Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@@H:12]([O:14][CH2:15][C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=3)[N:30]=[CH:31][C:24]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:10][CH2:11][C@@H:12]([O:14][CH2:15][C@H:16]([O:21][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=3)[N:30]=[CH:31][C:24]=12)[C:17]([O:19][CH3:20])=[O:18])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)CO[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO[C@@H](C)CO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
Sodium hydride (0.219 g, 5.48 mmol) was added to (S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-hydroxypropanoate (Intermediate AO1) (1.336 g, 4.57 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.216 g, 4.57 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 60% EtOAc in isohexane to give (2S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (1.658 g, 69.5%). m/z (ES+), (M+H)+=522.50; HPLC tR=3.35 min
Reaction SMILES: C(OC([NH:11][C:12]1([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(NC1(CO)CCCCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1(CO)CCCCC1

Procedure:
A slurry of 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane (4.0 g, 15 mmol) and 10% Pd/C (0.40 g) in MeOH (75 ml) was stirred under H2 (1 atm.) for 1 h, then treated with Celite®. The resulting mixture was filtered and concentrated under reduced pressure to give 1-amino-1-(hydroxymethyl)cyclohexane.
Reaction SMILES: C1(C)C=CC=CC=1.S(Cl)([Cl:10])=O.[O:12]=[C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[C:15]([C:22]([F:25])([F:24])[F:23])[N:14]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[O:12]=[C:13]1[C:18]([C:19]([Cl:10])=[O:20])=[CH:17][CH:16]=[C:15]([C:22]([F:25])([F:24])[F:23])[N:14]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)n(Cc2ccccc2)c1=O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(F)(F)F)n(Cc2ccccc2)c1=O

Procedure:
Toluene (20 mL), thionyl chloride (1.3 g, 10.7 mmol) and a catalytic amount of N,N′-dimethylformamide were added to 1,2-dihydro-2-oxo-1-phenylmethyl-6-(trifluoromethyl)pyri-dine-3-carboxylic acid (2.0 g, 7.2 mmol), and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 1,2-dihydro-2-oxo-1-phenylmethyl-6-(trifluoromethyl)pyridine-3-carbonyl chloride. The obtained acid chloride was dissolved in acetonitrile (30 mL), and 1,3-cyclohexanedione (0.9 g, 7.9 mmol) and sodium cyanide (0.8 g, 15.8 mmol) were added thereto. This mixture was stirred for a day at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After separating the inorganic substance by filtration, the solvent was distilled off under reduced pressure and thus obtained concentrated solution was purified by column chromatography, to obtain 1.5 g of a desired product (yield: 68%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:20]=[C:19]1[CH2:31][CH3:32])[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:23]([O-:42])=[CH:22][C:21]=2[N:20]=[C:19]1[CH2:31][CH3:32])[CH:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl[4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate in chloroform was added m-chloroperbenzoic acid (4 eq.) and stirred at ambient temperature for 2 hrs. Reaction mixture was then diluted with chloroform and washed with saturated sodium bicarbonate solution. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield sticky mass. Product was then purified using silica gel column chromatography to afford tert-butyl[4-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.F[C:9]1[C:10]2[C:14]([CH:15]=[CH:16][CH:17]=1)=[N:13][N:12]([CH3:18])[C:11]=2[S:19]([NH2:22])(=[O:21])=[O:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH:3]1([CH2:6][O:7][C:9]2[C:10]3[C:14]([CH:15]=[CH:16][CH:17]=2)=[N:13][N:12]([CH3:18])[C:11]=3[S:19]([NH2:22])(=[O:21])=[O:20])[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: Cn1nc2cccc(F)c2c1S(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1nc2cccc(OCC3CC3)c2c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
2.8 g (70 mmol) of 60% sodium hydride was suspended in 50 ml of DMSO, and 6 g (83 mmol) of cyclopropane methanol was dropwise added thereto. The mixture was stirred at room temperature for one hour, and then 5.4 g (24 mmol) of 4-fluoro-2-methyl-2H-indazole-3-sulfonamide was added thereto. The mixture was stirred at 130° C. for 3 hours. After the reaction, the mixture was poured into ice water, acidified with citric acid and extracted with ethyl acetate. The organic layer was washed with water and then concentrated. Formed crystals were collected by filtration, washed with IPE and then dried to obtain 5.8 g (yield: 90%) of the desired product. Melting point: 139°-141° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([F:13])=[CH:7][C:6]=1[Cl:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[Cl:14][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: COc1cc(F)cc(Cl)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: COc1cc(F)cc(Cl)c1-c1csc(N)n1
Yield: 28.5 %

Procedure:
A solution of 2-bromo-1-(2-chloro-4-fluoro-6-methoxyphenyl)ethanone (14-1, 0.84 g) and thiourea (0.27 g, 3.6 mmol) in 95% EtOH (8.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure, and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-chloro-4-fluoro-6-methoxyphenyl)thiazol-2-ylamine (14-2, 0.22 g, 0.85 mmol) as yellow solids in 28% yield: 1H NMR (500 MHz, CDCl3) δ 6.81 (m, 1 H), 6.60 (m, 1 H), 6.49 (s, 1 H), 3.79 (s, 3 H).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][O:28]COC)=[CH:22][CH:21]=3)=[C:17]([CH3:32])[CH:16]=[C:15]([CH3:33])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C[Si](C)(C)Br.C(=O)(O)[O-].[Na+]>ClCCl>[C@@H:1]1([O:12][C:13]2[C:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=3)=[C:17]([CH3:32])[CH:16]=[C:15]([CH3:33])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: COCOCCc1ccc(Cc2c(C)cc(C)nc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c(Cc2ccc(CCO)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n1
Reaction time: 0.17 h
Yield: 16.4 %

Procedure:
To a solution of 2-(β-D-glucopyranosyloxy)-3-[4-(2-methoxymethyloxyethyl)benzyl]-4,6-dimethylpyridine (0.054 g) in dichloromethane (1.2 mL) was trimethylbromosilane (0.061 mL) at −23° C., and the mixture was stirred for 10 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=6/1) to give 2-(β-D-glucopyranosyloxy)-3-[4-(2-hydroxyethyl)benzyl]-4,6-dimethylpyridine (0.008 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:16]([OH:17])[C:15]3[S:18][CH2:19][CH2:20][S:21][C:14]=3[C:13]1=[O:22])=[N:7]2.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27]>CN(C)C=O.CS(O)(=O)=O.C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:13]([O:22][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[O:27])[C:14]3[S:21][CH2:20][CH2:19][S:18][C:15]=3[C:16]1=[O:17])=[N:7]2
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2c(Cl)ccnc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3c(Cl)ccnc3n2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
6-(5-Chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (11.9 g.) is added, at 0° C., to a suspension of sodium hydride (1.2 g.) in anhydrous dimethylformamide (120 cc.). The reaction mixture is stirred for 1 hour at 5° C., and 1-chlorocarbonyl-4-methylpiperazine (16.6 g.) dissolved in anhydrous dimethylformamide (80 cc.) is then added. After stirring for 21/2 hours at 5° C., the crystals which have appeared are filtered off and washed twice with diethyl ether (60 cc.). The product thus isolated is dissolved in an ice-cold 2N aqueous solution of methanesulphonic acid (200 cc.). The aqueous acid solution is washed with diethyl ether (80 cc.), and rendered alkaline by adding an excess of 10N sodium hydroxide solution. The oil which separates out is extracted twice with methylene chloride (total 400 cc.). The organic solution is washed three times with distilled water (total 240 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.2 g.) and evaporated. The crystals obtained (10.1 g.), m.p. 238° C., are dissolved in a boiling mixture of acetonitrile (200 cc.) and methylene chloride (180 cc.). After distilling off the methylene chloride and then cooling the residue for 1 hour at 2° C., the crystals which have appeared are filtered off, washed twice with ice-cold acetonitrile (total 40 cc.) and dried under reduced pressure (20 mm. Hg). 6-(5-Chloro-1,8-naphthyridin-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (8.0 g.), melting at 240° C., is thus obtained.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)C.COC(Cl)=O.C(=O)([O-])O.[Na+].O.NN>C(Cl)(Cl)Cl>[CH:1]1[C:17]2[CH2:16][C@H:15]3[NH:18][CH2:20][CH2:21][C@:7]45[C@H:8]([C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]34)[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: COC(=O)Cl
Agent: NN
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Oc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)NCC[C@@]341
Yield: 77.4 %

Procedure:
After melting 3.82 g of morphine in 190 ml of Chloroform, 20.9 g of methylchloroformate and 16.0 g of sodium hydrogencarbonate are added; then the thus obtained mixture is refluxed for 8 hours. Non-organic material is filtered from the reacted material; the filtered material is subjected to a dehydration with the aid of anhydrous sodium sulfate; and a solvent medium is evaporated under a reduced pressure to obtain a residue thereof having a light yellow color and a viscosity. Into the thus obtained residue, 11.4 ml of 97% hydrazine hydrate is added, and then 15.2 ml of 64% hydrazine hydrate is further added; then the residue with the hydrazine hydrate is refluxed for 12 hours to deposit crystal. The thus deposited crystal is washed with water, acetone and chloroform to obtain 2.81 g of normorphine. Whether the thus obtained substance is a desired normorphine is checked by a nuclear magnetic resonance (NMR) method.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].Cl[C:25]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:4][CH2:5][C:6]1=[O:8])([O:13][CH3:25])=[O:12]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: COc1ccc(C(C#N)(CCC(=O)O)CCC(=O)O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC)c2)CCC1=O
Yield: 94 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 34.25 gm. (0.098 mole) of the dimethyl ester of 4-cyano-4-(3.4-dimethoxyphenyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 640 ml. of the tetrahydrofuran, 22.0 gm. (0.196 mole) of the potassium tert-butoxide and 155 ml. of the 2.5 N of the aqueous acetic acid instead of the 700 ml. the 24.4 gm. (0.218 mole), and the 175 ml. respectively, there is prepared 29.2 gm. (94% yield) of 2-carbomethoxy-4-cyano-4-(3,4-dimethoxyphenyl)cyclohexanone as crystals having a melting range of 110° to 113° C. An analytical sample recrystallized from a mixture of ethyl acetate and cyclohexane melts in the range of 112.5° to 114.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[CH:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@H:3]1[C:21]([O:23]C(C)(C)C)=[O:22].Cl>ClCCl>[CH3:1][C:2]1([CH3:28])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]#[CH:20])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[C@H:3]1[C:21]([OH:23])=[O:22]
Reactant: C#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: C#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Through a solution of 0.271 g (0.638 mmol) of tert-butyl(3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholinecarboxylate in 10 mL of dichloromethane was bubbled hydrogen chloride gas for 10 minutes. The reaction was then stoppered and let sit overnight at room temperature. The solvent was evaporated to give 0.221 g of (3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec 368.2 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH:36]1([CH2:39]O)[CH2:38][CH2:37]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:36]1([CH2:39][O:22][C:21]([C:20]2[C:15]3[N:14]=[C:13]([C:24](=[O:35])[NH:25][CH:26]4[CH2:31][CH2:30][N:29]([CH:32]([CH3:33])[CH3:34])[CH2:28][CH2:27]4)[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:23])[CH2:38][CH2:37]1
Reactant: OCC1CC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)OCC4CC4)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
325.1 mg (0.57 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid were dissolved in 20 mL CH2Cl2. Subsequently 470 μl (5.7 mmol) cyclopropyl-methanol, 152.2 mg (0.74 mmol) DCC and 6.9 mg DMAP were added. The resulting mixture was stirred at room temperature for 16 h. The next day further 100 μl (2.28 mmol) cyclopropyl-methanol, 58.6 mg (0.29 mmol) DCC and 20 mg DMAP were added and the reaction mixture was stirred for 48 h. The solvent was removed under vacuo. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid cyclopropylmethyl ester as a white amorphous solid. The corresponding acetate was obtained by the following procedure: The above described material was dissolved in CH2Cl2 and washed with a saturated NaHCO3-solution. The organic layer was dried over anhydrous MgSO4 and concentrated. The resulting residue was diluted in 20 mL water containing 4 equiv. AcOH and lyophilized.
Reaction SMILES: [N:1]12[CH2:28][CH2:27][CH2:26][C@@H:25]1[C:24](=[O:29])[O:23][CH2:22][CH2:21][CH2:20][CH:19]=[CH:18][CH2:17][CH2:16][CH2:15][O:14][C:13](=[O:30])[C@@H:12]1[N:8]([CH2:9][CH2:10][CH2:11]1)[C:7](=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:32]>C(OC(=O)C)C.[Pd]>[N:1]12[CH2:28][CH2:27][CH2:26][C@@H:25]1[C:24](=[O:29])[O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13](=[O:30])[C@@H:12]1[N:8]([CH2:9][CH2:10][CH2:11]1)[C:7](=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:32]
Reactant: O=C1OCCCC=CCCCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1OCCCCCCCCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Yield: 60.4 %

Procedure:
A mixture of 400 mg (0.9 mmol) (12R,25R)-14,23-dioxa-1,8-diaza-tricyclo[23.3.0.0 8,12]octacos-18-ene-2,7,13,24-tetraone and 40 mg 10% palladium/carbon in 10 ml ethylacetate was hydrogenated over night. Filtration and removal of the solvent yielded 245 mg (61%) (12R,25R)-14,23-dioxa-1,8-diaza-tricyclo[23.3.0.0 8,12]octacosane-2,7,13,24-tetraone as a white solid, MS m/e (%): 451 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C[Mg]Br.[C:15]1([C:25](Cl)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:25]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=[O:26]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: COc1ccc2[nH]ccc2c1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc2[nH]cc(C(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a cooled solution at 0° C. of 5-methoxy-1H-indole 3 (7.4 g, 50 mmol) in diethyl ether (150 ml) under nitrogen was added dropwise a solution of methylmagnesium bromide (3M) in diethyl ether (17.5 ml) and the mixture was stirred for 2 h at room temperature. The solution was then cooled at 0° C. and to this solution was added a solution of 1-naphthoylchloride (9.5 g, 50 mmol) in diethyl ether (100 ml) dropwise over a period of 15 min. After the addition was completed the solution was warmed up at room temperature and stirred for 2 h followed by slow addition of saturated ammonium chloride solution (375 ml) and stirred overnight. The white solid formed was filtered, washed by ether and dried under high vacuum to give 5-methoxy-3-(1-naphthoyl)-1H-indole 4 (11.3 g, 75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]1(=[O:18])[O:17][CH:15]([CH3:16])[CH2:14][O:13]1>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][C:12](=[O:18])[O:13][CH2:14][CH:15]([OH:17])[CH3:16]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CC1COC(=O)O1
Product: CO[Si](CCCNC(=O)OCC(C)O)(OC)OC
Reaction time: 24 h

Procedure:
3-Aminopropyltrimethoxysilane (20 g, 0.111 mol) was mixed with propylene carbonate (11.39 g, 0.111 mol) under slow stirring. The mixture became slightly warm. Stirring continued for 24 hours to give 2-hydroxylpropyl N-(3-trimethoxysilylpropyl)carbamate. 2-Methyl-1-3 propanediol (38.8 g, 0.431 mol) was added drop-wise under stirring to a mixture of 2-hydroxylpropyl N-(3-trimethoxysilylpropyl)carbamate (31.4 g, 0.111 mol) and sulfuric acid (0.1 g) and then heated at 50° C. and 15 mm Hg pressure for 4 hours. The methanol that formed was removed by distillation. The product was a clear and slightly viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30](=[O:34])[CH2:31][C:32]#[N:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)([CH3:39])[CH:37]=O.N1CCCC1.[Si](Cl)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30]([C:31](=[CH:35][C:36]([CH3:39])([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH3:37])[C:32]#[N:33])=[O:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCOCC1
Reactant: N#CCC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C=C(C#N)C(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To the mixture of 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (90.6 mg, 0.200 mmol), 2-methyl-2-morpholino-propanal (98.3 mg, 0.590 mmol) in DCM (2 mL) in an ice bath was added pyrrolidine (0.1 mL, 1.19 mmol) and TMS-Cl (0.1 mL, 0.79 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour and the reaction mixture directly loaded on silca gel plate, purified by EtOH:CH2Cl2 5% to get pure product 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-morpholino-pent-2-enenitrile (23 mg) as a white powder. LC-MS (ES, m/z): 597 [M+H]