Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1([CH2:11][CH2:12][CH:13]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:5]1([CH2:11][CH2:12][CH2:13][NH:4][CH2:3][CH2:1][OH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=CCCC1CCCCC1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OCCNCCCC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethanolamine (0.44 g, 7.1 mmol) in DCM (15 mL) at 0° C. was added a solution of 3-cyclohexylpropionaldehyde (1.0 g, 7.1 mmol) in DCM (10 mL) followed by sodium triacetoxyborohydride (1.67 g, 7.86 mmol). The resulting mixture was warmed to room temperature. After 2.5 hours the desired product was observed by mass spectrometric analysis. The reaction mixture was stirred overnight, then diluted with DCM (50 mL), washed with saturated sodium bicarbonate (2×50 mL), and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give a clear oil (1.0 g) which was used in the next step without further purification. ((m/z): [M+H]+ calcd for C11H23NO, 186.20; found, 186.0).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[C:8]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:9][C:10]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[N:11][CH:12]=1.[C:27]([N:34]([CH3:40])[C@H:35]([C:37](O)=[O:38])[CH3:36])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)C(C)C)(C)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:10]2[N:9]=[C:8]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:38])[C@@H:35]([N:34]([CH3:40])[C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:36])=[CH:12][N:11]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(Nc2ncc(C#CCCCN)c(N3CCCC3)n2)cc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)NCCCC#Cc1cnc(Nc2ccc(C#N)cc2)nc1N1CCCC1)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 4-((5-(5-amino-1-pentyn-1-yl)-4-(pyrrolidin-1-yl)pyrimidin-2-yl)amino)benzonitrile (H4, 2.64 g), N-Boc-N-methyl-L-alanine (3.10 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.92 g) and 1-hydroxybenzotriazole monohydrate (2.06 g) in N,N-dimethylformamide (40 mL), N,N-diisopropylethylamine (3.98 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The solvent was evaporated under reduced pressure, and to the obtained residue, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 30 to 5% hexane in ethyl acetate). The obtained solid matter was washed with a mixed solvent of ethyl acetate and hexane, and then dried under reduced pressure to obtain (S)-tert-butyl (1 -((5-(2-((4-cyanophenyl)amino)-4-(pyrrolidin-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (H5, 2.39 g) as white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)n[nH]c2c1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Br)nn(CCN3CCCC3)c2c1
Temperature: 50 °C
Yield: 64.7 %

Procedure:
A mixture of 3-bromo-6-nitro-1H-indazole (1.0 g, 4.1 mmol) and potassium carbonate (2.9 g 21 mmol) in DMF (20 mL) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine (1.8 g, 10 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (900 mg, 64%). 1H NMR (300 MHz, DMSO-d6) ppm 1.61 (m, 4H), 2.47 (m, 4H), 2.90 (t, 2H, J=6.44), 4.69 (t, J=6.44, 2H), 7.82 (m, 1H), 8.02 (m, 1H), 8.86 (m, 1H); MS (DCI/NH3) m/z 339 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:6]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[N:5][S:4][N:3]=1.[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:7]1([C:6]2[C:2]([O:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:3][S:4][N:5]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: OCCN1CCCC1
Reactant: Clc1nsnc1-n1ccnc1
Product: c1cn(-c2nsnc2OCCN2CCCC2)cn1

Procedure:
Following the procedures of Example 1, the title compound is prepared from 3-chloro-4-(1H-imidazol-1-yl)-1,2,5-thiadiazole and 1-(2-hydroxyethyl)pyrrolidine.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Br)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Bromo-benzoic Acid.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[CH3:18]/[C:19](/[CH:27]=O)=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1>[CH3:18][C:19](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:27]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: C/C(C=O)=C\c1ccccc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C=CC(=O)O)=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Butyllithium (135 mL of 2.5 N solution) was added to 600 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (30.5 g) in 220 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. over a period of 60 minutes. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of α-methyl-trans-cinnamaldehyde (23.2 g) in 100 mL of anhydrous THF was added to the reaction at −65° C. over a period of 70 minutes. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. The reaction was then acidified with 5% hydrochloric acid (125 mL) to a pH of 2.8. The aqueous layer was extracted with 100 mL of ether twice and with 100 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 100 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 25.8 g of the desired 4-methyl-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.53 (d, 1H), 7.43 (m, 4H), 7.37 (dd, 1H), 6.97 (broad s, 1H), 6.02 (d, 1H), 2.07 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([NH:8][C:9](=[O:13])[CH:10]=NO)[CH:5]=[CH:6][CH:7]=1.[OH:15]S(O)(=O)=O>>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:5]([C:10](=[O:15])[C:9](=[O:13])[NH:8]2)=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)C=NO
Reactant: O=S(=O)(O)O
Product: Cc1c(Br)ccc2c1NC(=O)C2=O
Temperature: 0 °C

Procedure:
A mixture of N-(3-Bromo-2-methyl-phenyl)-2-hydroxyimino-acetamide (18.0 g, 0.07 mol), conc.H2SO4 (150 mL) is stirred at 80° C. for 1 h. After reaction, poured the reaction mixture to ice water (2 L) the mixture is filtered and the solid is dried under vacuum to give product.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH3:32])=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:33]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:34]([C:41](O)=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH:33]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:34]([C:41]([NH:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH3:32])=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:42])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
17.0 g H-D-Trp-Lys(BOC)-OMe are mixed with 80 ml THF. 9.2 g Z-Phg-OH are added to the grey suspension at RT. Addition of 4.4 g HOBt, rinsing with 20 ml THF. The turbid yellow solution is cooled down to 0° and a solution of 5.3 ml DICI in 15 ml THF added within 10 minutes. Stirring 2 hours at 0°, then 2 hours at RT. Then addition of a solution of 3.6 sulfuric acid in 57 ml water, extraction with 70 ml ethyl acetate, washing with water, saturated brine, 5% sodium hydrogencarbonate, 25% brine, drying over MgSO4 and evaporation. The white residue is stirred in 125 ml isopropyl acetate 2 hours at 40° and the suspension filtered. Drying of the residue at 40°: slightly yellow substance. HPLC: 96.3% b.a. (25.3 min).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]2=[O:21].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC.[Cl-].[Li+].[F-].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:15]1([CH2:14][CH2:13][N:6]2[C:5](=[O:21])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[CH2:23])[CH:3]=3)[NH:8][C:7]2=[O:12])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=c1[nH]c2ccc(I)cc2c(=O)n1CCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc2[nH]c(=O)n(CCc3ccccc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 322 %

Procedure:
A solution (40 mL) of 6-iodo-3-(2-phenylethyl)quinazoline-2,4(1H,3H)-dione (2.0 g), tributylvinyltin (1.9 g), lithium chloride (1.1 g), dichlorobis(triphenylphosphine)palladium (0.18 g) in N,N-dimethylformamide was stirred under argon atmosphere at 90° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and 15% potassium fluoride solution were added, and the mixture was stirred for 2 hr. Insoluble material was filtered off through celite. The organic layer of the filtrate was separated, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (4.8 g, 97%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:14][CH2:13][CH2:12][S:9]1(=[O:11])=[O:10])[CH:2]=[CH2:3].[CH3:15][Si:16]([CH3:26])([CH3:25])[O:17][CH:18]([SiH3:24])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C(C)=CC=CC=1>[CH3:21][Si:20]([CH3:23])([CH3:22])[O:19][CH:18]([SiH2:24][CH2:3][CH2:2][CH2:1][O:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:14][CH2:13][CH2:12][S:9]1(=[O:10])=[O:11])[O:17][Si:16]([CH3:26])([CH3:25])[CH3:15]
Reactant: C=CCOCCOC1CCCS1(=O)=O
Reactant: C[Si](C)(C)OC([SiH3])O[Si](C)(C)C
Solvent: Cc1ccccc1C
Product: C[Si](C)(C)OC(O[Si](C)(C)C)[SiH2]CCCOCCOC1CCCS1(=O)=O
Yield: 134.7 %

Procedure:
A 500 ml three neck round bottom flask equipped with a magnetic stirrer, condenser, additional funnel, and pot thermometer was charged with 165.0 g (0.75 mol) of allyloxyethoxy sulfolane under appositive pressure of nitrogen. After heating to 80° C.-90° C., 61.2 g (0.28 mol) of bis(trimethylsiloxy)methylsilane was added, followed by 1 ml of Pt(0)-divinyltetramethyldisiloxane solution in xylene (2 wt % Pt). The pot temperature rose from 86° C. to approximately 102° C. The rest of 122.4 g (0.55 mol) of bis(trimethylsiloxy)methylsilane was added while maintaining a pot temperature of between 86° C.-106° C. The mixture was then maintained at a temperature between 86° C.-96° C. for 16 h and was distilled. 167.0 g (50.3%) pure bis(trimethylsiloxy)methylsilylpropoxyethoxy sulfolane was obtained. The pure product had a boiling point of 194° C.-200° C. at 0.4 mm Hg and a density of 1.412 at 25° C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1.[BH4-].[Na+].CCN(C(C)C)C(C)C.[CH3:35][C:36]([O:39][C:40]([O:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:41])([CH3:38])[CH3:37]>CO.C(Cl)Cl>[C:36]([O:39][C:40](=[O:41])[N:12]([CH2:11][C:10]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:8]([C:7]([CH3:18])([CH3:17])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)[CH2:22][CH:19]1[CH2:20][CH2:21]1)([CH3:38])([CH3:37])[CH3:35].[CH3:38][C:36]([O:39][C:40]([O:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:41])([CH3:35])[CH3:37]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: O=CC1CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (2.00 g, 7.00 mmol) and cyclopropancarboxaldehyde (0.784 mL, 10.5 mmol) in MeOH (70 mL) was heated to reflux for 4 h. The mixture allowed to cool to rt. NaBH4 (397 mg, 10.5 mmol) was added in portion, and the mixture was stirred for 1 h at rt. The solvents were removed under reduced pressure, and the resulting oil was diluted with EtOAc. The resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-cyclopropylmethyl-amine. This crude product was dissolved in CH2Cl2 (70 mL). DIPEA (3.60 mL, 21.0 mmol) and Boc2O (2.30 g, 10.5 mmol) were added. The mixture was stirred at rt for 2 h, and the mixture was diluted with CH2Cl2 (30 mL). The resulting mixture was washed with aq. 1M HCl, aq. sat. NaHCO3, and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane→EtOAc/heptane 10:90) yielded the title compound contaminated with Boc2O (3.60 g, quantitative yield). LC-MS: tR=1.25 min; ES+: 440.80.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:20]([NH:21][C:22](=[O:30])[N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:19][N:18](C5CCCCO5)[N:17]=4)[NH:13][C:12]=3[CH:37]=2)[CH2:4][CH2:3]1.Cl>O1CCOCC1.[OH-].[Na+]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:20]([NH:21][C:22](=[O:30])[N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:19][NH:18][N:17]=4)[NH:13][C:12]=3[CH:37]=2)[CH2:4][CH2:3]1
Reactant: CCCN(CCC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCN(CCC)C(=O)Nc1c[nH]nc1-c1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Yield: 41 %

Procedure:
A solution of 190 mg of 3-[3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-dipropylurea in solution in 3.5 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for 4 hours. A solid precipitates. The solid is filtered off and washed with dioxane and with isopropyl ether. The solid becomes pasty. Filtrate and precipitate are grouped together with methanol and the mixture is concentrated. The reaction crude is dissolved in a 2N aqueous solution of NaOH, and a sticky paste forms, which does not dissolve. It is recovered with methanol and the product is concentrated. The concentrate is dissolved in 10 mL of water and extracted with 2 times 10 mL and 2 times 15 mL of ethyl acetate. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. The precipitate obtained is purified by preparative HPLC with, as eluent, a gradient of water/acetonitrile containing respectively 0.07% of trifluoroacetic acid. 65 mg of 3-{3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-1,1-dipropylurea are obtained in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 0.89 (t, J=7.5 Hz, 6H); 1.57 (m, 4H); 2.89 (s, 3H); 3.03 (m, 2H); 3.23 (m partially masked, 2H); 3.29 (m, 4H); 3.57 (m, 2H); 3.87 (m, 2H); 7.13 (d, J=2.0 Hz, 1H); 7.24 (broad d, J=9.0 Hz, 1H); 7.59 (d, J=9.0 Hz, 1H); 7.98 (s, 1H).
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=CC(OC)=CC=4OC)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:36]([CH2:39][CH:40]1[CH2:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:48]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH3:58])[C:42]=2[O:41]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[CH3:58][O:57][C:50]1[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:49]=1[C:48]1[C:42]2[O:41][CH:40]([CH2:39][NH2:36])[CH2:44][C:43]=2[CH:45]=[CH:46][CH:47]=1
Reactant: COc1ccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)c(OC)c1
Agent: [Pd]
Agent: COc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c(OC)c1
Agent: [N-]=[N+]=[N-]
Product: COc1ccc(-c2cccc3c2OC(CN)C3)c(OC)c1
Yield: 72 %

Procedure:
Treatment of (±)-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.0 g, 6.81 mmol) with sodium azide (1.77 g, 27.26 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.215 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.57 g (72%) of (±)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 175-178° C.; Anal. calcd. for C17H19NO3HCl: C, 63.45; H, 6.26; N, 4.35. Found: C, 62.59; H, 6.25; N, 4.01.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3OCC[O:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1COCC1>[CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCC1)c1ccc(C2OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)CC2CCCC2)cc1
Yield: 92.5 %

Procedure:
The product of Example D (2.8 g, 0.011 mole) was dissolved in 50 mls of THF and 5 mls of 1N HCl was added. The mixture was refluxed for 3 hours and cooled. The solvent was removed on the rotary evaporator. The residue was dissolved in ethyl acetate and washed with 7% NaHCO3. After drying the solution over Na2SO4, the organic layer was concentrated on the rotary evaporator and the residue was chromatographed on silica gel using 5% ethyl acetate/hexane to give 2.2 g of the title compound (95% yield) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:20][CH:19]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCOc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCOc1ccc(C2=CCNCC2)cc1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(4-hexyloxyphenyl)-4-hydroxypiperidine (6.856 g) in dichloromethane (34 ml) was added trifluoroacetic acid (17 ml) and stirred for 30 minutes at 4° C. The reaction mixture was adjusted to pH 12 with 2M aqueous NaOH. The organic layer was separated, washed with water and dried over magnesium sulfate and evaporated under reduced pressure to give 4-(4-hexyloxyphenyl)-1,2,3,6-tetrahydropiridine (3.59 g)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:18])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Procedure NN: 4′-Nitro-biphenyl-4-carboxylic acid 200 mg (0.82 mmol), 152 mg of (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.99 mmol), 515 mg of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) (0.99 mmol) and 100 mg of triethylamine (0.99 mmol) are put into 5 ml of dichloromethane and stirred at room temperature for overnight. The reaction mixture is diluted with dichloromethane, washed by brine, dried over Na2SO4 and evaporated. The crude product is applied to silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=20:1), followed by SCX column to give the product. 163 mg (52%) Observed mass; 380 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][CH:28]([CH3:29])[CH3:30])#[N:24]
Reactant: CC(C)COc1ccc(N)cc1C#N
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(OCC(C)C)c(C#N)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
1-(4-Fluorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g), 5-amino-2-isobutoxybenzonitrile (1.7 g), triethylamine (2.7 g) and diethyl cyanophosphate (2.2 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (1.2 g), melting point: 177–178° C.