Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C1CC=CC=1.[OH-].[Na+].C([C:15]1[C:16]([CH2:23][CH:24]=[CH2:25])=[C:17](CC=C)[CH2:18][CH:19]=1)C=C>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH2:3]([C:16]1([CH2:23][CH:24]=[CH2:25])[CH:15]=[CH:19][CH:18]=[CH:17]1)[CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: C=CCC1=CCC(CC=C)=C1CC=C
Agent: C1=CCC=C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Product: C=CCC1(CC=C)C=CC=C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 1.0 L double-walled reactor, provided with baffles, condenser, top stirrer, thermometer and dropping funnel equipped with a nitrogen inlet was charged with ALIQUAT 336 (7.7 g, 19 mmol), allylbromide (43.6 g, 0.36 mol) and freshly cracked cyclopentadiene (11.9 g, 0.18 mol). A 50 wt. % NaOH aqueous solution (147 g) was then added via the dropping funnel to the turbulently stirred reaction mixture. The reaction mixture was cooled with water during the addition of the base. After 3 hours of stirring at room temperature, GC analysis showed that 6% of mono-, 75% of di- and 19% of tri(allyl)cyclopentadiene were present in the mixture. The product was distilled at reduced pressure and after vacuum distillation, 9.75 g of di(allyl)cyclopentadiene were obtained. Characterization of the product took place with the aid of GC, GC-MS, 13C- and 1H-NMR.
Reaction SMILES: O1CCOCC1.[ClH:7].[O:8]=[C:9]1[NH:13][C:12](=[O:14])[O:11][N:10]1[CH2:15][C:16]1[CH:49]=[CH:48][C:19]([O:20][CH2:21][C:22]2[C:23]([CH3:47])=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][NH:38]C(=O)OC(C)(C)C)=[CH:30][C:29]=3[CH3:46])[CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1>C(OCC)(=O)C>[ClH:7].[NH2:38][CH2:37][CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][C:19]3[CH:48]=[CH:49][C:16]([CH2:15][N:10]4[C:9](=[O:8])[NH:13][C:12](=[O:14])[O:11]4)=[CH:17][CH:18]=3)[C:23]=2[CH3:47])=[C:29]([CH3:46])[CH:30]=1
Reactant: Cc1cc(OCCCNC(=O)OC(C)(C)C)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(OCCCN)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1C
Temperature: 0 °C

Procedure:
Under ice-cooling, a 4 M hydrogen chloride dioxane solution (15 ml) was added dropwise to a mixture of tert-butyl (3-{[3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-2,2′-dimethylbiphenyl-4-yl]oxy}propyl)carbamate (1.95 g) and ethyl acetate (5 ml), followed by stirring at 0° C. for a while and then stirring at room temperature for 1.5 hours. The solvent was evaporated under a reduced pressure, and the solid precipitated was collected by filtration and dried by heating under a reduced pressure to obtain 2-(4-{[4′-(3-aminopropoxy)-2,2′-dimethylbiphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione hydrochloride (1.53 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccnc(Oc2cccc(CO)c2)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(Oc2cccc(CCl)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
[3-(4-Methyl-pyridin-2-yloxy)-phenyl]-methanol from Step 1 (4.75 g, 22.1 mmol), in dichloromethane (50 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (1.93 mL, 26.5 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was stirred at rt for 5 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated by evaporation to afford the desired product (5.16 g, 99% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH:15]3[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[C:10]([C:19]([NH2:21])=O)[C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C.O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH:15]3[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[C:10]([C:19]#[N:21])[C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1sc2c(C(N)=O)ccc(OC3CCC3)c2c1N
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OC2CCC2)c2c(N)c(C(N)=O)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a stirred solution of the above amide (200 mg, 0.655 mmol) in DMF (3 mL) was added cyanuric chloride (60 mg, 0.325 mmol). The reaction was stirred at room temperature for 1 h. The mixture was slowly diluted with water (10 mL) and extracted with dichloromethane. The aqueous phase was allowed to stand for two weeks then the precipitate formed was collected by filtration, rinsed with MeOH and dried in vacuo to give the title compound (93.5 mg, 0.315 mmol, 48.1%).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[NH:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH2:8][CH2:7][CH:6]([CH2:4][O:5][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:18][C:17]2=1
Reactant: CCOC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3[nH]c4ccc(F)cc4c3C2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methanol (compound IV of Example 2) (5.975 g, 0.0272 mol) in anhydrous pyridine (15 mL) was cooled in ice bath and treated dropwise under vigorous stirring with an ice cold solution of para-toluenesulfonyl chloride (6.17 g) in anhydrous pyridine (10 mL). After stirring for one hour in the cold, the mixture was placed overnight in the refrigerator. It was then quenched with water (100 mL) under stirring and cooling. After 30 minutes the mixture was extracted with ethyl acetate (3×100 mL). The extracts were washed with cold 3N sulfuric acid (100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and evaporated to dryness. The crude material (light brown foam, 9.827 g) was used as such in the next step. MS (ES): [M−H]− @m/z 372.1.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][NH2:24].CCN(C(C)C)C(C)C>>[OH:20][CH2:21][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][NH:24][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: NCC(CO)c1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCC(CO)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 3-hydroxy-2-phenyl-propylamine and DIEA to give 2-(3-hydroxy-2-phenyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:20])[CH3:19])=[N:11]1.[NH:21]1[CH:25]=[CH:24][CH:23]=[N:22]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:25]2[CH:24]=[CH:23][NH:22][N:21]=2)[C:12]([NH:17][C:18](=[O:20])[CH3:19])=[N:11]1
Reactant: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br
Reactant: c1cn[nH]c1
Solvent: CCOC(C)=O
Product: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1c1cc[nH]n1
Temperature: 75 °C
Yield: 34.7 %

Procedure:
Next, 57 g (0.15 mol) of the 1-(2,4,6-trichlorophenyl)-3-acetylamino-4-bromo-5-oxo-2-pyrazoline and 41 g of pyrazole (0.6 mol) were mixed well, then heated for 6 hours at 75° C. in a stream of nitrogen gas to react, after which the reaction mixture was cooled to room temperature. Next the reaction mixture was dissolved in ethyl acetate and the solution was washed with water three times and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, acetonitrile was added to the residual oil, and the deposited crystals were filtered to obtain 20.1 g (34.7%) of 1-(2,4,6-trichlorophenyl)-3-acetylamino-4-pyrazolyl-5-oxo-2pyrazoline.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17]([OH:19])=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([C:17]([N:2]2[CH2:5][CH2:4][CH2:3]2)=[O:19])[CH2:16]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine hydrochloride salt (515 mg, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(azetidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(azetidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (260 mg, 37%). 1H NMR (CD3OD, 400 MHz) δ 4.19-4.08 (m, 2 H); 4.07-3.92 (m, 2 H); 3.91-3.78 (m, 2 H); 3.72-3.52 (m, 3 H) and 2.36-2.21 (m, 2 H).
Reaction SMILES: [Na+].[S:2]([O-:17])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:13]([O-:16])(=[O:15])=[S:14])(=[O:4])=[S:3].[Na+].Cl.[C:20]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[NH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:6]1([N+:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:27]([NH2:29])[NH2:28])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:6]1([N+:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:27]([NH2:26])[NH2:28])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:2]([O-:17])([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:13]([O-:16])(=[O:15])=[S:14])(=[O:4])=[S:3]
Reactant: N=C(Nc1ccccc1)Nc1ccccc1
Agent: Cl
Agent: O=S([O-])(=S)OCCCCCCOS(=O)([O-])=S
Agent: [Na+]
Solvent: O
Product: NC(N)=[N+](c1ccccc1)c1ccccc1

Procedure:
A solution of hexamethylene bis(thiosulphate) sodium salt (100 g. 0.282 mol) in 500 ml of water at 70° C. was added slowly to a stirred solution of 133 g (0.568 mol) of diphenylguanidine hydrochloride in 700 ml water. The mixture was cooled and the solid which separated was collected. Recrystallisation from a mixture of equal parts by volume of methanol and toluene gave 154 g (77.1%) of hexamethylene bis(thiosulphate) bis(diphenylguanidinium) salt, m.p. 151°-153° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18]>C(O)C>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:23]=[CH:24][CH:25]=1)#[CH:18]
Reactant: C#Cc1cccc(N)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 67.2 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.82 g (32.6 mmol) 3-ethynylaniline was heated to reflux under N2. Removed heat at 3.5 hours and added a solution of saturated sodium bicarbonate until basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Washed with water and dried in vacuo. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 4.544 g of yellow solid: mass spectrum (electrospray m/e): M+H=315.1.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.Cl.C(Cl)Cl.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:38]=[N:39][C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:36]>O.C(OCC)(=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10](=[O:12])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:38]=[N:39][C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:36])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccccc1C(=O)c1cnc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1C(=O)c1cnc2ccccc2c1
Reaction time: 45 h
Yield: 36 %

Procedure:
N-Boc-glycine (84.7 mg, 0.48 mmol) and EDCI HCl (92.6 mg, 0.48 mmol) were added to 6 mL of methylene chloride solution of (2-aminophenyl)-quinolin-3-yl-methanone (0.12 g, 0.48 mmol) under a nitrogen atmosphere at 0° C., followed by bringing back to room temperature and stirring for 45 hours. The resulting reaction solution was poured into 10 mL of ethyl acetate and 50 mL of water, and the aqueous layer was extracted with 100 mL of ethyl acetate, followed by washing the combined organic layer with 50 mL of brine and drying with magnesium sulfate. After filtering and concentrating, the resulting residue was purified by silica gel column chromatography to obtain {[2-(quinoline-3-carbonyl)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (0.07 g, yield: 36%), which was slightly yellow amorphous. Moreover, 1 mL of trifluoroacetic acid was added to this compound, followed by stirring at room temperature for 16 hours. The resulting reaction solution was poured into a mixture of 10 mL of ethyl acetate, 50 mL of saturated sodium bicarbonate water and 50 mL of water, the aqueous layer was extracted with 100 mL of ethyl acetate, and the combined organic layer was washed with 50 mL of brine, followed by extracting with magnesium sulfate. After filtering and concentrating, the resulting residue was dissolved in 10 mL of ethanol, and 0.5 g of acetic acid was added to the resulting solution. The solution was heated to reflux, and maintained for 30 minutes. The reaction solution was poured into a mixture of 100 mL of ethyl acetate, 50 mL of saturated sodium bicarbonate water and 50 mL of water, and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organic layer was washed with 50 mL of brine, followed by drying with magnesium sulfate. After filtering and concentrating, the resulting residue was purified by silica gel column chromatography to obtain the target compound (0.03 g, yield: 61%), which was slightly yellow amorphous.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][C@H:23]([C@@H:27]([OH:32])[C:28]([F:31])([F:30])[F:29])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][C@H:23]([C@@H:27]([OH:32])[C:28]([F:31])([F:29])[F:30])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)[C@@H](O)C(F)(F)F
Yield: 63.5 %

Procedure:
A solution of compound B (55 g) in ethanol (300 ml) was hydrogenated for 3 hours over 10% palladium on carbon catalyst (5.5 g), under a hydrogen pressure of 55 psi. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to give a viscous oil. The oil was triturated with diethyl ether (250 ml) for 16 hours and the resulting solid was collected by filtration to give (S)-1-[(S)-2-amino-3-methylbutyryl]-N-[(S)-2-methyl-1-((R)-2,2,2-trifluoro-1-hydroxyethyl)propyl]-pyrrolidine-2-carboxamide (C) (25.6 g) as a white solid; NMR(300 MHz, d6 -DMSO): 0.75-0.97(m,12H), 1.42(s,1H), 1.65-2.0(m,5H), 2.78,3.20(each d,total 1H), 3.45,3.60(each m,total 1H), 3.82(m,1H), 4.10(m,1H), 4.45, 4.57(each m,total 1H), 6.45(br d,1H), 7.45,7.60(each d, total 1H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>CNCCC1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:23]([CH3:26])[CH2:22][CH2:6][C:5]4[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: CNCCc1ccccc1
Solvent: CCO
Product: CN(CCc1ccccc1)C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and N-methylphenethylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=421.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].NC1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2C=1.[CH:47]1([S:50](Cl)(=[O:52])=[O:51])[CH2:49][CH2:48]1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][S:50]([CH:47]4[CH2:49][CH2:48]4)(=[O:52])=[O:51])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2nc3cc(NS(=O)(=O)C4CC4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Yield: 75.9 %

Procedure:
To a stirred solution of 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.100 g, 0.254 mmol) in pyridine (1.5 mL) was added dropwise cyclopropanesulfonyl chloride (71.0 mg, 0.510 mmol) at 0° C. The reaction mixture was slowly warmed to 23° C., and maintained at this temperature for 42 h. The reaction was quenched with sat. aq. sodium bicarbonate (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (10 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-55% EtOAc/hexanes) to yield the titled compound (96.0 mg, 76%), which was recovered as a 5:4 mixture of regioisomers. MS (ESI/CI): mass calcd. for C20H24ClN5O6S, 497.1; m/z found, 498.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.83 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 6.73 (s, 1H), 6.14 (s, 2H), 4.31-4.28 (m, 2H), 3.71-3.64 (m, 2H), 3.51-3.45 (m, 2H), 3.32 (s, 3H), 2.54-2.44 (m, 1H), 1.43-1.35 (m, 3H), 1.21-1.11 (m, 2H), 1.00-0.92 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:35](OCC)=[O:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:35]([C:27]2[N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=2)=[O:36])[CH2:4][CH2:3]1
Reactant: CCCCCCCCCCCCCCCCCCn1c(C(=O)OCC)nc2ccccc21
Reactant: CN1CCNCC1
Product: CCCCCCCCCCCCCCCCCCn1c(C(=O)N2CCN(C)CC2)nc2ccccc21
Temperature: 75 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
1-Methylpiperazine (1.811 g) was added to ethyl 1-octadecyl-1H-benzimidazole-2-carboxylate (1.601 g) and the mixture was stirred for 48 hours at 75° C. The reaction mixture was purified by silica gel column chromatography (silica gel 60 g, chloroform:methanol=1:0-50:1), thereby yielding the entitled compound (1.070 g) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH:11]=[CH2:12])[CH:6]=[CH:7][C:8]=1[OH:9].[CH2:13]([O:15][SiH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:14]>[Pt].[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][Si:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [Pt]
Agent: [H+]
Solvent: CC(C)O
Product: CCO[Si](CCCc1ccc(O)c(OC)c1)(OCC)OCC
Temperature: 55 °C
Yield: 88 %

Procedure:
Into a four-neck flask provided with a stirrer, a reflux condenser, a dropping funnel and a thermometer were added 164 g (1.0 mole) of 3-(3-methoxy-4-hydroxyphenyl)propene and 100 ppm in terms of platinum metal of a 2 mass % isopropanol solution of chloroplatinic acid. Then 164 g (1.0 mole) of triethoxysilane was dripped over the course of five hours from a dropping funnel and was reacted while the mixture was heated and stirred at a temperature in the range from 50 to 60° C. After the reaction was completed, vacuum distillation was performed and 289 g (0.88 mole) of the desired product (3-(3-methoxy-4-hydroxyphenyl)propyl triethoxysilane) were obtained. The yield was 88%.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37](C(OC(C)(C)C)=O)[CH:38]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[NH:36]1[CH:35]=[C:34]([C:2]2[CH:7]=[N:6][N:5]3[C:8]([C:11]4[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH:38]=[N:37]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Temperature: 100 °C

Procedure:
A mixture of N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (0.30 g, 0.81 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.29 g, 0.97 mmol), tetrakis(triphenylphosphine)palladium(0) (46.9 mg, 0.0406 mmol) and K3PO4 (0.43 g, 2.0 mmol) in 1,4-dioxane (4.0 mL) and water (2 mL) was heated at 100° C. under an atmosphere of nitrogen for 3 h. After cooling, the reaction mixture was extracted with ethyl acetate (3×30 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-15%) to afford the desired product. LCMS (M+H)+: m/z=402.1.