Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[NH:8][CH2:9][CH2:10][N:11]=2)=[C:5]([N+:12]([O-])=O)[C:4]([CH3:15])=[N:3]1.[CH2:16](OC(OCC)OCC)C.CS(O)(=O)=O>C(O)C>[CH3:1][N:2]1[C:6]2[C:7]3[N:8]([CH2:9][CH2:10][N:11]=3)[CH:16]=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1
Reactant: Cc1nn(C)c(C2=NCCN2)c1[N+](=O)[O-]
Reactant: CCOC(OCC)OCC
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1nn(C)c2c1N=CN1CCN=C21

Procedure:
The above nitro compound (8.4 g, 0.04 mol) is dissolved in 150 ml of methanol and hydrogenated (initial hydrogen pressure=51 psi) in the presence of 0.5 g of Raney nickel until the theoretical uptake of hydrogen is observed. The catalyst is removed by filtering; the filtrate is evaporated in vacuo to give 7.4 g (0.04 mol) of a purple oil (characterized by its IR-spectrum) of 2-(4-amino-1,3-dimethyl-5-pyrazolyl)imidazoline. This amine (7.4 g, 0.04 mol) is stirred under reflux 1.5 hr in a mixture of 20 ml absolute ethanol, 50 ml of triethylorthoformate and 1 ml of methanesulfonic acid. The mixture is evaporated in vacuo. The product is dissolved in methylenedichloride (100 ml) and washed with 100 ml of dilute ammonium hydroxide; the organic layer is dried over MgSO4 and evaporated in vacuo to give 7,8-dihydro-1,3-dimethyl-1H-imdazo[1,2-c]pyrazolo[3,4-e]pyrimidine 1.5 hydrate, mp 80°-82° C. from ethyl acetate-pet ether.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9](=[O:18])[CH2:10][C:11]2[NH:12][C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[C:22](OC)(=[O:25])[C:23]#[CH:24]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]1[CH:24]=[CH:23][C:22](=[O:25])[N:15]2[C:14]([CH3:16])=[C:13]([CH3:17])[NH:12][C:11]=12)=[O:18]
Reactant: Cc1nc(CC(=O)c2cccc(Cl)c2)[nH]c1C
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1[nH]c2c(C(=O)c3cccc(Cl)c3)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.70 mmol) of 1-(3-Chlorophenyl)-2-(4,5-dimethyl-1H-imidazol-2-yl)ethanone hydrochloride (example XXV), 65 mg (1.20 mmol) of sodium methylate and 59 mg (0.70 mmol) methyl propiolate.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[O:13])[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:6](=[O:36])[CH2:5]1.Br[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[N:40]=1.O>CN(C=O)C>[C:51]([O:50][C:48]([N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([CH2:38][CH:5]2[C:4](=[O:3])[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[O:13])[C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[N:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:6]2=[O:36])=[N:40]1)=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: COc1cccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
52 mg of Sodium hydride (60% in oil, 1.31 mmol) is added to a solution of 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(3-methoxy-phenyl) acetamide, prepared as in Part D, (500 mg, 1.09 mmol) in DMF (10 mL ) and the resultant mixture stirred at RT for 0.5 h prior to the addition of 3-Bromomethyl-1-tert-butoxycarbonyl-1H-indazole (339 mg, 1.09 mmol) to the reaction mixture. After stirring 18 h at RT, water (50 mL) is added and the resultant mixture extracted into ethyl acetate (3×50 mL). The combined organics were washed with water (3×20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo to afford the crude product which is purified by silica gel flash column chromatography using 5% methanol in methylene chloride as eluent to give the desired product (252 mg) as a cream foam: 1H NMR (300 MHz, CDCl3) δ8.07 (d, 1H, J=8.6), 7.91 (d, 1H, J=8.5), 7.5-6.8 (m, 15H), 5.03 (m, 1H, J=6.9), 4.39 (m, 3H), 3.94 (m, 2H), 3.84 (s, br, 4H), 3.60 (dd, 1H, J=10.1, 2.1), 1.6 (s, 9H), 1.16 (d, 6H, J=6.9).
Reaction SMILES: [OH-].[Na+:2].C(O)(=O)C(O)=O.[CH:9]([C:11]1[CH:24]=[C:23]([C:25]2[S:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C:26]=2[CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:37][CH:36]=2)[CH:22]=[CH:21][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:10].CO>C1COCC1>[Na+:2].[CH:9]([C:11]1[CH:24]=[C:23]([C:25]2[S:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C:26]=2[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]3[CH2:45][CH2:46][CH2:47][CH2:48]3)=[CH:39][CH:40]=2)[CH:22]=[CH:21][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:10]
Reactant: COC(=O)CCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1C=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1cc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)ccc1OCCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The title compound was prepared by adding 179 μL (0.179 mmol) of 1 N NaOH to a solution of 100 mg (0.179 mmol) methyl 4-[2-formyl-[3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophen-2-yl]phenoxy]]butyrate (Example 19, Part B) dissolved in 1.0 mL of 1:1 THF:MeOH mixture. The solution was stirred at room temperature for 22 h. The reaction mixture was then evaporated in vacuo and dried in a vacuum oven at 55° C. over P2O5 to yield the title compound (101.4 mg, 0.179 mmol, quantitative yield) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:31][N:32]([CH3:45])[S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:38]4[CH:37]=[C:36]([S:33]([N:32]([CH3:45])[CH3:31])(=[O:34])=[O:35])[CH:41]=[CH:40][CH:39]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Reactant: CN(C)S(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(S(=O)(=O)N(C)C)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 6.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(N,N-dimethylsulfamoyl)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzenesulfonamide (1.7 mg, 7%). 1H-NMR (MeOD): 2.47 (m, 1H), 2.62 (m, 1H), 2.71 (s, 6H), 3.29 (s, 3H), 5.28 (d, 0.3H), 5.89 (d, 0.7H), 7.19 (m, 1H), 7.47 (m, 6H), 7.69 (m, 2H), 7.75 (m, 1H), 7.93 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH2:16][CH3:17])[CH:2]=[CH:3][CH3:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH2:16][CH3:17])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1ccc(F)cc1
Reactant: CC=CCn1c(CC)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(CC)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Yield: 41.7 %

Procedure:
The title compound (trans) was prepared as a white powder in 41.7% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2-ethyl-3-methylpyrrolo[2,3-d]pyridazine (cis/trans=4/96) and 4-fluorobenzyl alcohol.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(=O)c4ccccc4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(=O)c4ccccc4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of methyl 3-(4-benzoylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (130 mg, 0.27 mmol) in methanol (15 ml) was added NaOH (37 mg, 0.93 mmol) in 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 3-(4-benzoylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (53.0 mg, 42%).
Reaction SMILES: Br[C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[N:5]=2.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[N:5]=2
Reactant: CC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Reaction time: 8 h

Procedure:
8-Bromo-2-{[(1S)-1-methylpropyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.79 g, 4.83 mmol) was dissolved in methanol (15 ml) and 25% sodium methoxide in methanol (3.2 ml, 4.83 mmol) was added and the mixture heated to reflux for 2.5 hours. The reaction mixture was left standing at room temperature overnight and then concentrated in vacuo and the residue partitioned between dichloromethane (40 ml) and saturated ammonium chloride solution (40 ml). The layers were separated using a hydrophobic frit and the aqueous phase was re-extracted with dichloromethane (40 ml). The combined organic extracts were concentrated in vacuo to give the title compound as a yellow foam (1.65 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:30][CH2:31][CH2:32][NH:33][S:34]([C:37]1[S:38][C:39]([Cl:43])=[C:40]([NH2:42])[CH:41]=1)(=[O:36])=[O:35]>>[Cl:43][C:39]1[S:38][C:37]([S:34](=[O:36])(=[O:35])[NH:33][CH2:32][CH2:31][OH:30])=[CH:41][C:40]=1[NH:42][C:27]([C:26]1[CH:25]=[N:24][N:17]2[C:18]([C:20]([F:22])([F:23])[F:21])=[CH:19][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:13])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[N:15][C:16]=12)=[O:28]
Reactant: Nc1cc(S(=O)(=O)NCCO)sc1Cl
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cc(S(=O)(=O)NCCO)sc4Cl)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (example B.6) according to general procedure II. Light yellow solid. MS (ISP) 656.0 [(M−H)−]; mp 250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].[C:15](=O)([O:18]C)[O:16][CH3:17].[H-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:13][CH2:12][CH:11]([C:15]([O:16][CH3:17])=[O:18])[C:10]1=[O:14]
Reactant: COC(=O)OC
Reactant: COc1ccccc1C1CCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(c2ccccc2OC)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 2-(2-methoxyphenyl)cyclopentanone (6.64 g, 34.9 mmol), dimethyl carbonate (58.8 ml, 698 mmol) and MeOH (4 drops) was stirred while sodium hydride (3.07 g, 60% wt, 77 mmol) was added slowly at 0° C. The mixture was wamed to RT and then heated to reflux for 2 hr and then stirred at RT overnight. The reaction was quenched with 1 N HCl (77 mL, 77 mmol) and extracted with ethyl acetate. The organic extracts were washed with water, dried with brine, and concentrated in vacuo. The crude product was purified by flash chromatography (SG, 0 to 75% EtOAc/Hexane) to get methyl 3-(2-methoxyphenyl)-2-oxocyclopentanecarboxylate (5.3 g, 21.35 mmol, 61.2% yield). LC-MS (M+Na)+=271.1. 1H NMR (500 MHz, CD3OD) δ 7.26-7.16 (m, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.92-6.84 (m, 2H), 3.73-3.69 (m, 3H), 3.68 (s, 3H), 3.60-3.49 (m, 1H), 3.49-3.40 (m, 1H), 2.40-2.31 (m, 1H), 2.31-2.17 (m, 2H), 2.16-2.01 (m, 1H).
Reaction SMILES: F[C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][S:33]([C:36]1[CH:41]=[C:40]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[CH:2][C:3]([C:22]4[S:26][C:25]([C:27]5([OH:31])[CH2:30][CH2:29][CH2:28]5)=[N:24][CH:23]=4)=[C:4]3[CH:10]=2)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)ccnc3[nH]2)c1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107C) (150 mg, 0.272 mmol) and 3-methylsulfonyl phenylboronic acid (54.4 mg, 0.272 mmol) in N,N-dimethylformamide (2.04 mL) was added saturated aqueous bicarbonate solution (680 μL) followed by bis(triphenylphosphine) palladium dichloride (13.37 mg, 0.019 mmol). The mixture was heated to 70° C. for 3 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. A solution of the residue in methanol (2.0 mL) and 2N sodium hydroxide solution (700 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.60 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.37 (d, J=7.93 Hz, 1H), 8.28 (d, J=5.04 Hz, 1H), 7.88 (d, J=6.71 Hz, 1H), 7.75 (t, J=7.78 Hz, 3H), 7.51 (s, 1H), 7.32 (d, J=5.04 Hz, 1H), 3.32 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 426.7 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:24])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH:21]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[O:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]([C:5]([OH:7])=[O:6])=[CH:9][C:10]=1[CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(C)c(Oc2ccc(OC)c(C(C)C)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Oc2c(C)cc(C(=O)O)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a solution of methyl 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzoate (8.53 g, 16.7 mmol, intermediate for the synthesis of Example 19-3) in methanol (60.0 mL) at 0° C. was added a solution of 1 N NaOH (28.15 mL, 28.15 mmol). The reaction mixture was stirred at room temperature for 16 h and acidified with cold concentrated HCl. The reaction mixture was extracted with ethyl acetate (10.0 mL) and the organic layer was dried over MgSO4. The solvent was removed under reduced pressure to afford 4-(3′-iso-propyl-4′-methoxyphenoxy)-3,5-dimethylbenzoic acid as a pink solid (1.38 g, 78%): 1H NMR (300 MHz, DMSO-d6): δ 12.88 (s, 1H), 7.76 (s, 2H), 6.85 (m, 1H), 6.75 (m, 1H), 6.34 (m, 1H), 3.73 (s, 3H), 3.20 (m, 1H), 2.11 (s, 6H), 1.12 (d, J=6.0 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (17:3); Rf=0.00.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][CH:38]=[C:39]2[O:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:34][CH:33]=1>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH:15]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[C:40](=[C:39]([O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:38]=[CH:37][CH:36]=2)[CH:41]=1)[CH:16]([CH3:17])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCCOc1cccc2ccc(CBr)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOc1cccc2ccc(CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C(C)C)cc12
Reaction time: 0.5 h

Procedure:
A solution of 0.31 g of 4(R)-benzyl-3-(3-methylbutyryl)oxazolidin-2-one in 2 ml of tetrahydrofuran is added dropwise at −78° C. to 1.2 ml of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofuran). After 30 minutes, a solution of 0.30 g of 7-bromomethyl-1-(2-methoxyethoxy)naphthalene in 2 ml of tetrahydrofuran is added dropwise and the reaction mixture is allowed to thaw from −78° C. to 0° C. over 2 hours. After 3 hours at 0° C., the reaction mixture is quenched with 5 ml of 1M ammonium chloride solution, diluted with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH3:32][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>COCCO>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:33]([CH3:32])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CNc1ccccn1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: COCCO
Product: CCOC(=O)c1c(CN(C)c2ccccn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 8.6 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (1.0 g), 2-(methylamino)pyridine (0.95 g) and 2-methoxyethanol (30 ml) was stirred under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with hexane - ethyl acetate (3:2, v/v) gave ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-[N-methyl-N-(2-pyridyl)aminomethyl]quinoline-3-carboxylate (0.1 g, 9%). This compound was recrystallized from dichloromethane-ethanol. Pale yellow prisms, mp. 174°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1ncccn1
Product: Brc1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
4-Bromoaniline (0.300 g, 1.74 mmol) and 2-chloropyrimidine (0.200 g, 1.74 mmol) were heated neat at 150° C. in a 25 mL flask for 2 h. The reaction mixture was cooled to ambient temperature, and purification of the residue by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 13.8-15.9 min) afforded N-(4-bromophenyl)-N-(2-pyrimidinyl)amine as a yellow solid (0.135 g, 0.54 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 11.08 min; 1H NMR (DMSO-d6, 400 MHz) δ 9.78 (s, 1H), 8.50 (d, 2H), 7.76 (d, 2H), 7.45 (d, 2H), 6.87 (t, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC2C=CC=CC=2)=[O:38])[CH:5]=1)([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]([C:4]1[C:9]2[C:10](=[O:32])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(OCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1cc(OCCCC(=O)O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Yield: 90.4 %

Procedure:
A mixture of 4-isopropyl-6-[3-(phenylmethyloxycarbonyl)propoxy]-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (820 mg) and 200 mg of 10% Pd/C in 40 ml of ethyl acetate was hydrogenated (hydrogen balloon). The catalyst was removed on a pad of CELIITEO and the filtrate was concentrated in vacuo to afford 640 mg (90%) of 4-isopropyl-6-[3-(carboxy)propoxy]-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)3CO2 as a foam.