Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH3:21])[C:9]2[C:18]3[CH:17]=[C:16]([CH3:19])[CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:20]=1.[OH-].[Na+].Cl.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[C:25]([NH:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH3:21])[C:9]2[C:18]3[CH:17]=[C:16]([CH3:19])[CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:20]=1)(=[O:27])[CH3:26]
Reactant: Cc1ccc2ncc3nc(CCCN)n(C)c3c2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCCCc1nc2cnc3ccc(C)cc3c2n1C

Procedure:
A sample of 2-(3-aminopropyl)-1,8-dimethyl-1H-imidazo[4,5-c]quinoline dihydrochloride (from Example 147) was dissolved in water. Excess sodium hydroxide was added to neutralize the hydrochloric acid and then excess acetic anhydride was added. The precipitate was separated by filtration, washed with water, and recrystallized from water to provide 2-(3-acetamidopropyl)-1,8-dimethyl-1H-imidazo[4,5-c]quinoline, m.p. 213°-215° C. Analysis: Calculated for C17H20N4O: %C, 68.9; %H, 6.8; %N, 18.9; Found: %C, 68.8; %H, 6.8; %N, 19.0.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1>>[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH:25][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1cc2cccc(N)c2o1
Product: Cc1cc2cccc(Nc3ccc4c(N)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=290.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and (2-methyl-1-benzofuran-7-yl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)=[O:28]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1csc(C(=O)CBr)n1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nc(C)cs2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden, William B. et al., Aust. J. Chem., 1985, 38, 1257).
Reaction SMILES: [N+]([O-])([O-])=O.[K+].S[CH2:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:20].[S:21]([Cl:25])(Cl)(=[O:23])=[O:22]>CC#N.ClCCl>[CH3:16][N:15]([CH3:17])[C:13]([C:12]1[CH:18]=[CH:19][C:9]([CH2:8][CH2:7][S:21]([Cl:25])(=[O:23])=[O:22])=[C:10]([CH3:20])[CH:11]=1)=[O:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(C(=O)N(C)C)ccc1CCS
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(C(=O)N(C)C)ccc1CCS(=O)(=O)Cl
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 73.7 %

Procedure:
Potassium nitrate (583 mg, 5.77 mmol) was added to a solution of 4-(2-mercapto-ethyl)-3,N,N-trimethyl-benzamide (514 mg, 2.30 mmol) in MeCN (23 ml) at room temperature. The mixture was cooled to −40° C., and sulfuryl chloride (1.68 M solution in dichloromethane, 3.46 ml, 5.81 mmol) was then added dropwise over 15 minutes. After stirring at −40° C. to −20° C. for 2.5 hours, the reaction mixture was diluted with dichloromethane (80 ml) and quenched with a saturated aqueous sodium bicarbonate solution (20 ml). The organic layer and the aqueous layer were separated, and the organic layer was then washed with a saturated aqueous sodium chloride solution (30 ml), dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→1/2) to give 2-(4-dimethylcarbamoyl-2-methyl-phenyl)-ethanesulfonyl chloride as a colorless solid (491 mg, 74%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][N:11](Cl)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:27]#[N:28])(C)C.O1CCOCC1>[I-].[Zn+2].[I-].O>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][CH:10]1[C:27]#[N:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: ClN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1
Agent: [I-]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: O
Product: N#CC1NC[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the toluene solution was added zinc iodide (0.5 g) and trimethylsilyl cyanide (20 ml, 160 mmol). The mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Dioxan (5 ml) and water (5 ml) were added and stirring was continued for 11/2 hour at room temperature. Water (150 ml) was added, the organic phase isolated and washed with water (200 ml), dried with magnesium sulphate and evaporated to dryness in vacuo to give the title compound as an oil. Purification of the crude product on a silica gel column (Eluent: ethyl acetate) afforded (3R,4R)-3,4-dibenzyloxy-pyrrolidine-2-carbonitrile (13.5 g, yield: 82% overall) as an oil.
Reaction SMILES: C[O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:15]([CH2:28][CH3:29])=[C:14]2[CH2:30][C:31]([NH2:33])=[O:32])(=[O:6])[O:4]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[NH2:33][C:31](=[O:32])[CH2:30][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][P:3](=[O:2])([OH:6])[OH:4])[CH:12]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:15]=1[CH2:28][CH3:29]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1cccc(Cl)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(O)O)ccc2n1Cc1cccc(Cl)c1
Reaction time: 0.75 h
Yield: 64.5 %

Procedure:
[[3-[[3-(2-Amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (99 mg, 0.2 mmol) and 0.21 mL (1.6 mmol) of trimethylsilyl bromide in 2 mL of methylene chloride was stirred for 16 hours, 5 mL of MeOH added, stirred 0.75 hours and concentrated at reduced pressure. The residue was crystallized from EtOAc/MeCN/HOAc/water to give 60 mg (65% yield) of [3-[[3-(2-amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-5-yl]oxy]propyl]phosphonic acid, mp, 203-205° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([F:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([F:11])([C:5]2[CH:6]=[CH:7][C:2]([C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)=[CH:3][CH:4]=2)[CH2:9][NH2:10])=[CH:13][CH:14]=1
Reactant: NCC(F)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: c1cn[nH]c1
Product: NCC(F)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reaction time: 0.08 h

Procedure:
2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine was reacted with 4,4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 except that heating was carried out at 100° C. for 5 minutes using 300 W power in a CEM microwave, to obtain the title compound. LCMS (PS-B4) Rt 6.69 min [M−F−]+296. 1H NMR (Me-d3-OD) δ 4.04 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H, d).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CO[C:9](=O)[NH:10][CH2:11][CH2:12][CH:13]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[NH:24]1[C:25]2[C:21](=[C:20]([CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][NH:10][CH3:9])[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: COC(=O)NCCC(c1ccccc1)c1cccc2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1cccc2[nH]ccc12
Temperature: 0 °C
Yield: 75.7 %

Procedure:
To a 0° C. stirring suspension of LiAlH4 (0.062 g, 1.69 mmol) in THF (12 ml) under N2 was added a solution [3-(1H-indol-4-yl)-3-phenyl-propyl]-carbamic acid methylester (V) (0.46 g, 1.5 mmol) in THF (7 ml). The resulting mixture was stirred for 15 minutes at room temperature, after which a suspension of LiAlH4 (0.11 g, 3 mmol) in THF (5 ml) was added. The reaction mixture was then refluxed for about 2.5 hours, cooled to about 0° C., and quenched by addition of freshly ground Na2SO4. 10H2O (8 g). The resulting mixture was stirred vigorously for about 30 minutes and filtered with the aid of EtOAc. The filtrate was concentrate and purified via flash chromatography (DCM/MeOH/NH4OH) affording [3-(1H-Indol-4-yl)-3-phenyl-propyl]-methyl-amine (0.30 g, 75% yield). To a 0° C. stirring solution of the above amine (0.24 g, 0.90 mmol) in Et2O (10 ml) was added HCl (2 M in Et2O, 0.5 ml, 1.0 mmol). The resulting precipitate was filtered and washed with water and Et2O. The white solid was dried in vacuo affording [3-(1H-indol-4-yl)-3-phenyl-propyl]-methyl-amine (VI) as a hydrochloride salt, (0.21 g, 78% yield). MS (M+H)=265.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)=[CH:4][N:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:16][CH2:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:8]=2)=[CH:17][CH:18]=1
Reactant: O=C(NC1(CO)CCCCC1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Clc1ccc(C2=NC3(CCCCC3)CO2)cn1
Yield: 55 %

Procedure:
To a solution of 6-chloro-N-[1-(hydroxymethyl)cyclohexyl]nicotinamide ax47 (2.17 g, 8.06 mmol, 1 eq) in chloroform (80 ml) is added thionyl chloride (1.8 ml, 24.18 mmol, 3 eq). The mixture is stirred at reflux for 2 h 30 before removing the volatiles under vacuum. The residue is dissolved in acetone and treated with potassium carbonate (2 eq), at reflux. After an aqueous work-up, the organic phase is dried over magnesium sulfate and concentrated in vacuo to give 1.86 g of a yellow solid. Purification over silicagel (eluent: dichloromethane/methanol/ammonia 99:1:0.1) finally yields 0.56 g of 2-(6-chloropyridin-3-yl)-3-oxa-1-azaspiro[4.5]dec-1-ene ax49.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][CH2:10][O:11][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (1.1 g) obtained in Example 321 (2) was dissolved in tetrahydrofuran (20 ml), and thereto was added portionwise sodium hydride (410 mg, 60% dispersion in oil) in several portions under nitrogen atmosphere in an ice bath, and the mixture was stirred for 30 minutes. To the reaction mixture was added ethyl bromoacetate (0.45 ml), and the mixture was warmed to room temperature, and then stirred for 6 hours. The reaction mixture was poured into a 5% aqueous citric acid solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (8:2)] to give the title compound (980 mg) as colorless oil. (2) [2-((tert-Butoxycarbonyl){3-[2-[(4-chloro-2-methoxyphenyl)imino]-4-(4-fluorophenyl)thiazol-3(2H)-yl]propyl}amino)ethoxy]acetic Acid
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.O>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:17][CH2:18][C@@H:14]([OH:13])[CH2:15]1
Reactant: OC1CCNC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O)C1
Temperature: 110 °C
Yield: 81.2 %

Procedure:
A mixture of 2-chloro-5-nitroanisole (0.59 g, 3.1 mmol) and 3-hydroxy pyrrolidine (0.55 g, 6.2 mmol) was heated neat to 110° C. over night. Reaction mass was diluted with ethyl acetate and the organic layer was given water and brine wash, dried over Na2SO4, concentration yields dark red solid (0.6 g, 82% yield). LC-MS, [M+H]+=239.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[CH2:5][C:4](=O)[CH2:3]1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:23])=[C:20]([SH:22])[CH:21]=1>CS(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]2[C:19](=[CH:18][CH:17]=1)[NH:23][C:4]1[CH2:3][CH:2]([CH3:1])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[C:5]=1[S:22]2
Reactant: Nc1ccc(Cl)cc1S
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1C
Solvent: CS(C)=O
Product: CCOC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(Cl)cc1S2

Procedure:
A mixture of ethyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7b (2.6 g, 13.1 mmole) and 5-chloro-2-aminobenzenethiol, 6 (X=Cl, 2.0 g, 13.1 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from EtOH and proves to be identical. An analytical sample of 4f, (R=Cl), mp 229-230° C. occurs as light orange crystals; yield: 2.05 g (49.4%).
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[Cl:39]C1C=CC(N)=CC=1C(F)(F)F>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:39])=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Product: Cc1ccc(C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(N)nccc12
Yield: 24 %

Procedure:
The procedures of Steps (1), (2) and (3) of Example 2 and Step (4) of Example 1 were repeated step by step, except for using 4-chloro-3-(trifluoromethyl)aniline instead of aniline in Step (1) of Example 2 to obtain the title compound (30 mg, 24%).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([N:3]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCN(CCc1ccccn1)C(=O)CCc1ccc(O)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCc1ccccn1)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
N-Ethyl-3-(4-hydroxyphenyl)-N-(2-pyridin-2-ylethyl)propanamide (0.35 g, 1.17 mmol) and methyl 2-(bromomethyl)benzoate (0.30 g, 1.29 mmol) were dissolved in acetonitrile (5 ml) and potassium carbonate (324 mg, 2.34 mmol) was added. The mixture was stirred at 60° C. for three hours. Polymer supported trisamine (0.3 eqv) was added and stirred overnight. The polymer was filtered off, solvent was removed by evaporation, EtOAc (10 ml) was added and the organic phase was washed with three portions of water. After drying the organic layer (MgSO4), the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 135 mg of methyl 2-[(4-{3-[ethyl(2-pyridin-2-ylethyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (yield 25.8%).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.[CH2:13]([NH:16][C:17]([NH2:19])=[O:18])[CH2:14][CH3:15].Cl>O.C(O)C>[CH2:13]([N:16]1[C:2](=[O:10])[CH2:3][C:4](=[O:6])[NH:19][C:17]1=[O:18])[CH2:14][CH3:15]
Reactant: CCCNC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCN1C(=O)CC(=O)NC1=O

Procedure:
Metallic sodium (2.6 g, 113 mmol) is added to ethanol (60 ml). The mixture is stirred until the sodium has completely finished reacting. Diethyl malonate (116 ml, 105 mmol) and n-propylurea (10 g, 98 mmol) are then added and the mixture is stirred under reflux for 5 h. After conc. HCl (5 ml) and hot water (45 ml) have been added, the mixture is filtered and the filtrate is concentrated in vacuo. Ethanol is added to the residue and the mixture is stirred. The solid is filtered off with suction and dried.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([C:25]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][N:33]=5)[N:28]=[C:27]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[F:41])[CH:26]=4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C=O.[OH-].[Na+]>C(O)=O>[F:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]4)[CH:18]=3)[CH:24]=2)[C:34]2[C:29]([N:28]=1)=[N:30][CH:31]=[CH:32][N:33]=2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cncc(-c4cc(-c5ccccc5F)nc5nccnc45)c3)cn2)CC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCC(n2cc(-c3cncc(-c4cc(-c5ccccc5F)nc5nccnc45)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 85 mg (0.15 mmol) 4-(4-{5-[6-(2-fluoro-phenyl)-pyrido[2,3-b]pyrazin-8-yl]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 0.5 ml formic acid was treated with 36 μl (0.45 mmol) 35% aqueous formaldehyde solution and heated to 80° C. The reaction mixture was stirred at this temperature for 4 hours. The volume of the reaction mixture was reduced under vacuum and 2 N aqueous NaOH was added. The resulting precipitate was filtered off, washed with water and dried. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 6-(2-fluoro-phenyl)-8-{5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-3-yl}-pyrido[2,3-b]pyrazine as off-white solid; HPLC/MS: 1.47 min, [M+H] 466.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:38][CH:39]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (75 mg, 0.337 mmol). The final product was collected as a white solid (60 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H) 8.61 (t, J=4.93 Hz, 1H) 8.45 (d, J=2.27 Hz, 1H) 8.34 (s, 1H) 8.00 (s, 1H) 7.90 (dd, J=8.59, 2.53 Hz, 1H) 7.78 (s, 1H) 6.55 (d, J=8.59 Hz, 1H) 6.10-6.17 (m, 2H) 5.91 (s, 1H) 5.13 (quin, J=6.57 Hz, 1H) 4.42 (br. s., 1H) 4.41 (br. s., 1H) 2.52-2.56 (m, 2H) 2.13 (s, 3H) 1.51-1.57 (m, 2H) 1.50 (s, 3H) 1.48 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=459.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH2:13][C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13](=[CH:27][C:23]3[CH:24]=[CH:25][C:26]4[C:21](=[CH:20][CH:19]=[CH:18][N:17]=4)[N:22]=3)[C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CSC(NCCc2cccc(F)c2)=N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1N=C(NCCc2cccc(F)c2)SC1=Cc1ccc2ncccc2n1
Temperature: 130 °C
Yield: 36.8 %

Procedure:
To a suspension of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (38.1 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 10 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-[2-(3-fluoro-phenyl)-ethylamino]-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (22.3 mg, 36.9%). HR-ES (+) m/e calcd. for C20H15FN4OS: (M+H)+ 379.1024. Found: 379.1024.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[N:26])[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:9]2[N:8]([CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(Cn2c(NC3CCN(CC#N)CC3)nc3ccccc32)o1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc(Cn2c(NC3CCN(CCN)CC3)nc3ccccc32)o1

Procedure:
A mixture of 6 parts of 4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile and 200 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 6 parts of N-[1-(2-amino-ethyl)-4-piperidinyl]-1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-amine as a residue (int. 37).