Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:11][CH2:12][O:13][N:14]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br)[C:16]([O:18][CH3:19])=[O:17].NC(N)=S.[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:11][CH2:12][O:13][N:14]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(=NOCF)c1ccccc1CBr
Reactant: Cc1ccccc1O
Agent: NC(N)=S
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(=NOCF)c1ccccc1COc1ccccc1C
Temperature: 30 °C

Procedure:
A solution of 1.84 g of o-cresol in 15 ml of dimethylformamide is added dropwise at 20° C. to a suspension of 0.4 g of sodium hydride in 5 ml of dimethylformamide. After 3 hours a solution of 5.0 g of 2-(bromomethyl)-phenylglyoxalic acid methyl ester O-fluoromethyl oxime in 25 ml of dimethylformamide is added dropwise to the brown suspension. After 16 hours 0.3 g of thiourea is added thereto and the reaction mixture is heated at 30° C. for 0.5 hour. The reaction mixture is then poured onto a saturated sodium chloride solution and extraction is carried out with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (9:1) yields pure 2-(2-methylphenoxymethyl)-phenylglyoxalic acid methyl ester O-fluoromethyl oxime; m.p. 101°-102° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (21 mg, 0.068 mmol) in dichloromethane (1 mL) was added 4-phenylpiperidine (17 mg, 0.068 mmol, 1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O2: 346.1681, found 346.1685.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[C:22](OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C(C)(C)C/C=C/C(=O)O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (5.00 g; 20.6 mmol) was dissolved in tetrahydrofuran (70 ml). Methyliodide (10.3 ml; 164 mmol) was added and the solution was cooled to 0° C. Sodium hydride (60% in oil)(2.07 g; 61.6 mmol) was added in portions and the solution was stirred at room temperature for four days. Ethyl acetate (70 ml) and water (60 ml) was added dropwise and the solvent was removed in vacuo. The crude product was dissolved in water (40 ml) and ether (40 ml). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The aqueous phases were mixed and 5% aqueous citric acid was added to pH 3. The aqueous phase was extracted with ethylacetate (4×50 ml). The organic phase was washed with water (2×40 ml), an aqueous solution of sodium thiosulfate (5%; 40 ml), water (40 ml), dried over MgSO4 and the solvent was removed in vacuo. The residue was dissolved in ethylacetate (45 ml) and washed with an aqueous solution of sodium hydrogensulfate (10%; 3×30 ml), dried over MgSO4 and concentrated in vacuo to give 4.00 g of (2E)-5-(N-(tert Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C@H:11]2[CH2:13][O:12]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:14].[OH:15][CH2:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1>C(O)C>[OH:12][C@@H:11]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:14])[O:5][CH2:4]2)[CH2:13][N:22]1[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][C@H:17]1[CH2:16][OH:15]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@H](O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O

Procedure:
(S)-4-Methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (0.75 g, 3.95 mmol) and (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.02 g, 4.73 mmol) in ethanol (12 mL) were heated in microwave at 150° C. for 1.5 h. The reaction solution was concentrated and the residue was purified by MPLC on a Biotage system using 40-100% ethyl acetate/hexane to give the title compound. LC/MS: (M+1)+: 407.15.
Reaction SMILES: OO.O.[OH-].[Li+].[CH2:6]([O:26][C@@H:27]([CH2:43][CH3:44])[C:28](N1[C@@H](C)[C@@H](C2C=CC=CC=2)OC1=O)=[O:29])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25].[O-:45]S([O-])=O.[Na+].[Na+].Cl>O1CCCC1.O>[CH2:6]([O:26][C@@H:27]([CH2:43][CH3:44])[C:28]([OH:29])=[O:45])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO[C@@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO[C@@H](CC)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Hydrogen peroxide (35% in water, 0.75 mL, 8.54 mmol) and lithium hydroxide monohydrate (0.18 g, 4.27 mmol) was added to a solution of (4S,5R)-3-((S)-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoyl)-4-methyl-5-phenyloxazolidin-2-one (1.10 g, 2.13 mmol) in tetrahydrofuran (12 mL) and water (4 mL) held at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes. 10% Na2SO3(aq) (30 mL) was added, the pH was adjusted to ˜2 with 2M HCl and the mixture was extracted twice with heptane (30 mL). The combined organic extract was dried (Na2SO4), filtered and concentrated. The residue was subjected to flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (98:8→1:1) as eluent. Concentration of the appropriate fractions afforded 0.48 g (60% yield) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3): δ 0.90-1.00 (m, 6H), 1.48 (m, 2H), 1.65 (m, 2H), 1.85 (m, 2H), 2.10 (m, 4H), 2.80-2.90 (m, 8H), 3.55 (m, 1H), 3.60 (m, 1H), 3.88 (t, 1H), 5.35-5.45 (m, 10H); MS (electro spray): 373.3 [M−H]−; [α]D+37° (c=0.104, ethanol)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH3:9].C(N(CC)CC)C.Cl.Cl[C:19]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=1)=[O:20]>CN(C)C=O>[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][CH2:5][N:4]2[CH2:8][CH3:9])=[O:20])=[CH:22][N:23]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: CCN1CCCC1CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1ccc(NC(C)=O)nc1
Temperature: 50 °C
Yield: 59.9 %

Procedure:
A mixture of 12.8 g (0.1 mole) of 2-aminomethyl-1-ethyl pyrrolidine and 22.2 g (0.11 mole) of triethylamine was added at a temperature ≤20°C, to a solution of 23.5 g (0.1 mole) of 3-chlorocarbonyl-6-acetamido pyridine hydrochloride (itself prepared starting from 6-acetamido nicotinic acid) in 250 ml of anhydrous dimethylformamide. After the completion of the addition, the mixture was heated to 50°C for 1 hour then dimethylformamide was eliminated under reduced pressure. The oily residue was triturated with 200 ml of water and 100 ml of ether. The so-obtained base crystallized and there were obtained 17.4 g of 2-(6-acetamido nicotinamidomethyl)-1-ethyl pyrrolidine in the form of beige crystals melting (Kofler) at 162°-163°C. This compound was deacetylated according to the above described method and there were finally obtained 9.8 g of 2-(6-amino nicotinamidomethyl)-1-ethyl pyrrolidine, melting (Kofler) at 136°C.
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][C@@H:8]([CH3:10])[CH2:7][N:6](CC2C=CC=CC=2)[CH2:5]1)[CH:2]=[CH2:3].[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>[Pd]>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:10][C@H:8]1[O:9][C@@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][NH:6][CH2:7]1
Reactant: C=CC[C@@H]1CN(Cc2ccccc2)C[C@H](C)O1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H]1CNC[C@@H](C)O1
Reaction time: 17 h

Procedure:
A mixture of cis-2-allyl-4-benzyl-6-methylmorpholine (520 m, 2.25 mmol), trifluoroacetic acid (0.5 mL, Aldrich) and 5% palladium on carbon (54 mg, 10% w/w, Aldrich) is sealed in a Parr bottle under 40 PSI of H2, and is shaken for 17 hours. The mixture is filtered and the solvent removed by rotary evaporation yielding cis-2-methyl-6-propylmorpholine trifluoroacetate as a light golden oil. The oil is taken up in CH3CN (8 mL) and treated with N,N-diisopropylethylamine (1.2 mL, 6.9 mmol, Aldrich). 2-Fluoro-5-nitrobenzaldehyde (419 mg, 2.48 mmol, Oakwood) is added and the mixture is shaken at 60° C. for 21 hours. N,N,N′-trimethylethylenediamine (1.0 mL) is added and the reaction is shaken for an additional 30 minutes @60° C. after which the solvent is removed by rotary evaporation. The residue is taken up in EtOAc (100 mL) and washed with 1.0 M HCl, saturated NaHCO3 and brine (100 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 40M+ using 20% EtOAc in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum at 60° C. yielding a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Cl[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:33][C:32](=[O:34])[O:31][C:30]([CH3:36])([CH3:35])[C:29]=2[CH:37]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]3[NH:33][C:32](=[O:34])[O:31][C:30]([CH3:36])([CH3:35])[C:29]=3[CH:37]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Br)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quantities of 6.23 gm (0.033 mol) of 4-bromothiophenol and 8.28 gm (0.06 mol) of potassium carbonate are stirred into 100 ml of dimethylsulfoxide, dried over a molecular sieve in a nitrogen atmosphere at ambient temperature for 15 minutes, and then mixed with 8.51 gm (0.03 mol) of 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one. After stirring for one hour at ambient temperature, water is added in batches until a thick crystal slurry is produced. This is subjected to suction filtration, dried, and recrystallized from ethyl acetate/diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][CH:20]=3)=[CH:11][NH:10]2)[CH:4]=1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][CH:20]=3)=[CH:11][N:10]2[CH2:27][CH3:28])[CH:4]=1
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(C(F)(F)F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A 4 gram portion of 1,4-bis-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one (from Example 4) was heated with 20 ml. ethyl iodide, 3 grams potassium carbonate, and 40 ml. ethanol at reflux temperature for about 4 hours. The reaction product mixture was concentrated in vacuo and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the drying agent filtered off and the filtrate concentrated in vacuo. On standing overnight the residue solidified and was recrystallized from a mixture of hexane and benzene. The solid was chromatographed on a silica gel column using a mixture of ethyl acetate and hexane in the ratio of 1:2. The product from the column was then recrystallized from a mixture of hexane and benzene to yield the desired product, m.p. 110°-111° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:15]=[C:14]([CH:16]2[O:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[CH2:17]2)[O:13][N:12]=1)([CH3:10])[CH3:9].[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C1COCC1>[C:24]([CH:19]1[C:18](=[O:23])[CH2:17][CH:16]([C:14]2[O:13][N:12]=[C:11]([CH:8]([CH3:10])[CH3:9])[CH:15]=2)[O:21][C:20]1=[O:22])(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)c1cc(C2CC(=O)CC(=O)O2)on1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)C1C(=O)CC(c2cc(C(C)C)no2)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
12.6 g of triethylamine was added to 27.9 g of 6-(3-isopropylisoxazol-5-yl)-tetrahydropyran-2,4-dione in 200 ml of THF. At 0° C., 13.3 g of butyryl chloride was dripped in and the mixture was stirred for one hour at 0° C. The mixture was evaporated, followed by partitioning between methylene chloride and water. The organic phase was worked up, i.e., extracted with water, 10% strength sodium carbonate solution and again with water, dried with sodium sulfate and evaporated again. The residue was dissolved in anhydrous methylene chloride and stirred for 48 hours with 1.3 g of 4-(N,N-dimethylamino)-pyridine. Removal of the solvent was followed by chromatography over silica gel with methylene chloride and methanol (98.5:1.5). The isolated compound was recrystallized from a small amount of cyclohexane. There was obtained 13 g of product.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[CH3:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:13]([OH:18])([CH2:14][CH2:15][CH2:16][CH3:17])[CH3:12]
Reactant: CCCCC(C)=O
Reactant: Brc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(C)(O)c1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromothiophene (24.3 g, 0.15 mol) in dry THF (120 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (2.5 M, 66.0 mL, 0.17 mol) was then added slowly, and the resulting mixture was stirred at −78° C. for 2 hours, before 2-hexanone (18.1 g, 0.18 mol) was added slowly. This mixture was stirred at −78° C. for an additional 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. Most of the solvent was removed in vacuo, and the residue was subjected to flash column chromatography on silica gel with a hexane:EtOAc (4:1, slowly up to 3:1, v/v) mixture, leading to a slightly yellow oil as the product (21.4 g, 77.7%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][N:16]=[CH:15][C:14]=1[O:21][CH3:22])C.O>C1COCC1>[CH3:20][O:19][C:18]1[CH:17]=[N:16][CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[CH2:12][CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CCc1c(OC)cncc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cncc(OC)c1CCCO
Yield: 98 %

Procedure:
Lithium aluminum hydride (1.1 g, 30 mmol) is suspended in THF (50 ml), and thereto is added with stirring 3-(3,5-dimethoxypyridin-4-yl)propionic acid ethyl ester (3.5 g, 15 mmol) obtained in Reference Example 22 at 50° C. over a period of time for 40 minutes. The mixture is further heated under reflux for 30 minutes, and thereto are added successively water (1.1 ml), a 15% aqueous sodium hydroxide solution (1.1 ml) and water (3.3 ml) in order to quench the reaction. The reaction solution is filtered, and the insoluble materials are removed, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol), and further recrystallized from isopropyl ether/hexane to give the title compound (2.9 g) as colorless crystals, m.p. 88-89° C.
Reaction SMILES: [O:1]=[C:2]([O:23][C@@H:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)[CH:3]([NH:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[C:14]([O:16]CC=C)=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCCCC1>C1COCC1>[O:1]=[C:2]([O:23][CH:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)[C@H:3]([NH:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[C:14]([OH:16])=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: O=C(O)c1cccc(N[C@@H](C(=O)OC2CN3CCC2CC3)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
To a solution of allyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethyl-amino)benzoate (I4) (1.40 g, 3.33 mmol) in dry THF (45 ml), were added tetrakis-(triphenylphosphine)palladium(0) (1.15 g, 1.00 mmol) and piperidine (0.99 ml, 1.00 mmol) and the reaction mixture was stirred at 60° C. for 1.5 hours. The solvent was removed in vacuo and the crude was purified by flash chromatography (DCM/MeOH=9/1 to MeOH) to obtain (R)-3-(2-oxo-1-phenyl-2-(quinuclidin-3-yloxy)ethylamino)benzoic acid (500 mg, 39.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]3[NH:30][CH:29]=[C:28]([C:31]([O:33]C)=[O:32])[CH:27]=3)[CH:21]=2)=[CH:15][CH:14]=1)=[O:11].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]3[NH:30][CH:29]=[C:28]([C:31]([OH:33])=[O:32])[CH:27]=3)[CH:21]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)c1c[nH]c(-c2cc(Sc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Sc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Temperature: 66 °C

Procedure:
To a stirred solution of methyl 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylate (86 mg, 0.18 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 2 ml of 1M NaOH (2 mmol) solution. The mixture was heated in a 66° C. bath for 7 hours, cooled to room temperature and poured into 100 ml of water. 2M HCl was added until pH=3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 73 mg, 88%.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@H:20]([OH:21])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][N:25]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH3:26])[C:17]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:16]=3[S:15]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C@@H:20]([O:21][C:1](=[O:4])[CH2:2][CH3:3])[C:19](=[O:22])[N:18]([CH2:23][CH2:24][N:25]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])[CH3:26])[C:17]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:16]=3[S:15]2)=[CH:10][CH:9]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: CCC(=O)O[C@H]1C(=O)N(CCN(C)C(=O)OCc2ccccc2)c2ccc(Cl)cc2S[C@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
490 mg of propionyl chloride are added under ice-cooling to a solution of 2.15 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in 20 ml of pyridine, and the mixture is stirred at room temperature for 3 hours. Then, the mixture is evaporated under reduced pressure. The residue is several times evaporated together with benzene, and ice-water is added to said residue. The aqueous mixture is extracted with ethyl acetate, and the extract is washed with water, 10% hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and water, successively. Said extract is dried and evaporated under reduced pressure to remove solvent. 2.19 g of (-)-cis-2-(4-methoxyphenyl)-3-propionyloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as caramel.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=1>>[CH:21]([C:18]1[S:19][CH:20]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[N:17]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1nc(Br)cs1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1csc(C(C)C)n1
Yield: 15 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 4-bromo-2-isopropylthiazole instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 23 mg, 15%) which was obtained as a yellow oil. MS: m/e=309.3 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:16]=1)[CH2:12][CH3:13])(C)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][C:32]=1[CH3:40]>>[CH2:12]([N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:39][CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[C:32]([CH3:40])[CH:33]=3)[N:22]=2)[CH:16]=1)[CH2:10][CH2:9][CH2:8][NH2:7])[CH3:13]
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: COc1ccc(CCN)cc1C
Product: CCN(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(OC)c(C)c3)n2)c1

Procedure:
Intermediate 3 was coupled with 2-(4-Methoxy-3-methyl-phenyl)-ethylamine following procedure F. The resulting product was deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 434. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (m, 2H) 8.0 (s, 1H) 7.6-7.8 (m, 2H) 7.47 (d, 1H) 6.82 (d, 1H) 6.67 (m, 2H) 4.5 (s, 2H) 3.81 (s, 3H) 3.4 (m, 4H) 3.28 (m, 4H) 3.03 (t, 2H) 2.68 (t, 2H) 2.16 (m, 2H) 1.4 (t, 3H).