask (22 L), saturated sodium bicarbonate (10.7 L) and dichloromethane (1.1 L) were charged and cooled to 15° C. While maintaining a temperature below 20° C., the reaction mixture was added to the sodium bicarbonate/dichloromethane mixture. The quench was stirred for 15 minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (1×550 mL, 1×300 mL). The combined organics were dried with magnesium sulfate and concentrated to dryness to give 105 g of an orange solid (94% crude yield, 97.7% AUC by HPLC).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][N:6]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].C(O)(C)(C)C>O>[CH2:9]([N:6]1[CH2:7][CH2:8][CH:5]1[C:3]([OH:4])=[O:2])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1CCN1Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C1CCN1Cc1ccccc1
Reaction time: 2 h

Procedure:
N-Benzylazetidine-2-carboxylic acid methyl ester (1 g), 90 mg of t-butanol, 90 mg of water were mixed at 20 to 25° C. and 180 mg of Chirazyme L-2 were mixed and the resulting solution was heated to40° C. and stirred for 2 hours. Thereafter 1 ml of water was added thereto and washed with 4 ml of t-butyl methyl ether thrice to obtain an aqueous solution of optically active N-benzylazetidine-2-carboxylic acid. Combined organic phase gave a solution of N-Benzylazetidine-2-carboxylic acid methyl ester.