Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH:3]=[O:4].C([OH:46])(C)(C)C.CC(=CC)C.Cl([O-])=O.[Na+]>O>[CH3:5][C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)=[CH:32][C:25]=3[S:24]4)=[CH:19][CH:20]=2)=[O:13])[CH:7]=1)([CH3:1])[C:3]([OH:46])=[O:4]
Reactant: CC(C)(C)O
Reactant: CC(C)(C=O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: CC(C)(C(=O)O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C

Procedure:
2-Methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5) is prepared by following a general procedure given in J. Org. Chem. 2002, 67, 411. To a stirred solution of 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a) (1 equivalent) in a 5:1 mixture of tert-butanol and water at rt are added sequentially dihydrogen sodium phosphate (3 equivalents), 2-methyl-2-butene (6 equivalents), and sodium chlorite (1 to 1.5 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The separated aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane. The combined organic layers are washed with water or brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propionic acid (I-5).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:16][C:17]1[N:18]([CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][N:21]=1.O>C1COCC1>[CH3:1][N:2]([CH2:16][C:17]1[N:18]([CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][N:21]=1)[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: CCCn1ccnc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1ccnc1CN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
N-methyl-4-nitroaniline (2.3 g) was dissolved in THF (92 ml), 60% sodium hydride (1.85 g) was added to the solution at 0° C., and the mixture was stirred for 1 hour at room temperature. 2-chloromethyl-1-propylimidazole hydrochloride (3.54 g) was added to the mixture at room temperature and the mixture was stirred for 240 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give N-methyl-4-nitro-N-[(1-propylimidazol-2-yl)methyl]aniline (2.7 g).
Reaction SMILES: CO.[OH:3][CH2:4][CH2:5][NH:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:8]=1[NH2:9].Cl.[C:24](=N)(OC)[CH3:25]>O>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:7]2[N:6]([CH2:5][CH2:4][OH:3])[C:24]([CH3:25])=[N:9][C:8]=2[CH:10]=1
Reactant: COC(C)=N
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCCO
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCO
Yield: 42.6 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(2-hydroxyethyl)aminoanilin-5-yl)benzoxazole (see Working Example 88-1) (0.10 g, 0.4 mmol) was added methyl acetimidate hydrochloride (0.08 g, 0.7 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.05 g, 49% yield) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:20][CH2:21][N:22]([CH2:33][CH2:34]Cl)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>O>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[N:6]=[CH:7][C:2]=1[N:1]1[CH2:34][CH2:33][N:22]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:21][CH2:20]1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: Cc1cc(C)c(N)cn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCN(c3cnc(C)cc3C)CC2)cc1
Yield: 15.7 %

Procedure:
To 5-amino-2,4-dimethylpyridine (883 mg) were added N,N-diisopropylethylamine (2.1 mL) and N,N-bis(2-chloroethyl)-p-toluenesulfonamide (2.08 g), and the mixture was stirred with heating under reflux. After completion of the reaction, water was added to the reaction mixture, the mixture was extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-(4,6-dimethylpyridin-3-yl)-4-(toluene-4-sulfonyl)piperazine (380 mg). The obtained 1-(4,6-dimethylpyridin-3-yl)-4-(toluene-4-sulfonyl)piperazine (380 mg) was dissolved in acetic acid (2 mL), 40% hydrobromic acid (2 mL) was added, and the mixture was stirred at 100° C. After completion of the reaction, the reaction mixture was neutralized with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (131 mg).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([O:18]C)[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)c1ccc(O)c(Cl)c1Cl
Temperature: 200 °C

Procedure:
A mixture of 39.5 g of 2,3-dichloro-4-methoxy-4'-fluorobenzophenone and 160 g of pyridine hydrochloride is heated at 200° C. for one hour. The reaction mixture is poured into ice water with stirring and a precipitate forms. The precipitate is filtered and dried for about 18 hours to yield 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[N:12]=[CH:11]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3cc(Br)ccc32)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of KOtBu (8.13 g, 72.4 mmol) in THF (60 mL) was added 5-bromo-1H-indazole (12.98 g, 65.9 mmol) in THF (60 mL). After 30 min, 4-methoxybenzyl chloride (9.38 mL, 69.2 mmol) was added (neat) and the resulting pale yellow solution was stirred 48 h. The reaction was quenched by addition of saturated NH4Cl solution, and the mixture was extracted with EtOAc. Evaporation of the organic phase followed by column chromatography of the residue on silica gel, eluting with 1/9—EtOAc/heptane, afforded the title compound, which was recrystallized from toluene/heptane (1/5) to afford the title compound as colorless cubes (7.65 g, 37%). Also recovered from the chromatography was 5-bromo-2-(4-methoxybenzyl)-2H-indazole (8.0 g, 38%)
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].[OH-].[Na+]>>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCBr
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: ClCCCSc1ccccc1
Yield: 56.7 %

Procedure:
A mixture of 54.0 g (490 mmols) of thiophenol, 160.0 g (1016 mmols) of 1-bromo-3-chloropropane and 250 ml of a 2.2 M aqueous sodium hydroxide solution was heated under reflux for 30 hours. After cooling, the reaction mixture was extracted with methylene chloride. The methylene chloride layer was washed with an aqueous dil. sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure (138 -140° C./13 mmHg) to afford 51.9 g (yield: 57%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32](Cl)[CH:31]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:41](B(O)O)([CH3:43])=[CH2:42].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:41]([CH3:43])=[CH2:42])[CH:31]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(C)B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)ccc1F
Temperature: 100 °C

Procedure:
In a tube was placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3′-chloro-4′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 146) (30.2 mg, 0.0504 mmol), isopropenylboronic acid (27 mg, 0.31 mmol), 1,1-bis(di-t-butylphosphino)ferrocene palladium chloride (5.5 mg, 8.4×10−3 mmol), THF (350 μL) and 1 M aq. K2CO3 (350 μL). The tube was degassed with nitrogen, sealed, and heated at 100° C. for 5 hours. The reaction was then cooled to room temperature, diluted with EtOAc (50 mL) and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.29 (15% EtOAc/hexanes). LCMS=606.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.70 (s, 3H), 7.64 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.23 (dd, J=7.8, 2.0 Hz, 1H), 7.12-7.17 (m, 2H), 5.54 (d, J=8.0 Hz, 1H), 5.28 (s, 1H), 5.26 (s, 1H), 4.90 (d, J=15.8 Hz, 1H), 4.18 (d, J=15.8 Hz, 1H), 3.78 (m, 1H), 2.16 (s, 3H), 0.47 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][OH:14])[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:4]1)[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>>[CH2:1]([C:3]1([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:4]1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCC1(CO)CCC2(CCOCC2)O1
Agent: [H-]
Agent: [Na+]
Product: CCC1(COCc2ccccc2)CCC2(CCOCC2)O1
Yield: 24.8 %

Procedure:
Following procedures similar to those of Embodiments XVII-XIX, 2.50 g of 2-ethyl-1,8-dioxaspiro[4.5]decane-2-methanol was treated with 2.35 g of benzyl bromide in the presence of sodium hydride to yield 0.90 g of the desired product as a clear liquid, b.p. 130° C. (0.15 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH3:43][N:44]([CH2:46][CH2:47][CH2:48][NH2:49])[CH3:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:49][CH2:48][CH2:47][CH2:46][N:44]([CH3:45])[CH3:43])=[O:25]
Reactant: CN(C)CCCN
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)CCCNC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and dimethylaminopropylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=2)=[CH:4][CH:3]=1.[I:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([I:13])=[C:10]([CH3:12])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)s2)n[nH]1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]nc(-c2ccc(Cl)s2)c1I
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
3-(5-Chloro-2-thienyl)-5-methyl-1H-pyrazole (40.3 mmol) was dissolved in 70 mL dry N,N-dimethylformamide and cooled to 0° C. under nitrogen atmosphere. N-Iodosuccinimide (42.7 mmol) was added in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was poured into a mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution (1:1) at room temperature. The precipitate was filtered, washed thoroughly with water, dissolved in ethyl acetate, dried over MgSO4, filtered and evaporated to afford 9.9 g of 3-(5-chloro-2-thienyl)-4-iodo-5-methyl-1H-pyrazole (76% yield) that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: CC(C)c1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Product: CC(C)c1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from 2-bromo-4-isopropyl-phenol (example B.a6) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless solid after short path distillation at 2×10−3 mbar.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:8]([NH2:11])=[N:9][CH:10]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C.CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([C:4]#[C:3][CH2:2][NH:1][C:26]([NH2:25])=[O:27])=[CH:6][C:7]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(3-aminoprop-1-ynyl)-3-benzothiazol-2-ylpyridin-2-ylamine (10.0 mg, 0.0357 mmol), trimethylsilyl isocyanate (5.31 uL, 0.0392 mmol), DMF (1 mL, 0.01 mol) and DIPEA (0.03 mL, 0.2 mmol) was stirred at rt for 3 h. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=4.14 (s, 2H), 7.39-7.45 (m, 1H), 7.47-7.52 (m, 1H), 7.93 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H). MS (ES+): m/z=324.10 (100) [MH+]. HPLC: tR=2.85 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cnccn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cnccn1

Procedure:
The title compound, MS: m/e=295.3 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloropyrazine.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:10]=[C:9]([C:11](O)=[O:12])[N:8]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:7]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:10]=[C:9]([C:11]([Cl:3])=[O:12])[N:8]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
1.5 ml of thionyl chloride and 2 drops of dimethylformamide were added to a mixed solution comprising 1.5 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and 10 ml of toluene, followed by reflux with heating for 1 hour, and thionyl chloride and toluene were distilled off to obtain crude product of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:21])(=[O:20])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([O:16]C(C)C)=[CH:9][CH:8]=3>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.Br>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:21])(=[O:20])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3
Reactant: CC(C)Oc1ccc2c(c1)Oc1cc(F)ccc1S2(=O)=O
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Product: O=S1(=O)c2ccc(O)cc2Oc2cc(F)ccc21
Reaction time: 0.75 h
Yield: 99.3 %

Procedure:
A mixture of 3-fluoro-7-isopropoxyphenoxathiin 10,10-dioxide (Example 9) (3.51 g, 11.39 mmoles), tetrabutylammonium hydrogen sulfate (Aldrich) (0.654 g, 1.93 mmoles) and 48% aqueous hydrogen bromide (Acros) (80 mL) was refluxed with stirring for 45 minutes. The reaction was allowed to cool on an ice-bath, and the solid was collected, washed with water and dried in vacuo to give 3.010 g (99%) of 3-fluoro-7-hydroxyphenoxathiin 10,10-dioxide, mp 258-260° C. Recrystallization from ethyl acetate:hexanes gave the analytical sample, m.p. 250-260° C.
Reaction SMILES: [C:1]([C:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([O:10][C:8]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CN2N=C(C(C)(C)C)CC2=O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of methyl 4-[(3-tert-butyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)methyl]benzoate (2.00 g, 6.94 mmol), benzyl bromide (0.91 mL, 7.7 mmol), potassium carbonate (0.96 g, 6.9 mmol) and N,N-dimethylformamide (25 mL) was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (2.14 g, yield 81%) as a yellow oil. 1H NMR (CDCl3) δ: 1.29 (9H, s), 3.90 (3H, s), 5.01 (2H, s), 5.19 (2H, s), 5.49 (1H, s), 7.00-7.37 (7H, m), 7.92-8.00 (2H, m).
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([CH3:20])[CH:6]=[CH:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[O:9].[CH2:21](I)[CH3:22]>CN(C)C=O>[CH3:20][N:5]([CH3:4])[CH:6]=[CH:7][C:8]([C:10]1[CH:11]=[C:12]([N:16]([CH2:21][CH3:22])[C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CCI
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
17.5 gm Sodium methoxide was added portion wise to a clear solution of 50 gm N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]-phenyl] acetamide and 85 gm ethyl iodide in 500 ml dimethyl formamide. After 6 hrs of stirring at room temperature, the reaction mass was quenched in 5 liters of water and extracted in dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulphate and concentrated under vacuum to get oil, which upon trituration in hexane gave the title product as a solid.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].CO.[Cl-]>C(C(C)=O)C.O.C(N(CC)CC)C>[C:13]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)Cl
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(C)C2CC3CC(C2)CC1C3
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Into a reaction vessel were charges 33.26 g of methyl ethyl ketone, 16.63 g (0.1 mol) of 2-methyl-2-adamantanol and 30.36 (0.3 mol) of triethylamine, and their temperature was elevated to 60° C. under stirring. To the mixture, a solution prepared by dissolving 13.58 g (0.15 mol) of acryloyl chloride in 16.63 g of methyl ethyl ketone was added dropwise. At the end of dropwise addition, the temperature was reached 77° C. and the mixture was boiling with the reaction heat. The mixture was kept in a boiling state for 3 hours with stirring to complete the reaction. After cooling, 3.20 g (0.1 mol) of methanol was added dropwise to deactivate the unreacted acryloly chloride while keeping the temperature below 40° C. Then, 103 g of water was added to wash the mixture and thereafter the mixture was separated into layers. To the brown organic layer, 10 g of active carbon (Carborafin) was added and stirred. The mixture was thereafter filtered and the residue was washed with methyl ethyl ketone. The filtrate and washing effluents were combined and concentrated at a bath temperature of 45° C. to obtain 21.68 g of reddish orange crude 2-methyl-2-adamantyl acrylate.