Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.O.[NH2:33][NH2:34]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:34][N:33]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]4)=[CH:14][CH:13]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(C(=O)CC(=O)c3ccc(Cl)cc3)cc2)C1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(-c3cc(-c4ccc(Cl)cc4)[nH]n3)cc2)C1
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(4-(3-(4-chlorophenyl)-3-oxopropanoyl)phenyl)morpholine-4-carboxylate (210 mg, 0.473 mmol) and hydrazine hydrate (35.5 mg, 0.70 mmol) in ethanol (3.5 ml) was heated to reflux with stirring overnight. The clear yellow solution was evaporated under reduced pressure, water was added and ethyl acetate. The organic layer was separated, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (10 g silica gel, 10 to 50% ethyl acetate in heptane) to yield a white solid (208 mg, 89%). MS (ISP neg): 438.3 ([{35Cl}M−H]+), 440.4 ([{37Cl}M−H]+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:44][C:45]1[O:46][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:49]=1.ClCC1C=NC(OC)=NC=1>>[F:51][C:50]([F:53])([F:52])[C:47]1[O:46][C:45]([CH2:44][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:49][CH:48]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: COc1ncc(CCl)cn1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@]12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 5-(chloromethyl)-2-methoxypyrimidine, (3S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: mp 64-65° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.32-7.26 (m, 1H), 7.20 (d, J=7.4 Hz, 1H), 7.10-7.05 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.75-6.74 (m, 1H), 6.45 (s, 1H), 6.42 (s, 2H), 5.12 (d, J=16.2 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.85 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6 Hz, 2H), 3.07-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.4, 161.8, 161.1, 151.9, 141.9, 141.2, 132.5, 128.8, 123.9, 123.7, 120.5, 120.0 (2C), 118.7, 112.6, 112.5, 109.2, 108.7, 93.1, 80.3, 72.3, 57.6, 36.8, 28.9; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@:4]2([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:37])[C@H:19]([NH:29]C(=O)OC(C)(C)C)[CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13]2)[C:3]1=[O:38].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C@H:19]([CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@:4]2([C:3](=[O:38])[N:2]([CH3:1])[CH2:6][C@H:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:37]
Reactant: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@H](N)CCOc3ccccc3)C2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl (R)-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxo-4-phenoxybutan-2-ylcarbamate (242 mg; 0.464 mmol) was solubilised in DCM (1 ml). TFA (0.894 ml; 11.60 mmol) was added and the solution stirred at RT for 20 minutes before being concentrated in vacuo. The residual oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo yielding (4S,5R)-7-((R)-2-amino-4-phenoxybutanoyl)-2-methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:24]=[N:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19]([OH:21])=O)[CH2:16][N:17]=1)=[CH:9]2)[CH3:2].[NH4+].O[N:35]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:22][C:23]2[CH:24]=[N:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19]([NH2:35])=[O:21])[CH2:16][N:17]=1)=[CH:9]2)[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 0 °C
Yield: 88.6 %

Procedure:
To an ice-cooled and stirred mixture of [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (95 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole ammonium salt (61 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (84 mg) as colorless crystals. Recrystallization from ethyl acetate-hexane gave the title compound (71 mg, 76%) as colorless crystals. MS 475 (MH+). mp 195-196° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[Cl:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=1[S:55](=[O:58])(=[O:57])[NH2:56].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:50]([C:49]4[CH:53]=[CH:54][C:46]([Cl:45])=[C:47]([S:55]([NH2:56])(=[O:57])=[O:58])[CH:48]=4)=[O:51])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3-sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 gradient to give 5-[(4-(1,3-benzodioxol-5-yl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl) carbonyl]-2-chlorobenzenesulfonamide as a solid (0.09 g, 17%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.17 (m, 2H), 6.94 (s, 1H), 6.81-6.86 (m, 2H), 5.93 (s, 2H), 4.74 (m, 1H), 4.11 (m, 1H), 3.52 (m, 1H), 3.30 (m, 4H), 2.52 (s, 3H), 2.44 (m, 2H), 2.39 (m, 1H), 2.18 (m, 1H), 1.80-2.04 (m, 12H), 1.70 (m, 2H). HRMS C36H40ClN5O5 m/z 690.2517 (M+H)Cal., 690.2538 (M+H)Obs..
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].P([O-])(O)(O)=[O:16].[Na+].Cl([O-])=O.[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:4]=1[C:5]([OH:16])=[O:6]
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.2 %

Procedure:
3.0 g of 2-methoxy-4-(trifluoromethyl)benzaldehyde was dissolved in 50 ml dimethyl sulfoxide and an aqueous solution (20 ml) of 1.6 g sodium dihydrogenphosphate, followed by adding dropwise an aqueous solution (30 ml) of 8.0 g sodium chlorite thereinto. After stirring at room temperature for 3 days, water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 0.8 g of 2-methoxy-4-(trifluoromethyl)benzoic acid as a colorless solid from fractions eluted with hexane-ethyl acetate (3:7).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=1.C(O)C.[OH-].[K+].Cl>O>[CH3:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCC(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A solution of 5 g. of ethyl 4-(13,13-dimethyltetradecyl)aminobenzoate in 75 ml. 95% ethanol is saponified with 2.5 g. of 85% potassium hydroxide by refluxing for 5 hours. The warm solution is diluted with 150 ml. water and adjusted to pH 5 with 37% hydrochloric acid. The precipitate is filtered, washed with water, dried in vacuo and crystallized from acetic acid to yield the title compound as a creamcolored, amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23]CO)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:23])[N:15]=[C:16]([C:17]3[CH:22]=[C:21]([C:28]#[C:27][CH2:26][OH:29])[CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: C#CCO
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(C#CCO)c2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A mixture of 4-chloro-3-(3-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 7, Example 32) (80 mg, 0.18 mmol), propargyl alcohol (41 mg, 0.74 mmol), triethylamine (87 μl, 0.63 mmol), CuI (3.5 mg, 0.018 mmol), triphenylphosphine (5 mg, 0.018 mmol) and Pd(PPh3)4 (20 mg, 0.018 mmol) in 1,4-dioxane (1.5 mL) was heated at 100° C. for 4 h in a sealed tube. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated and dried using a phase separating cartridge then concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 20-30% ethyl acetate/isohexane), yielding Compound 30 as a solid (26 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:16]=[CH:15][C:12](C#N)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C[Mg]Br.C([O:22][CH2:23][CH3:24])C.Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:23](=[O:22])[CH3:24])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc(C#N)cc2)CC1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(CN2CCN(C)CC2)cc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
0.73 g of 4-(4-methyl-piperazin-1-yl-methyl)-benzonitrile (3.40 mmol) were dissolved in toluene (13 ml) and added to a solution of 3 M methyl magnesium bromide in diethyl ether (3.4 ml, 10.2 mmol) under nitrogen atmosphere. The resulting suspension was heated under reflux for 4 hours. The reaction was cooled down to 0° C., acidified with 10% HCl and then heated under reflux for 1 hour. The two phases were separated and the aqueous phase rinsed with AcOEt, then brought to basic conditions with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo to dryness to obtain 0.71 g of 1-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-ethanone as a yellow oil.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15]([I:18])=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2S(C)(=O)=O)=[CH:3][CH:2]=1.[OH:30][CH:31]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O.O>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15]([I:18])=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:30][CH:31]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCC(O)C1
Reactant: CS(=O)(=O)c1nc2c(F)c(I)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Temperature: 80 °C

Procedure:
To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.650 g, 1.24 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.784 g, 4.96 mmol) in 4 mL of DMF was added DBU (0.747 mL, 4.96 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (3-25% EtOAc/hexanes) afforded the desired product. LCMS: calculated for C28H25F2IN2O3 602.41, observed m/e 602.9 (M+H)+ (Rt 2.57/4 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1>CC(O)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[N:17]([C:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)co1
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: CC(=O)O
Product: Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Temperature: 160 °C

Procedure:
To a suspension of 6.6 g (30.5 mmol) 5-(benzyloxy)-2-methyl-4H-pyran-4-one in 150 ml 30% AcOH was added 7.5 g (45.8 mmol) m-aminobiphenyl. The reaction mixture was heated at 160° C. for 18 h, then cooled to rt, extracted with 300 ml EtOAc, washed with brine, and concentrated in vacuo. Purification by flash chromatography (330 g silica gel, 0-20% MeOH:EtOAc) afforded 5-(benzyloxy)-1-biphenyl-3-yl-2-methylpyridin-4(1H)-one. LCMS (M+H)+=368.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([CH:8]([NH2:11])[CH2:9][CH3:10])[CH:7]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33]([NH:11][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:9][CH3:10])=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CCC(N)c1cc(Cl)ccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(CC)c2cc(Cl)ccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from 1-(5-chloro-2-piperidino-phenyl)-1-propylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[CH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=Cc1cccc2ccccc12)CC(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(=O)O)Cc1cccc2ccccc12
Yield: 72.5 %

Procedure:
A solution of 2.0 g of 3-ethoxycarbonyl-4-(1-naphthyl)-3-butenoic acid in 100 ml of acetic acid was hydrogenated over 900 mg of a 10% palladium/charcoal under a hydrogen atmosphere at room temperature. After filtration of the catalyst, the reaction solution was concentrated under reduced pressure to obtain 1.46 g of 3-ethoxycarbonyl-4-(1-naphthyl)butyric acid as a brown oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:7]=1)C.C([NH2:26])=O.CO[Na]>CN(C=O)C.CO.C(O)(C)C>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:8]2[N:7]=[C:6]([CH2:5][C:4]([NH2:26])=[O:3])[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:17][CH2:18]1
Reactant: CCOC(=O)Cc1nc(N2CCN(C)CC2)cc2ccccc12
Reactant: NC=O
Agent: CO[Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(c2cc3ccccc3c(CC(N)=O)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of [3-(4-Methyl-piperazin-1-yl)-isoquinolin-1-yl]-acetic acid ethyl ester (1.7 g, 5.4 mmol) in DMF, formamide (0.72 ml, 18.1 mmol) is added under argon. After heating up to 100° C. 5.4N MeONa in methanol (1 ml) is added in 10 portions (0.1 ml each) over a period of 45 minutes. After 60 minutes at 100° C. the reaction is cooled to RT and diluted with isopropanol (100 ml). The solvents are removed under reduced pressure, the residue is dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate solution (5%). The organic phase is dried (Na2SO4) and concentrated. The resulting crude is purified on silica gel using methylene chloride/methanol (90/10→80/20) as eluent obtaining the product as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[NH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C)C=O>[CH3:15][O:14][C:12]([C:10]1[N:11]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:2])[C:8]=2[N:9]=1)=[O:13]
Reactant: COC(=O)c1nc2cccc(CO)c2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(C)cccc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The stirred solution of 1.60 g of methyl 7-hydroxymethyl-1H-benzoimidazole-2-carboxylate and 13.0 ml of N,N-dimethylformamide is admixed at 0° C. with 0.274 g of sodium hydride dispersion (55%) and, after 60 minutes, with 1.33 ml of 2-(trimethylsilyl)ethoxymethyl chloride. The mixture is stirred at room temperature over 3 hours, subsequently poured onto ice-water (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed successively with water (100 ml) and brine (100 ml), dried over sodium sulphate and concentrated. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (1:2 EtOAc-heptane); Rt=5.16; m.p. 59.6-59.8° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1O)[C:5]([OH:7])=[O:6].CC(C)[O-:14].[Ti+4:16].CC(C)[O-:19].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([O-:1])[C:3]=1[O-:14])([OH:7])=[O:6].[Ti+4:16].[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([O-:1])[C:3]=1[O-:19])([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CC(C)[O-]
Agent: [Ti+4]
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc([O-])c1[O-]
Temperature: 100 °C

Procedure:
A solution of 3,4-dihydroxybenzoic acid (30.8 g, 200 mmol) and toluene (220 ml) was dehydrated by distilling 20 mL of the solution. Thereafter, 28.4 g (100 mmol) of titanium(IV) isopropoxide (TTIP) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (3,4-dihydroxybenzoic acid-titanium complex) was brown in color. The yield amount was 35.0 g (99.4 mmol), and the yield percentage was 99%. 3.52 g of 3,4-dihydroxybenzoic acid-titanium complex was dissolved into 100 mL of 1:4 acetylacetone/ethyl acetate to produce a coating liquid.
Reaction SMILES: [O-][N+:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[N:12]3[C@@H:18]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][O:16][CH2:15][C:13]3=[N:14][C:4]=2[CH:3]=1.[NH4+:23].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:23][C:3]1[C:4]2[N:14]=[C:13]3[CH2:15][O:16][CH2:17][C@H:18]([C:19]([OH:22])([CH3:21])[CH3:20])[N:12]3[C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=1
Reactant: CC(C)(O)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
2-[(11R)-5-Oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (798 mg, 2.67 mmol) was dissolved in 25 mL of CH2Cl2 and treated with 5 mL of concentrated NH4OH solution. The mixture was stirred rapidly and p-toluenesulfonyl chloride (534 mg, 2.80 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was then treated with 25 mL of H2O and the layers were separated. The aqueous portion was extracted with additional CH2Cl2 (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% methanol/CHCl3) gave a light yellow foam. Crystallization from ethyl acetate gave 2-[(11R)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (220 mg) as white crystals, mp 216-217° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:22][CH3:23])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]O)[CH3:14]>>[C:1]([O:12][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:15]([CH2:22][CH3:23])[CH2:13][CH3:14])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCN(CC)CCOCCO
Product: CCCCCCC/C=C/C(=O)OCCOCCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(2-(diethylamino)ethoxy)ethanol as starting materials to give the aimed compound.