Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH2:16]3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[CH3:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28](Cl)=[O:29]>>[CH3:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([N:18]1[CH2:19][CH2:20][C:13]2([C:12](=[O:22])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:23])[F:24])=[CH:6][CH:7]=3)[CH2:15][CH2:14]2)[CH2:16][C:17]1=[O:21])=[O:29]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O
Product: CC(C)(C)CC(=O)N1CCC2(CCN(c3ccc(OCC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 3) from 2-(4-(2,2,2-trifluoroethoxy)phenyl)-2,8-diazaspiro[4.5]decane-1,7-dione and 3,3-dimethyl-butyryl chloride. MS (ESI): 441.19 (MH+).
Reaction SMILES: [CH2:1]1[O:26][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([O:22][CH3:23])[CH:14]=4)=[N:11][NH:10][C:9](=[O:24])[CH2:8][C:7]=3[CH:25]=[C:3]2[O:2]1.C(O)C.O>CC(C)=O.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:26][CH2:1][O:2][C:3]4=[CH:25][C:7]=3[CH2:8][C:9](=[O:24])[NH:10][N:11]=2)=[CH:14][C:15]=1[O:22][CH3:23]
Reactant: COc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a solution of 7,8-methylenedioxy-1-(3-methoxy-4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (136 mg, 0.387 mmol) in acetone (6 mL) was added ethanol (3 mL), water (4 mL), 5% Pd/C (33 mg) and HCO2NH4 (240 mg, 3.81 mmol). The mixture was stirred at room temperature for 3 h. The catalyst was filtered out. The filtrate was concentrated in vacuo and the resulting residue was collected by filtration, washed with water, and dried in vacuo to afford the title compound as a light yellow solid (98 mg, 0.31 mmol, 80%), mp: 147°-150° C. 1H NMR (CDCl3) 8.32 (s, 1H), 7.24 (d, J=1.9, 1H), 6.87 (dd, J=1.9, 8.0, 1H), 6.82 (s, 1H), 6.73 (s, 1H), 6.02 (s, 2H), 4.08 (s, 2H), 3.90 (s, 3H), 3.43 (s, 211). Anal. calcd. for C17H15N3O4.(3/8)H2O: C, 61.49; H, 4.78; N, 12.65. Found: C, 61.33; H, 4.39; N, 12.54.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]ccc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-indole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.69 (dt, J=2.3, 1.4 Hz, 1H), 7.55 (t, J=2.7 Hz, 1H), 7.62-7.70 (m, 2H), 7.94 (dd, J=8.8, 1.7 Hz, 1H), 8.46 (dt, J=8.1, 1.9 Hz, 1H), 8.49-8.52 (m, 1H), 8.81 (dd, J=4.7, 1.7 Hz, 1H), 9.27 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 263 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[O:14][CH3:15])[CH3:2].C(N(CC)C1C=CC=CC=1)C.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1(C)C=CC=CC=1>[Cl:10][C:9]1[CH:8]=[C:7]([NH:11][C:29](=[O:30])[O:31][CH:32]([CH3:34])[CH3:33])[CH:6]=[C:5]([NH:12][C:13]([O:14][CH3:15])=[O:16])[C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1c(Cl)cc(N)cc1NC(=O)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOc1c(Cl)cc(NC(=O)OC(C)C)cc1NC(=O)OC
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
Methyl N-(2-ethoxy-3-chloro-5-aminophenyl)carbamate (1.39 g) and N,N-diethylaniline (0.85 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.70 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The reside was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-ethoxy-5-methoxycarbonylaminophenyl)carbamate (Compound No. 2) (1.73 g) in a yield of 92.0%. M.P., 140° C.-142° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl.[CH3:15]O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CO
Reactant: Cc1n[nH]c2cc(C(=O)O)ccc12
Agent: Cl
Product: COC(=O)c1ccc2c(C)n[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-methyl-indazole-6-carboxylic acid (1.57 g, Reference Example 45) in methanol (75 ml) was treated with hydrogen chloride gas for 10 minutes. The reaction mixture was stirred for 12 hours at room temperature then evaporated. The residue was partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was washed with hexane to give the title compound (1.56 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][CH2:10][C:12]2[NH:13][CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1c[nH]cn1
Reactant: Nc1cccc(Cl)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Fc1c(Cl)cccc1NCc1cnc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 3-chloro-2-fluoroaniline (0.44 g, 3 mmol) in methanol (5 ml) was added 4-formylimidazole (0.29 g, 3 mmol). After stirring the mixture overnight at 60° C. the solution was cooled and sodium borohydride (0.57 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column filtration (heptane/ethyl acetate=1:1) to yield a light yellow liquid (0.55 mg, 81%); MS (ISP): 226.3 ((M+H)+.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:24][CH:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14](=[O:16])[O:15][CH:11]2[CH:10]([CH3:25])[CH2:9]1.[Br:26][C:27]1[N:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]>CCOC(C)=O>[Br:26][C:27]1[N:32]=[C:31]([C:33]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH:8]2[CH2:24][CH:12]3[N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:14](=[O:16])[O:15][CH:11]3[CH:10]([CH3:25])[CH2:9]2)=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]
Reactant: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: CC1CC(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)CC2C1OC(=O)N2C(=O)OC(C)(C)C

Procedure:
Following Method 9, (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, (+/−)-tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate was obtained. LCMS (m/z): 549.2/551.2 (MN), Rt=0.78 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2].[Br:15][C:16]1[C:21]([NH2:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([S:11]([NH:22][C:21]2[C:16]([Br:15])=[N:17][CH:18]=[C:19]([Cl:23])[CH:20]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2]
Reactant: Nc1cc(Cl)cnc1Br
Reactant: CC(=O)c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl

Procedure:
Prepared from 1.6 g (6.32 mmol) of 3-acetyl-4-chloro-benzenesulfonyl chloride and 1.3 g (6.28 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 8 mL pyridine using procedure x. Yield: 1.3 g of a white solid. LC-MSD, m/z for C13H9BrCl2N2O3S [M+H]+=422.8, 424.8, 426.8.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]([NH2:10])=[S:9].CC(C)=[O:13]>>[ClH:1].[NH2:7][C:8]1[S:9][CH:5]=[C:3]([CH2:2][OH:13])[N:10]=1
Reactant: CC(C)=O
Reactant: O=C(CCl)CCl
Reactant: NC(N)=S
Product: Cl
Product: Nc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,3-dichloroacetone (917 mg, 7.23 mmol) in acetone (6 mL) was added a solution of thiourea (550 mg, 7.23 mmol) in acetone (30 mL) at a fairly fast speed. The mixture was stirred at room temperature overnight. The formed solid was filtered and the filtrate was concentrated to give 524 mg of (2-amino-thiazol-4-yl)-methanol monohydrochloride as colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]2[CH2:11][O:10][CH2:9][CH2:8][C:5]=2[NH:6][N:7]=1.Cl[CH2:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20]2[N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:25]=[CH:26][C:19]1=2)=[O:17].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:24]2[C:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][N:6]4[C:5]5[CH2:8][CH2:9][O:10][CH2:11][C:4]=5[C:3]([C:2]([F:12])([F:1])[F:13])=[N:7]4)[C:19]=3[CH:26]=[N:25]2)=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1n[nH]c2c1COCC2
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCOC2)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 55 °C
Yield: 45.8 %

Procedure:
A mixture of 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (0.050 g, 0.26 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.050 g, 0.17 mmol) and K2CO3 (0.130 g, 0.94 mmol) in THF (0.8 mL) and DMF (0.4 mL) was heated at 55° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.035 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.17 (dd, J=8.8, 8.0 Hz, 2H), 5.13 (s, 2H), 4.75 (s, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 2.10 (m, 2H); MS: (ES) m/z calculated for C21H19F4N5O2 [M+H]+ 450.1, found 450.1.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1COCC1>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12](=[O:13])[CH2:2][C:1]#[N:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
To a stirred solution of acetonitrile (2.0 mL, 38.2 mmol) in THF (50 mL) at −78° C. was added nBuLi (1.81 M in hexane, 16 mL, 28.7 mmol). The resulting slurry was kept at −78° C. for 15 min and 2,4-dichlorobenzoyl chloride (2.0 g, 9.55 mmol) was added dropwise to the acetonitrile anion. After 40 min, the reaction was quenched by addition of saturated NH4Cl (30 mL). THF was removed under reduced pressure and the suspension was filtered. The solid was washed with H2O (100 mL) and dried to give 3-(2,4-dichlorophenyl)-3-oxopropanenitrile (2.0 g, 98%, >95% purity) as a light yellow solid.
Reaction SMILES: [ClH:1].Cl.N[C@@H](CC)[C@H](O)C(NC1CC1)=[O:7].[NH2:15][C@@H:16]([CH2:19][CH2:20][CH3:21])[CH2:17][OH:18].[N+:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[C-:23]>>[ClH:1].[ClH:1].[NH2:15][C@@H:16]([CH2:19][CH2:20][CH3:21])[C@H:17]([OH:18])[C:23]([NH:22][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CCC[C@H](N)CO
Reactant: [C-]#[N+]Cc1ccccc1
Agent: Cl
Product: CCC[C@H](N)[C@H](O)C(=O)NCc1ccccc1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-2-aminopentan-1-ol in the first step (A1), and using (isocyanomethyl)benzene in the third step (A3).
Reaction SMILES: C1(C)C=CC=CC=1.S(=O)(=O)(O)O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:31])[C:21]([NH:23][C:24]([C:29]#N)([CH3:28])[CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:16][CH:15]=1.[OH-:32].[Na+]>O.C(O)(=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:21]2[O:22][C:28](=[O:32])[C:24]([CH:25]([CH3:27])[CH3:26])([CH3:29])[N:23]=2)[CH3:31])=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: CC(C(=O)NC(C)(C#N)C(C)C)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Yield: 99.6 %

Procedure:
450 ml of toluene, 45 g (0.44 mole) of concentrated sulfuric acid and 45 ml of glacial acetic acid were added to 126.7 g (0.45 mole) of 2-(4-chlorophenyl)-N-(1-cyano-1,2-dimethylpropyl)propanamide. The mixture was refluxed for 4 hours with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled and dropwise added to a solution of 18.2 g (0.45 moles) of sodium hydroxide dissolved in 300 ml of water. The organic layer was separated, then washed with a saturated aqueous sodium bicarbonate solution and water, and concentrated to obtain 125 g (0.448 mole) of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one (yield=99.6%).
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:16]1[CH:17]=[C:12]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc(Oc2cccc3ccccc23)cc1
Product: Clc1cc(Oc2cccc3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of Example 137 A (4.50 g; 19.0 mmol) in phosphoryl chloride (50 ml) is heated to reflux temperature in the course of 1.5 h and stirred at this temperature overnight. The phosphoryl chloride is stripped off in vacuo, the residue is treated with ice water and the mixture is extracted with dichloromethane. The organic phase is washed with sat. NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The residue is chromatographed on silica gel using toluene:EA (5:1).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[S:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([NH2:38])=[CH:33][CH:32]=[CH:31]2.CCN(CC)CC>C(Cl)Cl>[N:38]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[CH:36]=[CH:37][C:28]([O:27][C:18]1[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=1)=[CH:29]2)=[C:1]=[S:2]
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc4c(N=C=S)cccc4c3)c2cc1OC
Reaction time: 0.25 h

Procedure:
Thiocarbonyl diimidazole (108 mg, 0.606 mmol) was added to a solution of 6-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-1-amine (210, 0.606 mmol) and NEt3 (84.5 μL, 0.606) in DCM (1.52 mL) in one portion at RT. After 15 minutes of stirring, LCMS and TLC indicated that the reaction was complete. The crude mixture was purified by silica gel chromatography (Hex:EtOAc). MS (ESI, pos. ion) m/z: 389.0 (M+1). Mass Calc'd for C18H15NO3: 388.45.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(O)[CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24]O)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:48])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:22](\[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[CH2:23][CH2:24][Cl:48])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCC/C(=C(\c1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1)c1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1-{4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl}-1,2-diphenyl-butane-1,4-diol (10.0 g, 19.5 mmol) is dissolved in toluene (50 ml). Triethylamine (2.17 g, 21.4 mmol) is added to the solution and the mixture is cooled to −10° C. Thionyl chloride (6.9 g, 58.5 mmol) is added to the mixture at −10-±0° C. The mixture is stirred for 1 hour at 0-5° C., warmed up to 70° C. and stirred at this temperature for 4 hours. Solvent is evaporated, the residue is dissolved to toluene, washed three times with 1M HCl solution and twice with water. The Z-isomer of the product is crystallized from isopropanol-ethyl acetate. Yield 3.0 g. The filtrate is purified by flash chromatography to give E-isomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:29][Si:30]([C:33]#[C:34][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1)([CH3:32])[CH3:31]
Reactant: N#Cc1cc(Br)ccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-pyridinecarbonitrile [Cesko-Slovenska Farmacie 25(5),181 (1976)] (0.73 g, 4.0 mmol) was dissolved in 18 mL dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (31 mg, 0.12 mmol) and bis(triphenylphosphine)palladium(II) chloride (141 mg, 0.20 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I) iodide (23 mg, 0.12 mmol) and trimethylsilyl-acetylene (590 mg, 6.0 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with 100 ml of ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/methylene chloride 1:2). The desired product was obtained as a yellow oil (329 mg, 41%), MS: m/e=201.3 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[O:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:27]5[O:28][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1ccc(C(F)(F)F)o1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)o4)cc3=O)cc21
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg) and (5-(trifluoromethyl)-2-furyl)methanol (462 mg) in THF (40 ml) were added tributylphosphine (1.06 ml) and 1,1′-(azodicarbonyl)dipiperidine (1.08 g) at 60° C., and the mixture was stirred for 3 h. After the solvent was evaporated, the residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). Then the resulting solid was recrystallized from EtOH-hexane to give the title compound (313 mg) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[NH:29][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:36]([C:32]2[CH:31]=[C:30]3[C:35]([C:27]([Cl:26])=[CH:28][NH:29]3)=[CH:34][CH:33]=2)=[O:37])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2F)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2F)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (600 mg, 1.7 mmol) and 3-chloroindole-6-carboxylic acid (367 mg, 1.9 mmol) afforded, after purification (SiO2: 10 DCM: 2 EtOAc: 2 Hexane: 0 to 0.125 isopropyl amine), 800 mg (90%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31](C(OC(C)(C)C)=O)[C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [OH:1]S(O)(=O)=O.[O:6]=[C:7]([CH2:9]N(C(=N)N)C)[OH:8].[C:15]1([OH:25])[C:24]2[C:19](=CC=CC=2)C=CC=1>[OH-].[Na+]>[CH3:19][CH:24]([O:8][C:7]([CH3:9])=[O:6])[C:15]([OH:25])=[O:1]
Reactant: Oc1cccc2ccccc12
Reactant: CN(CC(=O)O)C(=N)N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)OC(C)C(=O)O
Temperature: 55 °C

Procedure:
Tubes containing assay mix were temperature equilibrated at 30° prior to addition of permeabilized cells to start each reaction. Reactions were stopped by addition of 0.1 mL 6N H2SO4 or 0.1 mL 2.5N NaOH. The tubes were heated for 15 minutes at 55° and then 0.4 mL of 0.5% creatine was added. followed by 0.4 mL of 4% α-naphthol in 2.5 N NaOH, with vigorous mixing after each addition. The tubes were heated again at 55° C. for 5 minutes and centrifuged to remove precipitate. Optical density at 530 nm was then determined. This assay measures acetoin. Acetolactate formed by enzymatic reaction is converted to acetoin by acidification in reactions stopped with H2SO4. Thus the difference in OD530 readings of acid-stopped and base-stopped reactions is a measure of acetolactate formation over background acetoin formation.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Li].FC1C=CC=CC=1I>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: [Li]c1ccccc1F
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Agent: Fc1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2F)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (from Example 1) and a solution of 2-fluorophenyllithium (˜3 equiv, freshly prepared from 1-fluoro-2-iodobenzene as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-fluoro-phenyl)-methanone. MS (M+H)+: 278.