Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](Cl)[CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: COc1cc(-c2nn(-c3ccnc(Cl)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2nn(-c3ccnc(N4CCOCC4)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A suspension of N2-{4-[4-amino-1-(2-chloro-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.120 g, 0.00023 mol) and morpholine (10 mL) was heated at 100° C. for 6 days. The solvent was removed in vacuo and the residue was slurried in water (25 mL) for 4 hours. The mixture was filtered and the crude solid was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 25 cm; 35%-80% acetonitrile—0.050 M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give N2-{4-[4-amino-1-(2-morpholino-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.048 g, 0.00008 mol) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]1[O:12][CH:11]([C:13]([OH:15])=O)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>C(Cl)Cl.CN(C=O)C.O>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:13]([CH:11]2[CH2:10][CH2:9][C:8](=[O:7])[O:12]2)=[O:15])=[N:27][CH:28]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C1CCC(C(=O)O)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(NC(=O)C2CCC(=O)O2)nc1
Reaction time: 3 h
Yield: 38 %

Procedure:
Oxalyl chloride (0.252 g, 1.63 mmol) in DCM (5 mL) was added slowly to a stirred solution of 5-oxotetrahydrofuran-2-carboxylic acid (Step 1) (0.215 g, 1.65 mmol) in DCM (10 ml) and DMF (50 μl) at 0° C. After 3 hrs at ambient temperature, gas evolution had subsided. DIPEA (0.64, 4.95 mmol) was added followed by the addition of 2-amino-5-picoline (0.357 g, 3.3 mmol) in DCM (5 mL). The reaction mixture was kept at ambient temperature for 3 hrs. Water (0.5 mL) was added and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with a gradient consisting of 0-40% MeOH in DCM) to give the title compound as a colorless oil (0.138 g). 1H NMR (500 MHz, CDCl3) δ 8.74 (br s, 1H), 8.13 (d, 1H), 8.08 (d, 1H), 7.54 (dd, 1H), 4.99 (t, 1H), 2.71 (m, 1H), 2.63 (m, 2H), 2.48 (m, 1H), 2.31 (s, 3H).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[CH3:28])=[C:18]([F:29])[C:14]2[NH:15][CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:10]>Cl.CO.C(O)C>[OH:7][NH:8][C:9]([C:11]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[CH3:28])=[C:18]([F:29])[C:14]2[NH:15][CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOC2CCCCO2)cc2nc[nH]c2c1F
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(I)ccc1Nc1c(C(=O)NO)cc2nc[nH]c2c1F

Procedure:
The compound 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is dissolved in an appropriate hydrogen chloride-saturated solvent like methanol or ethanol. Once homogeneous, the solution is concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like chloroform or dichloromethane if further purification is necessary.
Reaction SMILES: B(Cl)(Cl)Cl.[CH2:5]([NH:7][C:8]([C:10]1[S:35][C:13]2[N:14]=[C:15]([NH2:34])[N:16]=[C:17]([C:18]3[CH:23]=[C:22]([O:24]CC4C=CC=CC=4)[C:21]([Cl:32])=[CH:20][C:19]=3[Cl:33])[C:12]=2[CH:11]=1)=[O:9])[CH3:6].CO>ClCCl>[CH2:5]([NH:7][C:8]([C:10]1[S:35][C:13]2[N:14]=[C:15]([NH2:34])[N:16]=[C:17]([C:18]3[CH:23]=[C:22]([OH:24])[C:21]([Cl:32])=[CH:20][C:19]=3[Cl:33])[C:12]=2[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)c1cc2c(-c3cc(OCc4ccccc4)c(Cl)cc3Cl)nc(N)nc2s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron trichloride solution (1M in dichloromethane) was added to a suspension of 2-Amino-4-(5-benzyloxy-2,4-dichlorophenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in dichloromethane, at −78° C. under a nitrogen atmosphere. The suspension was stirred for ˜3 hrs at room temperature. The suspension was cooled in ice and methanol added, the resulting mixture was stirred for ˜1 hr. and concentrated to a yellow green solid. The solids were suspended in aqueous sodium acetate (10%) and extracted with ethyl acetate. The extracts were washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale brown solid, washed with hexane dried in vacuo.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][CH:27]1[C:32]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:29]1[CH2:30][CH2:31][C:32]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH:27]([CH3:26])[CH2:28]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CNCCC12C=Cc1ccccc12
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(C=Cc5ccccc54)C(C)C3)cnc12
Yield: 89.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.066 g, 0.194 mmol) obtained in Example 21, step 4 and 3′-methylspiro[inden-1,4′-piperidine] (WO2004/028459, 0.043 g, 0.213 mmol), the title compound (0.091 g, 90%) was obtained.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:24][CH2:23][C@@:13]34[C:14]5[CH:15]=[C:16]([O:21]C)[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@:8]3([OH:26])[CH2:9][CH2:10][C@@H:11]([OH:25])[CH2:12]4)[CH2:4][CH2:3][CH2:2]1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH:1]1([CH2:5][N:6]2[CH2:24][CH2:23][C@@:13]34[C:14]5[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@:8]3([OH:26])[CH2:9][CH2:10][C:11](=[O:25])[CH2:12]4)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ccc2c(c1)[C@]13CCN(CC4CCC4)[C@H](C2)[C@]1(O)CC[C@@H](O)C3
Agent: O=C(c1ccccc1)c1ccccc1
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CCC2)C1

Procedure:
One gram of potassium metal is reacted with t-butyl alcohol in anhydrous benzene to give potassium-t-butoxide. This suspension is heated with 2.5 g of N-cyclobutylmethyl-3-methoxy-6β,14β-dihydroxy-morphinan and 16 g of benzophenone under reflux for 3 hours. The reaction mixture is then extracted with three 20 ml portions of 2N hydrochloric acid, the combined acid extracts are made alkaline to a pH of 9.0, re-extracted with chloroform, and the solvent removed, after drying, in vacuo. The product is extracted from the insolubles with ether, and then the methoxy group is removed as follows to give N-cyclobutylmethyl-3,14β-dihydroxy-6-ketomorphinan: 15 g of the methoxy compound and 30 g of pyridine hydrochloride are heated together under a N2 atmosphere at 190°-196° C. for 4 hours, and the pyridine is distilled off during the heating period. After cooling to room temperature, 25 ml of water is added and the mixture is poured into an additional 100 ml. cold water. The pH is adjusted to 11.5 with 20% aqueous NaOH with cooling and insoluble material filtered off. The pH of the filtrate is then adjusted to 8.5-9.0 with HCl and stirred for 4 hours until crystallization occurs. The product is filtered off and recrystallized from acetone-methanol.
Reaction SMILES: [I:1]Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1.O>ClCCl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]([I:1])=[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(-c2cc3n(n2)CCCC3)cc1
Reactant: ClI
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(-c2nn3c(c2I)CCCC3)cc1
Reaction time: 12 h

Procedure:
A solution of 2.20 g (13.5 mmol) of iodine monochloride in 5 ml of dichloromethane is added dropwise to a solution of 2.66 g (12.3 mmol) of 2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine in 50 ml of dichloromethane, and the mixture is stirred for 12 h. 100 ml of water are added, and the reaction mixture is extracted with 3×50 ml of dichloromethane. The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. This gives 4.40 g (98%) of the desired product; log P(HCOOH): 3.79; 1H-NMR (MeCN-d3): 7.82 (dd, 2H), 7.18 (dd, 2H), 4.11 (dd, 2H), 2.67 (dd, 2H), 2.06 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1.[CH3:24][O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:25][C:26](=[O:31])[C:27]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:3]2[C:2]([CH3:23])([CH3:1])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:9]=3)[NH:4]2)[CH:17]=1)([CH3:29])[CH3:28]
Reactant: CC1(C)Cc2cc(C(F)(F)F)ccc2NC1c1cccc(N)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(F)(F)F)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 20.2 %

Procedure:
A mixture of 3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1.5 g, 4.7 mmol), 2-bromo-2-methyl-propionic acid methyl ester (2.55 g, 14.1 mmol) and potassium carbonate (3.24 g, 23.5 mmol) in N,N-dimethylformamide (12 mL) was stirred at 25° C. for 5 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(30% ethyl acetate/hexanes) to afford 2-[3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (400 mg, 20%) as a brown oil. LC/MS m/e calcd for C23H27F3N2O2 (M+H)+: 421.48, observed: 421.1.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:11]([O-:13])=[O:12])[C:5](=[O:9])[NH:4][C:3]1=[O:10]
Reactant: Cc1cc(=O)[nH]c(=O)n1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c([N+](=O)[O-])c(=O)[nH]c(=O)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 1,6-dimethylpyrimidine-2,4(1H,3H)-dione (5 g, 0.035 mol) in H2SO4 (20 mL) at 0° C. was added dropwise a solution of KNO3 (4.69 g, 0.046 mol) in H2SO4 (10 mL). The reaction was stirred 0° C. for 2 h, warmed to RT, stirred for 18 h, poured into ice then extracted with EA (5×50 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1,6-dimethyl-5-nitropyrimidine-2,4(1H,3H)-dione (4.3 g, 68.1% yield) as a yellow solid. 1H NMR (DMSO-d6) δ: 12.09 (s, 1H), 3.32 (s, 3H), 2.36 (s, 3H) LCMS: MH+ 186 and TR=0.610 min. Used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[H][H]>C(O)(=O)C.[Pt]=O>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: [H][H]
Reactant: Nc1cccc2cnccc12
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Nc1cccc2c1CCNC2

Procedure:
A solution of 5-aminoisoquinoline (20 g) in glacial acetic acid (500 ml) was shaken under hydrogen in the presence of a platinum oxide catalyst (2.0 g) at room temperature and approximately 345 kilopascals pressure until uptake of hydrogen stopped. The catalyst was removed by filtration and the filtrate was evaporated to a small volume under reduced pressure. Residual solvent was removed by co-evaporation with water, then isopropyl alcohol, and the resulting solid was recrystallized from isopropyl alcohol to give 5-amino-1,2,3,4-tetrahydroisoquinoline as a white solid, 19 g, m.p. 153°-154° C.
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[N+](C1C=C([N+]([O-])=O)C=CC=1O[C:19](=[O:22])[CH2:20][Br:21])([O-])=O>C(Cl)Cl>[Br:21][CH2:20][C:19]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:5])=[O:22]
Reactant: CNC(C)C
Reactant: O=C(CBr)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)N(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isopropyl-methyl-amine (154 μL, 1.48 mmol) was added to a stirred solution of bromo-acetic acid 2,4-dinitro-phenyl ester (450 mg, 1.48 mmol) in DCM (4 mL). After stirring for 3 h at room temperature the organic layer was extracted twice with 0.1 M NaOH solution (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 194.0 [M+H+].
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][C:13]4[C:19]([C:23]([NH2:25])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=4[C:11]=3[N:10]=2)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>[OH-].[NH4+]>[OH:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][C:13]4[C:19]([C:23]([NH2:25])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=4[C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CNc2ncc3c(n2)-c2c(c(C(N)=O)nn2C)CC3)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cn1nc(C(N)=O)c2c1-c1nc(NCc3ccc(O)cc3)ncc1CC2
Yield: 53 %

Procedure:
To a well stirred solution of 8-[(4-methoxybenzyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (242 mg, 0.7 mmol) in chloroform (30 mL) boron tribromide (1 M in dichloromethane, 5.12 mL, 5.1 mmol) was added dropwise over a 5 minutes period, at room temperature. The mixture was heated to reflux for 8 hours. A solution of 10% aqueous ammonium hydroxide (30 mL) was added dropwise at 0° C. over a 10 minutes period. A precipitate was formed and, after 2 hours, it was filtered and washed with water and dried at 40° C. under vacuum. There were obtained 130 mg of the title compound.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=3[C:17]#[N:18])=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].Cl[C:29]1[N:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C:16]1[CH:19]=[CH:20][C:21]([O:23][C:29]2[N:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][CH:30]=2)=[CH:22][C:15]=1[C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH2:5][CH:3]3[CH2:4][C:2]3([F:1])[F:27])[S:7](=[O:26])(=[O:25])[N:8]([CH3:24])[C:9]=2[CH:14]=1)#[N:18]
Reactant: N#Cc1cccc(Cl)n1
Reactant: CN1c2cc(-c3cc(O)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1c2cc(-c3cc(Oc4cccc(C#N)n4)ccc3C#N)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 140 °C

Procedure:
2-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-4-hydroxybenzonitrile (12-2) (300 mg, 0.77 mmol, 1 eq) was dissolved in acetonitrile (2.5 mL) and 6-chloropyridine-2-carbonitrile (212 mg, 1.5 mmol, 2 eq) and potassium carbonate (424 mg, 3.1 mmol, 4 eq) were added. The resulting mixture was heated in the microwave at 140° C. for 1.5 hours. The mixture was filtered washing with acetonitrile. The crude mixture was purified by reverse phase chromatography (Waters Sunfire MSC18, 10-100% acetonitrile in water with 0.1% TFA modifier) to afford 6-(4-cyano-3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}phenoxy)pyridine-2-carbonitrile (12-3) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (t, J=8.0 Hz, 1 H); 7.82 (d, J=8.4 Hz, 1 H); 7.50 (d, J=7.2 Hz, 1H); 7.34 (s, 1H); 7.29 (t, J=10.4 Hz, 1 H); 6.99 (s, 2 H); 6.92 (d, J=8.0 Hz, 2H), 3.92 (d, J=6.8 Hz, 2H); 3.36 (s, 3 H); 2.14 (m, 1 H); 1.65 (m, 1 H); 1.41 (m, 1 H). HRMS m/z (M+H) 494.1097 found, 494.1093 required.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[C:10]([CH3:17])[CH:9]=1.[F:18][C:19]([F:37])([F:36])[C:20]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:22]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:7][C:8]1[C:13]([C:14]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([N:22]3[C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:20]([C:19]([F:37])([F:36])[F:18])=[N:21]3)=[CH:35][CH:34]=2)=[O:16])=[CH:12][N:11]=[C:10]([CH3:17])[CH:9]=1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: Cc1cc(C)c(C(=O)O)cn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)Nc2ccc(-n3nc(C(F)(F)F)cc3C(F)(F)F)cc2)cn1
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Oxalyl chloride (8.7 ml) was added to a mixture of 4,6-dimethylnicotinic acid (15.1 g) and dichloromethane (150 ml) under ice cooling, followed by stirring at 15 to 20° C. for one hour. A mixture of 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline (23.59 g) and dichloromethane (300 ml) was added to the resulting reaction solution, followed by stirring at room temperature for 18 hours. An aqueous 20% potassium carbonate solution (about 200 ml) was added to the reaction solution, from which the organic layer was separated. Subsequently, the aqueous layer was extracted with dichloromethane (about 50 ml). The organic layer and the extract solution were combined together and subsequently concentrated under reduced pressure. The resulting residue was recrystallized from a mixed solvent (270 ml) of ethanol and water (2:1, respectively), to obtain 4,6-dimethyl-4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]nicotinanilide (26.70 g) as bluish white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[N:10][C:11](SC)=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1.ClC1C=C(C=CC=1)C(OO)=O.CCN(C(C)C)C(C)C.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[N:10][C:11]([NH:47][C:46]3[CH:45]=[CH:44][C:43]([N:40]4[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]4)=[CH:49][CH:48]=3)=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CSc1ncc2c(=O)n(C)nc(C)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of Example 1C (100 mg, 0.450 mmol) in dichloromethane (1.5 mL) was added meta-chloroperoxybenzoic acid (122 mg, 0.495 mmol) in a single portion. After 1 hour, the reaction mixture was partitioned between 10% sodium thiosulfate solution and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL). Hunig's base (157 μl, 0.900 mmol) and 4-(4-methylpiperazin-1-yl)aniline (86 mg, 0.450 mmol) were added to the solution, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure. The crude residue was purified by RP-MPLC (125 g C-18 silica gel), eluting with a gradient of 5 to 50% acetonitrile in water each containing 0.1% TFA, to provide the title compound. MS ESI(+) m/z 366.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ ppm 10.33 (s, 1H), 9.22 (s, 1H), 7.77-7.62 (m, 2H), 6.99-6.91 (m, 2H), 3.63 (s, 3H), 3.20-3.02 (m, 4H), 2.46-2.43 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=O)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(O)C.CCCCCC>[CH3:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]3[O:21][C:20](=[O:22])/[C:19](=[CH:33]/[C:32]4[CH:35]=[CH:36][C:29]([O:28][C:27]([F:26])([F:37])[F:38])=[CH:30][CH:31]=4)/[N:18]=3)=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CN(C)c1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CN(C)c1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(OC(F)(F)F)cc4)C(=O)O3)cc2)cc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
A mixture of N-(4-{2-[4-(dimethylamino)phenyl]ethoxy}benzoyl)glycine (241 mg, 0.676 mmol) prepared in Example 23 (23b), 4-(trifluoromethoxy)benzaldehyde (106 pt, 0.742 mmol), sodium acetate (83.9 mg, 1.02 mmol), and acetic anhydride (319 μL, 3.38 mmol) was stirred at 120° C. for 15 minutes and then allowed to cool to room temperature. A saturated sodium hydrogen carbonate aqueous solution, hexane, and ethanol were added to the resulting solidified product which was washed by ultrasonic vibration. The precipitate was collected by filtration and dried by heating under reduced pressure to give 234 mg of the title compound (orange solid, yield: 70%).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:14][S:15](O)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: O=S(=O)(O)Cl
Reactant: CC1(c2ccccc2)CCOCC1
Solvent: ClCCl
Product: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 4-methyl-4-phenyl-tetrahydro-pyran (1.10 g, 6.24 mmol) in dry methylene chloride (50 mL) cooled in an ice bath was added 2.07 mL of chlorosulfonic acid (3.64 g, 31.2 mmol) dropwise under dry nitrogen. The reaction was stirred overnight at room temperature; the reaction was added to ice and the product was extracted with methylene chloride (3×100 mL). The organic layer was washed with saturated brine, dried (MgSO4), filtered and concentrated. e product was chromatographed on silica gel using ethyl acetate-hexane mixtures (2-20% hexane). Removal of solvent provided pure product as a colorless syrup which crystallized on standing: 1H NMR (CDCl3) δ 7.99 (d, 2H, J=8.8 Hz), 7.56 (d, 2H, J=8.8 Hz), 3.79 (ddd, 1H, J=11.7 Hz, J=8.4 Hz, J=3.3 Hz), 3.70 (ddd, 1H, J=11.7 Hz, J=6.0 Hz, J=3.8 Hz), 2.11 (ddd, 1H, J=13.8 Hz, J=8.4 Hz, J=3.8 Hz), 1.81 (dm, 1H, J=13.8 Hz), 1.35 (s, 3H). MS: m/z 275 (M++1).