Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COC([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:19]=[N:20][N:21]3[C:26]([OH:27])=[N:25][CH:24]=[N:23][C:22]=23)(C2C=CC=CC=2)O1.Cl.[OH2:29].CO>CC(C)=O>[C:18]([C:16]1[CH:17]=[CH:12][C:13]([C:18]2[CH:19]=[N:20][N:21]3[C:26]([OH:27])=[N:25][CH:24]=[N:23][C:22]=23)=[CH:14][CH:15]=1)(=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1
Reactant: Oc1ncnc2c(-c3ccccc3C3(c4ccccc4)OCCO3)cnn12
Reactant: O
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(-c2cnn3c(O)ncnc23)cc1
Reaction time: 2 h

Procedure:
A mixture of 8-(4-α,α-ethylenedioxybenzylphenyl)-4-hydroxypyrazolo[1,5-a]-1,3,5-triazine (0.20 g), conc. hydrochloric acid (0.5 ml), water (1 ml), methanol (4 ml) and acetone (1 ml) is stirred at 45°-60° C. for 2 hours. After cooling, the resulting precipitate is separated by filtration, washed with water and dried to give the title compound (0.15 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[C:32]([CH3:40])[C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[N:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[C:32]([CH3:40])=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:28]([CH3:27])[N:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1c(B(O)O)ccc2c1cnn2C
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6c(cnn6C)c5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1,4-dimethyl-indazole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.88 min; Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[C:13]2=[N:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([OH:25])[CH2:23][CH3:24])[C:16]=3[N:12]2[CH2:11][CH2:10][CH2:9]1.[O:29]1CC[CH2:31][CH2:30]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:30]([O:25][CH:22]([C:17]1[C:16]2[N:12]3[CH2:11][CH2:10][CH2:9][N:8]([C:7]4[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][C:2]=4[Cl:1])[C:13]3=[N:14][C:15]=2[C:20]([Cl:21])=[CH:19][CH:18]=1)[CH2:23][CH3:24])(=[O:29])[CH3:31]
Reactant: C1CCOC1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)=O)cc1Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
To a solution of 1-{3-Chloro-4-[9-chloro-6-(1-hydroxypropyl)-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl]phenyl}ethanone (120.0 mg, 0.287 mmol) in pyridine (0.2 mL)/tetrahydrofuran (0.5 mL) was added acetic anhydride (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from ethanol/n-hexane to give the title compound as a colorless powder (92.5 mg, 0.201 mmol, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=O)=[CH:28][CH:27]=1)#[N:25].O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:30]([C:29]1[CH:33]=[CH:34][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1)[O:14]2
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 1.5 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (45 mg, 0.190 mmol) and K2CO3 (130 mg, 0.948 mmol) in acetone (3 mL) was added 4-cyanobenzoyl chloride 33 mg, 0.20 mmol). The reaction vessel was sealed and heated to 60° C. for 14 h. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was suspended in 50% EtOAc/hexanes and filtered to yield 1 mg (1%) of 4-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.C(=O)([O-])O.[Na+].[C:19](Cl)(Cl)=[S:20]>C(Cl)(Cl)Cl>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]=[C:19]=[S:20])[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(F)cc1N=C=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Methyl 2-amino-4-fluorobenzoate (7.3 g, 43.2 mmol) was dissolved in chloro-form, followed by addition of water (150 mL) and sodium hydrogencarbonate (36.3 g, 432 mmol). Thiophosgene (3.73 mL, 47.5 mmol) was added and the mixture was stirred at RT for 2 h. Water (250 mL) was added and the mixture was extracted with DCM. The combined organics were dried (MgSO4) and evaporated to give the title compound (8.90 g, 98%).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12.[CH3:25][S:26]SC>CCCCCC.O1CCCC1>[CH3:25][S:26][CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12
Reactant: CSSC
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(C)=C21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CSC)=C21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The starting material is prepared as follows: 36.4 ml of 2.5 M n-butyl lithium in hexane are added dropwise under nitrogen and at room temperature to the stirred suspension of 7.8 g of 1-methyl-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]-azepin-2-one in 70 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 45 minutes and cooled in a dry ice-acetone bath. The solution of 5.45 ml of dimethyl disulfide in 60 ml of tetrahydrofuran is added dropwise and the mixture stirred with said cooling for 2 hours. It is quenched by the slow addition of 150 ml of water, the mixture is extracted with chloroform, the extract is dried and evaporated. The residue is crystallized from diethyl ether and recrystallized from ethyl acetate, to give the 1-methylthiomethyl-3,4,5,5a,6,7-hexahydro9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 182°-184°.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1.[I:20]I>CCCCCC.O1CCCC1>[I:20][C:13]1[CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:10]=[N:9][C:8]=1[O:7][CH3:6]
Reactant: COc1ccc(-c2ccncc2)nn1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1nnc(-c2ccncc2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
45 ml 1.6M solution of n-butyllithium in hexane are added at −30° C. to a 10.2 g 2,2,6,6-tertamethylpiperidine in 100 ml THF and the mixture stirred at 0° C. for 30 min. After cooling to −75° C. 11.2 g 3-methoxy-6-pyridin-4-yl-pyridazine dissolved 300 ml THF are added and the solution stirred at −75° C. for 35 min. The cold (−75° C.) reaction mixture is subsequently added at a cold (−75° C.) solution of 18.3 g iodine in 400 ml THF (tetrahydrofuran) and stirred at −75° C. for 1.5 h. The reaction is quenched by adding 80 ml methanol/THF (1:1) at −75° C. and 300 ml saturated aqueous NaHCO3 at room temperature and extracted with dichloromethane. The organic layer is ished with 5% aqueous Na2S2O3 and saturated sodium chloride solution, dried (MgSO4) and the solvens removed. The crude product is purified by chromatography on silica gel to yield 14.4 g of 4-iodo-3-methoxy-6-pyridin-4-yl-pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=[O:21])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][C:18]3=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc3c(c2)C(=O)CC3)cc1
Yield: 99.4 %

Procedure:
4-methoxybenzylchloride (9.19 mL, 67.5 mmol) was added to a mixture of 6-hydroxy-1-indanone (10 g, 67.5 mmol) and potassium carbonate (14 g, 101 mmol) in 15 mL DMF. The mixture was reacted at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was separated and the solvents were removed by evaporation. The residue was dissolved in DCM and filtered through a plug of activated basic alumina. 6-(4-Methoxy-benzyloxy)-indan-1-one (18 g, 99%) was obtained after evaporation of the filtrate. The material was taken to the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].Cl.[CH2:11]([C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH3:12].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:11]([C@H:13]1[CH2:18][N:17]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:26]([F:28])([F:29])[F:27])[C:30]([F:31])([F:32])[F:33])=[CH:21][CH:20]=1)[CH3:12]
Reactant: CC[C@H]1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 19 h
Yield: 17.2 %

Procedure:
2-Thiophenesulfonyl chloride (0.28 g, 1.5 mmol, Sigma-Aldrich, St. Louis, Mo.) was added to a stirring solution of 2-(4-((2S)-2-ethyl-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol hydrochloride (0.55 g, 1.5 mmol), Hünig's base (0.81 mL, 4.6 mmol), and DMF (7.7 mL) at room temperature. After 19 h, the reaction mixture was partitioned between EtOAc (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The layers were separated, and the organic material was washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (Na2SO4) and purified via column chromatography (40 g of silica, 20 to 33% EtOAc in hexanes) to give 2-(4-((2S)-2-ethyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.13 g) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J=5.1 Hz, 1H), 7.59-7.49 (m, 3H), 7.19-7.13 (m, 1H), 6.83 (d, J=8.0 Hz, 2H), 3.77 (d, J=11.0 Hz, 3H), 3.49 (d, J=12.7 Hz, 1H), 3.32 (dt, J=3.1, 11.9 Hz, 1H), 3.24 (s, 1H), 2.74-2.51 (m, 2H), 1.89 (ddd, J=7.3, 9.3, 14.0 Hz, 1H), 1.60-1.47 (m, 1H), 0.94 (t, J=7.4 Hz, 3H); m/z (ESI, +ve ion) 503.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.679 μM; GK-GKRP EC50 (LC MS/MS)=1.37 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7]O.[CH3:9][C:10]([CH3:12])=O.[OH-].[Na+].CCOCC>CCOC(C)=O.O=[Mn]=O>[CH3:12][C:10]1[N:1]=[C:2]2[CH:6]=[CH:5][S:4][C:3]2=[CH:7][CH:9]=1
Reactant: Nc1ccsc1CO
Reactant: CC(C)=O
Agent: O=[Mn]=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc2sccc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 5 L three neck flask was charged with 562 g (4.35 mol) of 3-amino-2-hydroxymethylthiophene (Step 1). It was suspended in 3 L of EtOAc and cooled to 0° C. (ice bath). 2.0 Kg of MnO2 (23.0 mol.; 5.3 eq) was added portionwise (250 g) over 45 min. with mechanical stirring. Upon addition of the MnO2 the reaction temperature rose to 20° C. The reaction mixture was stirred at 20° C. for 1 h until total consumption of starting material by TLC (Hex/EtOAc 1:1). The solids were removed by filtration over 2 L of celite and washed 3 times with 2 L of EtOAc/THF (1:1). The combined filtrates were evaporated to dryness to give a black residue. The residue was dissolved in 1.28 L of acetone (17.4 mol, 4.0 eq) and transferred to a 10 L three neck flask charged with 3 L of 2.5% NaOH. The mixture was then stirred at 70° C. for 1 h. The two phase mixture was cooled to 20° C., 2 L of ether was added and stirred for 15 min. The phases were separated and the aqueous phase was backwashed with 2×1 L of ether. The organic fractions were combined, washed with 2 L of brine and evaporated to dryness to give a black oil. The latter was distilled under vacuum (@70° C., 0.3 mm Hg) to give the title compound: 492 g; 76%.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[OH:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[N:29]=[CH:28][CH:27]=[N:26]1.Cl[C:32]1[CH:37]=[N:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=1>C1COCC1>[N:29]1[N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([NH:17][C@H:13]2[CH2:14][CH2:15][CH2:16][C@H:12]2[O:11][C:32]2[CH:37]=[N:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=2)=[O:30])[N:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: O=C(N[C@H]1CCC[C@H]1O)c1ccccc1-n1nccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1CCC[C@H]1Oc1cnc(C(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS in THF (1.0 M, 0.477 ml, 0.477 mmol) was added to a solution of N-[(1S,2R)-2-hydroxycyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 10; 0.100 g, 0.37 mmol) in THF (3 ml) at 0° C. under nitrogen. The reaction was stirred at this temperature for 1 hour and then 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 0.059 ml, 0.48 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction was then quenched with water (2 ml) and extracted with ethyl acetate (30 ml). The organics were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[C:4]([O:14][CH3:15])[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[S:24]([NH2:27])(=[O:26])=[O:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[S:24]([NH2:27])(=[O:25])=[O:26])(=[O:12])=[O:11])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Solvent: c1ccncc1
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Nc1ccc(C)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
2-(4-Chloro-2-methoxy-phenyl)-ethenesulfonyl chloride (0.50 g, 1.87 mmol) was added slowly to a solution of 2-amino-5-methyl-benzenesulfonamide (0.38 g, 2.05 mmol) in anhydrous pyridine (10 mL) and the reaction mixture was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL). The organic phase was washed with 1 M hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave 0.42 g (54% yield) of the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([O:43][CH3:44])[CH:42]=1)[C:37](O)=[O:38].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[C:41]([O:43][CH3:44])[CH:42]=[C:34]([O:33][CH3:32])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)cc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 102 mg (0.561 mmol) of 3,5-dimethoxybenzoic acid, 143 mg (0.561 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine in analogy to Example 4. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.31, FD-MS: M+ =591.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[O:22][CH2:23][C:24]([O:26]CC)=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O1CCCC1.Cl>O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[O:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 9a (170 mg, 0.31 mmol) and lithium hydroxide (71 mg, 3.0 mmol) were added to 20 mL of a mixed solvent of tetrahydrofuran and water (V/V=1:1) and then the reaction solution was stirred for 3 h. 1M of hydrochloric acid was added dropwise until the pH of the reaction solution was 5, and then it was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetic acid 9b (160 mg, a yellow oil), which was used directly in the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][O:28][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=1[C:25](=[O:27])[CH3:26]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 318) (77 mg), morpholine (49 mg), and potassium carbonate (131 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (60 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:39]=[C:38]([Cl:40])[C:21]([O:22][CH:23]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[C:24]([O:26]CC)=[O:25])=[C:20]([Cl:41])[CH:19]=1>CN(C=O)C>[C:24]([CH:23]([C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[O:22][C:21]1[C:20]([Cl:41])=[CH:19][C:18]([CH2:17][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:13])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:39][C:38]=1[Cl:40])([OH:26])=[O:25]
Reactant: CCOC(=O)C(Oc1c(Cl)cc(CBr)cc1Cl)c1ccc2c(c1)OCO2
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cc(Cl)c(OC(C(=O)O)c2ccc3c(c2)OCO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a solution of 0.034 g (0.20 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine in 0.5 mL anhydrous DMF was added 8.6 mg (0.22 mmol) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. A solution of 0.100 g (0.22 mmol) of the product of Step B in 0.9 mL of DMF was added and the reaction was stirred an additional 1.5 hour at room temperature. The reaction mixture was partitioned between EtOAc and 5% aqueous NH4Cl, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.081 g (74%) of the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[F:15])=[N:5][N:6]=1.[CH3:16][NH:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1>CN1C(=O)CCC1.C([O-])(O)=O.[Na+].O>[F:15][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[C:4]1[S:3][C:2]([N:17]([CH3:16])[CH:18]2[CH2:19][C:20]([CH3:26])([CH3:27])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]2)=[N:6][N:5]=1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Reactant: COc1cccc(F)c1-c1nnc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(F)c1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Yield: 27.6 %

Procedure:
A stirred solution of 2-bromo-5-(2-fluoro-6-methoxyphenyl)-1,3,4-thiadiazole (335 mg, 1.159 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (197 mg, 1.159 mmol) in NMP (2.5 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was diluted with saturated NaHCO3(aq) (30 mL), water (20 mL), and extracted with DCM (75 mL). The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 298 nm. The product containing fractions were combined and loaded onto a 5 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an orange oil (121 mg, 28% yield). LC-MS: Rt 0.88 min; MS m/z 379.4 [M+H]+; [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (td, J=8.34, 6.57 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 6.97 (t, J=9.09 Hz, 1H), 4.26-4.36 (m, 1H), 3.86 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.62, 2.53 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H).