Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:14])=[CH:4][C:3]=2O1.[C:15](=O)([O:19]CC)[O:16][CH2:17]C.[CH3:23][O-:24].[Na+]>CO>[CH2:7]1[C:6]2[C:23]([OH:24])=[C:11]3[C:10]([CH2:5][CH2:4][CH:3]([C:15]([O:16][CH3:17])=[O:19])[C:12]3=[O:13])=[C:9]([OH:14])[C:8]1=2
Reactant: C[O-]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCc2cc3c(cc21)OCO3
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCc2c(O)c3c(c(O)c2C1=O)C3

Procedure:
A mixture of 6,7-methylenedioxy-3,4-dihydro-1(2H)-naphthalenone (3.8 g), diethyl carbonate (36 g) and sodium methylate powder [prepared by subjecting a 28% methanol solution (14 g) of sodium methylate to drying under reduced pressure] is heated under reflux for 3 hours in a nitrogen stream. After cooling, methanol (20 ml) is added to the reaction mixture. The mixture is acidified with concentrated hydrochloric acid, and mixed with water (200 ml) and ethyl acetate (200 ml), followed by extraction. The organic layer is washed with water, dried and concentrated under reduced pressure to leave methyl 6,7-methylenedioxy1-oxo-1,2,3,4-tetrahydro-2-naphthoate as oily product. This product is dissolved in methanol (50 ml). Sodium borohydride (0.5 g) is added to the mixture under ice-cooling, and the mixture is stirred. Thirty minutes later, sodium borohydride (0.5 g) is supplemented, and the mixture is stirred for 30 minutes, followed by subjecting it to extraction with the addition of water and ethyl acetate. The organic layer is washed with water, dried, concentrated to dryness under reduced pressure. To the residue is added ethyl acetate (10 ml), and the mixture is left standing to allow crystals to precipitate. The crystals are collected by filtration to afford methyl 1-hydroxy-6,7-methylenedioxy-1,2,3,4-tetrahydro-2-naphthoate (1 g) as colorless prisms. The filtrate is concentrated to dryness under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane: ethyl acetate=2:1- 1:1) to thereby obtain the same product (1 g). The overall yield is 2 g. Melting point=120°-130°C.
Reaction SMILES: C1C([N+]([O-])=O)=CC=C([Cl-][C:11]([O-])=[O:12])C=1.[CH:14]1([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:14]1([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:11]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:12])[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: OC1CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.6 %

Procedure:
To a stirred RT solution of 4-nitrophenylchloroformate (2.63 g, 13.05 mmol) in DCM (10 ml) was added drop wise a solution of 1-cyclobutyl-1,4-diazepane (1.83 g, 11.86 mmol) and pyridine (1.03 g, 13.05 mmol) in DCM (2 ml). The resulting mixture was stirred at RT for approximately 3 days. The solvent was evaporated in vacuo and the residue dissolved in MeOH/IPA (1:3, 40 ml). Azetidin-3-ol hydrochloride (1.3 g, 11.86 mmol) and DIPEA (3.37 g, 26.1 mmol) were added and the resulting mixture was heated to reflux (˜90° C.) overnight. After cooling to RT, the solvent was evaporated and the residue partitioned between DCM (40 ml) and 2M K2CO3 aq (20 ml). The organic layer was separated and the aq. phase re-extracted with DCM (20 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by silica flash column chromatography (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as yellow solid (1.16 g, 39%).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].[NH2-].[Li+].Cl>C(#N)C>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:14]=2[F:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1c(F)cc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [NH2-]
Solvent: CC#N
Product: O=C(O)c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Temperature: 60 °C
Yield: 59.2 %

Procedure:
2,4,6-Trifluorobenzoic acid (643 mg, 3.65 mmol) and 2-fluoro-4-iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile (30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) and the mixture was heated to 60° C. under a nitrogen atmosphere for one hour. On cooling to room temperature the mixture was added to 1 N aqueous hydrochloric acid (100 mL) and the precipitate formed was collected by filtration and washed once with water then hexanes and dried in vacuo to give 2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (849 mg, 59% yield) as a tan solid. 1H-NMR (400 MHz, D6-DMSO): 13.72 (br s, 1H), 9.46 (s, 1H), 7.75 (d, 1H), 7.56 (d, 1H) 7.28 (tr, 1H), 6.73-6.67 (m, 1H), 6.53 (d, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[CH2:5][C@@H:4]([CH3:20])[O:3]1.Cl.Cl.[NH2:23][C@H:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>>[N:26]12[CH2:25][C@@H:24]([NH:23][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:10]4[O:9][C:8]([N:6]5[CH2:5][C@@H:4]([CH3:20])[O:3][C@@H:2]([CH3:1])[CH2:7]5)=[N:12][C:11]=34)=[O:19])[CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: C[C@@H]1CN(c2nc3c(C(=O)O)cccc3o2)C[C@H](C)O1
Agent: Cl
Product: C[C@@H]1CN(c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cccc3o2)C[C@H](C)O1

Procedure:
Following general procedure GP-C1, a mixture of 2-[(2S,6R)-2,6-dimethylmorpholino]benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-((2S,6R)-2,6-dimethylmorpholino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:9][CH2:10][OH:11].[ClH:12]>CCOCC>[ClH:12].[CH2:10]([O:11][C:1](=[NH:2])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:9]
Reactant: CCOC(=O)CC#N
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)CC(=O)OCC
Temperature: 22 °C
Reaction time: 20 h

Procedure:
A stirred solution of ethyl cyanoacetate (30 mL, 281 mmol) and EtOH (18.1 mL, 278 mmol) in anhydrous Et2O (28.1 mL), at 0° C., was bubbled with HCl gas until saturated. The reaction was stirred at 22° C. for 20 hours, and then concentrated to give the title product. 1H NMR (400 MHz, CDCl3) δ 4.73 (q, J=7.1 Hz, 2H); 4.24 (q, J=7.2 Hz, 2H); 3.89 (s, 2H); 1.51 (t, J=7.0 Hz, 3H); 1.30 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([Br:8])=[CH:6][CH:7]=1.[Br:10]Br>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([Br:8])=[CH:6][CH:7]=1)[CH2:9][Br:10]
Reactant: Cc1cc(Br)ccc1Br
Reactant: BrBr
Product: BrCc1cc(Br)ccc1Br
Temperature: 25 °C

Procedure:
In a 250 ml three-necked round-bottom flask equipped with a reflux condenser, thermometer, dropping funnel with pressure-equalizing, and magnetic stirring bar, and containing 74.9 g (0.30 mol) of 3,6-dibromotoluene, 15.5 ml (47.9 g, 0.30 mmol) of bromine was added dropwise under exposure to 500 W lamp for 3 hours at 190° C. The resulting mixture was cooled to room temperature. Fractional distillation gave colorless liquid, b.p. 132-135° C./3 mm Hg. Yield 84.3 g (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[CH2:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1.C12BC(CCC1)CCC2.C1C[O:31]CC1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]([CH2:16][OH:31])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: C=C1c2ccccc2C=Cc2cc(OC)ccc21
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: COc1ccc2c(c1)C=Cc1ccccc1C2CO
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-methoxy-5-methylene-dibenzo [a,d]cycloheptene (12.8 g) in dry THF (50 ml), under an inert atmosphere, was added 9-borabicyclo[3,3,1]nonane (116 ml of a 0.5 molar solution in THF) at ambient temperature, and the reaction mixture was then refluxed for 3h. After cooling in an ice bath the reaction was quenched by the slow addition of 2N sodium hydroxide solution (150 ml) and 30% hydrogen peroxide (30 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a period of 2h then extracted with diethyl ether (3×200 ml). The combined organic layers were washed with brine (1×300 ml), dried (Na2SO4), filtered and concentrated in vacuo to leave a residue, which was purified by chromatography on flash silica with 30% ethyl acetate in hexane as eluent, to give the title compound (10.9 g) as an oil. δ(360 MHz, CDCl3) 3.77-3.81 (2H, d, J=8.1 Hz, CH2), 3.80 (3H, s, OCH3), 4.16 (1H, t. J=8.1 Hz, CH--CH2OH), 6.79 (1H, d, J=11.9 Hz, ArCHA =CHB --Ar), 6.33 (1H, d, J=2.6 Hz, CH=C(OCH3)--CH), 6.85 (1H, d, J=11.9 Hz, Ar--CHA =CHB --Ar), 6.89 (1H, dd, J=8.3 and 2.6 Hz, CH=C(OCH3)CH) and 7.23-7.33 (5H, m, aromatics). m/e (CI+) 253 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:31][CH2:30][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]2=[O:29])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CCOCC>[CH2:22]([N:13]1[C:12](=[O:29])[C:11]2([CH2:30][CH2:31][NH:8][CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccccc1)CN2c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C1N(Cc2ccccc2)CN(c2ccccc2)C12CCNCC2

Procedure:
A solution of 2.16 g (5.12 mmol) 3-benzyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester in 43 ml ethyl acetate and 25 ml of a saturated solution of HCl in ether was stirred at ambient temperature for 90 min. The resulting suspension was filtered, the filtrate was dissolved in water and treated with saturated NaHCO3 and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to provide 3-benzyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as a brown solid; MS (ISP): 322.5 MH+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH2:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26](=O)[C:27](OC)=[O:28])=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH3:16].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH2:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[CH3:16]
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: CCc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 30 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (370 mg, 1.97 mmol) and methyl 2-(6-ethyl-1H-indol-3-yl)oxoacetate (446 mg, 1.93 mmol) in DMF (8.0 mL) at 4° C. under N2, was added a 1.0 M solution of potassium tert-butoxide in THF (6.0 mL, 6.0 mmol) dropwise over 20 min. The reaction was heated to 50° C. and stirred for 7 h at this temperature. The reaction mixture was then cooled to room temp and quenched with 1.0 N hydrochloric acid (5.0 mL), extracted with EtOAc (2×15 mL), washed with saturated NaHCO3 (30 mL), saturated NaCl (30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 50% EtOAc/hexanes containing 1% TEA) gave the title compound (214 mg, 30%) as a red solid, mp 98–100° C. 1H NMR (DMSO-d6) δ 11.69 (s, 1H), 11.06 (s, 1H), 7.78 (m, 1H), 7.60 (m, 1H), 7.28 (m, 1H), 7.16 (s, 1H), 6.95 (m, 1H), 6.86 (m, 1H), 6.50 (m, 1H), 6.32 (m, 1H), 6.20 (m, 1H), 3.69 (s, 3H), 3.32 (m, 2H), 1.11 (m, 3H). MS (ESI, negative mode): m/z=368 [C23H19N3O2−H]−
Reaction SMILES: F[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][NH2:12].C(Cl)Cl>C(O)CO>[CH3:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:12][N:11]=1
Reactant: NN
Reactant: CC(=O)c1cccnc1F
Solvent: ClCCl
Solvent: OCCO
Product: Cc1n[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1.10 g (7.91 mmol) of 1-(2-fluoropyridin-3-yl)ethanone in 5 mL of ethylene glycol under nitrogen was treated with 265 μL (8.31 mmol) of hydrazine. This solution was stirred for 2 hours at room temperature and then heated at 165° C. for 1.5 hours. The solution was cooled to room temperature, poured into CH2Cl2 (25 mL), and extracted with H2O (2×50 mL). The organic portions were combined, dried (MgSO4), filtered and concentrated in vacuo to give the title product as a fluffy off-white solid. 1H NMR (CDCl3): 2.61 (s, 3H), 7.14 (m, 1H), 8.06 (dd, 1H), 8.58 (dd, 1H), 11.18 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:11][C:10]=1[F:33])[C:2]1C=CC=CC=1.BrCC#[N:37]>>[C:2]([CH2:1][O:8][C:9]1[C:10]([F:33])=[CH:11][C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:13][C:14]=1[F:15])#[N:37]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)oc2c1
Reactant: N#CCBr
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC#N)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and bromoacetonitrile, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6](C3C=C4C(=CC=3)C=C(NC(C3SC=CC=3)=O)C=C4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH4+:29].[Cl-:30]>[Fe].CCO.O>[Cl:30][C:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:29])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: O=C(Nc1ccc2cc(-c3cccc4cnccc34)ccc2c1)c1cccs1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Cl)nccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 175.4 %

Procedure:
To a 1000 mL 3-neck round-bottomed flask containing 1-chloro-5-nitroisoquinoline (Step 1, 8.200 g, 39.3 mmol) was added Iron powder (11.80 g, 211.2 mmol), while under a flow of inert gas. A 3:1 mixture of EtOH/H2O (240 mL), and NH4Cl (1.19 g, 22.4 mmol) were added. The mixture was heated to 80° C., while stirring under inert atmosphere for 1 hour. The oil bath was removed and the mixture was allowed to cool to ambient temperature. The crude material was filtered through a plug of Celite, and the filtrate was concentrated in-vacuo. Recrystallization from DCM/Hexanes, and further washing the solid with hexanes (3×100 mL) afforded a brown crystalline solid, which was titled product (7.015 g, 39.3 mmol). MS (ESI pos. ion) m/z: 179 (M+H). Calc'd Exact Mass for C9H7N2Cl: 178.5
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH2:16](Br)/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19].O>CS(C)=O>[CH2:16]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/Cn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
This example illustrates a synthesis of 1-(3,7-Dimethyl-2,3,6,7-dioxidoctyl)-3,7-dimethylxanthine (inventive compound no. 2552). Sodium hydride (95%) (0.28 g, 12 mmol) was added to a solution of theobromine (2.16 g, 12 mmol) in dimethylsulfoxide (50 mL). After 20 minutes of stirring, geranyl bromide (2.17 g, 10 mmol) was added. After 6 hours of stirring at room temperature, the reaction mixture was warmed to 60° C. for 3 hours and then poured into a separatory funnel containing 150 mL of water and extracted with dichloromethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 30% acetone/petroleum ether eluant to yield 2.1 g (66.5% yield) 1-(Geranyl)-3,7-dimethylxanthine (inventive compound no. 2545).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]2)[CH:4]=[CH:3][CH:2]=1.C1(CN)C=CC=CC=1>CO.[Pd]>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)CN1CCC(Nc2nc3ccccc3n2-c2cccc3cccnc23)CC1
Agent: [Pd]
Solvent: NCc1ccccc1
Solvent: CO
Product: CC(C)C(=O)CN1CCC(Nc2nc3ccccc3n2-c2cccc3c2NCCC3)CC1
Reaction time: 24 h
Yield: 27.1 %

Procedure:
A mixture of 1-[4-[[1-(8-quinolinyl)-1H-benzimidazol-2-yl]amino]1-piperidinyl]-3-methyl-2-butanone (0.0222 mol) and benzenemethanamine (0.0666 mol) in methanol (250 ml) was hydrogenated at 40° C. under a 3 bar pressure for 24 hours with palladium on activated carbon (1.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH2Cl2 and CH3OH and the filtrate was evaporated. Palladium on activated carbon (1.5 g) and methanol (250 ml) were added again. Hydrogenation was continued at 40° C. under a 3 bar pressure for 24 hours. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH2Cl2 and the filtrate was evaporated. The residue (22 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1 and 85/15/1; 20–45 μm). Three pure fractions were collected and their solvents were evaporated, yielding 2.6 g 1-[4-[[1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-3-methyl-2-butanone (interm. 40) (fraction 1), 2.9 g of fraction 2 and 0.7 g of fraction 3. Fraction 2 and 3 were crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.82 g (±)-N-[1-[3-methyl-2-[(phenylmethyl)amino]butyl]4-piperidinyl]-1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine; mp. 126° C. and 0.55 g of N-(4-piperidinyl)-1-(1,2,3,4-tetrahydro-8-quinolinyl)-1H-benzimidazol-2-amine; mp. 205° C. (comp. 48).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc(C(F)(F)F)c1
Yield: 100.4 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 3-trifluoromethylbenzenesulfonyl chloride (200 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (244 mg, 100%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:14][C:13]([CH3:16])([CH3:15])[C:12]([NH:11][C:9]1[N:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)=[O:17]
Reactant: CCOC(=O)c1cc(NC(=O)C(C)(C)C)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
2.3 g (7.42 mmol) of 5-(2,2-Dimethyl-propionylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 15 ml ethanol and 16 ml (16 mmol, 2.16 eq) of 1N NaOH is added and the reaction mixture stirred overnight at RT. After evaporation of the solvent the residue is taken up in a mixture of 10 ml CH2Cl2 and 10 ml 0.1N HCl, the organic phase is separated, dried over Na2SO4 and the solvent removed in vacuo to obtain 5-(2,2-Dimethyl-propionylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid in a yield of 89% (1.9 g)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:22]([O:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[CH2:23][CH3:24])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li+].[OH-].Cl>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:22]([O:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[CH2:23][CH3:24])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 16 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,4R)-methyl 1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylate (all material from step 2, 1.53 g, 3.57 mmol), THF (10 mL) and MeOH (10 mL). To the solution was added aq. LiOH (1.0 M, 5.36 mL). The mixture was stirred at room temperatuer for 16 h; then was concentrated in vacuo to afford an aqueous solution. The solution was acidified with aq HCl (1M) and then transferred to a separatory funnel. The solution was twice extracted with EtOAc. The combined organics were dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylic acid as a white solid (1.28 g, 86% over two steps).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[OH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[N:3]=[CH:4][N:5]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: O=Cc1c(Cl)ncnc1Cl
Product: O=Cc1c(Cl)ncnc1Oc1ccc2[nH]ccc2c1

Procedure:
Using the procedure of Example 1, 4,6-dichloro-pyrimidine-5-carbaldehyde Compound 2a (0.10 g) and 5-hydroxy-indole Compound 3a (75 mg) were reacted to provide 4-chloro-6-(1H-indol-5-yloxy)-pyrimidine-5-carbaldehyde Compound 3b (15 mg, 10%). 1H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 8.60 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 6.95 (dd, 1H), 6.55 (d, 1H). MS (ESI) m/z: 306 (M+H+).