Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[N:5]1[N:6]2[CH2:17][CH2:16][CH2:15][C:7]2=[CH:8][C:9]=1[C:10]([O:12]CC)=[O:11].N1N2CCCC2=C(C(OCC)=O)C=1>C(O)C>[N:5]1[N:6]2[CH2:17][CH2:16][CH2:15][C:7]2=[CH:8][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1cc2n(n1)CCC2
Agent: CCOC(=O)c1cnn2c1CCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cc2n(n1)CCC2
Temperature: 18.5 °C
Reaction time: 10 h
Yield: 48 %

Procedure:
Sodium ethoxide solution, in denaturated ethanol (21 wt %, 12 ml, 38 mmol) is added to 6.9 g (38 mmol) of the crude mixture of esters, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate and ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate in 3A ethanol (containing 3, 7% water, 15 ml) and the mixture is stirred for 10 hours under a nitrogen atmosphere at 15-22° C. Consumption of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, is monitored by HPLC [Prodigy ODS3 4.6×150 mm column, 10 minutes gradient from 90:10 to 10:90 water/acetonitrile with 0.02% trifluoroacetic acid, UV detection at 215 nm. Retention times under these conditions were: 2.6-2.7 min. for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (the desired, more polar isomer), 2.8-2.9 minutes for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (the undesired, less polar isomer) and 0.86 minutes for 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid]. The resulting mixture is evaporated under diminished pressure to a residue as a syrup. The syrup is mixed with ether (25 ml), and the resulting precipitate is collected on a filter. The hygroscopic filter cake is washed with diethyl ether (100 ml) and then dissolved in water (10 ml). The pH of the solution is adjusted to a value of 2 with 1N hydrochloric acid and the mixture extracted with ethyl acetate (3×25 ml). The combined organic extract is dried over magnesium sulfate and evaporated to give 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid as an off-white solid (1.40 g, 48%), m.p. 140-145° C., which is characterized by NMR, mass spectrum, elemental analysis, and HPLC (Prodigy ODS3 4.6×150 mm column, with a 20 min gradient from 95:5 to 30:70 using water/acetonitrile with 0.02% trifluoroacetic acid and UV detection at 215 nm. The retention time for 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid was 7.2 minutes) The product of the example is used directly in the next step (see example 13).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.ClC1C=C(C=C(Cl)C=1)CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc(Cl)c(-c2ccc(F)cc2)c(Cl)c1
Agent: OCc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(-c2ccc(F)cc2)c(Cl)c1
Reaction time: 20 h

Procedure:
To a solution of 2,6-dichloro-4′-fluorobiphenyl-4-carboxylic acid (350 mg, 1.155 mmol) in THF (5 mL) was added 2M borane-methyl sulfide complex in THF (0.35 mL, 0.70 mmol) at room temperature. After 20 hours, the reaction was quenched with 2M HCl and water and was extracted twice with ethyl acetate. The organic layers were washed with brine containing some aqueous sodium bicarbonate, dried over sodium sulfate, combined and concentrated. The residue was purified on silica gel (COMBI FLASH 12 gm column, 100% DCM, then a gradient of 2-10% ethyl acetate/DCM) to give a single main band by TLC (65 mg) containing a 1:1 mixture of title intermediate and 3,5-dichlorobenzyl alcohol from the Step 1 bi-product impurity. The mixture was used directly in Step 3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:21][CH2:22]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(O)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCC(OS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To 16.3 g (0.05 mol) of 1-(1-tert-butoxycarbonyl-4-piperidylacetyl)-4-hydroxypiperidine [5], 147.1 g of toluene and 6.58 g (0.065 mol) of triethylamine were added. 6.30 g (0.055 mol) of mesyl chloride was added dropwise to the mixture at a temperature in the range of 0 to 5° C. and the reaction was allowed to proceed for 2 hours at the temperature in the range. Toluene was added to the reaction mixture. Thereafter, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride, and concentrated under a reduced pressure. 70.8 g of toluene was added to the concentrated residue, and the temperature of the mixture was increased. After the residue was dissolved in toluene, filtration was carried out. Thereafter, the filtrate was cooled to room temperature and the crystals which precipitated at room temperature were collected by filtration. The resultant wet crystals were dried under a reduced pressure, whereby 17.2 g of the title compound in the state of white crystalline powder was obtained (the yield was 84.8%). The values obtained by the analysis of 1HNMR, 13CNMR and mass spectroscopy were substantially the same as those obtained in Step 5a of Example 2.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2)=[O:5])C.[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19]>C1(C)C=CC=CC=1>[OH:19][CH2:18][C:17]([NH:16][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2)=[O:5])([CH3:21])[CH3:20]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1ccc2c(c1)COC2=O
Solvent: Cc1ccccc1
Product: CC(C)(CO)NC(=O)c1ccc2c(c1)COC2=O

Procedure:
Method B): 5-Ethoxycarbonylphthalid (82 g, 0.4 mole) is added to a solution of 2-amino-2-methylpropan-1-ol (44.6 g. 0.5 mole) in toluene (100 ml). The mixture is heated to reflux temperature for 24 hours. Upon cooling the title compound is filtered off and recrystallised from hot toluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][C:10]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][CH:10]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(Br)cc1
Temperature: 50 °C
Yield: 64.9 %

Procedure:
To a solution of diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-phenylethyl)malonate (7.89 g, 17.1 mmol) in acetone (18.5 mL) and ethanol (17.0 mL) was added 1 N aqueous sodium hydroxide solution (17.1 mL), and the resulting solution was heated at 50° C. for 3 h. Solvent was then removed under reduced pressure via rotary evaporation and the resulting residue was further concentrated under high vacuum for 1 h. The residue was redissolved in dimethoxyethane (18.5 mL) and the solution was heated at 80° C. for 2.5 h. The mixture was cooled to rt, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under high vacuum. The resulting residue was purified by flash chromatography (Biotage flash 75, 10:90 ethyl acetate/hexane) to afford ethyl 4-(4-bromophenyl)-4-oxo-2-(2-phenylethyl)butanoate (4.32 g, 65%). LC-MS ret. time 3.79 min, m/z 389.2 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.20 (t, 3H), 1.78-1.94 (m, 2H), 2.62 (t, 2H), 2.86-3.01 (m, 2H), 3.26-3.36 (m, 1H), 4.10 (q, 2H), 7.05-7.11 (m, 3H), 7.18-7.23 (m, 2H), 7.51 (d, 2H), 7.72 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CC(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])[CH:5]=[O:6]
Reactant: CC(=O)OCCBr
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)OCCOc1ccc(C=O)cc1Cl
Yield: 41.5 %

Procedure:
A mixture of 3-chloro-4-hydroxybenzaldehyde (10 g, 63.9 mmol), K2CO3 (26.5 g, 191.6 mmol) and 2-bromoethyl acetate (26.7 g, 159.7 mmol) in acetone (250 mL) is refluxed for 18 h before it is diluted with diethyl ether (200 mL) and washed with water (3×200 mL). The washings are extracted with diethyl ether (200 mL). The combined organic extracts are dried over MgSO4 and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to afford the title compound (6.44 g) as colourless solid. 1H NMR (CDCl3): δ 9.85 (s, 1H9, 7.91 (d, J=1.8 Hz, 1H), 7.75 (dd, J=1.8, 8.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.53-4.49 (m, 2H), 4.35-4.31 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[CH3:20]I>C1COCC1.CCOC(C)=O>[F:3][C:4]1[CH:5]=[C:6]([N:13]([CH3:20])[C:14]2[CH:19]=[N:18][CH:17]=[N:16][CH:15]=2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(F)cc(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
NaH (4.5 mg, 0.18 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (0.4 mL) was added. The slurry was cooled to 0° C. and compound 30 (40 mg, 0.17 mmol, 1.0 eq) was added as a solution in THF (0.4 mL). After stirring at 0° C. for 30 minutes methyl iodide (12 μL, 0.18 mmol, 1.1 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 13 mg (31%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.79 (s, 2H), 7.58 (dt, J=2.1, 8.5 Hz, 1H), 7.52 (t, J=1.8 Hz, 1H), 7.33 (dt, J=2.3, 11.2 Hz, 1H), 3.42 (s, 3H); ES-MS [M+1]+: 249.1.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[Cl:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][O:22][N:23]=[C:24]1[C:28]2([CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)[CH2:27][NH:26][CH2:25]1.C(#N)C>C(N(CC)CC)C>[C:35]([O:34][C:32]([N:30]1[CH2:31][C:28]2([C:24](=[N:23][O:22][CH3:21])[CH2:25][N:26]([C:11]3[C:12]([Cl:14])=[C:13]4[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:16])[CH2:27]2)[CH2:29]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CN(C(=O)OC(C)(C)C)C2
Reaction time: 4 h
Yield: 31.6 %

Procedure:
300 mg of 1cyclopropyl-6,7-difluoro-8-chloro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 530 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 2 g of Amberlite® IRA-420 were added to 10 ml of acetonitrile and thereto 1 ml of triethylamine was added by dropping. The resulting mixture was refluxed for 72 hours and then the resulting solid was filtered off. The filtrate was concentrated under the reduced pressure and thereto 10 ml of ethylacetate was added and the resulting solution was stirred for 4 hours. The precipitated solid was filtered and dried to give 169 mg of the titled compound(yield: 31.4%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: Cc1cnc(NC(=O)OC(C)(C)C)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Temperature: 85 °C

Procedure:
A solution of tert-butyl 5-methylpyrazin-2-ylcarbamate (2.79 g, 13.33 mmol), NBS (2.61 g, 14.67 mmol) and AlBN (0.219 g, 1.33 mmol) in CCl4 (45 mL) was purged with Argon, then the solution was heated with 85° C. oil bath for 4 h. The reaction mixture was cooled to room temperature, concentrated and the residue was redissolved in EtOAc (˜50 mL), washed with dilute aqueous NaOH twice (10 mL 1 N NaOH diluted in 20 mL H2O), brine (30 mL), dried (Na2SO4) and concentrated. The residue was further purified by flash chromatography on silica gel eluted with gradient EtOAc/CH2Cl2 (0-30%) and tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate was obtained in off-white solid. LCMS (m/z): 288.1/290.1 (MH+), 0.82 min; 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (s, 1H), 8.32 (d, J=1.2 Hz, 1H), 7.62 (br. s., 1H), 4.56 (s, 2H), 1.56 (s, 9H).
Reaction SMILES: [CH:1]([NH2:3])=[S:2].Cl[CH:5]([CH:11]=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7]>CC(C)=O>[S:2]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:3]=[CH:1]1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: NC=S
Solvent: CC(C)=O
Product: CCOC(=O)c1cncs1
Yield: 60 %

Procedure:
To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl 2-chloro-2-formylacetate. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf=0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl3) δ1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95 (s, 1H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]Br)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H]1CC[C@H](CBr)CC1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC[C@H]1CC[C@H](COc2ccc(O)cc2)CC1
Temperature: 0 °C

Procedure:
A mixture of 5.0 g of (trans-4-heptylcyclohexyl)methyl bromide, 10.0 g of hydroquinone, 10.0 g of anhydrous potassium carbonate and 100 ml of absolute dimethylformamide was heated under reflux overnight. The cooled reaction mixture was subsequently poured into ice-water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 500 ml of water, dried over magnesium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) gave 1.8 g of 4-[(trans-4-heptylcyclohexyl)methoxy]phenol; m.p. 107°-108° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.C([Li])CCC.[I:23]I>C1COCC1>[I:23][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: II
Reactant: C[Si](C)(C)CCOCn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(I)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 63.2 %

Procedure:
A solution of 1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole (5.029 g, 20.25 mmol) (see Witten et al., J. Org. Chem., 51, 1891-1894 (1986)) in THF (50 mL) was cooled to −78° C. and added dropwise over 12 min via cannula to a flask containing n-butyllithium (2.5 M in hexanes, 12.2 mL) in THF (30 mL) at −78° C. under argon. After stirring for 25 min at −78° C., the flask was warmed to 0° C. for 10 min, then cooled again to −78° C. This solution was then added via cannula to a second flask containing iodine (25.7 g, 101 mmol) in THF (50 mL) at −78° C. Once the addition was complete (˜5 min), the cooling bath was removed, and stirring was continued for 30 min. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium metabisulfite (2×100 mL) to remove the dark iodine color, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (10% to 50% ethyl acetate/hexanes) yielded 4.79 g (63%) of pure 2-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-benzoimidazole as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, J=8.1 Hz), 0.92 (t, 2H, J=8.1 Hz), −0.03 (s, 9H). Anal. (C13H19IN2OS) C, H. Calculated: C, 41.71; H, 5.12; I, 33.90; N, 7.48. Found: C, 41.90; H, 5.09; I, 34.00; N, 7.37.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]3=[O:25])[N:8]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[C-:32]#[N:33].[Na+]>CS(C)=O>[CH:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:13]([CH2:12][C:9]2[N:8]([CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][C:32]#[N:33])[C:11]=3[N:10]=2)[C:14]1=[O:25])([CH3:23])[CH3:24]
Reactant: [C-]#N
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CCl)cccc21
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CC#N)cccc21

Procedure:
A solution containing 1-[4-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one; HCl salt (69 mg, 0.15 mmol) and sodium cyanide (30 mg, 0.62 mmol) in DMSO (1.5 mL) was stirred at room temperature for 1.5 h. The mixture was quenched with water (15 mL) and 1M NaOH (0.5 mL). The aqueous suspension was extracted with diethyl ether (2×10 mL) and the combined organic extracts washed with water, brine and dried (MgSO4). [2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-4-yl]-acetonitrile was obtained after concentration as a white solid (55 mg, 89%) and was used in the next step without purification:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1)[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=4[F:11])=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOc1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 160 °C
Yield: 38.5 %

Procedure:
A mixture of 4-ethoxy-2-fluoro-phenol (Intermediate 5; 125 mg, 0.801 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 270 mg, 0.801 mmol), and potassium carbonate (244 mg, 1.761 mmol) in 4 mL of dimethylformamide was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, the precipitate was filtered and the filtrate was extracted with ethyl acetate three times and the combined organic extracts were washed with saturated brine, and dried over sodium sulfate. The mixture was filtered, concentrated and purified by flash silica gel chromatography (4% methanol in dichloromethane) to afford 4-[4-(4-ethoxy-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (141 mg, 39%) as a white solid. Mass spectrum M+H-Boc=358.
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1)#[CH:2].Cl[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH2:13]([N:14]1[CH2:15][CH2:16][CH2:17][C:1]([C:3]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=2)=[CH:2]1)[CH2:12][CH3:11]
Reactant: CCCNCCCCl
Reactant: C#CC1=CC(=O)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCN1C=C(C2=CC(=O)CCC2)CCC1

Procedure:
3-Ethynyl-cyclohex-2-enone (3.20 g, 26.8 mmol) (from a) above) and (3-Chloro-propyl)-propyl-amine (4.50 g, 33.2 mmol) were mixed in acetonitril (50 mL). Cs2CO3 (100 mg) and KI (200 mg) were added and the mixture was refluxed under N2 for 10 h. After cooling the mixture was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The resulting dark oil was purified by column chromatography (silica, ethyl acetate) to give a yellow red oil. Yield 5.1 g, 23.3 mmol (87%). IR (neat) 2932, 2871, 1589, 1538, 1157 cm−; 1H-NMR (CDCl3) δ6.84 (s, 1H), 5.69 (s, 1H), 3.04-3.12 (m, 4H), 2.44 (t, 2H), 2.33 (t,2H), 2.18 (t, 2H), 1.83-2.03 (m, 4H), 1.49-1.64 (m, 2H), 0.87 (t, 3H) ppm; 13C-NMR (CDCl3) δ197.0, 158.5, 140.1, 112.1, 102.4, 56.6, 44.3, 35.6, 23.6, 21.4, 20.2, 20.1, 19.7, 9.6 ppm; MS (CI) m/z 220 (M+1).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[S:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=1)#[N:4]>C(O)C>[C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)#[N:4]
Reactant: N#Cc1cc(C=O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(CO)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
3.47 g (91.8 mmol) of sodium borohydride were added, a little at a time, to a suspension of 12.6 g (91.8 mmol) of 2-cyano-4-formylthiophene in 200 ml of ethanol and stirred at room temperature for 2 hours, during which process the reaction mixture slowly formed a clear solution. After concentration in vacuo, the residue was taken up in ethyl acetate, washed in succession with saturated sodium chloride solution, 5% strength citric acid and saturated sodium chloride solution, and the organic phase was dried using sodium sulfate and concentrated in vacuo. 11.7 g of almost pure product resulted (yield 91.5%).