Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([CH3:19])([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:4][C:3]=1[CH3:20].[OH-].[Na+]>CO.O>[Br:1][C:2]1[S:6][C:5]([C:7]([CH3:18])([CH3:19])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(C(C)(C)C(=O)OCc2ccccc2)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(C)(C)C(=O)O)sc1Br

Procedure:
A mixture of the benzyl 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoate and sodium hydroxide (0.33 g, 8.3 mmol) in methanol (10 ml) and water (2.5 ml) was heated under reflux for 1 hour. The solvent was evaporated and the residue triturated with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and then evaporated to leave 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoic acid as a yellow gum which was used in the next step without purification. 1H NMR (CDCl3): 2.09 (s, 6H), 2.13 (s, 3H), 6.69 (s, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.I[CH2:15][CH2:16][CH3:17].CN(C)C=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH2:16][CH3:17])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCI
Reactant: CC(=O)Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCN(C(C)=O)c1cccc(Br)c1

Procedure:
In a manner similar to that of Example (27b), by reaction of 820 mg (20.5 mmol, 1.1 eq) of 60% sodium hydride, 4.0 g (18.7 mmol, 1 eq) of N-(3-bromophenyl)acetamide (prepared in Example 27a) and 2.20 mL (22.4 mmol, 1.2 eq) of 1-iodopropane in 15 ml of tetrahydrofuran in the presence of 1.5 ml of dimethylformamide, N-(3-bromophenyl)-N-propylacetamide is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[C:4](Cl)[N:3]=1.[Na].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[C:4]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(N)c(Br)c(Cl)n1
Agent: [Na]
Product: Nc1nc(N)c(Br)c(OCc2ccccc2)n1
Temperature: 130 °C

Procedure:
2,4-Diamino-5-bromo-6-chloropyrimidine ( Phillips et. al., J. Org. Chem., 29, 1488-1490 (1963)) (2.3 g, 10 mmol) was added to a solution of sodium(0.29 g, 12.5 mmol) in benzyl alcohol ( 10 mL) under argon. The solution was heated in a 130° C. oil bath for 3 h and the benzyl alcohol was evaporated under reduced pressure to give a white solid. This solid was washed with water, and air dried. Crystallization from 50% aqueous ethanol gave white crystalline needles of 3f: yield, 2.32 g (76%); mp 165-166 ° C. (lit. 136° C.; Kosary et. al., Acta Pharm. Hung., 49, 241-247 (1989)); UV (pH 1) λmax236 nm (ε=0.873×104), 291 (1.388×104O); (pH 6.9) 236 (0.850×104), 277 (0.835×104); (pH 13) 234 (0.869×104), 277 (0.827×104 ); 1H NMR δ 5.30 (s, 2 H, ArCH2), 6.15 (s, 2 H, NH2, exchange with D2O), 6.32 (s, 2 H, NH2, exchange with D2O), 7.31-7.45 (m, 5 H, ArH); MS (EI) calcd. m/z for C11H11N4O79Br 294.0115, found 294.0127; calcd. m/z for C11H11N4O81Br 296.0094, found 296.0083; Anal. (C11H11N4OBr) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:14]([S:30]([CH3:29])(=[O:32])=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](c1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of alcohol 15 (1.94 g, 6.81 mmol) and triethylamine (1.25 g, 12.4 mmol) at 0° C. in Cl2CH2 (15 mL), methanesulfonyl chloride (0.96 g, 8.4 mmol) was added. The reaction mixture was allowed to stir at 0° C. for 20 min. It was quenched with cold dilute HCl, diluted with Cl2CH2 and the organic layer was washed with an aqueous solution of NaHCO3 followed by brine and dried over Na2SO4. The solvent was removed in vacuo and the crude mesylate 16 was obtained as a foamy white solid, which was used in the next step without further purification. 1H NMR (CDCl3).δ1.394 (s, 9H), 2.916 (s, 3H), 3.718 (s, 3H), 4.878 (dd, J=8.7, 5.0 Hz, 1H, H-2), 5.231 (bd, J=8.7 Hz, 1H, H--N), 5.917 (d, J =5.0 Hz, 1H, H-3), 7.379-7.425 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][C:20](C2C=CC=CC=2)(C2C=CC=CC=2)[C:21]2[CH:26]=CC=CC=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].N1C=CC=CC=1.BrC(C)C(Br)=[O:48]>CCOCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:19][C:20](=[O:48])[C@H:21]([CH3:26])[O:15][C@:5](/[CH:10]=[CH:11]/[CH:12]3[CH2:14][CH2:13]3)([C:6]([F:9])([F:8])[F:7])[C:4]=2[CH:3]=1
Reactant: CC(Br)C(=O)Br
Reactant: OC(C#CC1CC1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 987 mg of trans-6-amino-3 -chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part B) in 50 mL of dry ether was added 0.350 mL of dry pyridine and 1.66 g of α-bromopropionyl bromide. The cooling bath was removed and then after 30 min at ambient temperature, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 50 mL of dry DMF, 2.35 g of lithium iodide and 2.3 g of cesium carbonate was added, and the resulting heterogeneous mixture was stirred at room temperature for 3 days. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to crude product. The title compound was obtained by crystallization from ethyl acetate/hexanes, and recrystallization from ethyl acetate afforded 650 mg of pure title compound: mp 171-172°; HRMS: Calcd. for C16H168NO2F3Cl (M+H)+: 346.082166. Found: 346.080681: mp 147-147.5°; HRMS: Calcd. for C17H18NO2F3Cl (M+H)+: 360.097816. Found: 360.097869
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:27]1([N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:9][CH2:10][N:11]([C:40]([NH:39][CH:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[O:41])[CH2:12][CH2:13]2)[CH2:7]1)(=[O:4])=[O:5]
Reactant: O=C(NC1CCN(c2ccccc2)CC1)Oc1ccccc1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3CCN(c4ccccc4)CC3)CC2)c2ccccc21
Yield: 31.6 %

Procedure:
1-Methanesulfonyl-spiro[indoline-3,4′-piperidine] hydrochloride (37 mg) and triethylamine (170 μL) were added to a solution of phenyl N-(1-phenyl-4-piperidyl)carbamate (36 mg) in chloroform (3 mL), and the mixture was heated to reflux for 15 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from diethyl ether to give the title compound (18 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:4]([NH:6][NH2:7])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C.C(O)(=O)C>[CH3:1][O:2][CH:3]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)[C:4]([NH:6]/[N:7]=[CH:23]/[C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:5]
Reactant: COC(C(=O)NN)c1cccc2ncccc12
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(/C=N/NC(=O)C(OC)c2cccc3ncccc23)cc(OC)c1OC
Temperature: 60 °C
Yield: 74 %

Procedure:
To a mixture of 2-methoxy-2-(quinolin-5-yl)acetohydrazide (0.149 g, 0.65 mmol) and 3,4,5-trimethoxybenzaldehyde (0.138 g, 0.70 mmol) in absolute ethanol (5 mL) was added acetic acid (1 drop). The mixture was heated at 60° C. for 17 hours. After cooling to room temperature, the solid was collected on a Büchner funnel and rinsed with ethanol and diethyl ether then dried in vacuo to give (E)-2-methoxy-2-(quinolin-5-yl)-N′-(3,4,5-trimethoxybenzylidene)acetohydrazide (6-1) as a white powder (0.197 g, 75% yield).
Reaction SMILES: O[C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:20][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:18]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5][O:4][CH2:3]1.CCN(S(F)(F)[F:39])CC>ClCCl>[F:39][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:20][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:18]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5][O:4][CH2:3]1
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(O)COC2)nc1C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(F)COC2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(1-(3-(2-(3-hydroxyoxetan-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 192, 200 mg, 0.47 mmol) in dichloromethane (5 mL). This was followed by the addition of a solution of DAST (76.2 μL, 0.58 mmol) in dichloromethane (1 mL) dropwise at −78° C. The resulting solution was stirred for 1 h at room temperature, then quenched by the addition of 2 mL of sodium bicarbonate (sat.). The resulting solution was diluted with 60 mL of EtOAc and additional water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and MeCN (18.0% MeCN up to 28.0% in 9 min, up to 100.0% in 2 min, down to 18.0% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 15.1 mg (8%) of the title compound as a white solid. m/z (ES+) 431 (M+H)+.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:30]1[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[N:31]=1>O1CCCC1>[CH:3]1([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[N:35]([CH3:36])[C:34](=[O:37])[CH:33]=[C:32]([C:38]5[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=5)[N:31]=4)[CH2:17]3)=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1cc(C2CCCNC2)ccc1NC1CCCCC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCCC(c3ccc(NC4CCCCC4)cc3)C2)nc(-c2ccncc2)cc1=O
Reaction time: 12 h
Yield: 95.8 %

Procedure:
To a solution of 3-(4-cyclohexylaminophenyl)-piperidine dihydrochloride salt (1.0 g, 3.02 mmol) and triethylamine (1.5 g, 14.8 mmol) in tetrahydrofuran (20 mL) was added 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.64 g, 2.89 mmol) portionwise. After stirring for 12 h, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 2-(3-(4-cyclohexylaminophenyl)-piperidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.23 g, 2.77 mmol, 96%) as white crystals.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33]CC)[CH:27]=4)[CH2:23][CH2:22][C:21]([C:36]([O:38]C)=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.[O:45]1CCC[CH2:46]1>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][C:31]=4[O:45][CH3:46])[CH2:23][CH2:22][C:21]([C:36]([OH:38])=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cccc(OCCC)c2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cc(OC)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (290 mg) in a mixture of tetrahydrofuran (21 ml) and methanol (21 ml) was added 1N sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 4 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (237 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([Cl:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:14]([Cl:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCc1ccc(O)c(Cl)c1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1Cl
Temperature: 60 °C

Procedure:
3-(3-Chloro-4-hydroxy-phenyl)-propionic acid benzyl ester (step 1) (5.9 g, 20.3 mmol) in DMF (60 ml) was treated with potassium carbonate (5.61 g, 40.6 mmol) followed by t-butyl bromoacetate (4.49 ml, 30.4 mmol) and the mixture was heated at 60° C. overnight. The reaction mixture was diluted with water (500 ml), and the product extracted into EtOAc (450 ml). The organic portion was washed with water (200 ml), brine (200 ml), dried over MgSO4 and the solvent removed in vacuo to yield a yellow oil. Purification by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34 (6H, m), 7.11 (1H, d), 6.89 (1H, d), 5.07 (2H, s), 4.74 (2H, s), 2.81 (2H, t), 2.68 (2H, t), 1.42 (9H,s). LC-MS Rt 1.64 mins; 427.3 [M+Na]+, Method 2minLC_v002.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12](OC)=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1.[NH3:26].O.Cl>COCCOCCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:5]=[C:6]([Br:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:26])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c([N+](=O)[O-])c2)c(Br)c1
Reactant: N
Agent: Cl
Solvent: COCCOCCO
Solvent: O
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(N)c([N+](=O)[O-])c2)c(Br)c1
Reaction time: 24 h
Yield: 84 %

Procedure:
To methyl [3,5-dibromo-4-(4-methoxy-3-nitrophenoxy)phenyl]acetate (5 g), dissolved in 2-(2-methoxyethoxy)ethanol (50 mL) was added an aqueous solution of ammonia (32%, 7 mL). The reaction mixture was heated at 150° C. for, with continuos refill of ammonia. After 24 hours, water was added followed by an aqueous solution of hydrochloric acid. This was continued until the acidity of the solution reached pH 2. The aqueous phase was extracted with chloroform, washed with brine and dried over magnesium sulphate. After concentration of the organic phase, 4.1 g (84%) of methyl [3,5-dibromo-4-(4-amino-3-nitrophenoxy)phenyl]acetate was obtained as an yellow solid mass.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[C-:10]#[N:11].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][C:10]#[N:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: ClCc1cccnc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cccnc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
To a solution of the compound (20.5 g) obtained in step 2 in DMSO (100 mL) was added sodium cyanide (12.4 g), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was poured into a mixture of water and ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane) to give (2-chloropyridin-3-yl)acetonitrile (11.7 g, 61%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:24][C:25]([F:29])([F:28])[C:26]#[CH:27]>>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:23])([C:19]([F:21])([F:22])[F:20])[C:27]#[C:26][C:25]([F:29])([F:28])[F:24])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Reactant: C#CC(F)(F)F
Product: CN(c1ccc(C(O)(C#CC(F)(F)F)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1

Procedure:
The compound was prepared from N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide (Example 22, Step A) and 3,3,3-trifluoroprop-1-yne following the procedure described in Example 29. 1H NMR (CDCl3) δ 3.19 (s, 3 H), 4.30 (br s, 1H), 7.11-7.63 (m, 9 H). Mass Spectrum (CI+) m/e=438 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)=[C:4]([F:10])[CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: ClCCCl
Product: Fc1cc(Br)ccc1C1OCCO1

Procedure:
4-bromo-2-fluorobenzaldehyde (9.4 g, 46.3 mmol), ethylene glycol (13.2 mL), triethyl orthoformate (6.6 mL) and p-toluenesulfonic acid (0.09 g, 0.473 mmol) were stirred in DCE (50 mL) at 80° C. for 2.5 hours. Room temperature was attained and the solution was washed successively with saturated NaHCO3, H2O and brine, dried over MgSO4 and concentrated in vacuo to give the product (pale yellow oil). 1H NMR (CDCl3) δ 7.41 (t, J=8.1 Hz, 1H), 7.30 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (dd, J=9.6, 1.8 Hz, 1H), 6.02 (s, 1H), 4.13 (m, 2H), 4.04 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8]([CH2:10][CH2:11][OH:12])=[O:9])[CH:2]=1.[CH3:13]C(C)([O-])C.[K+].C=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[S:8](=[O:9])[CH2:10][CH2:11][O:12][CH2:13]2)[CH:2]=1
Reactant: CC(C)(C)[O-]
Reactant: O=S(CCO)Cc1cccnc1
Agent: C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1CCOCC1c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 338 %

Procedure:
A stirred solution of 2-(3-pyridylmethylsulphinyl)ethanol (0.25 g, 1.35 mmol) in dimethylformamide (25 ml) at 0° C. was treated portionwise with potassium tert-butoxide (0.15 g, 1.35 mmol) and stirred for 10 mins. Formaldehyde gas [generated by heating paraformaldehyde (45 mg, 1.5 mmol) at 150° C.] was passed into the reaction mixture in a rapid stream of argon whilst cooling in an ice bath. When addition of the formaldehyde was completed the cooling bath was removed and the mixture allowed to warm to room temperature over 15 mins. The solution was poured into ethanol (30 ml), neutralised with concentrated hydrochloric acid and filtered to give a clear solution which was evaporated in vacuo and the residue was purified by flash chromatography on silica, eluting with 7% methanol in dichloromethane, to give 3-(3-pyridyl)-1,4-oxathiane 4-oxide (900 mg), as a colourless crystalline solid, m.p. 74°-76° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[C:24](=[O:25])[CH:23]=[CH:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Li]>C(OCC)C>[Si:1]([O:18][CH2:19][C@H:20]1[C@@:24]([CH3:26])([OH:25])[CH:23]=[CH:22][CH2:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: CC(C)(C)[Si](OC[C@@H]1CC=CC1=O)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)[Si](OC[C@@H]1CC=C[C@]1(C)O)(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution of (5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopent-2-en-1-one (250. mg, 0.713 mmol) in diethyl ether (10.0 mL) tinder an atmosphere of nitrogen was cooled to −40° C. and a 1.60 M solution of methyllithium in diethyl ether (0.579 mL, 0.926 mmol) was added slowly and the mixture was stirred at −40° C. for 3 h. TLC indicated complete conversion, and the reaction was quenched via addition of saturated aqueous ammonium chloride (5.00 mL), extracted with EtOAc (3×10.0 mL), dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes afforded the title compound (190 mg, 73%). Stereochemistry of the product was confirmed using ROESY analysis. LC/MS: Rt=2.55 min, ES+ 367 (AA standard).
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[NH:4]C[CH2:2]1.[CH2:10](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.BrCC(C12CC3CC(CC(C3)C1)C2)=O>C1COCC1>[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[C@H:6]([CH2:1][CH3:2])[CH3:10]
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 221.8 %

Procedure:
Using the procedure described in Example 5 and Example 17, L-homoproline-L-isoleucine benzylamide (75 mg, 0.22 mmol), was treated with triethylamine (0.15 mL, 1.12 mmol, 5 eq), 1-adamantyl bromomethyl ketone (92 mg, 0.36 mmol, 1.6 eq), and THF (10 mL), to provide 64 mg (56%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-homoproline] benzylamide.