Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1[NH:25][C:24]2[C:26]3[C:12]=1[CH2:13][C@@H:14]1[C@@H:19]([C:20]=3[CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]([NH:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])[CH2:16][N:15]1[CH3:35])=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH2:33]([N:30]([CH2:31][CH3:32])[C:28](=[O:29])[NH:27][C@H:17]1[CH2:18][C@H:19]2[C@@H:14]([CH2:13][C:12]3[C:26]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]2=4)[NH:25][C:11]=3[C:9]([OH:10])=[O:8])[N:15]([CH3:35])[CH2:16]1)[CH3:34]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C(=O)OCc5ccccc5)c(c34)C[C@H]2N(C)C1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C(=O)O)c(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
104 mg (0.22 mmol) of 8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid benzyl ester is dissolved in 20 ml of methanol and, after adding 50 mg of palladium black, hydrogenated for 30 minutes under normal pressure at room temperature. After the catalyst has been filtered off and the mixture concentrated, 8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid is obtained in a 100% yield, mp: decomposition starting with 230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=O)[CH3:11].Cl.[NH2:14][OH:15].N1C=CC=CC=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[N:14][OH:15])[CH3:11]
Reactant: CC(=O)Cc1ccc(Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(Cc1ccc(Cl)cc1Cl)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A solution of 1-(2,4-dichlorophenyl)-propan-2-one (3.46 g, 16.7 mmole) in methanol (40 ml) was treated with hydroxylamine hydrochloride (1.40 g, 20.6 mmol) followed by pyridine (1.7 ml, 20.6 mmol). The resulting mixture was stirred at ambient temperature over night for 16 hours. The reaction mixture was poured onto water (200 ml). The solid product was collected by filtration, washed with water and dried (40° C., 100 mbar). 3.63 g (100% of theory) of 1-(2,4-dichlorophenyl)-propan-2-one oxime was obtained in form of a white solid (m.p. 120-124° C.).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].[C:22]([O:26][C:27](=[O:39])[NH:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36](Br)[CH:37]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:39])[NH:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[N:34][CH:35]=[C:36]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH:37]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCOc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)OC(C)(C)C)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [C], 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to [2-(5-bromo-pyridin-3-yloxy)-ethyl]-carbamic acid tert-butyl ester (intermediate A-7) to give the title compound as a white solid. MS: 398.1 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[S:9][CH2:8][CH2:7]1)(=O)[CH3:4]>C1C=CC=CC=1.CO>[CH3:1][N:2]=[C:3]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[S:9][CH2:8][CH2:7]1)[CH3:4]
Reactant: CN
Reactant: CC(=O)C1CCSc2[nH]c3ccccc3c21
Solvent: CO
Solvent: c1ccccc1
Product: CN=C(C)C1CCSc2[nH]c3ccccc3c21
Temperature: 100 °C

Procedure:
To a solution of the product (1.70 g) in the above (2) in benzene (36 ml) is added a 30% solution of methylamine in methanol (36 ml). The mixture is heated at 100° C. in a sealed tube for 18 hours and then evaporated to give 4-(1-methyliminoethyl)-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole. The product is dissolved in a mixture of tetrahydrofuran (50 ml) and methanol (50 ml) and sodium borohydride (562 mg) is added thereto with stirring on an ice bath. The mixture is stirred at room temperature for 40 minutes and evaporated. The residue is extracted with ether after addition of some pieces of ice and a 10% aqueous solution of sodium hydroxide. The extract is washed with water, dried and evaporated to give the title compound (1.77 g). Recrystallization from acetone gives colorless prisms melting at 179°-187° C. Yield: 64%.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[C:2]1S.[OH-].[Na+].OO>O.[OH-].[Na+]>[S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: Sc1nc2cnc3ccccc3c2s1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)ncc1ncsc12
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
Thiazolo[4,5-c]quinoline-2-thiol (8.7 g, 0.04 mole) was suspended in a solution of sodium hydroxide (1.4 g, 0.04 mole) in water. A few drops of 50% sodium hydroxide were added to the suspension until most of the solid dissolved. Hydrogen peroxide (13.5 mL of 30%, 0.08 mole) was added dropwise over a period of 30 minutes while maintaining the temperature of the reaction mixture at 25-35° C. with a cold water bath. The bath was removed and the reaction mixture was stirred for 15 minutes. Sulfuric acid (2.5 g of 95.98%) was added dropwise to the reaction mixture. After 30 minutes the reaction was made basic (pH 9-9.5) with 50% sodium hydroxide. The reaction mixture was acidified (pH 2.5) with hydrochloric acid, a tan solid precipitated. The mixture was then heated on a steam bath for 15 minutes and the precipitate dissolved. The solution was allowed to cool to ambient temperature and a precipitate formed. The mixture was made basic (pH 9) with 50% sodium hydroxide. The resulting oily product was extracted with ethyl acetate. The extracts were combined, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide 3.3 g of thiazolo[4,5-c]quinoline as a tan solid, m.p. 104.4-105° C. Analysis: Calculated for C10H6N2S: %C, 64.19; %H, 3.25; %N, 15.04; Found: %C, 64.15; %H, 3.26; %N, 14.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:13])=[O:12].[Na+].[CH2:15]1[O:18][CH:16]1[CH3:17].S(=O)(=O)(O)O>O>[OH:18][CH:16]([CH3:17])[CH2:15][S:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:13])=[O:12]
Reactant: CC1CO1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
150 g (0.5 mol) of 81% pure sodium 2-chloro-5-nitrobenzenesulphinate are presented in 300 ml of water at pH 8-8.5 and 60° C. To this are added dropwise in the couse of about 8 hours 200 ml of propylene oxide while the pH of the reaction mixture is constantly maintained between 7.5 and 9.5 with 20% strength sulphuric acid. After cooling down, the solids are filtered off with suction and washed twice with 200 ml of water. Drying at 70° C. in vacuo gives 118 g of colourless 2-chloro-5-nitrophenyl 2-hydroxypropyl sulphone.
Reaction SMILES: [F:1][C:2]1[C:27](F)=[CH:26][C:5]2=[N:6][C:7]3[N:8]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>CS(C)=O>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[N:8]1[C:7]2[N:6]=[C:5]3[CH:26]=[C:27]([N:39]4[CH2:38][CH2:37][N:36]([C:33]5[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=5)[CH2:41][CH2:40]4)[C:2]([F:1])=[CH:3][C:4]3=[CH:13][C:12]=2[C:11](=[O:14])[C:10]([C:15]([OH:17])=[O:16])=[CH:9]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Yield: 63.9 %

Procedure:
1-(2,4-Difluorophenyl)-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 1, but from 1.55 g of 7,8-difluoro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.58 g of 4-(4-fluorophenyl)piperazine in 15 cm3 of dimethyl sulphoxide. After recrystallizing once from 55 cm3 of dimethylformamide, 1.4 g of 1-(2,4-difluorophenyl)-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 322° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: CN1CCNCC1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)CC3)nn12
Temperature: 170 °C
Reaction time: 2 h

Procedure:
(rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 69 mg, 0.20 mmol), KF (58 mg, 1.0 mmol) and N-methyl-piperazine (60 mg, 0.60 mmol) were suspended in NMP (1.0 mL). The RM was stirred at 170° C. for 2 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a yellow foam (tR 2.83 min (conditions 1), MH+=409.1).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>ClCCl>[C:14]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CC(C)=CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OCC=C(C)C
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A 1-liter flask was charged with 43.9 g (0.51 mol) of 3-methyl-2-buten-1-ol, 51.6 g (0.51 mol) of triethylamine and 300 ml of dichloromethane, and the mixture was cooled down to 0° C. While stirring the mixture at 0° C., 45.3 g (0.50 mol) of acryloyl chloride were added dropwise over 1 hour, and the mixture was stirred additionally for 5 hours at room temperature. Solids were separated by filtration from the resultant reaction mixture, and the filtrate was washed 3 times with water and then distilled in the presence of 5 g of p-methoxyphenol to obtain 50.5 g of 3-methyl-2-butenyl acrylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[S:9][C:10]([Br:29])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[OH:18])[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1ccsc1NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1cc(Br)sc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamoyl}-thiophene-2-yl) carbamic acid t-butyl ester (the compound of Preparation Example 96) (6 g) in N,N-dimethylformamide (50 mL) was added N-bromosuccinimide (2.6 g) in small amounts on an ice bath. After stirring at room temperature for 1 hour, water was added, the solution was extracted with ethyl acetate. After the organic layer was washed with water, an aqueous solution of sodium bicarbonate and saturated sodium chloride water, and was dried with anhydrous magnesium sulfate. The extract was purified by passing through a column of NH silica gel, and the title compound (6.6 g) was obtained as a colorless candy-like substance.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][C:11]([C:14](OC)=[O:15])=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C(=O)OC)ccc2[nH]1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCc1nc2cc(CO)ccc2[nH]1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A solution of 2.1 g of 2-butyl-6-carbomethoxybenzimidazole in 50 mL of tetrahydrofuran was cooled with ice. To this solution was added dropwise 18 mL of 25% diisobutylaluminum hydride (DiBAl-H) in toluene. After the addition, the reacted mixture was stirred for 30 minutes with ice cooling and then for an additional 1 hour at room temperature. The reaction mixture was cooled back down to 0° and the reaction quenched by adding 15 mL of saturated ammonium chloride (NH4Cl) solution. The mixture was then filtered through celite and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (100% EtOAc elution) to give 1.23 g of the desired product as a thick colorless oil.
Reaction SMILES: [CH2:1]([OH:77])[C@H:2]1[O:7][C@@H:6]2[O:8][C@H:9]3[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]4[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]5[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]6[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]7[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]8[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]1[C@H:4]([OH:76])[C@H:5]2[OH:75])[O:56][C@@H:55]8[CH2:63][OH:64])[O:47][C@@H:46]7[CH2:65][OH:66])[O:38][C@@H:37]6[CH2:67][OH:68])[O:29][C@@H:28]5[CH2:69][OH:70])[O:20][C@@H:19]4[CH2:71][OH:72])[O:11][C@@H:10]3[CH2:73][OH:74].[CH2:78]1[O:81][CH:79]1[CH3:80]>[OH-].[Na+]>[CH3:3][CH:2]([OH:7])[CH2:1][O:70][CH2:69][C@H:28]1[O:29][C@@H:30]2[O:35][C@H:36]3[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]4[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]5[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]6[C@H:4]([OH:76])[C@@H:5]([OH:75])[C@@H:6]([O:8][C@H:9]7[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]8[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]1[C@H:32]([OH:33])[C@H:31]2[OH:34])[O:20][C@@H:19]8[CH2:71][O:72][CH2:41][CH:36]([OH:35])[CH3:37])[O:11][C@@H:10]7[CH2:73][O:74][CH2:14][CH:9]([OH:8])[CH3:10])[O:7][C@@H:2]6[CH2:1][O:77][CH2:28][CH:27]([OH:26])[CH3:32])[O:56][C@@H:55]5[CH2:63][O:64][CH2:46][CH:45]([OH:44])[CH3:50])[O:47][C@@H:46]4[CH2:65][O:66][CH2:19][CH:18]([OH:17])[CH3:23])[O:38][C@@H:37]3[CH2:67][O:68][CH2:78][CH:79]([OH:81])[CH3:80]
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Reactant: CC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CC(O)COC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCC(C)O)O[C@@H]7COCC(C)O)O[C@@H]6COCC(C)O)O[C@@H]5COCC(C)O)O[C@@H]4COCC(C)O)O[C@@H]3COCC(C)O
Yield: 90 %

Procedure:
In HU 202889, β-cyclodextrin (β-CD) is reacted with propylene oxide in aqueous sodium hydroxide solution to give hydroxypropyl-β-cyclodextrin. The resulting sodium chloride and the propylene glycol are removed by ion exchange and precipitation of the hydroxypropylated β-cyclodextrin in large amounts of acetone, filtration, taking up the filter cake in water, distillation and, finally, spray-drying. The yield is around 90%, and the salt and propylene glycol content is 0.1%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C@H:3]([CH3:14])[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[CH2:59][NH:58][CH2:57]3)[CH2:50][CH2:49]1>CN(C=O)C>[O:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[C:56]3[C:60](=[CH:61][CH:62]=2)[CH2:59][N:58]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C@@H:3]([CH3:14])[C:2]([F:1])([F:16])[F:15])=[O:9])[CH2:57]3)[CH2:50][CH2:49]1
Reactant: c1cc2c(cc1C1CCOCC1)CNC2
Reactant: C[C@H](Oc1ccccc1C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccccc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of 0.9 g (3.8 mmol) 2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid in 9 ml DMF under argon at room temperature, was added 1.4 g (4.2 mmol) TBTU, 3.3 ml (19.2 mmol) N-ethyldiisopropylamine and finally 0.8 g (3.8 mmol) 5-(tetrahydro-pyran-4-yl)-2,3-dihydro-1H-isoindole (CAS: 905274-50-2). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed twice with water and twice with sat. NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 1.5 g (93%) of the title compound as a yellow oil. MS (m/e): 420.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][C:21]2[CH:28]=[CH:27][CH:26]=[C:23]([CH3:24])[CH:22]=2)[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(C)c3)cc2N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
A mixture of the product from Example 38b (28 mg, 0.085 mmol), 3-methylbenzyl bromide (13 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the tile compound (32 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:14]([N:16]=[C:17](CC)[O-])#[N:15]>C(O)C>[C:14]([NH:16][CH:17]=[N:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)=[CH:3][C:2]=1[CH3:1])#[N:15]
Reactant: CCC([O-])=NC#N
Reactant: Cc1cc(-c2c[nH]cn2)ccc1N
Solvent: CCO
Product: Cc1cc(-c2c[nH]cn2)ccc1N=CNC#N

Procedure:
A solution of 4-(3-Methyl-4-amino-phenyl)-1-H-imidazole (15.9 g) and N-Cyano-ethylformimidate (9 g) in ethanol (100 ml) was stirred overnight at room temperature. The solid which crystallized out was filtered off and dried to give 11.3 of the desired compound. M.p. 200°-202° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([N:15]([CH2:23][CH3:24])C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>>[CH2:1]([O:8][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH:15][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(=O)OC(C)(C)C)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Product: CCNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To tert-butyl N-(3-benzyloxy-2-nitrophenyl)-N-ethylcarbamate (3.30 g) was added 4N hydrogen chloride—ethyl acetate solution (15 ml) under ice-cooling, and the mixture was stirred for 10 minutes at the same temperature and then for 30 minutes at ambient temperature. The solvent was removed in vacuo, saturated sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 3-benzyloxy-N-ethyl-2-nitroaniline (2.29 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:20])([CH3:19])[CH:8]2[C:11]2[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[CH3:19][C:7]1([CH3:20])[CH2:6][C:5]2[C:9](=[CH:10][C:2]([NH:1][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])=[CH:3][CH:4]=2)[CH:8]1[C:11]1[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=1
Reactant: CSc1ncncc1C1c2cc(N)ccc2CC1(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ncncc1C1c2cc(NS(=O)(=O)c3ccccc3)ccc2CC1(C)C

Procedure:
To a solution of 1.0 g (3.5 mmol) of 5-(6-amino-2,2-dimethylindan-1-yl)-4-methylthiopyrimidine in 20 mL of dry pyridine was added with stirring 0.45 g (3.7 mmol) of benzenesulfonyl chloride. The mixture was allowed to react for 16 hr and was then poured into dilute aqueous hydrochloric acid with stirring. The resulting mixture was extracted with ether and the ethereal extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The remaining oil was diluted with a small amount of dichloromethane and then hexane was added. The precipitate that formed was collected by filtration and dried under reduced pressure to obtain 700 mg (88 percent of theory) of the title compound as a tan solid melting at 174°-176° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH2:2].[C:8](Cl)([Cl:10])=[O:9].Cl>>[CH2:4]([O:3][CH:1]=[CH:2][C:8]([Cl:10])=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: C=COCC(C)C
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CC(C)COC=CC(=O)Cl
Temperature: 52.5 °C

Procedure:
100 g (1 mol) of isobutyl vinyl ether are initially charged in a 2 1 stirred apparatus and heated to 50-55° C. 1024 g (10.4 mol) of phosgene are subsequently introduced over a period of 21 h, and 900 g (9 mol) of isobutyl vinyl ether are added dropwise over a period of 19 h. After an extra reaction time of 0.5 hours, the reaction mixture is heated to 80° C. with nitrogen stripping to eliminate hydrogen chloride. The low-boilers are then distilled off via a 15 cm Vigreux column, and the residue is analyzed by gas chromatography. This gives 1551 g (80%) of crude isobutoxyacrylolyl chloride (calc. 100%).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH:32]1[CH2:38][OH:39]>>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:39][CH2:38][CH:32]2[CH2:33][N:34]([CH3:37])[CH2:35][CH2:36][N:31]2[CH3:30])/[N:7]([CH2:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cn(C[C@@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: CN1CCN(C)C(CO)C1
Product: CN1CCN(C)C(COc2ccc(C(F)(F)F)cc2C(=O)/N=c2\sc(C(C)(C)C)cn2C[C@@H]2CCCO2)C1

Procedure:
A mixture of Example 32B (108 mg, 0.25 mmol) and (1,4-dimethylpiperazin-2-yl)methanol (72 mg, 0.5 mmol) were processed using method described in Example 32B to afford the title compound. 1H NMR (500 MHz, pyridine-d5) δ ppm 1.17-1.26 (m, 9 H), 1.50-1.72 (m, 3 H), 1.86 (dd, J=12.5, 6.1 Hz, 1 H), 2.25 (s, 3 H), 2.31-2.55 (m, 7 H), 2.62 (d, J=10.1 Hz, 1 H), 2.74 (d, J=11.3 Hz, 1 H), 3.19 (d, J=10.7 Hz, 1 H), 3.65 (q, J=7.2 Hz, 1 H), 3.82 (q, J=6.9 Hz, 1 H), 4.16-4.38 (m, 3 H), 4.43-4.56 (m, 2 H), 7.20 (s, 1 H), 7.27 (d, J=8.5 Hz, 1 H), 7.71-7.80 (m, 1 H), 8.55 (s, 1 H); MS (DCI/NH3) m/z 555 (M+H)+.