Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:26])([C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:5][OH:6].Cl[CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1>CN(C)C=O>[F:3][C:4]([F:26])([C:7]([F:24])([F:25])[C:8]([F:22])([F:23])[C:9]([F:20])([F:21])[C:10]([F:18])([F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:5][O:6][CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1
Reactant: CC1(CCl)COC1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dispersion of 50 weight percent sodium hydride (4.0 g, 83 mmol) in mineral oil was washed with hexanes and suspended in 200 milliliters of dimethylformamide. A solution of 30 grams of 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol (75 mmol) in 50 milliliters of dimethylformamide was added over a period of 3 hours, and the resulting mixture was stirred at room temperature for one hour. Next, a solution of 9.3 grams (77 mmol) of 3-chloromethyl-3-methyloxetane in 20 milliliters of dimethylformamide was added and the resulting mixture was heated at 75° C. for 16 hours. The mixture was cooled to room temperature and slowly poured into 1 liter of ice/water and extracted with two volumes of Freon 113. The combined organic extracts were washed twice with water, once with 2 weight percent aqueous hydrochloric acid and once with brine, dried over magnesium sulfate, filtered, and evaporated to give 32 grams of crude product. The crude product was distilled under reduced pressure to give 26.5 grams (73%) of analytically pure 3-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctoxymethy)-3-methyloxetane (i.e., 15-FOX), an oil with a boiling point of 68 to 70° C./1.6 mm-Hg. The experimental analyses were: 1H NMR (CDCl3 /Freon 113) δ4.49 and 4.37 (AB, J=5.5 Hz, 4 H), 4.00 (triplet, J=13.2 Hz, 2 H), 3.70 (singlet, 2 H), and 1.32 (singlet, 3 H); 13C NMR δ21.02, 40.33, 68.77 (triplet, J=146.2 Hz), 78.60, and 79.87 (signals from carbon bearing fluorine are not included due to complex splitting patterns and low peak intensities); 19F NMR δ-81.3 (3 F), -119.9 (2F), -122.6 (2 F), -123.3 (2 F), -123.5 (2 F), -123.9 (2 F) and -126.8 (2 F). The elemental analysis was: Calculated for C13H11F15O2 : C, 32.2; H, 2.3; F, 58.9. Found: C, 32.2; H, 2.2; F, 58.3.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][CH:13]=[O:14])=[CH:4][CH:3]=1.Cl[CH2:16][C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2>>[N:21]12[CH2:22][CH2:23][CH2:24][C:17]1([CH2:16][N:12]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=1)[CH:13]=[O:14])[CH2:18][CH2:19][CH2:20]2
Reactant: O=CNc1ccc(F)c2ccccc12
Reactant: ClCC12CCCN1CCC2
Product: O=CN(CC12CCCN1CCC2)c1ccc(F)c2ccccc12

Procedure:
The procedures described in Example 2 were repeated except that 4-fluoro-N-formyl-1-naphthylamine (1.90 g, 10.0 mmol) and 5-chloromethyl-1-azabicyclo[3.3.0]octane (hydrochloride, 2.17 g, 11.l mmol) were employed. In this case, the desired compound was obtained as a pale yellow liquid (2.90 g, 92.8%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:18])[CH2:16][OH:17]>CN(C)C=O>[OH:17][CH2:16][CH2:15][NH:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NCCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO

Procedure:
112.8 g (0.5 mol) of 4-chloro-3-nitrobenzotrifluoride and 61.1 g (1 mol) of 2-ethanolamine were heated in 50 ml of dimethylformamide at 100° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and water was added to the residue. The precipitate was filtered off with suction and recrystallized from cyclohexane.
Reaction SMILES: [NH2:1][C:2](=[N:32][N+:33]([O-:35])=[O:34])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[NH:8]C(OC(C)(C)C)=O.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[NH2:1][C:2](=[N:32][N+:33]([O-:35])=[O:34])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH:19]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[NH2:8].[F:36][C:37]([F:42])([F:41])[C:38]([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NC(c1ccccc1)c1ccccc1
Product: O=C([O-])C(F)(F)F
Yield: 95 %

Procedure:
Prepared analogously to Example 5e) from (R)-N5 -[amino(nitroimino)methyl]-N2 -[(tert.-butyloxy)carbonyl]-N-(diphenylmethyl)-ornithinamide by the action of trifluoroacetic acid in a yield of 95% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH:5]=[CH:6][C:7]=1SC.Cl[C:21]1C=C(C=CC=1)C(OO)=O.[S:31](=[O:34])(O)[O-:32].[Na+]>ClCCl>[CH:17]1([C:15]([C:11]2[CH:12]=[N:13][O:14][C:10]=2[C:4]2[CH:5]=[CH:6][C:7]([S:31]([CH3:21])(=[O:34])=[O:32])=[C:2]([Cl:1])[CH:3]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: O=S([O-])O
Reactant: CSc1ccc(-c2oncc2C(=O)C2CC2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2oncc2C(=O)C2CC2)cc1Cl
Reaction time: 8 h

Procedure:
A mixture of 5-[3-chloro4-(methylsulphenyl)phenyl]4-cyclopropylcarbonyl-isoxazole (1.0 g) and 3-chloroperoxybenzoic acid (2.3g, 50%) in dichloromethane was stirred overnight. A saturated solution of sodium bisulphite was added and the layers were separated. The organic phase was washed with sodium bicarbonate solution, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-cyclopropylcarbonyl-5-[3-chloro-4-(methylsulphonyl)phenyl]isoxazole (compound 5, 1.11 g) as a white solid, m.p. 148°-150° C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=C2C(=C[CH:39]=1)C=C(C(OC)=O)C=C2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)C(C)C.OC([C:73]1[CH:74]=[C:75]2[C:80](=[CH:81][CH:82]=1)[CH:79]=[C:78]([C:83]([OH:85])=O)[CH:77]=[CH:76]2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH3:87][NH:88][CH3:89]>>[OH:1][C:2]([C:79]1[C:80]2[C:75](=[CH:74][CH:73]=[CH:82][CH:81]=2)[CH:76]=[CH:77][C:78]=1[C:83]([N:88]([CH3:89])[CH3:87])=[O:85])([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:30]([CH3:39])[CH3:31]
Reactant: CNC
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: CC(C)C(O)(c1c[nH]cn1)c1c(C(=O)N(C)C)ccc2ccccc12

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.0 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with dimethylamine hydrochloride (346 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.87 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[I-].[K+].[OH:13][CH2:14][C:15]1[CH:27]=[C:26]2[N:17]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:13][CH2:14][C:15]1[CH:27]=[C:26]2[N:17]([C:18](=[O:28])[N:19]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[N:16]=1
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(Cn2c(=O)n3nc(CO)cc3c3ccccc32)cc1

Procedure:
210 g of p-methoxybenzyl bromide and 40 g of potassium iodide are added to 114 g of 2-(hydroxymethyl)pyrazolo[1,5-c]-quinazolin-5(6H)-one and 276 g of potassium carbonate in 2 1. of methanol. After refluxing for 5 hours, the reaction is cooled, poured into 6 1. of water and the title compound is filtered off and dried.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[OH-].[K+]>CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Brc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(c1ccc(F)cc1)c1cccnc1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
In a 1 liter 3 neck round bottomed flask was charged 20.0 g. of 4-fluorobenzyl cyanide (1.0 eq., 0.15 moles), in 300 ml. dimethylsulfoxide (DMSO) (dried over molecular sieves), and 46.8 g. of 3-bromopyridine (2.0 eq., 0.30 moles) while stirring under N2. The reaction mixture was heated to 60° C. at which time 12.4 g of KOH (1.5 eq., 0.22 moles) as powdered pellets was added neat. The reaction exotherms to 80° C. and was monitored by GLC. After 30 min., an additional 2.4 g. of potassium hydroxide (KOH) was added (0.3 eq., 0.043 moles) and 1 hr. later GLC showed 6% unreacted nitrile. The reaction was quenched by the addition of 500 ml. of water and then extracted with 1 liter of ether. The organic phase was washed 3 times 250 ml. H2O, dried over MgSO4 and concentrated to give 50 g. of oil. The crude product was distilled under vacuum to give 15.7 g. of oil (49.4% yield) bp 160°-170° C. @1-2 mm. Hg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28](Cl)(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=1>ClCCl>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH3:32])[C:24]([S:28]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C@H:2]2[CH2:10][OH:11])(=[O:29])=[O:30])=[C:25]([CH3:27])[CH:26]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OC[C@@H]1Cc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2CO)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a cold (0° C.) solution of (S)-indolin-2-ylmethanol (4.60 mmol, 1.2 equiv.) and triethylamine (2.5 equiv.) in dichloromethane (20 ml) was added dropwise 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (3.83 mmol, 1.0 equiv.) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane, washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. Yield: 72%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:16][C:8]2[N:9]=[C:10](SC)[N:11]=[C:12]([Cl:13])[C:7]=2[CH:6]=1)=[O:4].O[O:18][S:19]([O-:21])=O.[K+].[CH2:23]1COCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:16][C:8]2[N:9]=[C:10]([S:19]([CH3:23])(=[O:21])=[O:18])[N:11]=[C:12]([Cl:13])[C:7]=2[CH:6]=1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2c(Cl)nc(SC)nc2s1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc2c(Cl)nc(S(C)(=O)=O)nc2s1
Reaction time: 18 h

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (3.3 g, 12.0 mmol) in THF (150 mL) was added a solution of Oxone (15.5 g, 25.2 mmol) in H2O (80 mL) dropwise at RT. After 18 h, the solvent was removed and the residue was diluted with CH2Cl2. The organic fraction was washed with water (1×), brine (1×), dried over. MgSO4, and concentrated. The residue was used without further purification. ESIMS calcd 307 (M++H), found 307 (M++H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[F:20][C:21]([F:37])([F:36])[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[CH2:32][C:33](O)=[O:34].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C>CN(C=O)C.O>[F:20][C:21]([F:36])([F:37])[C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=1[CH2:32][C:33]([N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1)=[O:34]
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (420 mg) in DMF (10 mL) were added [2,4-bis(trifluoromethyl)phenyl]acetic acid (426 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (1.17 mL) and N-[(dimethylamino) (3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (595 mg). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (498 mg).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18][OH:19])[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24]([O:43]C)(=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(O)(=O)C>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([OH:43])=[O:42].[CH2:1]([OH:23])[CH:2]1[O:7][CH:6]([O:8][C:9]2([CH2:18][OH:19])[O:13][CH:12]([CH2:14][OH:15])[CH:11]([OH:16])[CH:10]2[OH:17])[CH:5]([OH:20])[CH:4]([OH:21])[CH:3]1[OH:22]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)O
Product: OCC1OC(OC2(CO)OC(CO)C(O)C2O)C(O)C(O)C1O
Yield: 75.8 %

Procedure:
In 4 l of dimethylformamide was dissolved 1 kg (2.93 mols) of sucrose at 90° C., followed by addition of 10 g of potassium carbonate and 600 g (2 mols) of methyl stearate, and the mixture was reacted under a reduced pressure of 70-90 mmHg at 90° C. for 3 hours. Then, 8 ml of acetic acid was added and the solvent was removed under reduced pressure. The residue was dissolved in 5 l of methyl ethyl ketone and the solution was washed with 3 portions of water. The methyl ethyl ketone was then removed under reduced pressure and the residue was recrystallized from acetone to provide 950 g of sucrose stearic acid ester.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[NH:39][N:38]=[N:37][N:36]=2)[CH:30]=1)[C:8]1[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[C:16]([OH:23])[C:15]=2[CH2:24][CH2:25][CH3:26])=[CH:10][CH:9]=1>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([CH:7]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[NH:39][N:38]=[N:37][N:36]=4)[CH:30]=3)[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][CH:27]=2)=[C:15]([CH2:24][CH2:25][CH3:26])[C:16]=1[OH:23])(=[O:22])[CH3:21]
Reactant: CCCc1c(OCc2ccc(C(N)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Reactant: CS(=O)(=O)Cl
Product: CCCc1c(OCc2ccc(C(NS(C)(=O)=O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared essentially as described in Example 74 employing methane sulfonyl chloride and 1-[4-(4-{amino-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone to give 22 mg, 28%, as a white solid. 1H NMR (DMSO-d6) δ 12.86 (s, 1H), 8.49 (d, 1H), 8.17 (s, 1H), 7.91-7.94 (m, 1H), 7.80 (d, 1H), 7.60-7.62 (m, 2H), 7.44-7.51 (m, 4H), 6.72 (d, 1H), 5.81 (d, 1H), 5.25 (s, 2H), 2.75 (s, 3H), 2.57-2.62 (m, 5H), 1.46-1.53 (m, 2H), 0.87 (t, 3H). LCMS M+1 536.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=O)[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C(OCC)(=O)C>CCCCCC>[C:7]1(=[O:12])[N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A mixture of β-alanine (89 g) and phthalic anhydride (148 g) was heated at 180° C. to 190° C. for 30 min. The mixture was cooled to 60° C. and ethyl acetate (500 ml) was added, and the mixture was stirred at 0° C. for 1 hr. n-Hexane is added to the reaction mixture and the reactant crystals were collected filteration to afford 219.5 g of 3-phthalimidopropionic acid in colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:34][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:22]5[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:33])[N:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=5)=[N:19][NH:20][CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:32][N:30]([CH3:31])[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[C:17]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:34][C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:1][N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[CH:8][CH:7]=5)=[CH:10][C:11]=34)=[CH:21][NH:20][N:19]=2)=[CH:23][CH:24]=1)=[O:33]
Reactant: C1CCNC1
Reactant: CN(C)C(=O)Nc1ccc(-c2n[nH]cc2-c2ccnc3[nH]c(-c4ccc(C=O)cc4)cc23)cc1
Product: CN(C)C(=O)Nc1ccc(-c2n[nH]cc2-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)cc1

Procedure:
Following the procedure described for Intermediate 101 using N′-(4-{4-[2-(4-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea and pyrrolidine provided the title compound. ESMS [M+H]+: 506.4
Reaction SMILES: C[O:2][C:3]([C:5]1[N:14]=[C:13]2[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)[N:6]=1)=[O:4].CO.O.[Li+].[OH-]>C1COCC1>[Cl:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]3[N:7]([N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:14]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:18]=1
Reactant: COC(=O)c1nc2n(n1)CCOc1cc(Cl)ccc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2n(n1)CCOc1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Methyl-9-chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylate (0.144 g, 0.515 mmol) was dissolved in 3:2:1 THF:MeOH:H2O (5.0 mL), and treated with 4 N aqueous LiOH (0.644 mL). The mixture was stirred for 30 min at 25° C. The reaction was quenched with 1 N aq. HCl (10 mL) and the solution was extracted with EtOAc (3×20 mL). The combined organic extracts were dried with Na2SO4 and concentrated in vacuo to give 9-Chloro-5,6-dihydrobenzo[f][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylic acid (89% yield)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH:11](C(OC)=O)[C:12]([O:14][CH3:15])=[O:13])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[Cl-].[Li+]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]

Procedure:
A solution of dimethyl 2-(4-fluoro-2,6-dinitrophenyl)malonate from Step A (20.5 g, 64.9 mmol) and lithium chloride (5.50 g, 130 mmol) in DMSO (120 mL) and water (2.34 mL) was heated at 90° C. for 3 h, then cooled and poured onto H2O (400 mL). The aqueous layer was extracted with Et2O (3×250 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=259 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1csc(Br)n1

Procedure:
Similarly, 2-bromo-4-t-butylaminocarbonylthiazole is prepared by following the same procedure but using 2-bromo-4-carboxythiazole in place of the 5-position isomer. Similarly, by replacing t-butylamine with the amine reagents set forth in Preparation 2, the corresponding 2-bromo-4- and 5-substituted aminocarbonylthiazoles are respectively prepared.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]([O:13]CC)=O)[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[NH3:16]>CO>[N:1]1[CH:2]=[C:3]([CH2:10][C:11]([NH2:16])=[O:13])[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: CCOC(=O)Cc1cnc2n1CCCC2
Reactant: N
Solvent: CO
Product: NC(=O)Cc1cnc2n1CCCC2
Temperature: 25 °C

Procedure:
Hydrogenate a mixture 2-(imidazo[1,2-a]pyridin-3-yl)acetamide (0.64 gm) and 0.158 gm platinum oxide in 200 mL ethanol saturated with hydrogen chloride at 60 p.s.i. for 2 hours at room temperature. Filter the reaction mixture and concentrate the filtrate under reduced pressure to provide 0.58 gm ethyl 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)acetate. Heat a solution of this ester in 40 mL 2 M ammonia in methanol in a sealed tube at 100° C. for 2 hours. Cool the reaction mixture to room temperature and concentrate under reduced pressure to a volume of about 5 mL. Dilute with ethyl acetate and filter the resulting solid to provide the title compound.
Reaction SMILES: C([Br:3])C.[Mg:4].C12(C([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=O)CC3CC(CC(C3)C1)C2>O1CCCC1>[CH2:20]([Mg:4][Br:3])[CH3:21].[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCBr
Reactant: [Mg]
Reactant: CCCCOC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Product: CC[Mg]Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, a 13% by weight ethylmagnesium bromide-tetrahydrofuran solution was prepared from ethyl bromide and metallic magnesium, and 61.51 g (0.060 mol) of the solution was placed in a flask. To this solution was added dropwise a solution of 4.76 g (0.02 mol) of n-butyl 1-adamantanecarboxylate in 7.21 g of tetrahydrofuran while maintaining the inner temperature not exceeding 35° C., followed by stirring at room temperature for 1 hour.