Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH:14]([CH3:25])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[ClH:26].[ClH:26].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH3:25])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC1CN(Cc2cc(N)cc3ccoc23)CCN1C(=O)OC(C)(C)C
Product: CC1CN(Cc2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CCN1
Product: Cl
Yield: 75.2 %

Procedure:
The title compound was prepared according to the procedure of Example 115, Step 4, starting from tert-butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-2-methylpiperazine-1-carboxylate (41 mg crude starting material, 0.11 mmol; obtained in Example 115, Step 3) and 2-chlorobenzenesulfonyl chloride (22 μL, 0.17 mmol). The title compound (21 mg, 39%) was obtained as an off-white solid. HPLC 100%, RT=1.42 min (System A; 10-97% MeCN over 3 min), 100%, RT=1.26 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 1.41 (d, J=6.53 Hz, 3H) 3.32-3.37 (m, 1H) 3.45-3.59 (m, 2H) 3.63-3.76 (m, 3H) 3.78-3.89 (m, 1H) 4.70 (s, 2H) 6.86 (d, J=2.26 Hz, 1H) 7.36-7.41 (m, 1H) 7.42 (d, J=2.01 Hz, 1H) 7.49-7.54 (m, 1H) 7.54-7.58 (m, 2H) 7.86 (d, J=2.01 Hz, 1H) 8.02 (dd, J=7.91, 1.63 Hz, 1H). MS (ESI+) for C20H22ClN3O3S m/z 420 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[C:4]([O:22][CH:23]([F:25])[F:24])[CH:3]=1.Cl.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([F:46])=[CH:30][N:29]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[F:25][CH:23]([F:24])[O:22][C:4]1[CH:3]=[C:2]([NH:1][C:28]2[N:33]=[C:32]([NH:34][C@@H:35]3[CH2:43][C@H:42]4[N:38]([CH2:39][CH2:40][CH2:41]4)[C:37]([CH3:44])([CH3:45])[CH2:36]3)[C:31]([F:46])=[CH:30][N:29]=2)[CH:21]=[CH:20][C:5]=1[O:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2OC(F)F)CC1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OC4CCNCC4)c(OC(F)F)c3)ncc2F)C[C@@H]2CCCN21
Yield: 58.3 %

Procedure:
The general displacement procedure described herein was used with tert-butyl 4-(4-amino-2-(difluoromethoxy)phenoxy)piperidine-1-carboxylate (113 mg, 0.3 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (106 mg, 0.3 mmol) and pTsOH.H2O (42 mg, 0.2 mmol) in IPA (3 mL) at reflux to give the product (91 mg, 55% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 85:15) as eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:34])[C:17]([C:18]3[S:19][C:20]([C:29]4[NH:33][CH:32]=[N:31][N:30]=4)=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:34])[C:17]([C:18]3[S:19][C:20]([C:29]4[N:33]=[CH:32][N:31]([CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][O:35]5)[N:30]=4)=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn2ccc(OCc3ccccc3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 60 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A mixture of 5-(benzyloxy)-2-methyl-3-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridine (440 mg, 0.94 mmol) produced in Example 30-B(x), 3,4-dihydro-2H-pyran (0.17 mL, 1.9 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) and tetrahydrofuran (10 mL) was stirred at 60° C. for 1 day. The reaction mixture was concentrated under reduced pressure, aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0). The obtained solution was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give 5-(benzyloxy)-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridine (430 mg, 84%) as a colorless solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1Cl

Procedure:
110 mg (72%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.289 mmol), 1-(3,4-dichlorophenyl)piperazine (67 mg, 0.289 mmol), DIPEA (0.076 mL, 0.434 mmol) and NaBH(OAc)3 (184 mg, 0.868 mmol).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.[F-:13].[K+]>C(#N)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([F:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)F)cc1

Procedure:
A 25.0 gm (0.13 mole) portion of p-toluenesulfonyl chloride was dissolved in 100 ml of acetonitrile and combined in a 250 ml round bottom flask with 25.0 ml of water containing 1.5 gm (0.196 mole) of potassium fluoride. This mixture was stirred and heated under reflux for one hour. Acetonitrile was then removed under reduced pressure in a rotary evaporator. This resulted in crystallization of p-toluenesulfonyl fluoride which was removed by filtration, washed twice with water, and dried, giving 20.7 gm (91% yield) of product with mp 41°-41.2° C; (literature is 41°-42° C; W. Davies and J. H. Dick, J. Chem. Soc., 2104, 1931). The NMR and IR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[CH3:14])=[C:9]([CH:11]=1)[NH2:10])(=[O:4])=[O:3].[H][H]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([CH:11]=1)[NH2:10])(=[O:3])=[O:4]
Reactant: C/C=C/c1ccc(S(C)(=O)=O)cc1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc(S(C)(=O)=O)cc1N

Procedure:
A mixture of 5-(methylsulfonyl)-2-[(1E)-prop-1-en-1-yl]aniline (Intermediate 60; 1.50 g; 6.84 mmol) and 10% Pd/C (196 mg) in MeOH (39 ml) was placed in a PARR reactor and treated with a pressure of 20 atm of hydrogen for 3 hours.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].O>C(OCC)(=O)C>[C:18]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(C)c1ccccc1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(C)C
Reaction time: 1 h

Procedure:
2-Isopropylphenol (5.0 kg, 36.7 mol) is dissolved in ethyl acetate (20.8 L) and to this is added triethylamine (4.48 kg, 44.1 mmol). This solution is cooled to -12° and to this is added acetyl chloride (3.15 kg, 40.2 tool) over a period of 2.5 hours keeping the temperature below -10°. Triethylamine hydrochloride precipitates immediately. After the addition is complete stirring is continued for 1 hour at 15° at which time a solid mass is formed. This is dissolved by the addition of water (12L). After separation of the layers the organic layer is further washed with water (233 12L) and evaporated in vacuo (50°, 2 Torr) and then at 70°, 2 Torr to give 2-isopropyl-phenyl acetate as a residual amber oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][S:13]([CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][CH2:24][C:25]1[C:33]2[S:32][C:31](=[O:34])[NH:30][C:29]=2[C:28]([OH:35])=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O>[OH:35][C:28]1[C:29]2[NH:30][C:31](=[O:34])[S:32][C:33]=2[C:25]([CH2:24][CH2:23][NH:22][C:18](=[O:20])[CH2:17][CH2:16][S:13]([NH:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:14])=[O:15])=[CH:26][CH:27]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(O)CCS(=O)(=O)NCCOCCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCS(=O)(=O)NCCOCCc1ccccc1)NCCc1ccc(O)c2[nH]c(=O)sc12
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
A solution of the product from step b) (3.89 g), 7-(2-aminoethyl)4-hydroxy-1,3-benzothiazol-2(3H)-one hydrochloride (3.22 g), bromotripyrrolidinophosphonium hexafluorophosphate, PyBroP, (6.32 g) in dimethylformamide (50 ml) was cooled to -15° C. and diisopropylethylamine (9.0 ml) was added dropwise over 5 minutes. The solution was stirred at -15° C. for 5 min then allowed to warm to 13° C. over 4 hours. This mixture was then added dropwise over 40 min to dilute hydrochloric acid (2N, 500 ml) and after stirring over the weekend the solid was collected by filtration. This solid was dried in vacuo to give the subtitle compound (4.5 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>FC1C=C(C=CC=1)CN.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH2:26][C:4]4[CH:5]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: NCc1cccc(F)c1
Solvent: CCO
Product: O[C@H](CNCc1cccc(F)c1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 3-fluorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=411.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@@H:9](OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@H:24]1[CH2:30][S:29][CH:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH2:27][N:26]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25]1=[O:44].C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([O:12][C:10]([C@@H:9]([NH:23][C@H:24]1[CH2:30][S:29][CH:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH2:27][N:26]([CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:25]1=[O:44])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SC[C@H](N)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A solution of 4.0 g of ethyl 4-phenyl-2-(R)-trifluoromethanesulfonyloxybutyrate in 15 ml of methylene chloride was added dropwise to a solution of 4.0 g of t-butyl α-[6(R)-amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] and 1.62 ml of triethylamine in 50 ml of methylene chloride. The reaction mixture was stirred for 2 hours at room temperature, after which it was washed with water and dried over anhydrous magnesium sulfate; the solvent was then evaporated off under reduced pressure. The residue was purified by silica gel column chromatography, using a 20:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 5.5 g of the title compound in the form of a syrup.
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:18][C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].OO.C(O)(=[O:23])C.[OH2:25]>>[CH2:1]([S:7]([C:8]1[S:18][C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)(=[O:23])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O
Reactant: CC(=O)O
Reactant: CCCCCCSc1nn2c(=O)cc(C)nc2s1
Agent: OO
Product: CCCCCCS(=O)(=O)c1nn2c(=O)cc(C)nc2s1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A mixture of 6.1 g of 2-hexylthio-7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 9.1 g of a 30% hydrogen peroxide solution and 14 ml of acetic acid was heated to 65°-75° C. and stirred for 2 hours and 15 minutes. After cooling, water was added to the mixture and the resulting mixture was extracted with chloroform. The organic layer was washed with a sodium thiosulfate and water respectively, and dried over anhydrous sodium sulfate anhydrate. The solvent was distilled off. The residue was recrystallized from ethanol and thus 3.2 g of 2-hexanesulfonyl-7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 111°-115° C. Yield 45%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])OC(C)(C)C)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:21][O:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[C:31](=O)C(OCC)=O.[NH4+].[Cl-:39]>CCOCC.CCCCC.C1COCC1>[Cl:39][C:31]1([C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:23]=2[O:22][CH3:21])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:9]1=[O:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)c1cccc(OC)c1OC
Reactant: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: COc1cccc(C2(Cl)C(=O)Nc3ccc(Cl)cc32)c1OC
Temperature: -40 °C
Reaction time: 3 h

Procedure:
A mixture of 11.4 g of tert-butyl 4-chlorophenylcarbamate in 100 ml of ether is cooled to −40° C., under an atmosphere of dry nitrogen, 80 ml of a 1.5 M solution of tert-butyllithium in pentane are added dropwise and the mixture is stirred at −20° C. for 3 hours. The reaction mixture is cooled to −40° C., a solution of 14 g of the compound obtained in step A in 50 ml of THF is added over one hour and the mixture is stirred for 4 days at RT. The reaction mixture is poured into saturated NH4Cl solution and the precipitate formed is spin-filtered off and dried. 10.2 g of the expected product are obtained and are used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[N:11]([C@H:22]([C:24]3[CH:41]=[CH:40][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:42][C:43]([F:59])([F:58])[O:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50](B(O)O)[CH:49]=[CH:48]2>C(COC)OC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:50]3[CH:49]=[CH:48][C:47]4[C:52](=[CH:53][CH:54]=[C:45]([O:44][C:43]([F:42])([F:59])[F:58])[CH:46]=4)[CH:51]=3)[N:11]([C@H:22]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:40][CH:41]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[C@@H](c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc2cc(OC(F)(F)F)ccc2c1
Solvent: COCCOC
Product: C[C@@H](c1ccc(C(=O)NCCC(=O)O)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2cc(OC(F)(F)F)ccc2c1
Temperature: 100 °C

Procedure:
tert-Butyl N-{4-[(1S)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoyl}-β-alaninate (10 mg, 0.016 mmol), 6-trifluoromethoxy-2-naphthylboronic acid (5.1 mg, 0.02 mmol), and TEA (14 ul, 0.1 mmol) were dissolved in dimethoxyethane (0.5 ml) and deoxygenated by vacuum-N2 fill cycles. The catalyst Pd(PPh3)4 (2 mg, 10% mol) was added and the mixture was deoxygenated again before heated in microwave reactor to 100° C. for 10 min. The mixture was quenched with 1.5 ml of CH3CN:H2O (3:1, with 5% TFA) and product separated through reverse phase preparative HPLC. The collected product was treated with 1 ml of TFA-DCM (1:2) for 30 min, and the residue lyophilized to give N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine as fine powder. NMR (500 MHz, DMSO-d6) δ: 1.91 (d, J=7.0 Hz, 3H); 2.46 (t, J=7.0 Hz, 2H); 3.41 (q, J=7.0 Hz, 2H); 5.78 (q, J=7.0 Hz, 1H); 7.21 (d, J=8.4 Hz, 2H); 7.22 (s, 1H); 7.57 (t, J=1.9 Hz, 1H; 7.58˜7.60 (m, 2H); 7.72 (d, J=8.4 Hz, 2H); 7.94 (d, J=1.9 Hz, 2H); 8.04 (br s, 1H); 8.06 (br s, 1H); 8.09 (d, J=9.1 Hz, 1H); 8.13 (d, J=8.6 Hz, 1H); 8.44 (t, J=5.5 Hz, 1H). MS C32H24Cl2F3N3O4 Cald: 641.11; Obsd (M+1): 642.22.
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([CH3:24])=[CH2:23])=[CH:20][CH:19]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:22]([C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)([CH3:24])[CH2:23][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)C1

Procedure:
The compound of Example 6 (1.0 gm) was converted to the title compound (0.6 gm) by adaptation of the procedure of Example 9 to 4-chloro-α-methyl styrene (2.5 ml). The product was a yellow oil. NMR (CDCl3) 7.3-6.8 (m, ArH, 8H), 4.3 (q, 2H, CH2), 3.3 (m, 2H, CH2), 1.8 (s, 3H, CH3), 1.3 (t, 3H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([O:30]C)=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:23]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([OH:30])=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(S(C)(=O)=O)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)quinoxaline-6-carboxylate (100 mg, 0.22 mmol) in methanol (10 ml) was added NaOH (36 mg, 0.9 mmol) and water (1 ml). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (25.0 mg, 25%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:18])([CH2:16][CH3:17])[C:11]2=[O:19])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:18])([CH2:16][CH3:17])[C:11]2=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: CCC1(C)CC(=O)N(c2cccc([N+](=O)[O-])c2)C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC1(C)CC(=O)N(c2cccc(N)c2)C1=O

Procedure:
Seventy-four g. of N-m-nitrophenyl-2-methyl-2-ethylsuccinimide, as prepared in Example VI, was added portion wise to 60 g. of iron powder, 4 ml. of concentrated HCl, 200 ml. of ethanol and 160 ml. of water at reflux. When addition was complete and the temperature had fallen to 70° C., the mixture was treated with 4 g. of 50% NaOH and filtered immediately. The filtercake was washed with hot ethyl alcohol and the filtrate stripped under vacuum. The product which crystallized on removal of the ethyl alcohol weighed 49 g. when dry and had a m.p. of 100°-102° C. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:13])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C(Cl)Cl.CO>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([F:13])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)c(F)cc1N
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(OC)c(N)cc1F
Reaction time: 0.5 h

Procedure:
To an amount of 4-amino-2-fluoro-5-methoxybenzoic acid (4 g, 21.62 mmole) that was dissolved in DCM (40 ml) and MeOH (11 mL), was added TMS-diazomethane (16.2 mL, 32.43 mmole) slowly. The mixture was stirred at r.t for 30 mins. After the removal of solvent, the resulting tan solid (4.0 g, 93%) carried onto the next reaction without any purification. [M+H] calc'd for C9H10FNO3, 200; found 200.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:14])[NH:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13].[C:17]1([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:12][C:9]1[C:8]([CH3:13])=[C:7]([NH:6][C:5]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:14])[O:11][N:10]=1
Reactant: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3cc(-c4ccccc4)ccn3)CC2)c1C
Yield: 36.8 %

Procedure:
A solution of 2,2,2-trichloroethyl(3,4-dimethylisoxazol-5-yl)carbamate (120 mg, 0.418 mmol), 1-(4-phenylpyridin-2-yl)piperazine (100 mg, 0.418 mmol), diisopropylethylamine (0.146 ml, 0.836 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 3 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was recrystallized from ethyl acetate to give the titled compound 58.0 mg (36.7%) as solid product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10](=[O:15])([O:13]C)[O:11][CH3:12]>C(=O)([O-])[O-].[K+].[K+].CO>[CH3:12][O:11][C:10](=[O:13])[OH:15].[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: OCCN1CCOCC1
Agent: [K+]
Solvent: CO
Product: COC(=O)O
Reaction time: 0.25 h

Procedure:
A total of 13.1 grams (0.1 moles) of 4-(2-hydroxyethyl)morpholine, 27.0 grams (0.3 moles) of dimethyl carbonate and 0.4 grams of anhydrous Potassium carbonate were combined in a 50 milliliter 3-neck round bottom flask equipped with a 4 inch vacuum-jacketed vigreaux column and a distillation head. The contents were heated to reflux under nitrogen, and after a period of 15 minutes (kettle temperature of 93° C. and a head temperature of 63° C.) methanol (with some dimethyl carbonate) was slowly removed overhead. After a period of about 2.5 hours, an additional 4.5 grams of dimethyl carbonate was added and the contents heated to reflux for another 1.5 hours. Capillary gas chromatographic analysis showed complete reaction of 4-(2-hydroxyethyl)morpholine. The flask was then cooled, filtered to remove potassium carbonate and charged to a clean 50 milliliter round bottom flask. The contents were distilled under vacuum (5 mm Hg) to give 9.14 grams (boiling point 117-119° C. at 5 mm Hg) of 4-(2-hydroxyethyl)morpholine methyl carbonate (99 percent). The kettle residue (4.3 grams) analyzed (area percent) by capillary gas chromatography as follows: 4-(2-hydroxyethyl)morpholine methyl carbonate (32.8 percent) and bis(2-N-morpholinoethyl)carbonate (65.5 percent).