Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[O:32][N:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:37])[O:32][N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c2cc1OC
Yield: 68 %

Procedure:
The title compound was prepared as described in Example 113C by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline described in Example 117B (102 mg, 0.3 mmol) and phenyl 3-tert-butylisoxazol-5-ylcarbamate described in Example 132A (101 mg, 0.39 mmol) to give 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (103 mg, 68%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H), 7.58 (s, 2H), 7.42 (t, 2H), 7.30 (d, 1H), 6.99 (d, 1H), 6.04 (s, 1H), 4.34 (bs, 2H), 3.99 (s, 3H), 3.77 (bs, 2H), 3.36 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].[H-].[Na+]>O1CCCC1.CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:34])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NS(C)(=O)=O)c3ccccn3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (4.5 mmol) of 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide and 0.73 g (4.7 mmol) of carbonyldiimidazole were dissolved in 80 ml of tetrahydrofuran and 5 ml of dimethylformamide and stirred for 30 minutes at ambient temperature and for 2 hours at 90° C. In parallel 0.55 g (5.8 mmol) of methansulphonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 ml of dimethylformamide and stirred for 2 hours at ambient temperature. Then this suspension was added at ambient temperature to the tetrahydrofuran solution. After 12 hours at ambient temperature 50 ml of water were added and the pH value was adjusted to 6.8. The solution was extracted 4× with methylene chloride, the combined organic phases were dried over sodium sulphate and evaporated down. The crude product was chromatographed on silica gel (methylene chloride/ethanol (40:1)). The desired fractions were combined and evaporated down. Yield: 1.05 g (44% of theory), C26H25N7O4S (531.6) Rf value: 0.72 (silica gel; dichloromethane/methanol=9:1)
Reaction SMILES: CC(C)([O-])C.[K+].CN(C)C=O.[N+:12]([CH3:15])([O-:14])=[O:13].N(CN[C:20]1[CH2:21][C:22](=[O:37])[N:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=O>O.C(O)(=O)C>[C:31]1([N:23]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[NH:26][C:20](=[CH:15][N+:12]([O-:14])=[O:13])[CH2:21][C:22]2=[O:37])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[N+](=O)[O-]
Reactant: O=NCNC1=Nc2ccccc2N(c2ccccc2)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(=C[N+](=O)[O-])Nc2ccccc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide, 3.15 g (0.0281 moles) was added to a mixture of 70 ml of dimethylformamide and 14 ml of nitromethane. After stirring for 30 min at room temperature under nitrogen, 6.9 g (0.0234 moles) of 3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one, was added and stirring was continued for 48 hours. The mixture was acidified with acetic acid and diluted with water. The precipitate was collected, washed with water and recrystallized from methylene chloride/ethanol to yield end product with mp 231°-234°. Recrystallization for analysis from the same solvents raised the melting point to 233°-235°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:20]([N:23]([C:27]2[CH:31]=[CH:30][S:29][C:28]=2[C:32]([O:34][CH3:35])=[O:33])COC)(=[O:22])=[O:21])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:20]([NH:23][C:27]2[CH:31]=[CH:30][S:29][C:28]=2[C:32]([O:34][CH3:35])=[O:33])(=[O:21])=[O:22])=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1-c1ccc(N(C)C)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1-c1ccc(N(C)C)cc1
Temperature: 75 °C
Yield: 35.9 %

Procedure:
To a solution of 13 (150.0 mg; 0.30 mmol) in tetrahydrofuran (6 mL) was added aqueous hydrochloric acid (1.0 mL; 2.0 mmol; 2N). The reaction mixture was heated at 75° C. for 4 hours, and then additional aqueous hydrochloric acid (3.0 mL; 6N) was added and the reaction mixture further heated at reflux for 4-5 hours. The reaction mixture was allowed to cool to room temperature and then extracted with ethyl acetate (15 mL). The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting white solid residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) to give the title product as a clear oil (50.9 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][NH:20]2)=[CH:16][CH:15]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:22]=3)[CH2:18][CH2:19]2)[N:3]=1
Reactant: FC(F)(F)c1ccc2c(c1)NCC2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: FC(F)(F)c1ccc2c(c1)N(c1nc(Cl)nc3[nH]cnc13)CC2
Reaction time: 23 h
Yield: 92.4 %

Procedure:
756 mg of 2,6-dichloropurine, 8 ml of butanol and 897 mg of 6-(trifluoromethyl)indoline are mixed and brought to a temperature of 90° C. for approximately 23 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum at 50° C. are carried out, and 1.256 g of expected product are obtained, in the form of beige crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[F:14][C:15]1[CH:22]=[C:21](F)[C:20]([F:24])=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:14][C:15]1[CH:22]=[C:21]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([C:10]([F:11])([F:12])[F:13])[CH:4]=2)[C:20]([F:24])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(OCc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)-benzylalcohol (0.27 g, 1.28 mmol) and 2,4,5-trifluorobenzonitrile (0.2 g, 1.28 mmol) in DMSO (5 mL) was added potassium carbonate (0.33 g, 0.25 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between water (15 mL) and EtOAc (20 mL). The organic layer was separated, dried over magnesium sulphate, filtered and evaporated to yield the title compound (0.43 g, 97%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([CH:10]4[CH2:11][CH2:12][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:8][CH2:9]4)=[O:14])[CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)N3CCNCC3)cc2)cc1
Product: Cc1ccc(-c2ccc(S(=O)(=O)N3CCN(C(=O)C4CCN(c5ccncc5)CC4)CC3)cc2)cc1
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-(4′-methylbiphenyl-4-ylsulphonyl)piperazine to give 1-(4′-methylbiphenyl-4-ylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 67% yield, m.p. 213-217° C.;
Reaction SMILES: C([O:3][C:4]([C:6]1[S:16][C:9]2[NH:10][C:11](=[O:15])[C:12](=[O:14])[NH:13][C:8]=2[C:7]=1[CH2:17][CH3:18])=[O:5])C.[OH-].[Na+].Cl.O>O1CCCC1>[C:4]([C:6]1[S:16][C:9]2[NH:10][C:11](=[O:15])[C:12](=[O:14])[NH:13][C:8]=2[C:7]=1[CH2:17][CH3:18])([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc2[nH]c(=O)c(=O)[nH]c2c1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)sc2[nH]c(=O)c(=O)[nH]c12
Temperature: 0 °C
Yield: 65 %

Procedure:
A mixture of 6-ethoxycarbonyl-7-ethylthieno[2,3-b]-pyrazine-2,3(1H,4H)-dione (24.5 g, 91 mmol) and sodium hydroxide (10.96 g, 274 mmol) in 50% aqueous tetrahydrofuran (340 ml) was heated at 50°-60° C. for 16 h. The reaction mixture was cooled to 0° C. and acidified (pH=2) with hydrochloric acid. Water (300 ml) was added, the precipitate filtered off, washed with water and dried. Purification was performed by dissolving in 2 M sodium hydroxide solution, extraction with dichloromethane and precipitation of the aqueous phase with hydrochloric acid. The precipitate was filtered off, washed with water and dried to afford 14.2 g (65%) of the title compound. M.p. 230°-232° C. 1H-NMR (DMSO-d6, δ) : 1. 09 (t, 3H) 3.03 (q, 2H), 11.90 (s, 1H), 12.50 (br. s, 1H), 12.92 (br. s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23]COC)=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:29][CH3:30])[C:4]1=[O:5])[CH3:2].Cl.[OH-].[Na+].O>O1CCCC1>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:29][CH3:30])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCOC)c(OC)c3)n2C)n(CC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(OC)c3)n2C)n(CC)c1=O
Yield: 80.5 %

Procedure:
Compound o (1.50 g, 3.62 mmol) obtained in Reference Example 14 was suspended in tetrahydrofuran (30 ml), and 2N HCl (9 ml) was added thereto, followed by heating under reflux for one hour. The reaction mixture was neutralized with a 2N aqueous solution of sodium hydroxide under ice-cooling, and water was added thereto. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 1.08 g (yield 81%) of Compound p as yellow plates.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1=C(COCCNCC(=O)OC)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 40.7 %

Procedure:
A solution of methyl bromoacetate (1.53 g) in acetonitrile (20 ml) was added dropwise over 30 minutes to a stirred, refluxing mixture of 2-[(2-aminoethoxy)methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (5.01 g) and potassium carbonate (2.76 g) in acetonitrile (60 ml). The mixture was then heated under reflux for 3 hours, filtered, and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (Na2SO4), and evaporated. The residue was chromatographed on silica (t.l.c. grade Merck Kieselgel 60H, [Trade Mark] 40 g) eluting with dichloromethane plus 0-3% methanol. Appropriate fractions were combined and evaporated to give the title compound (2.10 g), m.p. 96°-98°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29](=[O:31])[CH3:30].[Cl-].[NH4+]>C(#N)C>[CH2:28]([O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:20])=[C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])[CH:6]=1)[C:29]([CH3:30])=[O:31]
Reactant: CC(=O)CCl
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)COc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Yield: 70.9 %

Procedure:
An acetonitrile (10 mL) solution of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.59 g, 2.0 mmol), potassium carbonate (0.2 g, 2.2 mmol) and chloroacetone (0.18 mL, 2.2 mmol) was stirred for 5 hours under reflux. A saturated ammonium chloride solution (10 mL) was added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (10 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/2) to obtain a white solid of 2-(5-acetonyloxy-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [l,5-a] pyridine-1, 3[2H, 7H]-dione (0.50 g, yield:70.4%).
Reaction SMILES: [C:1]1([S:7]([N:10]([C:20]2[O:24][N:23]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]=2[Br:29])S(C2C=CC=CC=2)(=O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[Br:29][C:21]1[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[N:23][O:24][C:20]=1[NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: CC(C)(C)c1noc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1noc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
N-Benzenesulfonyl-N-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide (80 mg, 0.16 mmol) was dissolved in methanol (2 ml). Sodium hydroxide (0.120 g, 3.0 mmol) in methanol was added and the solution was stirred at 45° C. for 20 min. Methanol was removed under reduced pressure. The residue was dissolved in water, cooled to 0° C. and acidified to pH 3-4 with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide in 94% yield. Further purification was achieved by recrystallization from methanol/water, giving an off white solid, m.p. 108-109° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[N:18]1([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:29][CH2:28]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1>>[N:18]1([CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: NCCCCN1CCC(n2nnc3ccccc32)CC1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC(n2nnc3ccccc32)CC1

Procedure:
Batch size: 3.1 g (22.5 mmol) 3-(3-pyridyl)-acrylic acid, 5.4 ml (45 mmol) oxalyl chloride and 5.6 g (20.5 mmol) 4-(4-benzotriazol-1-yl-piperidin-1-yl)-butylamine.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[S:10]1[C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=5)[CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9]1
Reactant: COc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: BrCCc1ccc2ncsc2c1
Product: COc1ccc2c(c1)N(C1CCN(CCc3ccc4ncsc4c3)CC1)CC2
Yield: 82.6 %

Procedure:
6-(2-Bromoethyl)benzothiazole (0.108 g) and 1-(piperidin-4-yl)-6-methoxyindoline (0.105 g) were treated as in Example 2 to give the title compound (0.145 g) as a yellow oil (yield: 81.9%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])=[C:27]3[C:22]([NH:23][C:24]([CH3:42])([CH3:41])[C:25](=[O:40])[N:26]3[CH3:39])=[CH:21][CH:20]=2)=[C:15]([O:43][CH3:44])[CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:45]>O1CCOCC1.CCCCCC>[ClH:45].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])=[C:27]3[C:22]([NH:23][C:24]([CH3:42])([CH3:41])[C:25](=[O:40])[N:26]3[CH3:39])=[CH:21][CH:20]=2)=[C:15]([O:43][CH3:44])[CH:14]=1)=[O:11]
Reactant: COc1cc(NC(=O)CNC(=O)OC(C)(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COc1cc(NC(=O)CN)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
7-(4-tert-Butoxycarbonylaminoacetylamino-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 15-31, 10.5 mg, 0.0173 mmol) was dissolved in 1,4-dioxane (0.2 mL), 4N 1,4-dioxane solution of hydrochloride (41.3% L. 0.165 mmol) was added thereto. After the reaction mixture was stirred for 4 hours at room temperature, it was diluted with hexane (10 mL). The precipitated solid was filtered to give the titled compound (7.8 mg) as a pale yellow solid. (Yield 83%)
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[N:35][C:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48](O)=[O:49])[CH:46]=3)[C:41]([S:51]([CH3:53])=[O:52])=[CH:40]2)=[N:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[N:35][C:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]4[CH3:19])=[O:49])[CH:46]=3)[C:41]([S:51]([CH3:53])=[O:52])=[CH:40]2)=[N:37][CH:38]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: C[C@H]1COCCN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COCCN1C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Reaction time: 8 h

Procedure:
T3P (50 wt % solution in ethyl acetate, 179 μl, 0.304 mmol) was added to a solution of (S)-3-methylmorpholine (46 mg, 0.456 mmol) and 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid (60 mg, 0.152 mmol) in dichloromethane (3 mL) at room temperature and the mixture was stirred overnight. 1 M sodium carbonate solution (20 mL) was poured into the reaction mixture and stirring was continued for 1 h. The mixture was extracted with dichloromethane (3×) and the combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography [dichloromethane with 0-5% ethanol]. White foam. Yield: 68 mg (93% of theory).
Reaction SMILES: [CH3:1][C:2]1([NH:14]C(=O)OC(C)(C)C)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1([NH2:14])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(c2cnccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(N)CCN(c2cnccn2)CC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl [4-methyl-1-(2-pyrazinyl)-4-piperidinyl]carbamate obtained in Example 10-6 (508 mg) in dichloromethane (1 mL), was added trifluoroacetic acid (5 mL), and the mixture was stirred for 30 minutes at 20° C. The resulting mixture was evaporated in vacuo. The residue was neutralized with sodium hydrogencarbonate and extracted with chloroform three times. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the title compound as a pale yellow solid (281 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 57.8 %

Procedure:
Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.731 g, 4.49 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.181 mL, 4.49 mmol) dissolved in water (2 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.247 mL, 4.49 mmol) was added dropwise and stirring continued for 3 h. The mixture was then transferred to a prewarmed 80° C. solution of 6 M hydrogen chloride (23.18 mL, 139.09 mmol) and stirring was continued at 80° C. for 20 min. The solvent was evaporated and DCM (200 mL) and water (200 mL) were added. The phases were shaken, separated and the organic phase dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.921 g, 57.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.79-1.87 (m, 1H), 2.06-2.15 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.37 (m, 1H), 3.00-3.09 (m, 1H), 3.31-3.40 (m, 1H), 3.66 (s, 3H), 4.07-4.16 (m, 1H), 5.00-5.07 (m, 1H), 5.56 (s, 1H), 6.87-6.91 (m, 1H), 6.95 (dd, 1H), 7.29 (t, 1H). MS m/z 355 (M+H)+