Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH2:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl.O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:27][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NC(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 69 h
Yield: 91.3 %

Procedure:
4-Nitrobenzenesulfonyl chloride (2.51 g) was added to a methylene chloride solution (30 ml) containing benzhydrylamine (2.12 g) and triethylamine (1.62 g) under ice cooling, followed by stirring for 3 hours under ice cooling and for 69 hours at room temperature. Water (30 ml), 1 N hydrochloric acid (12 ml) and methylene chloride (5 ml) were added to the reaction mixture, followed by extraction and solution separation, and the aqueous layer was extracted again with methylene chloride (10 ml). The resulting extract was concentrated, and ethyl acetate (80 ml) and water (50 ml) were further added, followed by solution separation. The organic layer was washed in turn with saturated aqueous solution of sodium bicarbonate (10 ml) and water (25 ml), and concentrated. The resulting solid was washed with a mixed solution of ether (9 ml)/hexane (20 ml) and successively with hexane (10 ml), and dried under vacuum to obtain N-(4-nitrobenzenesulfonyl)benzhydrylamine (3.81 g; yield: 91.3%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH3:12][N:9]1[CH2:8][CH2:7][C:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C)CC2)cc1

Procedure:
1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared stardtng from 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (7.6 g, 20 mmol) dissolved in methanol (300 ml) and 10N NaOH (35 ml). The resulting reaction 1A mixture was worked up outlined in example 83. Yield 6.0 g (84%); white solid; mp 195° C.; MS: 356.4 (M+H)+
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C(O[C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)C.Cl>O1CCCC1>[C:1]([C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)#[CH:2]
Reactant: C#C[Mg]Br
Reactant: CCOC1=CC(=O)CCC1
Agent: Cl
Solvent: C1CCOC1
Product: C#CC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.5N ethynylmagnesium bromide in tetrahydrofuran (100 mL) was added under N2 and stirring 3-ethoxy-2-cyclohexen-1-one (3.75 9, 26.8 mmol) in tetrahydrofuran (12.5 mL). The mixture was stirred at RT for 20 h when it was acidified with 1N HCl (200 mL). After stirring for 15 min the acidic phase was extracted with dichloromethane (5×50 mL). The combined organic extracts were washed with water (2×50 mL) and dried (MgSO4). Evaporation of the solvent gave an oil that was purified by column chromatography (silica, ethyl acetate/hexane 1:9) to yield a yellow oil, 2.71 g, 22.6 mmol, 84%). Analysis were in agreement with literature data.
Reaction SMILES: [CH2:1]([C:3]1NC2C([CH:11]=1)=CC(C)=CC=2)[CH3:2].[C:13]([O:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([Li])(CC)C.C[O:35]N(C)C(=O)CC>>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH2:28][C:11](=[O:35])[CH2:3][CH2:1][CH3:2])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCC(=O)N(C)OC
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: CCc1cc2cc(C)ccc2[nH]1
Agent: [Li]C(C)CC
Product: CCCC(=O)Cc1cc(C)ccc1NC(=O)OC(C)(C)C

Procedure:
2-Ethyl-5-methyl-1H-indole. Using methods described in Example 1, Part D, 11.05 g (0.05 mol) of N-tert-butoxycarbonyl-2,4-dimethylaniline was reacted with 81 mL of 1.3M sec-butyl lithium and 6.1 g (0.05 mol) of N-methoxy-N-methylpropanamide to give the crude 1-[2-(tert-butoxycarbonylamino)-5-methylphenyl)-2-pentanone. Treatment of this material with trifluoroacetic and crystallization from EtOAc/hexane gave 1.82 g (13% yield) of 2-ethyl-5-methyl-1H-indole, mp, 77°-78° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH:20]=[C:19]2[C@:14]([CH3:22])([CH2:15][CH2:16][C:17](=[O:21])[CH2:18]2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([O:23][Si](C(C)(C)C)(C)C)[CH2:7][CH2:6]1)[CH3:2].N12CCCN=C1CCCCC2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH2:1]([C@H:3]1[CH2:20][C:19]2[C@:14]([CH3:22])([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC[C@H]1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]3[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7β-Ethyl-17β-tert-butyl-dimethylsilyloxy-androst-5-en-3-one (15.000 g, 34.824 mmol) from Example 16E or otherwise obtained is dissolved in THF (100 mL). To the solution is added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.20 mL, 8.024 mmol) and the reaction mixture is heated to reflux under nitrogen. After 1 hour, the reaction mixture is cooled to room temperature and tetrabutylammonium fluoride (1.0 M in THF; 36.0 mL, 36.00 mmol) is added. The desilylation reaction is allowed to occur over 90 minutes at room temperature with stirring. At the end of this time, the reaction mixture is diluted with EtOAc (500 mL) and washed with saturated aqueous NH4Cl (3×200 mL) and brine (200 mL), then dried over MgSO4, filtered, and evaporated to dryness. The residue is recrystalized from ethanol to give the title compound.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:23]=2)=[O:21])[CH2:11]1)=[O:7])(C)(C)C.[ClH:38].O1[CH2:44][CH2:43][O:42][CH2:41]C1>>[NH2:24][C:25]1[C:26]([Cl:38])=[CH:27][C:44]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:23]=3)=[O:21])[CH2:11]2)=[O:7])=[C:43]([O:42][CH3:41])[CH:30]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCNC(=O)c2cn(Cc3ccccc3)c3ccccc23)C1
Reactant: C1COCCO1
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCNC(=O)c2cn(Cc3ccccc3)c3ccccc23)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(4-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-1-benzyl-1 H-indole-3-carboxamide (1.35 g) was dissolved in 4N hydrochloric acid-dioxane solution (30 ml) and the mixture was stood at room temperature for 60 min. The reaction mixture was concentrated under reduced pressure. Dimethylformamide (30 ml) was added to the residue and the mixture was neutralized with triethylamine (0.74 ml). 4-Amino-5-chloro-2-methoxybenzoic acid (0.54 g) and 1-hydroxybenzotriazole (0.40 g) were added thereto, and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g) was added, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 1.03 g of N-(4-((3R)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)butyl)-l-benzyl-1 H-indole-3-carboxamide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][NH:4][C:5]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[S:6].I[CH3:17]>CO>[CH3:17][S:6][C:5]([N:7]1[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]=[N:8]1)=[N:4][CH2:3][C:2]([F:1])([F:14])[F:15]
Reactant: CI
Reactant: CCC1C=NN(C(=S)NCC(F)(F)F)C1
Solvent: CO
Product: CCC1C=NN(C(=NCC(F)(F)F)SC)C1
Temperature: 50 °C
Yield: 0.2 %

Procedure:
2.80 g (1 mol equiv.) 4-Ethyl-4,5-dihydro-pyrazole-1-carbothioic acid (2,2,2-trifluoro-ethyl)-amide was dissolved in 56 mL methanol; 7.3 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 4 hours. Volatiles were removed under reduced pressure, and the residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:PA=1:1) afforded 0.57 g (19%) 4-ethyl-N-(2,2,2-trifluoro-ethyl)-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J=7.5 Hz, 3H), 1.46-1.70 (m, 2H), 2.48 (s, 3H), 3.01-3.11 (m, 1H), 3.50 (dd, J=11.5, 7.8 Hz, 1H), 3.90 (t, J=11.5 Hz, 1H), 3.99-4.11 (m, 2H), 6.85 (d, J=1.5 Hz, 1H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[CH:10]=2)[NH:5][C:4]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>Cl>[ClH:1].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:10]=2)[NH:5][C:4]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CCc1ccc2[nH]c(-c3cccnc3)c(C)c2c1
Agent: Cl
Product: Cc1c(-c2cccnc2)[nH]c2ccc(CCC(=O)O)cc12

Procedure:
Heating a suspension of ethyl 3-methyl-2-(3-pyridyl)indole-5-propionate hydrochloride in 450 ml of 2N HCl at reflux temperature for 2 hours, cooling and collecting the resulting solid gave 3-methyl-2-(3-pyridyl)-indole-5-propionic acid hydrochloride, m.p. 290°. Similar hydrolysis of ethyl 3-methyl-2-(4-pyridyl)indole-5-propionate yielded 3-methyl-2-(4-pyridyl)indole-5-propionic acid hydrochloride, melting above 305°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Se](=O)=[O:13]>C(OCC)(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:13])=[CH:11][CH:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2nccnc2c1
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc2nccnc2c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
6-Methylquinoxaline (500 mg, 3.47 mmol) and selenium dioxide (423 mg, 3.81 mmol) in a sealed vessel were stirred at 160° C. for 7 h. After cooled to room temperature, the reaction mixture was dissolved in ethyl acetate. The solution was washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 60/40) to obtain the title compound as a pale brown solid (355 mg, 64%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:2].O.Cl>CO.[OH-].[Na+]>[CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:2]
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1C=O
Reaction time: 1 h
Yield: 93.4 %

Procedure:
1.72 g of methyl 4-formyl-3-methoxybenzoate was dissolved in 8.6 mL of methanol, to which 2.6 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and this solution was stirred for one hour at the same temperature. The reaction mixture, to which water was added, was adjusted to pH 2 with 6M hydrochloric acid, and resultant precipitate was filtered out therefrom and washed with water to yield 1.49 g of 4-formyl-3-methoxybenzoic acid as light yellow solid.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([Cl:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C(O)CCC.O.O.[P:19]([O-:23])([O-:22])([O-:21])=[O:20].[Na+].[Na+].[Na+]>O>[P:19]([OH:23])([O-:22])([O-:21])=[O:20].[CH2:1]([Sn+:5]([CH2:6][CH2:7][CH2:8][CH3:9])[Cl:10])[CH2:2][CH2:3][CH3:4].[CH2:1]([Sn+:5]([CH2:6][CH2:7][CH2:8][CH3:9])[Cl:10])[CH2:2][CH2:3][CH3:4]
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCCC[Sn+](Cl)CCCC
Product: O=P([O-])([O-])O

Procedure:
A glass reactor was charged with 91.1 g (0.3 mole) dibutyltin dichloride, 200 cc n-butanol, 50 cc water and 27.3 g (0.15 mole) dibasic sodium phosphate dihydrate. The resultant mixture was heated under a nitrogen atmosphere and the water removed by azeotropic distillation until the vapor temperature reached 117° C. The reaction mixture was then filtered and the liquid phase was concentrated under reduced pressure. The liquid residue solidified upon standing and weighed 83 g. The product was found to contain 34.60% tin, 11.18% chlorine and 4.42% phosphorus. The calculated values for these elements in the expected product are 37.53% tin, 11.21% chlorine and 4.90% phosphorus.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][N:3]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][N:3]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: CC(C)(O)c1cnc(Cl)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2ncc(C(C)(C)O)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of 2-(2-chloropyrimidin-5-yl)propan-2-ol (30 mg, 0.17 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under nitrogen. The mixture was stirred at room temperature for 1 hour. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.125 mmol) in EtOH (2 mL) was added, followed by addition of satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for 2 h. The reaction was quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (21 mg, yield 25%). LC-MS Method 2 tR=0.98 min, m/z=512, 490, 472, 432; 1H NMR (CD3OD): δ 1.02 (s, 3H), 1.13 (s, 3H), 1.50 (d, 3H), 1.61 (s, 6H), 2.02 (s, 1H), 2.18 (m, 5H), 2.30 (m, 1H), 2.75 (m, 1H), 5.66 (m, 1H), 7.00 (m, 2H), 7.20-7.33 (m, 5H), 8.10 (m, 2H), 8.92 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][CH:20]=[CH2:21])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][CH:16]=[CH:15]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:19][CH:20]=[CH2:21])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[N:17]([CH2:26][CH:25]=[CH2:24])[CH:16]=[CH:15]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: C=CCN(Cc1cccc2cc[nH]c12)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN(Cc1cccc2ccn(CC=C)c12)C(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a 0° C. solution of N-[tert-butoxycarbonyl]N-allyl N-[(1H-indol-7-yl)methyl]amine (6.6 g, 23 mmol) in anhydrous dimethylformamide was added slowly sodium hydride (60% dispersion in mineral oil, 1.75 g, 43.7 mmol). The mixture was warmed to 20-24° C. and stirred for 30 minutes, followed by the addition of allyl bromide (4.0 mL, 46 mmol). The reaction was then stirred at 20-24° C. overnight. The reaction mixture was diluted with ethyl acetate (450 mL), washed with water (2×100 mL), saturated aqueous sodium chloride (150 mL), and the organic layer dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 6.8 g (91%) of the desired compound as a light brown oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl.Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:35]1([CH2:41][CH2:42][C:43](O)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(N(CC)CC)C>[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:43](=[O:44])[CH2:42][CH2:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 93.6 %

Procedure:
N,N'-dicyclohexylcarbodiimide (18.77 g) was added to a methylene chloride solution (250 ml) containing L-proline benzylester hydrochloride (20.00 g), triethylamine (11.53 ml), and 3-phenylpropionic acid (13.67 g), and the mixture was stirred at 0° C. for 20 hours. After the precipitated dicyclohexylurea was filtered off, the filtrate was concentrated. The residue was dissolved in ethyl acetate, and the resultant solution was successively washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate, and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 26.13 g of N-(3-phenylpropionyl)-L-proline benzyl ester.
Reaction SMILES: [CH2:1]1[C@@H:3](N)[C@@H:2]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-:11].[K+].[OH2:13]>C(O)CO>[C:5]1([C:2]2([CH2:3][C:1]([OH:13])=[O:11])[CH2:6][CH2:5][CH2:2][CH2:1][CH2:3]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: OCCO
Product: O=C(O)CC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Yield: 88 %

Procedure:
Compound 1 (3.58 g, 17.96 mmol) and KOH (4.42 g, 78.77 mmol) in ethylene glycol (35 mL) was heated at 170° C. for 48 h then cooled to rt. The reaction mixture was diluted with H2O then extracted with Et2O (2×). The aqueous phase was acidified with 6N HCl then extracted with Et2O (3×) and dried over anhydrous sodium sulfate to give (1-phenyl-cyclohexyl)-acetic acid (3.43 mg, 88%) as a tan solid. Mass Spec [M+H]+=219.1.
Reaction SMILES: [OH-].[Li+].[C:3]([C:7]1[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[N:9]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>O1CCOCC1.O.CCO>[C:3]([C:7]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2ncccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)n(-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Lithium hydroxide (62 mg, 2.6 mmol) was added to a solution of ethyl 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-5-carboxylate (0.21 g, 0.65 mmol) in dioxane-H2O-EtOH (1:1:1, 6 mL). The reaction mixture was stirred overnight at RT. The solution was concentrated and the residue was dissolved in H2O (2 mL). 3M HCl was added and the precipitate was collected by filtration and washed with water. The solid was dried under vacuum to obtain 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-5-carboxylic acid (0.18 g, 94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (dd, J=2.0, 4.0 Hz, 1H), 8.47 (dd, J=1.2, 8.4 Hz, 1H), 8.09 (m, 1H), 8.06 (s, 1H), 7.82 (dd, J=2.8, 9.2 Hz, 1H), 7.61 (dd, J=4.8, 8.8 Hz, 1H), 7.01 (s, 1H), 1.33 (s, 9H); MS (ESI) m/z: 296.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH:45](I)I>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: IC(I)COCCOCC(I)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCOCCOCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 0.4 ml of 1,2-bis(diiodoethoxy)ethane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethylacetate 4:1). The product is obtained as an oil. C30H32F2INO5 (651) MS (ESI): M+-18
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:20]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
4-chloro-3-nitrobenzoic acid (100 g) was dissolved in 500 mL anhydrous ethanol and 35 mL concentrated sulfuric acid was added dropwise over a period of 5 minutes. The mixture was refluxed overnight then poured on 1 L ice. The precipitate was separated by filtration, washed four times with water and was then air dried. Recrystallization from 275 mL ethanol afforded a pale yellow product.