Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.[Br:17]Br.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C.O1CCOCC1>[Br:17][C:14]1[S:13][C:12]([C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])=[CH:16][CH:15]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cccs1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
To a stirred 0° C. mixture of 8.0 g (0.034 mole) of 2-(2-methoxy-4-nitrophenyl)thiophene (Example 4, Step A) in 180 ml of diethyl ether was added a mixture of 10.8 g (0.07 mole) of bromine in 15.0 ml of 1,4-dioxane and 20 ml of diethyl ether. The mixture was allowed to warm to room temperature and stir for approximately 18 hours. The reaction mixture was poured into a mixture of sodium sulfite and ice water. The resultant mixture was extracted with diethyl ether, and the extract dried over anhydrous sodium sulfate. The dried extract was filtered, and the solvent evaporated from the filtrate to leave a residue. The residue was purified by column chromatography using silica gel and eluting with toluene to yield 9.7 g of 2-bromo-5-(2-methoxy-4-nitrophenyl)thiophene.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].CON(C)[C:8](=[O:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCOCC>C1COCC1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:8](=[O:18])[C:1]#[CH:2])=[CH:16][CH:15]=1
Reactant: C#C[Mg]Br
Reactant: CON(C)C(=O)COc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(=O)COc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 209.7 %

Procedure:
A solution of ethynylmagnesium bromide (0.5 M in THF, 508 mL, 254 mmol), was added slowly, as a stream down the side of the flask, to an ice water cooled solution of N-methoxy-N-methyl-2-(4-fluorophenoxy)ethanamide (20.00 g, 74 mmol) in THF (100 mL). After an additional 30 minutes at 0° C., the reaction mixture was poured into a vigorously stirred mixture of 1M NaH2SO4 (1700 mL) and ether (1 L). The layers were separated and the aqueous layer then extracted with ether (700 mL). The combined organic phases were washed with brine and dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by eluting through a plug of silica gel (10 cm×3 cm) with 1:4 ether:pet. ether to afford 27.65 g (91% yield) of 4-(4-fluorophenoxy)-1-butyn-3-one, a compound of formula (AA), as a low melting solid; 1H NMR (CDCl3) δ 3.40 (s, 1H), 4.70 (s, 2H), 6.85 (m, 2H), 7.0 (t, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH3:15][NH:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1>CC(C)=O>[CH3:15][N:16]([C:12]1[S:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:13]=1)[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1
Reactant: N#C[S-]
Reactant: CNc1ccsc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [NH4+]
Solvent: CC(C)=O
Product: CN(c1ccsc1)c1nc(=O)c2cccnc2s1
Yield: 26.3 %

Procedure:
The reaction procedure of Example 102 was followed except that 560 mg of 2-chloronicotinoyl chloride, 242 mg of ammonium thiocyanate, 360 mg of 3-(methylamino)thiophene and 10 ml of acetone were used. The product was then recrystallized from a mixture of ethanol and chloroform to obtain 230 mg of 2-[N-methyl-N-(3-thienyl)amino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.Cl[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([O:27][CH3:28])[CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([C:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH:10]=2)[CH:22]=[CH:23][C:24]=1[N+:29]([O-:31])=[O:30]
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (1.09 g, 4.13 mmol) in dioxane (17 mL) was added 5-chloro-2-nitroanisole (0.64 g, 3.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) and 1.0 M Na2CO3 in H2O (10.32 mL, 10.32 mmol). The mixture was degassed by purging the reaction flask with vacuum/then N2 back-fill (5×). Under N2 the reaction was then heated to 80° C. and stirred overnight (approximately 16 h). The reaction was cooled to rt and diluted with EtOAc, then filtered through Celite, washing with EtOAc. The filtrate was concentrated under vacuum. The residue was taken up in EtOAc and H2O. The H2O layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step C (911 mg, 3.13 mmol, 91%) as an amber oil. MS (ESI): 292 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH:11]=[CH:12]C1C=CC=CC=1.[Al+3].[Cl-:21].[Cl-].[Cl-].BrC1C(F)=CC=C2C=1NC(=O)C=C2>ClC1C=CC=CC=1.O=P(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:10]([Cl:21])[CH:11]=[CH:12]2
Reactant: O=C(C=Cc1ccccc1)Nc1cccc(F)c1Br
Reactant: [Cl-]
Agent: O=c1ccc2ccc(F)c(Br)c2[nH]1
Agent: [Al+3]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Fc1ccc2ccc(Cl)nc2c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene, the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).
Reaction SMILES: [Na].CO[C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O.[NH2:11][C:12]([NH2:14])=[O:13].O>C(O)C>[CH3:9][CH:5]1[C:4](=[O:10])[NH:14][C:12](=[O:13])[NH:11][C:6]1=[O:8]
Reactant: NC(N)=O
Reactant: COC(=O)C(C)C(=O)O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1C(=O)NC(=O)NC1=O
Reaction time: 0.08 h

Procedure:
46 g (2 mols) of sodium are dissolved in 1 liter of absolute ethanol in a 5-liter flask. To this solution are firstly added 348 g (2 mols) of methyl malonic acid methyl ester; and there is then added dropwise at 70° C. with stirring, within about 5 minutes, a solution of 120 g (2 mols) of urea in 1 liter of absolute ethanol. There is formed a thin suspension, which is diluted with 3.5 liters of ethanol, refluxed for 16 hours and afterwards cooled. There are subsequently added 2 liters of water and, for clearing, a filtering auxiliary (HiFlo) is introduced, and the suspension is filtered. Concentrated hydrochloric acid is then added until a Congo blue colour is indicated, and the mixture is left to stand for several hours in a cool place. A fine white crystalline precipitate is formed, which is filtered and dried. The mother liquor is concentrated by evaporation, diluted with water, and the precipitate is likewise filtered and dried. The crude yield is 263 g of material, which melts at 200°-215° C. After recrystallisation from water, there remain 144 g of white crystals (58% of theory), which melt at 203°-204° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)=[CH:29][CH:28]=1>>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:35]2[CH2:36][CH2:37][CH:33]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:25])([F:38])[F:39])=[CH:28][CH:29]=3)[CH2:34]2)=[O:16])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)phenyl]pyrrolidine oxalate (18.3 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.5 mg). Calcd for C22H16F6N2O2: 454.1116, found 454.1116.
Reaction SMILES: Cl.N[C@@H]1C[C@H](NC2C(C)=NC3C(N=2)=C([C:18]2[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=2)C=CC=3)C1.ClC(Cl)(Cl)S(OCC(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[NH:26]1[C:25]2[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=2[CH:19]=[CH:18]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1C[C@@H](N)C1
Agent: Cl
Agent: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]ccc21
Temperature: 110 °C
Yield: 39.1 %

Procedure:
A solution of 2-(3-((cis-3-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (Example 435; 27.4 mg, 0.069 mmol), 2,2,2-trifluoroethyl trichloromethanesulfonate (Oakwood Products, Inc., West Columbia, S.C.; 0.073 mL, 0.446 mmol), and DIPEA (0.120 mL, 0.686 mmol) in a mixture of THF (1.0 mL) and DMF (1.0 mL) was heated in a sealed flask at 110° C. for 30 min. The reaction mixture was then cooled to RT, concentrated onto silica gel, and chromatographically purified (silica gel, 10-100% (3:1 EtOAc-EtOH)/hexanes). The product-containing fractions were concentrated in vacuo, and the residue was taken up in 5% MeOH/DCM (40 mL), sequentially washed with half-saturated aqueous NaHCO3 (30 mL) and water (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 2-(2-methyl-3-(1s,3s)-3-((2,2,2-trifluoroethyl)amino)cyclobutyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (11.8 mg, 0.027 mmol, 39% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.57 (1H, br. s.), 7.94 (1H, dd, J=7.5, 1.1 Hz), 7.68 (1H, dd, J=8.1, 1.1 Hz), 7.41 (1H, t, J=7.8 Hz), 7.14 (1H, d, J=2.2 Hz), 5.31 (1H, br. s.), 5.16 (1H, d, J=4.7 Hz), 4.13-4.27 (1H, m), 3.68 (2H, td, J=6.9, 2.4 Hz), 3.32-3.43 (1H, m), 3.23 (2H, q, J=9.4 Hz), 3.01-3.08 (2H, m), 2.99 (2H, t, J=6.8 Hz), 2.59 (3H, s), 1.80-1.94 (2H, m). 19F NMR (376 MHz, CDCl3) δ ppm −71.65 (3F, br. s.). m/z (ESI, +ve) 445.0 (M+H)+.
Reaction SMILES: COC1C=CC([O:7][CH2:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:17])=[O:10])=CC=1.N1C=CC=CC=1.[N+]([O-])([O-])=O.[Ce].[NH4+]>C(#N)C.O>[OH:7][CH2:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:17])=[O:10]
Reactant: COc1ccc(OCC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
(S)-2-[[(S)-2-[(p-Methoxyphenoxy)acetyl]-1-pyrrolidinyl] -carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (500 mg) was dissolved in acetonitrile (8 ml) and water (2 ml), and thereto were added pyridine (0.22 ml) and ammonium cerium nitrate (1.47 g). The mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (203 mg) (see Table 1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].I[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH:23]=[CH:22][N:21]=1.N(CC)CC>C1COCC1.[Cu](I)I.[Cu]I>[CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])([CH2:7][C:8]#[C:9][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)[C:3]1=[O:18]
Reactant: FC(F)(F)Oc1cccc(-c2ccnc(I)c2)c1
Reactant: C#CC[C@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Agent: I[Cu]I
Agent: [Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: CN1CC[C@](CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)(NC(=O)OC(C)(C)C)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
Copper Iodide (104.92 mg, 0.5500 mmol), followed by PdCl2(Ph3P)2 (193.34 mg, 0.2800 mmol) was added portionwise to a solution of the tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (2.78 g, 11.02 mmol) (which may be prepared as described in Description 8), 2-iodo-4-[3-(trifluoromethoxy)-phenyl]pyridine (6.03 g, 16.53 mmol) (which may be prepared as described in Description 9) and Et2NH (5.7 mL, 55.09 mmol) in THF (60 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. Additional PdCl2(Ph3P)2 (1.25 mol %) and CuI (2.5 mol %) catalyst was added. The reaction was left to stir for 3 days. The solvent was evaporated and the residue was suspended in EtOAc and washed with water/sat. aq. NaHCO3. The organics were collected, dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified using a Biotage SP4, with 100 g SNAP cartridge, eluting with 0 to 100% EtOAc in i-hexane. Clean fractions were collected and the solvent evaporated to afford a yellow oil. The remaining fractions were collected and re-columned using a SP4, 100 g SNAP cartridge, 0 to 10% MeOH/EtOAc and the product was collected and combined with the clean material from the first column to afford the tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (D10) (5.38 g, 10.991 mmol, 99.8% yield) as a yellow oil containing some Ph3P residues;
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[O:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].IC.[CH3:19]N(C)C=O.[H-].[Na+]>O>[CH3:19][N:11]1[N:10]=[C:9]([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:13][C:12]1=[O:14]
Reactant: O=c1[nH]nc(Cc2ccc([N+](=O)[O-])cc2)o1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1nc(Cc2ccc([N+](=O)[O-])cc2)oc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a mixture of 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one (1.0 g), iodomethane (0.97 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.20 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methyl-5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one as colorless crystals (0.75 g, yield 71%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[N:26]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=489.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])O.[Na+].[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>O1CCOCC1>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:21])=[O:20]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cccc(NS(C)(=O)=O)c1
Reaction time: 120 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 3-aminobenzoate (2.0 g, 12.1 mmol) and sodium hydrogen carbonate (1.2 g, 14.5 mmol) in 1,4-dioxane (24 ml) was added methanesulphonyl chloride (2.3 ml, 30.3 mmol). The mixture was stirred at room temperature for 3 h, before addition of water (10 ml), and the reaction mixture was stirred for a further 5 days. The mixture was partitioned between ethyl acetate and hydrochloric acid (2M) and the organic phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was passed through a plug of silica, eluting with ethyl acetate/cyclohexane [1:3] and the filtrate was concentrated in vacuo to give the title compound (2.4 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(Cc2ccccc2)CC1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCC(Cc2ccccc2)C1

Procedure:
A mixture of 5 g of 4-benzyl-cyclohexanone, 3.5 g of pyrrolidine, 500 mL of benzene and 10 mg of p-toluenesulfonic acid monohydrate was heated under a water separator apparatus for 48 h, removing the distillate periodically until there was about 50 mL remaining. The solution was cooled and concentrated to 8 g of an amber liquid. The NMR was consistent with complete conversion to the enamine.
Reaction SMILES: COC1C=[CH:7][C:6]([C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]=[C:11]([S:21][CH3:22])[N:10]=2)=CC=1.CO[CH:25](OC)[N:26](C)[CH3:27]>CN(C=O)C.C(Cl)Cl.O>[CH3:25][N:26]([CH3:27])/[CH:7]=[CH:6]/[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]=[C:11]([S:21][CH3:22])[N:10]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1-c1ccc(OC)cc1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc(SC)nc1/C=C/N(C)C
Temperature: 130 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To the solution of ethyl 4-(4-methoxyphenyl)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (0.67 g, 1.75 mmol) in 5 mL DMF was added N,N-dimethylformamide dimethyl acetal (0.32 mL, 2.50 mmol). The reaction mixture was stirred at 130° C. for 2 hours. After monitoring the reaction by TLC was cooled to room temperature, then the mixture was diluted with DCM and water. After extracted three times by DCM from the aqueous layer, the combined organic layer was dried over MgSO4. The solution was condensed under reduced pressure yielding crude mixture (467 mg). The mixture was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:14][S:15]SC>>[CH3:14][S:15][C:10]1[CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CSSC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: CSc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=235.0 [(M−H)−], was prepared in accordance with the general method of intermediate E from 4-(trifluoromethyl)benzoic acid and dimethyl disulfide.
Reaction SMILES: O(C1N(C2C=CC=CC=2)C2C(C=1C(O)=O)=CC=CC=2)C1C=CC=CC=1.[O:26]([C:33]1[N:34]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:35]2[C:40]([C:41]=1[CH:42]=[O:43])=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:50]1([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:60]([O:59][C:57]([N:50]1[CH2:56][CH2:55][CH2:54][N:53]([C:42]([C:41]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:33]=2[O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:43])[CH2:52][CH2:51]1)=[O:58])([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=Cc1c(Oc2ccccc2)n(-c2ccccc2)c2ccccc12
Agent: O=C(O)c1c(Oc2ccccc2)n(-c2ccccc2)c2ccccc12
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2c(Oc3ccccc3)n(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenoxy-1-phenyl-1H-indole-3-carboxylic acid (164 mg, 499 μmol; available by oxidation of 2-phenoxy-1-phenyl-1H-indole-3-carbaldehyde (DE 2707268) analogously as described in example 11, step 5), tert-butyl 1-homopiperazinecarboxylate (100 mg, 499 μmol), EDC (105 mg, 549 μmol) and HOAT (78.2 mg, 574 μmol) in DMF (2 ml) was added NMM (165 μl, 1.49 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was filtered and purified by preparative HPLC. The eluate was lyophilized overnight to give 169 mg of the title compound.