Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]([CH3:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[N+:1]([CH:4]([CH3:15])[CH:5]([O:14][C:21](=[O:23])[CH3:22])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(O)CCc1ccccc1)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)OC(CCc1ccccc1)C(C)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Crude 4-Nitro-1-phenyl-pentan-3-ol (179) from above was dissolved in CH2Cl2 (60 mL) and cooled in an ice bath under nitrogen. Concentrated sulfuric acid (0.76 mL, 14.2 mmol) then acetic anhydride (13.83 mL, 146.2 mmol) were added slowly, and the reaction was allowed to warm to room temperature, and was stirred until judged complete by HPLC (3 h, 40 min). (Note: The reaction turned black soon after the addition of the acetic anhydride). The reaction was quenched by pouring slowly into water, then the organic layer was removed, washed with aq. NaHCO3, dried, filtered, and concentrated. The crude product was purified by purified by silica gel chromatography (Combiflash column, 95:5 Hexanes:EtOAc) to achieve pure 180 (21.4447 g, 65.5%, 2 steps). HPLC: 10.45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]([CH2:22][CH2:23][CH2:24][N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[C:19]([OH:21])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:65]([O:84][NH2:85])([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>ClCCl>[C:65]([O:84][NH:85][C:19](=[O:21])[C@H:18]([NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:16])[CH2:22][CH2:23][CH2:24][N:25]1[C:26](=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]1=[O:34])([C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of the title compound of Example 1, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (304 mg, 0.593 mmol) and NMM (0.330 mL, 3.00 mmol) in 10 mL of dichloromethane is treated with 1-hydroxy-7-azabenzotriazole (89 mg, 0.654 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg, 0.886 mmol) at RT. After stirring for 30 min, O-tritylhydroxylamine (489 mg, 1.776 mmol) is added, and the reaction is stirred for 16 h. The mixture is partitioned between 60 mL of dichloromethane and 40 mL of water. The organic solution is washed with 30 mL of 1M aqueous NaHCO3, dried over anhydrous Na2SO4 and concentrated. Chomatography on silica gel (eluant; 4/6—ethyl acetate/hexane) affords 293 mg (64%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid O-tritylhydroxyamide as a waxy solid: NMR(CDCl3) 0.62-0.76 (br m, 1H), 1.08-1.24 (br m, 1H), 1.46-1.65 (br m, 1H), 1.72-1.87 (br m, 1H), 3.65-3.73 (m, 2H), 3.94 (t, 1H, J=8.7), 5.31 (d, 1H, J=9.2), 7.20-7.27 (m, 15H), 7.48 (d, 4H, J=8.4), 7.59 (d, 2H, J=8.5), 7.70 (d, 4H, J=8.3), 7.91 (d, 2H, J=8.3), 8.27 (s, 1H); IR 1770, 1710, 1349, 1166; ESI-MS 770 (M++1).
Reaction SMILES: [CH:1]([S:4]([CH2:7][C@H:8]1[C@@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:15]2=[O:32])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)(=[O:6])=[O:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([S:4]([CH2:7][C@H:8]1[C@@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:15]2=[O:32])[CH2:12][CH2:11][NH:10][CH2:9]1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)C[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Reaction time: 4 h
Yield: 85 %

Procedure:
A sample of (3R,4S)-tert-butyl 3-(isopropylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)piperidine-1-carboxylate (0.688 g) was dissolved in CH2Cl2 (10 mL) prior to the addition of trifluoroacetic acid (0.92 mL, 11.9 mMol). After 4 h, the reaction was made basic with saturated NaHCO3. Extracted with CH2Cl2. The organic layer was washed with brine and dried (MgSO4). Concentrated and dried in vacuo to yield the desired product, N—((S)-1-((3R,4S)-3-(isopropylsulfonylmethyl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide) (0.482 g, yield=85%). MS found: (M+H)+=476.31.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[CH:27][O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[CH:27][O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-oxazole-4-carboxylic acid (2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl)-amide (120 mg, 0.24 mmol) in dry THF (2.1 mL) was treated at 0° C. with TBAF (0.48 mL of a 1M solution in THF, 0.48 mmol). The reaction mixture was stirred at 0° C. for 45 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as a white foam. TLC:rf (19:1 CH2Cl2-MeOH)=0.19. LC-MS-conditions 02: tR=0.88 min; [M+H]+=381.23.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]([CH3:15])=[CH:11][C:12](O)=[O:13]>S(=O)(=O)(O)O>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:9])[O:5][C:4]=2[CH:3]=1
Reactant: CC(C)=CC(=O)O
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)c2ccc(O)cc2O1
Reaction time: 8 h
Yield: 62.5 %

Procedure:
Resorcinol (165 g) and 3,3-dimethylacrylic acid (100 g) were mixed, cooled in an ice bath, and treated carefully with concentrated sulfuric acid (180 mL). The internal temperature rose to 68° C. The mixture turned gradually to a viscous orange mass and the internal temperature dropped to 25° C. The ice bath was removed and stirring was continued overnight at room temperature (“RT”) during which the mixture solidified. Small amounts of water and ethyl acetate were carefully added alternatively until the mixture dissolved, and it was transferred to a 5 L conical flask with water (2 L) and ethyl acetate (1.5 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed once with water and carefully treated with solid sodium bicarbonate until effervescence stopped. The organic layer was washed with water, concentrated in vacuo, and the resulting white solid was dissolved in 10% sodium hydroxide. The resulting solution was adjusted to pH 2 with concentrated hydrochloric acid and the resulting solid was filtered, dissolved in boiling glacial acetic acid (220 mL), stirred, diluted with boiling water (220 mL), and immediately cooled. The resulting solid was filtered, washed, and dried in vacuo at 50° C. to give the title compound (120 g).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.I[CH2:32][CH3:33]>>[O:1]=[C:2]1[N:6]([CH2:32][CH3:33])[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=1
Reactant: C=CCOCC1(c2ccccc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CCI
Product: C=CCOCC1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CC

Procedure:
The procedure of Example 1, Step 1 applied to 0.23 g of 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile with 0.18 mL of iodoethane provides the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].O.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of EXAMPLE 23E (25 g, 127 mmol) in N,N-dimethylformamide (200 mL) was slowly added sodium hydride (3.37 g, 133 mmol) over several minutes. After stirring for 30 minutes in the cold water bath, benzenesulfonyl chloride (17.18 ml, 133 mmol) was added via a syringe. The solution was allowed to warm to room temperature overnight, quenched slowly with 500 mL water, stirred for 30 minutes, and then filtered. The solid obtained was washed with water, followed by 300 mL of hexanes, and dried over high-vacuum for 16 hours to afford the title compound which was used without further purification. MS (ESI+) m/z 338.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH:14][CH3:15])=[N:12][CH:13]=2)[CH:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH:14][CH3:15])=[N:12][CH:13]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: C1COCCN1
Reactant: CNc1ncc(-c2cc(Cl)nc(Cl)n2)cn1
Solvent: CC#N
Product: CNc1ncc(-c2cc(N3CCOCC3)nc(Cl)n2)cn1

Procedure:
According to Method 6, the reaction of 2,6-dichloro-N-methyl-4,5′-bipyrimidin-2′-amine with morpholine in acetonitrile gave 2-chloro-N-methyl-6-morpholino-4,5′-bipyrimidin-2′-amine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[CH:16](O)=O.C=O.[OH-].[Na+]>O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[N:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)N(c2ccc(Br)nc2)N1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1N(c2ccc(Br)nc2)C(=O)CC1(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
A suspension of 2-(6-bromo-pyridin-3-yl)-5,5-dimethyl-pyrazolidin-3-one (Example 12, step 1) (800 mg, 2.96 mmol) and formic acid (0.57 ml, 14.8 mmol, 5 equiv.) in water (8 ml) was heated to 100° C. At this temperature formaldehyde (36% in water) (1.13 ml, 14.8 mmol, 5 equiv.) was added drop wise. The mixture was stirred overnight at 100° C. The reaction mixture was cooled and basified carefully with 2N NaOH and extracted two times with a small amount of dichloromethane. The organic layers were loaded directly on a silica gel column and the crude product was purified by flash chromatography eluting with a heptane:ethyl acetate gradient 100:0 to 0:100. The desired 2-(6-bromo-pyridin-3-yl)-1,5,5-trimethyl-pyrazolidin-3-one (380 mg, 45% yield) was obtained as a colorless oil, MS: m/e=284.3/286.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1.O>CN(C=O)C>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:37])[CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:25][CH:24]=4)=[O:21])=[CH:13][C:12]=3[CH:38]=2)=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(O)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCc5ccccn5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.5 h
Yield: 2.2 %

Procedure:
In DMF (3.8 ml) was dissolved 7-(4-hydroxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (380 mg). To the mixture was added potassium carbonate (252 mg), and the mixture was stirred for 30 minutes. To the mixture was added 2-chloromethylpyridinehydrochloride (130 mg), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-pyridylmethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 108) (10 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:22])=[O:21])=[O:14])(=[O:3])[CH3:2].Cl[C:32]1C(C)=NOC=1N(COC)S(C1C=C(C)SC=1C(Cl)=O)(=O)=O>>[C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[S:16][C:17]([CH3:32])=[CH:18][C:19]=1[S:20]([NH:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[Cl:30])(=[O:21])=[O:22])=[O:14])(=[O:3])[CH3:2]
Reactant: COCN(c1onc(C)c1Cl)S(=O)(=O)c1cc(C)sc1C(=O)Cl
Reactant: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Product: CC(=O)c1cc(C)cc(C)c1NC(=O)c1sc(C)cc1S(=O)(=O)Nc1onc(C)c1Cl

Procedure:
N-(2-Acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide was synthesized in the same fashion as for N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide (Example 39) except that N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid chloride was used instead of N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxylic acid chloride.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11](O)[CH:10]=[CH:9][N:8]=2)[CH:2]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:3]2[CH:2]=[C:1]([CH3:14])[CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Cc1cccc(-c2nccc(O)n2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(-c2nccc(Cl)n2)c1
Temperature: 0 °C

Procedure:
A 23.91 g portion of 2-(3-tolyl)-4-pyrimidinol was mixed with 400 ml of phosphorous oxychloride in a one liter round bottom flask, under a drying tube and heated on a steam bath overnight. The mixture was allowed to cool and then poured over 2 liters of ice. The resulting solid was collected, washed with 50 ml of ether, dried and recrystallized from 100 ml of ethanol, giving 16.23 g of the desired intermediate, mp 74°-75° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C[N:18](C=O)C>O=S(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:5]=1[C:6]([NH2:18])=[O:7])([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: CCCOc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc([N+](=O)[O-])c(C(N)=O)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 2-nitro-5-propoxy-benzoic acid (1.97 g, 8.75 mmol) and DMF (0.1 mL) in SOCl2 (20 mL) was stirred at 65° C. for 2 h. After the reaction was completed, the mixture was cooled to room temperature. SOCl2 was removed in vacuo and the residue was dissolved in anhydrous CH2Cl2 (10 mL), which was added to NH3—H2O (28%) dropwise. After 1 h, the precipitate was collected and dried in vacuo to give 1.68 g of i-a as a yellow solid (85.2%). LCMS m/z=208.1 (M−16), 225.1 (M+1) (Method B) (retention time=1.88 min).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([CH:2]3[C:7](=[O:8])[NH:6][C:5]4[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=4[S:3]3)[CH2:22][CH2:21]2)[CH:15]=1
Reactant: O=C1Nc2ccccc2SC1Cl
Reactant: Cc1ccnc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2CCN(C3Sc4ccccc4NC3=O)CC2)c1
Yield: 16.8 %

Procedure:
7 g (=0.035 m) of 2-chloro-2H-1,4-benzothiazine-3(4H)-one, 6.2 g of N-(4-methylpyridin-2-yl)-piperazine, and 7 g of triethylamine were heated at reflux with stirring for 5 hours in 100 ml of toluene. The suspension was worked up by diluting it with 200 ml of toluene, and the resulting precipitate was filtered out and dissolved in 20% strength aqueous hydrochloric acid solution. The solution was rendered alkaline by adding an ammonium hydroxide solution, and the resulting precipitate was filtered out, washed with water and dried. 2 g of beige-colored crystalline 2-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]-2H-1,4-benzothiazine-3(4H)-one having a melting point of 245° C. were obtained.
Reaction SMILES: CCN(CC)CC.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]([C:30]2[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=2)[C:22](=[O:29])[NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:16][CH2:15]1>CN(C=O)C>[N:8]1([S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH:21]([CH2:20][CH:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[C:22]([NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[O:29])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reaction time: 0.17 h

Procedure:
NEt3 (120 μL, 868 μmol) and morpholine (76 μL, 868 μmol) were added to a stirred solution of 4-[2-(tetrahydropyran-4-yl)-1-(thiazol-2-ylcarbamoyl)ethyl]benzenesulfonyl chloride (Preparation 59, 300 mg, 723 μmol) in anhydrous DMF (4 mL). After 10 min, the solvents were removed in vacuo, then the residue was taken up in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with H2O (20 mL), 1M HCl (20 mL), H2O (20 mL), saturated aqueous Na2CO3 (20 mL), and brine 20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and recrystallisation (CH2Cl2-IH) gave the title compound: RTA=3.15 min; m/z (ES+)=466.1 [M+H]+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[NH:19][S:20]([NH2:23])(=[O:22])=[O:21])#[N:11].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O>[C:10]([C:12]1[CH:17]=[C:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][C:13]=1[NH:19][S:20]([NH2:23])(=[O:22])=[O:21])#[N:11]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)ccc1NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccccc2)ccc1NS(N)(=O)=O
Reaction time: 0.08 h

Procedure:
In a 2 mL microwave vial, phenyl boronic acid (75 mg, 0.6 mmol), N-(2-cyano-4-bromophenyl)sulfamide (Example 83b) (137 mg, 0.5 mmol), and potassium carbonate (400 mg, 1.5 mmol) were dissolved in DME/Water mixture (1.5 mL, DME/Water 4:1). The solution was degassed by bubbling N2 gas into the reaction solution for 5 minutes and Palladium tetrakis triphenylphospine (25 mg, 0.025 mmol) was added. The reaction was placed in a microwave reactor for 5 minutes at 150° C. The crude reaction was dissolved in water and washed with ethyl acetate. The aqueous solution was evaporated under vacuum to give N-(2-Cyano-4-phenylphenyl)sulfamide.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]Br.N1C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:34][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: Oc1ccccc1
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(Oc4ccccc4)cc3)nc12
Temperature: 130 °C
Yield: 49.2 %

Procedure:
A mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (35 mg, 0.074 mmol), phenol (14 mg, 0.15 mmol), copper(I) bromide (2 mg, 0.014 mmol), cesium carbonate (49 mg, 0.15 mmol) and pyridine (1 mL) was heated at 130° C. under nitrogen overnight, and then was cooled to room temperature, quenched with saturated sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-phenoxyphenyl)benzoxazole-4-carboxamide (16 mg, 50%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.66 (d, J=7.0 Hz, 1H), 8.20-8.17 (m, 3H), 7.70 (dd, J=8.0, 1.0 Hz, 1H), 7.47-7.42 (m, 3H), 7.23 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 4H), 4.35-4.28 (m, 1H), 3.52 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.09-2.81 (m, 5H), 2.17-2.07 (m, 2H), 1.80-1.62 (m, 3H); MS (ESI+) m/z 440 (M+H); HPLC>99% (AUC), tR=13.81 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:10]([C:12]([CH3:14])=O)=[CH2:11]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[N:7]=[CH:11][CH:10]=[C:12]2[CH3:14]
Reactant: COc1ccc(N)cc1
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COc1ccc2nccc(C)c2c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To a stirred solution of 4-methoxyaniline (1 g. 8.1 mmol.) in acetic acid (10 ml), activated silferc (1.3 g., ferric chloride 8.1 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.62 g, 8.9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.1 g. 8.1 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 58%.