Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]([F:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Fc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A solution of 3-chloro-2-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-2H-indazole (217 g) in conc. sulfuric acid (1 kg) was cooled to 5° C., and 99% nitric acid (67 g) was dropwise added thereto at a temperature below about 10° C., followed by stirring for 3 hours. After completion of the reaction, the reaction mixture was added to ice-water (10 kg), and the precipitated crystals were collected by filtration, washed and dried to give 3-chloro-2-(2,4-difluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (227 g). m.p., 117°-118° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:28])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([OH:25])[CH:23]=[CH2:24])=[C:16]([CH3:26])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:27]=2)=[C:4]([CH3:29])[CH:3]=1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:28])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([O:25][C:37](=[O:39])[CH3:38])[CH:23]=[CH2:24])=[C:16]([CH3:26])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:27]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a 25 mL round-bottom flask equipped with a magnetic stir bar was added 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.65 g, 1.7 mmol), THF (5 mL), triethylamine (0.52 g, 5.1 mmol) and acetic anhydride (0.22 g, 2.2 mmol). To the stirred suspension was then added DMAP (0.002 g, 0.02 mmol). After 1 hour, all reaction components were fully dissolved and the reaction was complete as determined by TLC analysis. To the reaction mixture was added saturated aqueous ammonium chloride (20 mL) and the solution was extracted with ethyl acetate (2×20 mL). The organic fractions were collected, washed with brine (1×20 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was further purified by silica gel chromatography, eluting with 2% methanol:DCM to provide acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.404 g, 55%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ ppm 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37-7.34 (m, 3H), 7.25 (td, 1H, J1=2.7 Hz, J2=8.2 Hz), 6.34 (app d, 1H, J=6.3 Hz), 6.17 (ddd, 1H, J1=6.3 Hz, J2=10.2 Hz, J3=16.8 Hz), 5.41 (app d, 1H, J=17.2 Hz), 5.33 (app d, 1H, J=10.2 Hz), 4.18 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); ESMS (m/z): found, 435.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:21]([C:20]3[CH:19]=[C:18]([CH:26]=[CH:25][CH:24]=3)[C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Agent: N
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
N′-Hydroxynicotinimidamide (274 mg, 2.00 mmol) was coupled with 3-(tert-butoxycarbonyl)benzoic acid (Aldrich) according to the procedure described in Example 8. 1H NMR (300 MHz, CD3OD) δ 1.65 (s, 9 H), 7.65 (ddd, J=7.9, 4.8, 0.8 Hz, 1 H), 7.71-7.77 (m, 1 H), 8.26 (ddd, J=7.7, 1.8, 1.6 Hz, 1 H), 8.42-8.46 (m, 1 H), 8.57 (dt, J=7.9, 2.0 Hz, 1 H), 8.73-8.78 (m, 2 H), 9.31 (dd, J=2.2, 1.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 324 (M+H)+.
Reaction SMILES: C1(S([C:10](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]#[N:12])(=O)=O)C=CC=CC=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:21]=[N:22][NH:23][C:10]=2[C:11]#[N:12])=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC(=Cc1ccc(O)cc1)S(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1[nH]nnc1-c1ccc(O)cc1

Procedure:
A mixture of 2-benzenesulfonyl-3-(4-hydroxyphenyl)acrylonitrile (2.08 g, 7.3 mmol) and sodium azide (0.47 g, 7.3 mmol) in DMF (50 mL) was heated at reflux temperature 2 hours. After cooling, the mixture was poured on ice. The mixture was evaporated in vacuo to almost dryness and toluene was added. After filtration, the organic phase was evaporated in vacuo. The residue was purified by silicagel chromatography eluting with a mixture of ethyl acetate and heptane (1:2). This afforded 1.2 g (76%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Ic1ccc(N(Cc2ccccn2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccccn2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 90.3 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (124 mg) was reacted with N-(4-iodophenyl)-N-((pyridin-2-yl)methyl)pyrimidin-2-amine (159 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyridin-2-ylmethyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (208 mg). Column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=1/1→1/2) was used for purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>C(O)C.O1CCOCC1>[ClH:27].[ClH:27].[C:21]1([C:18]2[CH:19]=[N:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccccc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: c1ccc(-c2cnc(NC3CCNCC3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-phenyl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.06 g, 3.00 mmol) in ethanol (10 mL) was added 4 M HCl in dioxane (10 mL) and the reaction mixture stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 255.6 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][C:16]2[C:21]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]3[CH3:28])=[N:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[OH-].[Na+]>ClCCCl.O>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][C:16]2[C:21]([N:22]3[CH2:27][CH2:26][N:25]([CH3:30])[CH2:24][C@H:23]3[CH3:28])=[N:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: C[C@@H]1CN(C)CCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{2-[{2-[2-(dimethylamino)ethoxy]pyridin-3-yl}oxy]ethoxy}-3-[(2R)-2-methylpiperazin-1-yl]pyrazine (from Example 1; 0.48 g, 1.19 mmol) in 1,2-dichloroethane (4 mL) was added sodium triacetoxyborohydride (1.3 g, 6.2 mmol) and 37% aqueous formaldehyde (0.072 g, 2.4 mmol), the slightly exothermic reaction was stirred at ambient temperature overnight. Water was added and the mixture was made basic (pH>13) by addition of 8 M NaOH. After being stirred for five minutes, the phases were separated and the aqueous phase was extracted twice with CHCl3. The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The resulting oil was chromatographed on a column of silica (80 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (95:5:0.2; 100 mL, followed by 90:10:0.2) as eluent to give 0.33 (67%) of the title compound as a colorless oil. HRMS m/z calcd for C21H32N6O3 (M)+ 416.2536. found 416.2523.
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([CH3:10])=[C:5]([F:11])[C:3]=1[NH2:4].[Br:12]Br>CO>[Cl:1][C:2]1[C:8]([F:9])=[C:7]([Br:12])[C:6]([CH3:10])=[C:5]([F:11])[C:3]=1[NH2:4]
Reactant: Cc1cc(F)c(Cl)c(N)c1F
Reactant: BrBr
Solvent: CO
Product: Cc1c(F)c(N)c(Cl)c(F)c1Br
Reaction time: 12 h

Procedure:
A solution of 2-chloro-5-methyl-3,6-difluoroaniline (5.0 g, 28 mmol) in anhydrous methanol (25 mL) is treated with elemental bromine (5.0 g, 3,1 mmol) at room temperature. After stirring for 12 hours, most of the solvent is removed by rotary evaporator and the residue partitioned between EtOAc (250 mL) and water (250 mL). The organic phase is washed with brine (150 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (7% EtOAc/hexanes) to give 2-chloro-4-bromo-5-methyl-3,6-difluoroaniline as a tan solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:29].CC([O-])(C)C.[K+].CO>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[N:3]=[C:2]2[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:21]1=[O:29]
Reactant: COc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nc(-c3cccnc3)nc(-n3c(=O)[nH]c4ccccc43)c2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a 50-mL two-neck round bottom flask equipped with a reflux condenser was added a mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (50 mg, 0.18 mmol, 1 eq.) and 1H-benzo[d]imidazol-2(3H)-one (27 mg, 0.21 mmol, 1.1 eq.) in 5 mL of dry 1,4-dioxane. Pd(PPh3)4 (10.6 mg, 0.009 mmol, 0.05 eq) and t-BuOK (41 mg, 0.36 mmol, 2 eq.) were added. The resulting mixture was stirred at 100° C. under N2 atmosphere overnight. After cooling, 20 mL of methanol was added. The mixture was filtered, the filtrate was concentrated in vacuo and then was purified with chromatography on silica gel (ethyl acetate/petroleum ether from 1:4 to 1:2) to give the crude product, which was further purified with reverse phase HPLC to afford 4.8 mg of vi-e as a pale yellow solid (7%). MS m/z=370.1 (M+1) (Method B) (retention time=1.680 min). 1H NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1H), 8.78 (d, J=8.0 Hz, 2H), 8.17 (d, J=9.2 Hz, 1H), 7.80 (dd, J=9.2, 2.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 2H), 7.16-7.08 (m, 1H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([O:8][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: OCCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, phenethylalcohol and DBU in DME. ES-MS m/e (%): 327 (M+H+, 100).
Reaction SMILES: [Na].[OH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.C[O:11][C:12](=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1>O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][O:2][C:12](=[O:11])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:22])[CH3:23])=[CH:16][CH:15]=2)[CH:5]=1
Reactant: COC(=O)Cc1ccc(CC(C)C)cc1
Reactant: OCc1cccnc1
Agent: [Na]
Solvent: O
Product: CC(C)Cc1ccc(CC(=O)OCc2cccnc2)cc1

Procedure:
A mixture of 0.05 g of sodium and 8 ml of 3-hydroxymethylpyridine was heated at 65°-70° C. for 10 hours. To this mixture was added 2.1 g of p-isobutylphenylacetic acid methyl ester, and the whole was heated at 95°-100° C. for 8 hours. After the reaction was complete, 100 ml of water was added. The resulting mixture was extracted with ether, and the ether layer separated was dehydrated and concentrated to leave an oily residue. This residue was distilled under reduced pressure to give 1.9 g of p-isobutylphenylacetic acid-3-pyridylmethyl ester as a colorless liquid, boiling at 142°-145° C./1 mmHg. Analysis-Calculated for C18H21NO2 : C, 76.29; H, 7.47; N, 4.94. Found: C, 76.02; H, 7.38; N, 4.79. Mass spectrum: parent ion 283 m/e.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:41][C:42]1[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[C:43]=1[C:44](Cl)=[O:45]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])[N:10]([C:44]([C:43]3[C:47]([F:52])=[CH:48][C:49]([F:51])=[CH:50][C:42]=3[F:41])=[O:45])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2NN=C(c3ccc(F)cc3)S2)c1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazole is added DIEA (3.09 mmol) and 2,4,6-tri-fluorobenzoyl chloride (3.09 mmol) and the reaction mixture is stirred for 12 hours at room temperature. After concentration, the residue is purified by automated column chromatography (hexane/EtOAc) to yield [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone.
Reaction SMILES: [N:1]1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:9]=3[S:8](=[O:21])(=[O:20])[N:7]=2)C=CN=[CH:2]1.[CH2:22](N)[CH2:23]C>>[CH2:2]([NH:1][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:21])[N:7]=1)[CH2:22][CH3:23]
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ccc(C(F)(F)F)cc21
Reactant: CCCN
Product: CCCNC1=NS(=O)(=O)c2cc(C(F)(F)F)ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide was treated with propylamine according to the general procedure Method A to give the title compound; m.p. 241-243° C.
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][C@@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=O)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([CH:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:19][O:18][C:17]3[CH:28]=[CH:29][C:14]([F:13])=[CH:15][CH:16]=3)[O:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCC[C@H](O)COc1ccc(F)cc1
Reactant: O=S(O)c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCCC[C@@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
25% HCl was added dropwise to sodium salt of benzenesulfinic acid (5 g, 30.5 mmol) until the solid dissolved. The reaction mixture was extracted with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfinic acid (3.9 g, 90%). To an ice-cold mixture of benzene sulfinic acid (1.8 g, 12.4 mmol) and CaCl2 (1.4 g, 12.5 mmol) in dry methylene chloride (50 ml) was added dropwise a solution of (6S)-7-(4-fluorophenoxy)-6-hydroxyheptanal (2 g, 8.3 mmol) in methylene chloride (10 ml). The reaction mixture was stirred for 3 hours and filtered through celite, and washed with methylene chloride. The combined organic layer was washed with saturated aqueous Na2CO3, water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using EtOAC-hexane (1:6) as eluent to give (2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.45 g, 80.8%); 1H-NMR (CDCl3, 200 Hz): δ 1.39-2.20 (m, 7H), 2.5 (m, 1H), 3.57-3.90 (m, 2H), 4.45 (m, 1H), 4.72 (dd, J=6.6, 12.0 Hz, 1H), 6.57-7.00 (m, 4H), 7.36-7.96 (m, 5H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][C:7]=2[NH2:8])[CH2:3][CH2:2]1.CO[C:24](OC)(OC)[CH3:25]>CO>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:24]([CH3:25])=[N:8][C:7]=2[CH:9]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCC1CC1
Reactant: COC(C)(OC)OC
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.5 %

Procedure:
To a methanol (5 mL) solution of 2-(2-cyclopropylmethylaminoanilin-5-yl)benzoxazole (see Working Example 54-1) (140 mg, 0.425 mmol) was added 1,1,1-trimethoxyethane (75 mg, 0.624 mmol), and this was stirred at room temperature for 10 hours. After the reaction was complete, this was concentrated, and the residue obtained was purified by silica gel column chromatography to yield the title compound (81.9 mg, 54% yield) as pink crystals.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1noc(N)c1Cl
Product: Cc1noc(NS(=O)(=O)c2ccccc2)c1Cl
Yield: 84 %

Procedure:
N-(4-Chloro-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared according to the method in Example 1b from 5-amino-4-chloro-3-methylisoxazole and benzenesuIfonyl chloride in 84% yield. The crude product was purified by recrystallization using hexanes/ethyl acetate, m.p. 140°-143° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[CH:14]=1)=[O:7].[CH3:30][N:31]([CH3:37])[CH2:32][CH2:33][CH2:34][NH:35][CH3:36]>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:35]([CH2:34][CH2:33][CH2:32][N:31]([CH3:37])[CH3:30])[CH3:36])=[CH:19][CH:18]=2)[CH:14]=1)=[O:7]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccccc1F
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(N(C)CCCN(C)C)cc1
Yield: 29 %

Procedure:
Using an analogous procedure to that described in Example 20, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-2-fluorobenzamide was reacted with N,N,N′-trimethyl-1,3-propanediamine to give the title compound in 29% yield; m.p. 178-179° C.; NMR Spectrum: (DMSOd6) 1.64 (m, 2H), 2.13 (s, 6H), 2.17 (s, 3H), 2.22 (t, 2H), 2.95 (m, 9H), 3.41 (t, 2H), 6.73 (d, 2H), 6.89 (m, 1H), 7.19 (m, 3H), 7.29 (t, 1H), 7.56 (m, 1H), 7.8 (d, 1H), 7.84 (d, 2H), 9.44 (s, 1H), 10.05 (s, 1H); Mass Spectrum: M+H+ 488.
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[CH3:10][CH:11]([CH3:15])[C:12](=[S:14])[NH2:13]>C1COCC1>[CH:11]([C:12]1[S:14][C:2]([CH3:9])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:13]=1)([CH3:15])[CH3:10]
Reactant: CC(C)C(N)=S
Reactant: COC(=O)C(=O)C(C)Br
Solvent: C1CCOC1
Product: COC(=O)c1nc(C(C)C)sc1C

Procedure:
A mixture of methyl 3-bromo-2-oxobutanoate (4.6 g) and 2-methylpropanethioamide (2.5 g) in THF (100 mL) was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.7 g.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[N:17][CH:18]=1
Reactant: Oc1cncc(F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cncc(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 5-fluoropyridin-3-ol.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][NH:14][NH2:15]>C(O)(=O)C>[CH2:10]([C:9]1[N:14]([CH3:13])[N:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1)[CH3:11]
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(=O)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2,4-dioxohexanoate (12 g) in glacial acetic acid (75 ml) was cooled in an ice-bath and treated with methylhydrazine (3.21 g) in a dropwise fashion over 5-10 m. On complete addition the ice cooling was removed and the yellow homogeneous solution stirred at room temperature for ca. 2 h. The acetic acid was then removed in vacuo and the residual oil re-dissolved in ethyl acetate (˜100 mls). The ethyl acetate solution was washed with saturated sodium hydrogen carbonate (3×) and brine. After drying over anhydrous magnesium sulphate the solvent was evaporated. The crude material was purified by silica gel chromatography eluting with 20-70% ethyl acetate/hexane giving the title compound as a pale yellow oil, (6.656 g, 52%); dH(CDCl3) 1.28 (3H, t, J7.6 Hz), 1.38 (3H, t, J7.1 Hz), 2.61 (2H, q, J7.6 Hz), 3.84 (3H, s), 4.38 (2H, q, J7.1 Hz) and 6.58 (1H, s).