Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:20][O:19][N:18]([CH3:17])[C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CON(C)C(=O)c1ccc(OCC(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
A mixture of 6-(2,2,2-trifluoroethoxy)nicotinic acid (10.4 g, 47.3 mmol, Step-1), N,O-dimethylhydroxylamine hydrochloride (5.08 g, 52.1 mmol), HOBT (9.59 g, 71.0 mmol), EDC (13.6 g, 71.0 mmol) and triethylamine (26.4 mL, 189 mmol) in N,N-dimethylacetamide (237 mL) is stirred at 60° C. for 16 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (300 mL) and extracted with ethyl acetate (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mL×2) and dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1) to give 6.54 g (52% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10](Cl)=[O:11].[NH2:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH2:26][CH3:27]>>[CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([NH:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH2:26][CH3:27])=[O:11]
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)Cl)[C@@H]1C2
Reactant: CCc1nc2ccccc2c(=O)n1N
Product: CCc1nc2ccccc2c(=O)n1NC(=O)C[C@@H]1CC[C@H]2C[C@@H]1C2(C)C

Procedure:
The product from Example 1C and 3-amino-2-ethylquinazolin-4(3H)-one (Aldrich) were processed using method analogous to that described in Example 1D to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.00 (d, J=9.5 Hz, 1H) 1.09 (s, 3H) 1.24 (d, 3H) 1.34 (t, J=7.3 Hz, 3H) 1.55-1.68 (m, 2H) 1.85-2.03 (m, 4H) 2.08-2.26 (m, 1H) 2.32-2.45 (m, 1H) 2.51-2.70 (m, 2H) 2.70-2.86 (m, 2H) 7.44 (t, J=7.3 Hz, 1H) 7.66-7.72 (m, 1H) 7.76 (t, J=7.1 Hz, 1H) 8.21 (d, J=7.9 Hz, 1H); MS (ESI+) m/z 354 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[CH2:11]Br)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[NH2:17][C:15]1[S:16][CH:11]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[N:14]=1
Reactant: CC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(N)=S
Solvent: CCO
Product: CC(=O)N1CCC(c2csc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
1-(1-acetylpiperidin-4-yl)-2-bromoethanone (2.37 g, 9.561 mmol) and thiourea (0.728 g, 9.561 mmol) were dissolved in ethanol (40 mL) and agitated at ambient temperature for 30 minutes. The mixture was heated to 80° C. and agitated an additional 1 hour. Upon cooling solvent was evaporated and the residue was distributed between 20 mL of 2M NaOH and 20 mL of chloroform. The organic phase was separated and discarded. The remaining aqueous phase (white slurry) was extracted with chloroform until all solids were extracted (4×200 mL). The organic extracts were combined, dried over magnesium sulfate and evaporated to give the desired product (1.600 g, 74.27% yield) as white solid.
Reaction SMILES: [CH:1]1([C@H:7]([NH:28]C(=O)OC(C)(C)C)[C:8](=[O:27])[N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][C@@H:10]2[C:18](=[O:26])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]1([NH:19][C:18]([C@@H:10]2[N:9]([C:8](=[O:27])[C@@H:7]([NH2:28])[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11]2)=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
For Intermediate 4: In a 100 mL round-bottomed flask, tert-butyl (R)-(1S)-1-cyclohexyl-2-oxo-2-(2-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethylcarbamate (100 mg, 209 μmol, Eq: 1.00) was combined with DCM (2 mL) to give a colorless solution. TFA (2 mL, 26.0 mmol, Eq: 124) was added and the reaction was stirred for 1 h. The crude reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO3 (5 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give (R)-1-((S)-2-amino-2-cyclohexyl-acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid phenylamide as a white solid (56 mg), m/z=379 (M+H).
Reaction SMILES: [CH2:1]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].CCOCC>CN(C=O)C>[CH2:1]([C@H:7]1[C@@H:12]([O:13][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[CH2:11][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCC[C@@H]1C[C@H](O)[C@H](CCCCCC)C(=O)O1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCCCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)O1
Reaction time: 48 h
Yield: 63.5 %

Procedure:
M)d) 1.5 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one were dissolved in 8 ml of DMF. 0.85 g of t-butyldimethylchlorosilane in 4 ml of DMF were then added dropwise. The mixture was stirred for 48 hours. The reaction mixtures was poured in to 100 ml of ether and washed with 1N hydrochloric acid. The organic phase was dried, filtered and evaporated. The material obtained was chromatographed on silica gel. There was obtained 1.26 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-[(t-butyldimethylsilyl)oxy]-6-undecyl-2H-pyran-2-one, MS: 411 (M+ -t-butyl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]4[CH:29]=[CH:28][N:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)[CH2:19][CH2:18]3)[C:11]=1[O:12][CH2:13][C:14](O)=[O:15])[N:8]=[CH:7][CH:6]=[CH:5]2.Cl.[CH3:37][O:38][C:39]([CH:41]1[CH2:44][NH:43][CH2:42]1)=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][O:38][C:39]([CH:41]1[CH2:44][N:43]([C:14](=[O:15])[CH2:13][O:12][C:11]2[C:10]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]4[CH:29]=[CH:28][N:27]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:26]=4)[CH2:19][CH2:18]3)=[C:9]3[C:4]([CH:5]=[CH:6][CH:7]=[N:8]3)=[CH:3][C:2]=2[CH3:1])[CH2:42]1)=[O:40]
Reactant: Cc1cc2cccnc2c(N2CCCN(Cc3ccn(-c4ccccc4)n3)CC2)c1OCC(=O)O
Reactant: COC(=O)C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)COc2c(C)cc3cccnc3c2N2CCCN(Cc3ccn(-c4ccccc4)n3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A mixture of {6-Methyl-8-[4-(1-phenyl-1H-pyrazol-3-ylmethyl)-[1,4]diazepan-1-yl]-quinolin-7-yloxy}-acetic acid (100 mg, 0.21 mmol), 3-Azetidinecarboxylic methyl ester HCl salt (35.4 mg, 0.23 mmol), HATU (97 mg, 0.25 mmol) and DIEA (0.222 ml) in DMF (1 ml) was stirred at rt for 2 hrs. After an aqueous workup, the mixture was purified by flash chromatography to give a light yellow solid (70 mg, 59%). MS (ES) m/z 569.3 (M+H+).
Reaction SMILES: [CH:1]#[CH:2].[N+:3]([C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl>O1CCCC1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([C:1]#[CH:2])([OH:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)([O-:5])=[O:4]
Reactant: C#C
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(O)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
Acetylene is introduced for 30 minutes into a 20°-22 °C mixture of 118 ml. of tetrahydrofuran and 16.8 g. of potassium-tert.butylate, and thereafter 22.7 g. of 4-nitro-benzophenone are added to the mixture. The introduction of acetylene is continued at 20° to 22 °C for additional 30 minutes, then the mixture is neutralized with 5 n hydrochloric acid under a nitrogen atmosphere. The organic phase is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off in vacuo. 23.1 g. (91 %) of 4-nitro-α-ethynyl-benzhydrol are obtained; m.p.: 88°-89 °C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7](O)[C:5]=2[N:6]=1.[CH3:18][N:19]1[CH:26]=[CH:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>>[Cl:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:25]3[C:23](=[O:24])[NH:22][C:20](=[O:21])[N:19]([CH3:18])[CH:26]=3)[C:5]=2[N:6]=1
Reactant: OC1c2ccc(Cl)cc2C=Cc2sc(Cl)nc21
Reactant: Cn1ccc(=O)[nH]c1=O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O

Procedure:
The title product was prepared from the product of step (vii) (1.27 g) and 1-methyluracil (1 g) according to the method of example 38 step (iv). Purification was by chromatography eluting with 50-60% ethyl acetate in isohexane.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][CH3:13].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH2:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH3:11])[C:4]=1[CH2:3][C:2]1[NH:17][CH2:16][CH2:15][N:18]=1)[CH3:13]
Reactant: NCCN
Reactant: CCc1cccc(CC)c1C=C(Br)Br
Product: CCc1cccc(CC)c1CC1=NCCN1

Procedure:
To 20 ml ethylene diamine were added at 0° C. 3.20 g (10 mmol) 2-(2,2-dibromo-vinyl)-1,3-diethyl-benzene and the mixture stirred at ambient temperature for 16 hours. The reaction was quenched by addition of aqueous 2N ammonia, extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in ethyl acetate and crystallization at −10° C. provided 2.85 g 2-(2,6-diethyl-benzyl)-4,5-dihydro-1H-imidazole as colourless solid: MS (ISP): 217.1 ((M+H)+.).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH3:31][NH2:32]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:32][CH3:31])=[O:16])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2cccc(N3CCOCC3)c2)C[C@@H]1C
Reactant: CN
Product: CNC(=O)c1ccc2c(c1)[C@H](Nc1cccc(N3CCOCC3)c1)C[C@H](C)N2C(C)=O
Yield: 73 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 31 mg of (2S,4R)-1-acetyl-2-methyl-4-[(3-morpholinophenyl)amino]-1,2 3,4-tetrahydroquinoline-6-carboxylic acid (compound 179) and monomethylamine. Thus, 23 mg (73%) of the title compound was obtained as a light yellow oily substance.
Reaction SMILES: [BH4-].[Na+].ClCCl.[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH:14]([CH3:34])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=1)=[O:16].[Cl-].[NH4+]>CO>[OH:16][CH:15]([C:17]1[CH:18]=[CH:19][C:20]([O:23][Si:24]([CH:25]([CH3:27])[CH3:26])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:29])[CH3:30])=[CH:21][CH:22]=1)[CH:14]([S:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6])[CH3:34]
Reactant: CC(Sc1ccccc1O)C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC(Sc1ccccc1O)C(O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reaction time: 2 h
Yield: 106.1 %

Procedure:
With cooling with ice, sodium borohydride (5.5 g, 134 mmol) was added to a dichloromethane (500 mL)/methanol (500 mL) mixed solution of 2-[(2-hydroxyphenyl)thio]-1-{4-[(triisopropylsilyl)oxy]phenyl}propan-1-one (48 g, 112 mmol) obtained in Reference Example 1-2, and stirred for 2 hours with cooling with ice, then restored to room temperature, and further stirred for 40 minutes. Aqueous saturated ammonium chloride solution was added, and stirred for a while, and then the solvent was almost completely evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and extracted with aqueous saturated ammonium chloride solution. The organic layer was dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude product (51.4 g) of the intended compound.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:15]=2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].CS(C)=O.Cl[C:36]1[C:37]2[CH2:44][C:43](=[O:45])[N:42]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH3:56])[C:38]=2[N:39]=[CH:40][N:41]=1>O>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[C:6]([C:27]([F:28])([F:29])[F:30])[CH:7]=2)[N:12]=[C:13]1[CH:21]1[CH2:26][CH2:25][N:24]([C:36]2[C:37]3[CH2:44][C:43](=[O:45])[N:42]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=4[O:55][CH3:56])[C:38]=3[N:39]=[CH:40][N:41]=2)[CH2:23][CH2:22]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)c(OC)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)c(OC)c1
Temperature: 62.5 °C
Reaction time: 6 h
Yield: 79.75 %

Procedure:
Combine 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine trihydrochloride (98.76 g, 1 eq), DMSO (395 mL) and 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.1 eq). Heat the resulting suspension to 60-65° C. then add TEA (6 eq). Stir for 6 hours. Add DMSO (395 mL) and water (150 mL) as a stream and stir the resulting suspension for 1 hour at 45-38° C. Filter the slurry and wash the solids with a mixture of DMSO (1 vol) and water (1 vol) two times. Further wash the solids with water (3×200 mL), methanol (3×200 mL) and heptane (3×200 mL). Dry the cake on the filter to afford the target compound (106.5 g, 79.75% yield) as a tan solid. 1H NMR (400 MHz, DMSO): 8.18 (s, 1H), 7.99-7.95 (m, 2H), 7.71 (s, 1H), 7.43-7.39 (m, 2H), 6.76 (d, J=7.1 Hz, 1H), 6.54 (d, J=2 Hz 1H), 6.38-6.35 (m, 1H), 4.67 (s, 2H), 4.49 (d, J=13.1 Hz, 2H), 4.03 (t, J=6.52, 2H), 3.89 (s, 2H), 3.78 (s, 3H), 3.69 (s, 3H), 3.15-3.09 (m, 3H), 2.57 (t, J=6.6 Hz, 2H), 2.18 (s, 6H), 1.89-1.74 (m, 4H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1>C(C(C)=O)C>[CH:4]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)([CH2:5][CH3:6])[CH3:36]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CCC(C)=O
Product: CCC(C)Nc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1

Procedure:
5-(4-(6-(4-Amino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride was used in place of 5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride of Production Example 4, and methyl ethyl ketone was used in place of acetaldehyde to give the title compound in similar manner to Production Example 4.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][CH:12]2[C:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]=3)[CH2:15][CH2:14][NH2+:13]2)=[CH:9][CH:8]=1>C(O)(C)C>[C:1]([O-:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C@@H:12]2[C:21]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH:20]=3)[CH2:15][CH2:14][NH2+:13]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(CC2[NH2+]CCC3CCCC=C32)cc1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: COc1ccc(C[C@H]2[NH2+]CC[C@@H]3CCCC=C32)cc1

Procedure:
Sufficient racemic (R,S)-1-(4-methoxybenzyl)-octahydroisoquinolinium acetate is dissolved in isopropanol to form a 52.6% by weight (R,S)-1-(4-methoxybenzyl)-octahydroisoquinolinium acetate solution. The solution is seeded at 20° C. with about 1%, relative to the weight of the solution, of (S)-acetate and is stirred at 0° C. for 2 to 3 hours. The crystallized (S)-acetate is filtered off with suction and washed with tert.-butyl methyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:36][C:35](=[S:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[NH:36][C:35](=[S:37])[O:34][N:33]=4)=[CH:30][CH:31]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2noc(=S)[nH]2)cc1
Product: CCC(C(=O)Nc1ccc(-c2noc(=S)[nH]2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
36 mg (0.10 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 30 mg (0.16 mmol, 1.5 eq.) of 3-(4-aminophenyl)-1,2,4-oxadiazole-5(4H)-thione were reacted according to General Method 7. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 21 mg (38% of theory)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:30]=[CH:29][C:21]2[O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:20]=2[CH:19]=1.O>CN(C=O)C>[CH:19]1[C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=2[CH:29]=[CH:30][C:18]=1[O:17][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3oc4ccccc4c3c2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-hydroxydibenzofuran (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(dibenzofuran-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(c1cc(Cl)ccn1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Aminophenol (122 mg, 1.12 mmol) is dissolved in DMF (3 ml) and treated with potassium-tert-butylate (131 mg, 1.16 mmol) at rt. The reaction mixture is stirred for 2 h to give a brown suspension. (4-Chloro-pyridin-2-yl)-pyrrolidin-1-yl-methanone (Stage 101.1; 236 mg, 1.12 mmol) and K2CO3 (82 mg, 0.59 mmol) are added. The reaction mixture is then stirred for 12 h at 80° C. It Is allowed to cool to rt again and the solvent is removed in vacuo. The residual brown oil is taken up in ethyl acetate and washed with brine. The organic layer is dried over MgSO4, concentrated and the residual crude product is purified by flash chromatography (SiO2; gradient CH2Cl2/MeOH 99:1 to 92:8) to give the title compound as a slightly brown solid: C16H17N3O2: M+=284.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>O1CCOCC1.O.O>[CH2:17]([NH:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:21])[CH3:18]
Reactant: CCN=C=O
Reactant: Cc1cccc(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cccc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To an ice cooled solution of 2-amino-6-methylbenzoic acid (500 mg, 3.3 mmol) and sodium bicarbonate (277 mg, 3.3 mmol) in 9 mL of dioxane/water (2:1) was added ethyl isocyanate (281 mg, 3.96 mmol). The reaction was slowly warmed to room temperature while stirring overnight. The reaction mixture was diluted with water and extracted with EtOAc. The acueous fraction was acidified with 2N HCl and extracted with EtOAc. The organic fraction was dried (MgSO4), filtered, and evaporated under reduced pressure affording 272 mg of 2-[[(ethylamino)carbonyl]amino]-6-methylbenzoic acid used directly in the next reaction: 1H-NMR (300 MHz, d6-DMSO) δ 1.02 (t, J=7 Hz, 3H), 2.32 (s, 3H), 3.03 (m, 2H), 6.67 (d, J=8 Hz, 1H), 6.87 (br. t, 1H, exchangeable), 6.99 (t, J=8 Hz, 1H), 7.79 (d. J=8 Hz, 1H), 9.46 (br. s, 1H, exchangeable).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:5]([C:27]([O:29][CH3:30])=[O:28])=[C:4]([CH3:31])[N:3]=1.[O:32]([CH2:39][CH2:40][CH2:41][NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:42][CH2:41][CH2:40][CH2:39][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5]([C:27]([O:29][CH3:30])=[O:28])=[C:4]([CH3:31])[N:3]=1
Reactant: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1cc([N+](=O)[O-])ccc1OCCCCBr
Reactant: NCCCOc1ccccc1
Solvent: CC#N
Product: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1cc([N+](=O)[O-])ccc1OCCCCNCCCOc1ccccc1

Procedure:
2.22 g of dimethyl 2,6-dimethyl-4-[(4-bromobutoxy)-5-nitro-phenyl]pyridine-3,5-dicarboxylate and 1.4 g of 3-phenoxypropylamine were dissolved in 30 ml of acetonitrile and refluxed with heating for two hours. After evaporating the solvent, the residue was subjected to silica gel column chromatography and eluted with chloroform - methanol (95:5) to give 1.8 g of caramel-like dimethyl 2,6-dimethyl-4-[5-nitro-2-[4-[(3-phenoxypropyl)amino]butoxy]phenyl]pyridine3,5-dicarboxylate. The compound thus obtained in 29 ml of ethanol was dissolved and to the solution was added a solution of 0.2 g of anhydrous oxalic acid in 5 ml of ethanol. The resultant solution was allowed to stand overnight at 4° C. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 1.5 g of dimethyl 2,6-dimethyl-4-[5-nitro-2-[4-[(3-phenoxypropyl)amino]butoxy]phenyl]pyridine-3,5-dicarboxylate oxalate. This compound has the following physico-chemical properties: