Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[CH:10]=[C:4]([CH2:5][C:6]=1[C:7](O)=O)[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]2=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>O.CN(C)C=O>[C:1]12[CH2:10][C:4](=[CH:5][C:6]=1[CH2:7][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]2=1
Reactant: O=C(O)C1=C2C=C(C1)c1ccccc12
Reactant: C1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C1=C2CC(=C1CN1CCCCC1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Benzobicyclo[2.2.1]heptenecarboxylic acid (0.4 g) was combined with piperidine (1 ml), diethylcyanophosphonate (1 ml), triethylamine (2 ml) and dimethylformamide (10 ml) and stirred for 2 hours at room temperature. Water (15 ml) was added and the mixture was extracted with ether (3×15 ml). The combined ether solutions were washed with water (2×25 ml) and the ether solution was dried over magnesium sulfate and the ether removed on a rotary evaporator. The residue was combined with tetrahydrofuran (25 ml) and lithium aluminum hydride (0.2 g) and heated to reflux for 12 hours. The mixture was cooled in an ice bath, treated with ethanol (1 ml) and water (0.5 ml) and the solids were removed by filtration. The filtrate was concentrated on a rotary evaporator and the residue was dissolved in 6N HCl (20 ml). The acidic solution was washed with ether (2×25 ml) and the aqueous solution was made basic with 50% sodium hydroxide solution. The mixture was extracted with ether (3×25 ml) and the combined ether solutions were dried over magnesium sulfate and the ether removed on a rotary evaporator. The residue was distilled on a Kugelrohr apparatus (80° C. at 0.05 mm Hg) to provide the product as a colorless oil. Analytical data are reported in Table I.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].Cl.[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][NH:24]1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[CH2:27][CH2:26][CH2:25][N:24]1[CH2:2][C:3]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:4]
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2CC(=O)NC2Cc3ccccc3C2)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and 1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
Reaction SMILES: [C:1]([S:5][NH:6][CH3:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([N:16]=[C:17]=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(N(CC)CC)C.O1CCCC1>[CH3:7][N:6]([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)=[O:18]
Reactant: CNSC(C)(C)C
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(SC(C)(C)C)C(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
12 g of tert.-butylmercapto monomethylamine, 20 g of 3,4-dichlorophenyl isocyanate and 3 drops of triethylamine were added to 120 ml of tetrahydrofuran and after stirring the mixture for 30 minutes, the solvent was distilled off under reduced pressure. The residue was crystallized from ethanol to obtain 25.6 g of N-methyl-N-tert.-butylthio-N'-(3,4-dichlorophenyl)-urea melting at 127° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.O1CCOCC1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1ccc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc2ncccc2c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
In a 100 ml flask was placed starting material quinolone (4.22 g) and dioxane (40 ml). POCl3 (4.6 g) was added, and the mixture was heated to 75° C. After 2 hours, HPLC showed the reaction finished (99.7% conversion). Reaction mixture was cooled to room temperature, and then poured to 100 ml saturated NaHCO3 solution and 20 ml EtOAc. The resulting suspension was stirred for 3 hours. Product was isolated by filtration, washing with EtOAc and drying under vacuum. Yield: 4.0 g, 90.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:21])([C:17]([F:18])([F:19])[F:20])[C:14]([O:16][CH3:26])=[O:15])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)C(C)(Oc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F

Procedure:
A solution of (±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid (3.0 g.) in ether (100 ml.) is treated with an excess of ethereal diazomethane at 0° C. The solvent is evaporated and the residue recrystallised from methanol to give (±)-methyl 2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionate, m.p. 87°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[C:11]([OH:18])[CH:10]=2)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12](/[C:15](=[N:28]/[OH:29])/[CH3:16])=[C:11]([OH:18])[CH:10]=2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)=O)c(O)c3)c2)CCOCC1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(/C(C)=N/O)c(O)c3)c2)CCOCC1
Yield: 77 %

Procedure:
Using an analogous procedure to that described in Example 7, 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2'-hydroxyacetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2'-hydroxyacetophenone oxime in 77% yield, m.p. 140°-142° C.;
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][C@H:16]([S:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][N:14]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)=[O:39].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[N+:48]([C:45]1[CH:44]=[CH:43][C:42]([CH2:41][O:40][C:38]([N:14]2[CH2:15][C@@H:16]([S:18][C:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][C@H:13]2[CH:12]=[O:11])=[O:39])=[CH:47][CH:46]=1)([O-:50])=[O:49]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (1.06 ml, 14.9 mmol) was added to a solution of oxalyl chloride (0.648 ml, 7.43 mmol) in methylene chloride (40 ml) at -78° C. in a nitrogen stream over 2 minutes. The resulting reaction solution was stirred at the same temperature for 10 minutes. To this reaction solution, a solution of (2S,4S)-2-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (2.47 g, 4.45 mmol) in methylene chloride (10 ml) was added dropwise over 5 minutes. This reaction mixed solution was stirred for 10 minutes and then triethylamine (3.11 ml, 22.3 mmol) was added dropwise over 2 minutes. This reaction solution was reverted to room temperature over 30 minutes, brought together with saturated aqueous ammonium chloride to terminate the reaction, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo to give a crude product of (2S,4S)-N-(p-nitrobenzyloxycarbonyl)-4-tritylthioprolinal.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH:16]([CH3:18])[CH3:17].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH:16]([CH3:18])[CH3:17])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CC(C)O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
20% palladium hydroxide (wet, 60 mg) was added to a solution of tert-butyl cis(±)-4-(benzylamino)-3-isopropoxypiperidine-1-carboxylate obtained in Example (147d) (120 mg, 0.345 mmol) in methanol (1.2 mL), and the mixture was catalytically hydrogenated at room temperature for three hours. The catalyst was filtered off, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the resulting residue, and the organic substance was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 74 mg of tert-butyl cis(±)-4-amino-3-isopropoxypiperidine-1-carboxylate as a colorless oily substance (83%). The resulting amine was dissolved in DMF (1 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 54 mg, 0.29 mmol) was added, and the mixture was cooled in an ice water bath. 1-Hydroxybenzotriazole (44 mg, 0.31 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (60 mg, 0.31 mmol) were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, sequentially washed with brine, water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol) to obtain 60.6 mg of the title compound as a colorless solid (50%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].CS(O)(=O)=O.[CH:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:12][CH:11]=1.C(O[K])(C)=O>O.C(O)C.C(COC)OC>[NH2:3][CH2:2][CH2:1][NH:4][C:18](=[O:19])[O:17][CH2:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: NCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(=O)O[K]
Agent: CS(=O)(=O)O
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: NCCNC(=O)OCc1ccccc1
Yield: 50.9 %

Procedure:
Ethylenediamine (1.0 g, 16.7 mmol) is dissolved in water (3.0 mL) containing bromoaresal green as an indicator. Methane sulfonic acid (2.8 g, 31 mmol) in water (3.0 ml) was added until a blue to pale yellow color transition is just achieved. The solution was diluted with ethanol (8.0 mL) and vigorously stirred. To the mixture was added the solution of Cbz-Cl (2.8 g, 16.7 mmol) in dimethoxyethane (4 mL) and 50% w/v aqueous AcOK (10 mL) at 20° C. simultaneously to maintain the pale yellow-green color of the indicator. After the additions are complete the mixture was stirred (RT, 1 h) and concentrated at low temperature under vacuum to removed the volatiles. The residue was shaken with water (20 mL) and filtered. The filtrate was then washed with toluene (3×50 mL), basified with excess 40% aqueous NaOH and extracted with toluene (3×50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and evaporated to give benzyl 2-aminoethylcarbamate as an oil (1.65 g, 51%). Mass calculated for C10H14N2O2=194.23; found: [M−H]+=193.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[C:11]1[S:12][C:13](/[CH:16]=[CH:17]/[C:18]2[O:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[CH:14][N:15]=1>C1COCC1>[C:23]([C:20]1[O:19][C:18](/[CH:17]=[CH:16]/[C:13]2[S:12][C:11]([N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]3[NH2:1])=[N:15][CH:14]=2)=[N:22][CH:21]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)c1cnc(/C=C/c2cnc(Br)s2)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cnc(/C=C/c2cnc(N3C=CC=CC3N)s2)o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-aminopyridine (238 mg, 2.56 mmol) in THF (8 mL) under argon was added sodium hydride (100 mg of 60% oil dispersion, 2.5 mmol) and the reaction stirred at 60 deg C. for 15 minutes, cooled to room temperature and 2-bromo-[(E)-5-(2-(5-t-butyl-oxazol-2-yl)-vinyl)-thiazole] (200 mg, 0.64 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes, quenched with hydrochloric acid, washed with water and extracted with ethyl acetate. The organic layers were separated and concentrated to give a crude product which was heated with ethyl acetate: hexanes (1:1), cooled, filtered, and dried under vacuum to give the desired product. C17H18N4OS, MS m/e 327 (M+H)+. HPLC-HI 100% at 4.24 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[OH:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(O)c1
Yield: 74.9 %

Procedure:
To a solution of (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (0.5 g, 1.7 mmol) and 3-hydroxyphenol (0.2 g, 2.1 mmol) in 20 mL of acetonitrile (CH3CN) was added potassium carbonate (0.35 g, 2.6 mmol). The reaction mixture was stirred under reflux and concentrated in a vacuum to remove the solvent. The residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum to remove the solvent. The concentrate was purified by silica gel chromatography to afford (E)-methyl 2-(2-((3-hydroxyphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (0.4 g, yield 74%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([CH:22]=[CH:23][CH:24]=[O:25])=[CH:20][CH:19]=1>O1CCCC1>[OH:25][CH:24]([CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:27][CH:26]=1)[CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: COc1ccc(C=CC=O)cc1
Reactant: Cc1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C=CC(O)Cc2cnccn2)cc1
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly to a solution of 2-methylpyrazine (9.4 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of p-methoxycinnamaldehyde (17.8 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedure of Example I to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C@:10]3([CH2:25][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:26])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[Pd]>[O:26]=[C:9]1[NH:8][C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[C@@:10]21[CH2:25][C:13]1=[N:14][CH:15]=[C:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH:17]=[C:12]1[CH2:11]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (6S)-4′-chloro-6′-oxo-5,6′,7,7′-tetrahydrospiro[cyclopenta[b]pyridine-6,5′-pyrrolo[2,3-d]pyrimidine]-3-carboxylate (200 mg, 0.537 mmol) in dry ethyl acetate (5.37 mL) was added triethylamine (299 μL, 2.15 mmol) and palladium on carbon (571 mg, 10%, 0.537 mmol). The reaction was placed on a Parr apparatus at 50 psi hydrogen gas. After 16 h, the reaction mixture was filtered under a nitrogen atmosphere through Celite®, washing with ethyl acetate. The filtrate was concentrated to give the title compound, along with one equivalent of triethylamine hydrochloride. MS: m/z=339.3 (M+1).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH3:11][N:12]([CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21])[CH3:13].[Cl-:28].[NH4+]>O1CCCC1>[ClH:28].[CH3:13][N:12]([CH:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)[OH:21])[CH3:11]
Reactant: COc1ccc(Br)cc1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCCC2C(c2ccccc2)N(C)C)cc1
Product: Cl
Temperature: 25 °C
Yield: 37.2 %

Procedure:
0.88 g (36.3 mmole) of magnesium turnings was stirred in 10 ml of tetrahydrofuran of analysis purity. 4.55 ml (36.3 mmole) of 4-bromoanisole dissolved in 30 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 7.0 g (30.3 mmole) of 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of tetrahydrofuran, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with in each case 100 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 10.5 g of crude base (102% of theory) were obtained. 4.24 g of 2-(dimethylaminophenylmethyl)-1-(4-methoxyphenyl)cyclohexanol, hydrochloride (37.2% of theory) were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 150° C.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:29]([F:32])([F:31])[F:30])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH:20](C(OC(C)(C)C)=O)[CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH2:1]([C:9]1[C:10]([C:29]([F:32])([F:31])[F:30])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a solution of tert-butyl 6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxylate (1.4 g; 3.1 mmol) in CH2Cl2 at 0° C. was added 4M HCl in 1,4-dioxane (3.8 mL, 15.4 mmol). The resulting solution was warmed to room temperature and stirred overnight. The solid was collected to yield 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (1.1 g).
Reaction SMILES: [C:1]([C:3]1([O:10][CH3:11])[CH2:8][CH2:7]N(C)[CH2:5][CH2:4]1)#[CH:2].[CH:12]1(N2CCC(C#C)(OC)CC2)CCCC1>>[C:1]([C:3]1([O:10][CH3:11])[CH2:8][CH2:7][CH2:12][CH2:5][CH2:4]1)#[CH:2]
Reactant: C#CC1(OC)CCN(C)CC1
Reactant: C#CC1(OC)CCN(C2CCCC2)CC1
Product: C#CC1(OC)CCCCC1

Procedure:
4-Ethynyl-4-methoxy-1-methyl-piperidine and 1-cyclopentyl-4-ethynyl-4-methoxypiperidine may be prepared analogously.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:25][C:26]1[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:19][CH:20]=1)#[N:33]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(O)cc1
Reactant: N#Cc1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 1.00 g of 1-(4-hydroxybenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 15 mL of DMF at 25° was added 0.185 g of sodium methylate, and the resulting mixture was stirred at 25° for 0.25 hours. To this mixture was then added a solution of 0.80 g of α-bromo-o-tolunitrile in 5 mL of DMF. The reaction mixture was stirred at 25° for 16 hours. The solvent was removed in vacuo, and the residue dissolved in ethyl acetate. This solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 10-25% ethyl acetate/benzene) provided 0.76 g of 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3): δ 7.73-7.59 (m, 3H); 7.44 (m, 1H); 6.96 (s, 4H); 5.23 (s, 2H); 5.14 (s, 2H); 4.50 (d, 2H); 2.57 (t, 2H); 1.66 (quint., 2H); 1.33 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25](=[O:31])[NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>CO>[CH3:30][O:29][CH2:28][CH2:27][NH:26][C:25]([C:24]1[C:18]2[N:17]=[C:16]([NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[NH:20][C:19]=2[CH:21]=[CH:22][CH:23]=1)=[O:31]
Reactant: COCCNC(=O)c1cccc2[nH]c(NCC3CCN(C(=O)OC(C)(C)C)CC3)nc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COCCNC(=O)c1cccc2[nH]c(NCC3CCNCC3)nc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
After dissolving 4-{[4-(2-methoxy-ethylcarbamoyl)-1H-benzimidazol-2-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 3.01 mmol) in methanol (1 ml), a 4N hydrogen chloride-1,4-dioxane solution (7.0 ml, 28.0 mmol) was added and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and vacuum dried to obtain 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid (2-methoxy-ethyl)-amide. The compound was identified by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[C:15]([N:20]([CH3:22])[CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:28]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]([C:14]2[C:15]([N:20]([CH3:22])[CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:28])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: CN(C)c1ncccc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C)c1ncccc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 12, from 4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-pyridin-3-yl)-nicotinamide and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Colorless oil (67%). MS (ESI): m/z=417.088 [M+H]+.