Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=[N:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 75 °C
Yield: 142.6 %

Procedure:
A mixture of 2-benzyloxy-5-bromobenzaldehyde (20 g) and hydroxylamine hydrochloride (9.55 g) in pyridine (50 ml) was heated at 75° C. for 45 minutes. The solvent was evaporated and the residue purified by chromatography, eluting with dichloromethane, to give 2-benzyloxy-5-bromobenzaldehyde oxime (30 g) (mp 132°-134° C.).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]3[C:26]([F:29])([F:28])[F:27])=[CH:10][C:5]=2[CH2:4][O:3]1.Cl>O1CCOCC1>[F:29][C:26]([F:27])([F:28])[CH:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2](=[O:1])[O:3][CH2:4][C:5]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2)COC3=O)C(C(F)(F)F)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1OCc2cc(CCN3CCNCC3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate (183 mg, 0.44 mmol) in 1,4-dioxane (2 ml) was added 4 N HCl in dioxane (1 mL) and the reaction stirred at room temperature for 12 h. LC-MS shows product formation. The reaction mixture was concentrated in vacuo and dried under high vacuum to provide 5-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}-2-benzofuran-1(3H)-one which was used directly without further purification. LC-MS (IE, m/z): 194.2 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: Cc1nccc(Br)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2-methylpyrimidine in Step 4. LC-MS Method 2 tR=1.159, m/z=450; 1H NMR (CDCl3) 1.33 (m, 3H), 1.52 (m, 3H), 1.63 (m, 3H), 1.80-1.95 (m, 2H), 2.15-2.30 (m, 3H), 2.75 (s, 3H), 2.90 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.99 (m, 4H), 7.20 (m, 2H), 7.41 (m, 1H), 7.79 (d, 2H), 8.60 (m, 1H).
Reaction SMILES: [CH2:1]1[O:17][C:4]2([CH:8]([OH:9])[CH2:7][C:6]3([CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]3)[N:5]2[CH3:16])[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH2:2]1[O:3][C:4]2([CH:8]([O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:7][C:6]3([CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]3)[N:5]2[CH3:16])[O:17][CH2:1]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2(CCC(=O)CC2)CC(O)C12OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2(CCC(=O)CC2)CC(OS(C)(=O)=O)C12OCCO2

Procedure:
To a mixture of 3-hydroxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal (1.0 g), triethylamine (1.73 mL) and methylene chloride (10 mL) was added methanesulfonyl chloride (950 mg) dissolved in methylene chloride (5 mL) in a dropwise fashion at 0° C. After 30 min the reaction mixture was washed with water, the organic layer dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was filtered through silica gel with ethyl acetate as the eluent to afford 3-mesyloxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal as an oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([OH:28])([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[OH:28][C:4]([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:29])=[O:2]
Reactant: COC(=O)C(O)(CC(C)C)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Yield: 93.6 %

Procedure:
A mixture of 430 mg (1.09 mmol) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid methyl ester in 6 ml tetrahydrofuran and of 50.1 mg (1.19 mmol) lithiumhydroxide monohydrate in 3 ml water was stirred overnight at room temperature. The solvent was evaporated and the residue extracted at pH 1 with ethylacetate to yield 390 mg (94%) (R/S)-2-hydroxy-4-methyl-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid, MS (m/e): 381.0 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2].[H-].[Na+].I[CH3:42]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][O:29][CH3:42])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COC)c2)c1CCC(=O)OCC
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.25 g, 2.1 mmol) in DMF (25 mL) were added sodium hydride (211 mg, 5.26 mmol) and iodomethane (747 mg, 5.26 mmol) at room temperature. The resulting suspension was stirred for 15 h and then the excess sodium hydride was quenched by slow addition of water (5 mL). The mixture was diluted with 1.0N hydrochloric acid (50 mL) and the organic compound was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine solution (100 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under vacuum afforded the crude residue which was purified by using an ISCO 40 g column, eluting with 0-30% ethyl acetate in hexanes to obtain 4-[3-[6-(3-bromo-5-methoxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.03 g, 81%) as a colorless viscous oil: EI(+)-HRMS m/e calcd for C31H43BrO7 (M+Na)+ 629.2084. found 629.2085.
Reaction SMILES: [Na].Cl[C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: CO
Agent: [Na]
Product: COc1nc(C)cc(C)c1C#N
Temperature: 70 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Sodium (23 g, 0.99 mol) was added to dry MeOH (800 mL) portion-wise. After the addition, the mixture was stirred for an hour until the sodium was mostly dissolved. To the reaction mixture was added 2-chloro-4,6-dimethylpyridine-3-carbonitrile (110 g, 0.66 mol). The resulting mixture was heated at 70° C. and stirred for four hours. The suspension was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10:1) to give 2-methoxy-4,6-dimethylpyridine-3-carbonitrile (Cpd S, 103 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Br:1]Br.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4]1.C([O-])(=O)C.[Na+].O>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:3][CH:4]=1
Reactant: c1ccc2sccc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Brc1csc2ccccc12

Procedure:
A solution of bromine (20.4 ml, 0.40 mole) in chloroform (100 ml) was added dropwise over 1 hour to a stirred mixture of benzothiophene (53.6 g, 0.40 mole) and anhydrous sodium acetate (54.4 g, 0.68 mole) in chloroform (300 ml) at room temperature. The reaction mixture became much thicker during the addition, so a further 300 ml of chloroform was added to aid stirring. After completing the addition, the reaction mixture was stirred for a further 2 hours and then water added (200 ml) to dissolve the inorganic solid. The chloroform layer was separated and washed with water (1×200 ml), sodium hydrogen carbonate solution (1×200 ml) and brine (1×200 ml); then dried (MgSO4) and evaporated to dryness to give a quantitative yield of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH3:16]
Reactant: C/C(=C\C(N)C(=O)O)CP(=O)(O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O

Procedure:
2.0 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole is saturated with hydrogen chloride gas for 21/2 hours at 50°. After concentration, the residue is dissolved in 20 ml of ethanol, 20 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/ethanol (1:3) yields E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 193°-194°.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=2)[N:11]([C:25](=[O:46])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])=[O:35])=[C:29]([O:44][CH3:45])[CH:28]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:45][O:44][C:29]1[CH:28]=[C:27]([CH2:26][C:25]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)[NH:8][CH2:9][CH2:10]2)=[O:46])[CH:32]=[CH:31][C:30]=1[NH:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH3:43])=[O:35]
Reactant: CCOC(=O)CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 0 °C
Yield: 67.4 %

Procedure:
A solution of 7-(-2-ethoxycarbonyl-ethyl)-4-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (0.3 g, Reference Example 2) in dichloromethane (3 ml), at 0° C., was treated dropwise with trifluoroacetic acid (0.5 ml). After stirring for 2 hours at 0° C. a further portion of trifluoroacetic acid (0.5 ml) was added and stirring was continued for a further hour at 10° C. The reaction mixture was poured on crushed ice (50 ml), the pH of this mixture was adjusted to 8 by dropwise addition of sodium hydroxide (20 ml, 1N) and then the mixture was extracted twice with dichloromethane (25 ml). The combined organic extracts were washed twice with water (5 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting white foamy solid (235 mg) was subjected to flash chromatography on silica (0.040-0.063 mm) eluting with a mixture of dichloromethane and methanol (99:1, v/v) to give the title compound (170 mg) as a white foamy solid. 1H NMR, 300 Hz, (CD3)2SO: δ1.2 (t, 3H); 2.3 (s, 3H); 2.6 (t, 2H); 2.8 (t, 2H); 3.25 (m, 2H); 3.7 (t, 2H); 3.85 (s, 2H); 3.9 (s, 3H); 4.1 (q, 2H); 5.8 (broad s, 1H); 6.4 (dd, J=8 Hz and 1.5 Hz, 1H); 6.5 (d, J=1.5 Hz, 1H); 6.7 (dd, J=8 Hz and 1.5 Hz, 1H); 6.85 (d, J=1.5 Hz, 1H); 7 (ddd, J=8, 8 and 1.5 Hz, 1H); 7.2 (m, 3H); 7.7 (broad d, J=8 Hz, 1H); 8 (d, J=8 Hz, 1H); 8.25 (s, 1H); 8.35 (s, 1H). MS (CI, NH3): MNH4+ 548, MH+ 531.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1)#[N:2].[CH3:32][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:32])=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
The reaction was carried out under argon. (4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (5.0 g, 11.7 mmol) was initially charged in absolute THF (500 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (13.5 ml, 13.5 mmol, 1.15 eq.) was added at −78° C. After 30 min of stirring, iodomethane (8.30 g, 58.5 mmol; 5 eq.) in THF was added, and the mixture was stirred with gradual warming from −78° C. to RT for 16 h. The reaction mixture was then concentrated under reduced pressure, and initially 1N hydrochloric acid (14.0 ml), and then MTBE (500 ml) were added. The organic phase was washed successively with water (2×), saturated sodium bicarbonate solution, saturated ammonium chloride solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (4.3 g, 83% of theory).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].O>C(Cl)Cl>[F:1][CH2:2][CH2:3][CH2:4][O:5][S:7]([CH3:6])(=[O:9])=[O:8]
Reactant: OCCCF
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCF
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
A solution of 3-fluoro-propan-1-ol (31.2 g, 400 mmol) in 300 mL of CH2Cl2 was treated with methanesulfonyl chloride (55 g, 38 mL, 480 mmol, 1.2 equiv) at 0° C. The resulting reaction mixture was gradually warmed to room temperature and stirred for 1-2 hours. When 1H NMR showed the reaction was complete, the reaction mixture was treated with H2O (100 mL), and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with H2O (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the desired methanesulfonic acid 3-fluoro-propyl ester (57.2 g, 91% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([O:18]C)=[O:17])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25].[OH-].[K+]>C1COCC1.CO>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([OH:18])=[O:17])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-methylbenzoate (15-4) (550 mg, 1.5 mmol, 1.0 eq.) was dissolved in THF (2.5 mL)/MeOH (2.5 mL) and potassium hydroxide (340 mg, 6.0 mmol, 4.0 eq.) was added. The mixture stirred overnight at ambient temperature. Upon completion, the reaction mixture was concentrated and 1N HCl was added. The mixture was then extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered and concentrated to afford 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-methylbenzoic acid (55-1) as a white solid. MS (M+H)+: observed=354.0, calculated=354.2.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH2:15][NH:16][C@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@H:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[N:11]([CH3:29])[C:10](=[O:30])[CH2:9][CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:38]1[O:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>O1CCOCC1>[O:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[N:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([NH:16][CH2:15][C:14]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][C:10](=[O:30])[N:11]3[CH3:29])=[CH:6][C:5]=2[O:4][CH3:3])[C@@H:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1CN[C@H]1CCCN(c3nc4ccccc4o3)[C@H]1c1ccccc1)N(C)C(=O)CC2
Yield: 56.7 %

Procedure:
To 6-Methoxy-1-methyl-7-[(2S,3S)-(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one dihydrochloride (50 mg, 0.11 mmol), freshly ground potassium carbonate (61 mg, 0.44 mmol), and catalytic KI in 3 mL of 1,4-dioxane was added 2-chlorobenzoxazole (126 mg, 0.11 mmol). After heating at reflux for 5 days, the reaction was cooled and partitioned between ethyl acetate and water. The organic portion was separated, dried over MgSO4, filtered, and concentrated. Silica gel chromatography (99:1 chloroform/methanol followed by 3:1 ethyl acetate/hexane) gave 31 mg (56%) of the title compound as a light brown oil. MS (M+H)+=497.2; 1H NMR (400 MHz, CDCl3): δ 1.75–1.85 (m, 1H), 1.85–1.95 (m, 3H), 2.55–2.60 (t, J=7 Hz, 2H), 2.80–2.85 (t, J=7 Hz, 2H), 3.15–3.25 (m, 1H), 3.30 (s, 3H), 3.30–3.40 (t, J=13 Hz, 1H), 3.71 (s, 3H), 3.82–3.92 (q, J=13.5 Hz, 2H), 4.16–4.21 (dd, J=13 Hz, 3.8 Hz, 1H), 5.74–5.76 (d, J=5.6 Hz, 1H), 6.62 (s, 1H), 6.90 (s, 1H), 6.95–6.99 (t, J=8.5 Hz, 1H), 7.10–7.14 (t, J=8.5 Hz, 1H), 7.19–7.21 (d, J=7.9 Hz, 1H), 7.24–7.28 (m, 4H), 7.68–7.70 (d, J=7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 24.2, 25.5, 26.8, 29.6, 31.7, 41.4, 46.0, 55.5, 56.9, 58.5, 108.5, 110.2, 116.0, 116.4, 120.3, 123.8, 125.7, 126.8, 127.5, 128.3, 129.3, 133.7, 137.7, 143.2, 148.5, 152.9, 162.3, 169.9. The dihydrochloride salt was prepared by the addition of 2 M HCl in ether to a solution of the product in ethyl acetate. Concentration gave a white solid (Mp=181–183° C.).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:17]>ClCCl>[O:17]1[CH2:3][CH:2]1[CH2:1][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 28.9 g (184 mmol) of tert-butyl allylcarbamate in 400 mL of dichloromethane was added 103 g (460 mmol) of 77% 3-chloroperoxybenzoic acid at room temperature. The reaction mixture was stirred at room temperature overnight. The solid was filtered and the filtrate was concentrated. The residue was taken up in diethyl ether and washed with 5% sodium hydrosulfite (3×), saturated sodium bicarbonate (3×), brine (3×), and dried over anhydrous magnesium sulfate. Removal of solvent gave 21 g (66%) of tert-butyl 2-oxiranylmethylcarbamate as a liquid. 1H-NMR (400 MHz, CDCl3): δ 4.73 (br s, 1H), 3.53 (br s, 1H), 3.21 (m, 1H), 3.08 (br s, 1H), 2.77 (t, J=4 Hz, 1H), 2.58 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Nc1ccccc1O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A flask with a stirrer was charged with 5.46 g of 2-aminophenol, 5.05 g of triethylamine and 100 ml of tetrahydrofuran, and a solution of 10.55 g of 4-chlorobenzenesulfonyl chloride in 20 ml of tetrahydrofuran was dropwise added with cooling with ice over 10 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethanol/n-hexane mixed solvents, to give 8.9 g of an end product. Melting point 82° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[C:8]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=3)(=[O:35])=[O:34])=[N:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1cccc2snc(NCCCN)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2snc(NCCCNS(=O)(=O)c3cccc(C(F)(F)F)c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
N1-(4-methylbenzo[d]isothiazol-3-yl)propane-1,3-diamine (100 mg, 0.45 mmol) was dissolved in anhydrous methylene chloride with diisopropylethylamine (0.12 mL, 0.63 mmol). The mixture was cooled in an ice-bath under nitrogen and a solution of 3-trifluoromethylbenzenesulfonyl chloride (0.09 mL, 0.54 mmol) in methylene chloride (5 mL) was added drop-wise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield N-(3-(4-methylbenzo[d]isothiazol-3-ylamino)propyl)-3-(trifluoromethyl)benzenesulfonamide (23 mg). 1H NMR (300 MHz, DMSO-d6): 7.75 (d, 1H), 7.30 (m, 2H), 7.25 (m, 2H), 6.92 (t, 1H), 6.28 (t, 1H), 3.22 (t, 2H), 2.98 (t, 2H), 2.81 (s, 3H), 2.15 (t, 2H), 1.80 ppm (m, 2H). MW=429 confirmed by LC-MS, tr=3.92 min (Method E) MH+=430.