Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:41][C:40]2[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=2)[CH:24]=1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: Fc1ccc(CCl)cc1
Product: COc1ccc(N(Cc2cnn(Cc3ccc(F)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.56 g) and 4-fluorobenzyl chloride (0.172 mL) as starting materials, 5-benzyloxy-N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.60 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 133, N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was obtained.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)/[CH:10]=[CH:11]/[CH:12]=[C:13]1[C:17](=[O:18])[C:16]([S:19][CH3:20])=[CH:15][C:14]1([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:21][Si](C)(C)C)(C(C)(C)C)(C)C.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[OH:8][CH:9]([CH2:37][CH2:38][CH2:39][OH:40])/[CH:10]=[CH:11]/[CH:12]=[C:13]1[C:17](=[O:18])[C:16]([S:19][CH3:20])=[CH:15][C:14]1([OH:21])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(=C/C=C/C(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Yield: 83.3 %

Procedure:
To a solution of 660 mg of 5-[(E)-4,7-bis(t-butyldimethylsilyloxy)-2-heptenylidene]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 75 dissolved in 50 ml of acetonitrile was added 4 ml of pyridine, under ice-cooling and stirring. A hydrogen-pyridine solution (2 ml) was added, and the mixture was stirred at 0° C. for 24 hours. The reaction mixture was poured onto saturated aqueous sodium hydrogencarbonate, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 320 mg (yield 83%) of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [CH3:1][C:2]1[CH2:21][C@@H:20]2[C@:7]([CH3:24])([CH2:8][C:9](=[O:23])[C@H:10]3[C@H:19]2[CH2:18][CH2:17][C@@H:16]2[C@:11]3([CH3:22])[CH2:12][CH:13]=[CH:14][CH2:15]2)[C:3]=1[C:4](=[O:6])[CH3:5].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[O:33]1[C@H:14]2[CH2:15][C@H:16]3[C@:11]([CH3:22])([CH2:12][C@@H:13]12)[C@@H:10]1[C@H:19]([C@H:20]2[C@:7]([CH3:24])([CH2:8][C:9]1=[O:23])[C:3]([C:4](=[O:6])[CH3:5])=[C:2]([CH3:1])[CH2:21]2)[CH2:18][CH2:17]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C1=C(C)C[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: ClCCl
Product: CC(=O)C1=C(C)C[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
16-Methyl-5α-pregna-2,16-diene-11,20-dione (800 mg.) in methylene chloride (50 ml.) was treated with m-chloroperbenzoic acid (85%; 535 mg.), and the solution was left to stand at room temperature overnight. More methylene chloride (50 ml.) was added and the solution washed with potassium bicarbonate solution (5%, 100 ml.) and with water (100 ml.), dried over sodium sulphate and evaporated to a crystalline solid (~ 1g.) which was purified by preparative TLC in ethyl acetate/petrol, 1/1 run twice. The main band yielded a white solid (650 mg.) which was recrystallised from acetone/ petrol to give title compound (515 mg.) as white crystals, m.p. 155°-157°, [α]D + 57.8° (c 0.9), λmax. (EtOH) 246.5 nm (ε 9150).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Yield: 87 %

Procedure:
A mixture of 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (638 mg, 2 mmol) and thionyl chloride (8 ml) was heated at reflux for 30 minutes. Excess thionyl chloride was removed by evaporation and by azeotroping with toluene (x2). The residue was suspended in methylene chloride and 10% aqueous solution of sodium hydrogen carbonate was added to the mixture. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, the solid was collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (590 mg, 87%).
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)#[N:2]>CCOC(C)=O.[Pd]>[NH2:24][C:23]1[C:3]([C:1]#[N:2])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.2 %

Procedure:
To a solution of (S)-tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 1e, 13 g, 36 mmol) in EtOAc (200 mL) was added Pd/C (3.82 g. 3.6 mmol 10% solution) and the mixture was stirred at room temperature under H2 for 6 hours until the reaction was complete. The mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (EtOAc/hexanes) to yield the title compound (11 g, 92.3%). (M+H)−Boc=232.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:16][C:15]=2[C:14]([OH:26])=[CH:13][CH:12]=1)[CH2:5][CH2:6][Cl:7].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C)C=O.O>[Cl:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][O:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:16][C:15]=2[C:14]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:13][CH:12]=1)[CH2:5][CH2:6][Cl:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1c2ccccc2sc2c(O)ccc(OCCN(CCCl)CCCl)c12
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCCN(CCCl)CCCl)c2c(=O)c3ccccc3sc12

Procedure:
A solution of 0.50 g of 1-(N,N-bischloroethylaminoethoxy)-4-hydroxythioxanthone in 10 ml of dimethylformamide is mixed with 0.22 g of tert-butyldimethylsilyl chloride, 0.20 g of imidazole and a catalytic amount of dimethylaminopyridine, and stirred at room temperature for 12 h. The solution is then added over water and extracted with ethyl acetate. The ethyl acetate extract is washed sequentially with saturated sodium bicarbonate and water, dried over sodium sulfate, concentrated and dissolved in a mixture of ethyl acetate: hexanes (1:4) and passed through a plug of alumina. The solid obtained after concentration is pure and weighed 0.48 g (70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:19])[N:8]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[CH:10]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[Cl:25]Cl>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:19])[N:8]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[C:10]=1[Cl:25])=[O:5])[CH3:2]
Reactant: ClCl
Reactant: CCOC(=O)c1cc(-c2ncc(Cl)cc2F)nn1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Cl)c(-c2ncc(Cl)cc2F)nn1C
Temperature: 0 °C
Yield: 95 %

Procedure:
22.9 g of 5-(5-chloro-3-fluoro-2-pyridyl)-2-methyl-[2H]-pyrazole-3-carboxylic acid ethyl ester (Example P19) are introduced together with 19.9 g of sodium acetate into 300 ml of glacial acetic acid at a temperature of 65° C. With stirring, 6.3 g of chlorine gas are passed over the solution at that temperature in the course of 1 hour. The reaction mixture is then poured into 2.5 liters of ice-water and subsequently stirred for 20 minutes. The resulting precipitate is filtered off, washed with ice-water and then dried in vacuo at 50° C. 24.4 g of the desired title compound are obtained in the form of a yellow solid having a melting point of 77-79° C.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29]Br.C(N(CC)CC)C>CC(C)=O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1
Reactant: O=C(CCCCBr)Nc1ccc2ccccc2c1
Reactant: CCCNC1CCc2ncsc2C1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCN(CCCCC(=O)Nc1ccc2ccccc2c1)C1CCc2ncsc2C1

Procedure:
9 is prepared from 1C and 9A using the same method as for 6 with acetone as solvent and triethylamine as base. Reaction temperature is 50° C. After evaporation of the solvent the residue is suspended in water, alkalized with sodium hydroxide solution and extracted three times with dichloromethane. After evaporation of the combined organic phases the product is crystallized as salt of maleic acid from acetonitrile/diethylether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[C:31]#[N:32])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.C(OCC)(=[O:40])C>CS(C)=O>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[C:31](=[O:40])[NH2:32])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C#N)c1
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 63 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
In analogy to GP 5, 386 mg of {3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamic acid tert-butyl ester (0.69 mmol, 1 eq) were dissolved in 4.8 ml of DMSO and 0.24 ml of 3 M aq. sodium hydroxide solution (0.72 mmol, 10-80 eq) were added. The mixture was heated to 63° C. and 1.85 ml of hydrogen peroxide solution (aq., 30%) were added over the course of 20 min. The mixture was stirred for another 2 h at 65° C. (bath temp.). The reaction mixture was poured onto 175 ml of ice water. 300 ml of ethyl acetate were added and the phases separated. The aqueous phase was extracted one more time with 150 ml of ethyl acetate. The combined organic layers were washed one time with brine, dried over sodium sulfate, filtered off and concentrated. The concentrate was purified (FlashMaster column chromatography, hexane/ethyl acetate 99/1-60/40) to afford 169 mg (42% yield, 0.29 mmol) of the desired product.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:8](=O)[CH2:9][CH3:10])[CH3:7]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([CH3:7])=[C:8]([CH2:9][CH3:10])[N:4]=1
Reactant: CCC(=O)C(C)Br
Reactant: NC(N)=S
Solvent: CCO
Product: CCc1nc(N)sc1C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
Thiourea (20.9 g., 0.275 mole) was dissolved in 250 ml. of refluxing ethanol. 2-Bromo-3-pentanone (41.3 g., 0.25 mole), dissolved in 50 ml. of ethanol, was added dropwise over 25 minutes to the refluxing thiourea solution. Following an additional 2 hours of reflux, the reaction was boiled down to approximately 100 ml., cooled and the crude product recovered as the hydrobromide salt by filtration. Purified 2-amino-4-ethyl-5-methylthiazole (15.1 g.; m.p. 45°-50° C.; m/e calcd: 142; found: 142) was obtained by dissolution in water and reprecipitation with aqueous 3 N potassium hydroxide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.C(OO)(=[O:17])C>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[N+:5]([O-:17])=[CH:6][CH:7]=1
Reactant: Cc1ccnc(-c2cc(C)ccn2)c1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2cc(C)cc[n+]2[O-])c1
Temperature: 23 °C
Reaction time: 50 h

Procedure:
27.6 g (0.15 mol) of 4,4'-dimethyl-2,2'-bipyridine are dissolved in 300 ml of dichloromethane. 86 ml of a 1.837-molar solution of peracetic acid in ethyl acetate are added dropwise at 23°-28° C. After stirring for 50 hours at 23° C., the mixture is concentrated in vacuo. 27.2 g (90% of theory) of 4.4'-dimethyl-2,2'-bipyridine 1-oxide crystallise from ethylbenzene/petroleum ether; melting point 80°-130° C. (over a range).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=2)[N:10]=[C:9]([O:18][CH3:19])[C:8]=1[CH2:20][C:21]1[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=1.[CH3:30][C:31]1[C:36]([C:37]([C:39]2[N:43]([CH3:44])[N:42]=[N:41][CH:40]=2)=[O:38])=[CH:35][CH:34]=[C:33]([CH3:45])[N:32]=1>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:37]([C:36]3[C:31]([CH3:30])=[N:32][C:33]([CH3:45])=[CH:34][CH:35]=3)([C:39]3[N:43]([CH3:44])[N:42]=[N:41][CH:40]=3)[OH:38])[CH:15]=2)[N:10]=[C:9]([O:18][CH3:19])[C:8]=1[CH2:20][C:21]1[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(N(C)C)cc1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(N(C)C)cc1
Reaction time: 0.03 h

Procedure:
A solution of n-butyllithium (2.5 M in hexanes, 0.27 mL, 0.66 mmol) was added dropwise by syringe to a stirring solution of 4-((4-chloro-6-iodo-2-methoxyquinolin-3-yl)methyl)-N,N-dimethylaniline (300 mg, 0.663 mmol, Intermediate 24: step c) in dry THF (5 mL) at −78° C. After 2 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (143 mg, 0.663 mmol, Intermediate 19: step b) in dry THF (1 mL) was added dropwise by syringe. After 3 minutes, the flask was removed from the cooling bath and allowed to warm. After 5 minutes, the flask was placed into an ice-water bath. After 15 minutes, water (5 mL) and ethyl acetate (25 mL) were added. The biphasic mixture was partitioned between half-saturated aqueous sodium chloride solution (20 mL) and ethyl acetate (25 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (4 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with 30% ethyl acetate-hexanes initially, grading to 90% ethyl acetate-hexanes provided the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.03 (s, 1H), 7.83-7.78 (m, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.23-7.17 (m, 2H), 7.00-6.90 (m, 3H), 6.68-6.61 (m, 2H), 4.19 (s, 2H), 4.11 (s, 3H), 3.92 (s, 3H), 3.45 (s, 1H), 2.88 (s, 6H), 2.55 (s, 3H), 2.39 (s, 3H); MS (ESI): mass calcd. for C30H31ClN6O2, 542.2. m/z found, 543.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: OC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCC(O)CC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxypiperidine (0.198 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH-CHCl3) to afford the title compound E24 as an off-white solid (0.20 g, 58%). mp 142-144° C.; HPLC: Hichrom RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 5.5); solvent B=CH3CN], Gradient elution program: T/%B=0/20, 10/20,25/80, 40/80, 55/60, 65/20, 70/20; 270 nm, Rt 40.56 min, 98.60% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 116 mg of 4-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.90 (t, 3H, J=6.8 Hz), 1.29 (m, 2H), 1.46 (m, 2H), 2.49 (t, 2H, J=7.6 Hz), 7.05 (d, 2H, J=8.4 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.40 (m. 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.56 (m, 3H), 7.76 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). MS: m/z 428.9 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>C1(C)C=CC=CC=1>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([NH:1][C:25]([NH:24][CH2:22][CH3:23])=[O:26])[CH:16]=2)=[CH:13][N:12]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1OC
Yield: 83.2 %

Procedure:
A solution of 5-(5-amino-2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.117 g, 0.4 mmol) and ethyl isocyanate (0.034 g, 0.5 mmol) in 4 mL of toluene was heated to 100° C. in a sealed tube. After 5 h the solution was cooled and concentrated in vacuo gave a brown solid. Purification via flash chromatography (CH2Cl2/MeOH 97:3) afforded 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-3-ethyl-urea (0.120 g, 83%) as a white solid; (M+H)=361.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:19][CH2:20][CH:21]([OH:23])[CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][O:15][C:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:19]([CH2:20][CH:21]([OH:23])[CH3:22])[C:5]=32)=[CH:10][CH:9]=1)=[O:14]
Reactant: CC(O)CN
Reactant: COC(=O)c1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.75 h
Yield: 81.2 %

Procedure:
A solution of 2.32 g of (RS)-2-(2-oxoethyl)-6-methoxycarbonyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.2 g (81%) of (RS)-1-(7-methoxycarbonyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([C:13]1[N:14]=[N+:15]([O-:35])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH:22]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:23]3)=[CH:19][C:17]=2[N:18]=1)[CH:11]=[CH2:12].C([O-])(=[O:38])C.[Na+].OO>C1COCC1.CO>[Si:28]([O:27][CH2:26][CH:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:16]3[N+:15]([O-:35])=[N:14][C:13]([CH2:10][CH2:11][CH2:12][OH:38])=[N:18][C:17]=3[CH:19]=2)[CH2:23]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: C=CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO[Si](C)(C)C(C)(C)C)C3
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC1Cc2cc3nc(CCCO)n[n+]([O-])c3cc2C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A solution of 9-BBN (0.5 M, 32.5 mL, 16.3 mmol) in THF was added to a stirred solution of alkene 137 (4.02 g, 10.8 mmol) in THF (50 mL) at 20° C. under N2 and the mixture was stirred at 20° C. for 30 min. The mixture was cooled to 0° C., a solution of sodium acetate (3 M, 25 mL, 75 mmol) and then H2O2 (70%, 25 mL, 468 mmol) were added carefully and stirred for 10 min. MeOH (100 mL) was added and the mixture stirred at 20° C. for 20 min. The mixture was partitioned between aqueous Na2CO3 solution and EtOAc. The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, using a gradient (50-70%) of EtOAc/pet. ether, to give alcohol 138 (2.08 g, 49%) as a pale yellow solid: mp (EtOAc/pet. ether) 93-94° C.; 1H NMR δ 8.22 (s, 1H, H-9), 7.72 (s, 1H, H-5), 3.79 (br q, J=5.1 Hz, 2H, CH2O), 3.59-3.67 (m, 2H, CH2OSi), 3.12-3.24 (m, 4H, CH2), 2.93-3.03 (m, 2H, CH2), 2.73-2.84 (m, 1H, H-7), 2.30 (br s, 1H, OH), 2.11-2.21 (m, 2H, CH2), 0.87 [s, 9H, SiC(CH3)3], 0.04 [s, 6H, Si(CH3)2]; 13C NMR δ 165.7, 154.2, 148.3, 147.3, 132.3, 122.8, 114.5, 65.4, 62.2, 42.0, 35.8, 35.5, 34.0, 30.6, 25.8 (3), 18.3, −5.41 (2). Anal. calcd for C20H31N3O3S.¼H2O: C, 61.7; H, 8.0; N, 10.8. Found: C, 61.5; H, 7.8; N, 10.9%.