Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:17])[N:11]([CH2:15][CH3:16])[C:12](=[O:14])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][CH:19]=1>ClCCl.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:20]4[CH2:21][CH2:22][CH:23]([CH:18]=[CH:19]4)[CH:13]2[C:12](=[O:14])[N:11]([CH2:15][CH3:16])[C:10]3=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1C(=O)C=C(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: C1=CCCC=C1
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Solvent: ClCCl
Product: CCN1C(=O)C2C3C=CC(CC3)C2(c2ccc(Cl)c(Cl)c2)C1=O
Yield: 57.4 %

Procedure:
A solution of 7.5 g of the above maleimide, 2.25 g of 1,3-cyclohexadiene, and 10 mg of methylene blue in 25 ml of dichloromethane was heated at reflux for 5 hours, then an additional one ml of the diene was added and the solution was heated for 24 hours. The cooled reaction mixture was subjected to high pressure liquid chromatography on a silica gel column eluting with hexane:ethyl acetate (4:1) and gave 5.58 g of 3a-(3,4-dichlorophenyl)-2-ethyl-3a,4,7,7a-tetrahydro-4,7-ethano-1H-isoindol-1,3(2H)-dione as a white solid, mp 122°-126° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([OH:10])(=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].N[CH2:12][C:13]([NH:15][C:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:24]([F:27])([F:26])[F:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]>CO>[C:3]([OH:10])(=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[CH3:1][NH:2][CH2:12][C:13]([NH:15][C:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:24]([F:26])([F:27])[F:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: NCC(=O)NC(Cc1ccccc1)(c1ccccc1)C(F)(F)F
Reactant: CN
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CNCC(=O)NC(Cc1ccccc1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.4 %

Procedure:
To a stirred solution of monomethylamine (50 ml, 1.13 mol) in 150 ml of methanol at 0° C. under nitrogen, was added 2-chloro-N-[(1,2-diphenyl-1-(trifluoromethyl)ethyl]acetamide (from Example 1) (10.2 g) followed by 100 ml of methanol to effect solution. The mixture was allowed to slowly warm to ambient temperature and stirred for 24 hours. The solvent was evaporated and the resulting semi-solid was dissolved in 150 ml of chloroform, 100 ml of water and 20 ml of 15% NaOH. The phases were separated, the aqueous phase extracted with chloroform (2×125 ml) and the combined organic phases washed with brine (150 ml), decolorized with charcoal, dried and evaporated to a yellow-orange oil, 9.8 g. This was dissolved in 150 ml of methanol, treated with 3.4 g of maleic acid and the solvent removed under vacuum to yield a solid which was recrystallized from methanol (150 ml) and ethyl acetate (150 ml), then from methanol (30 ml) and ethyl acetate (75 ml) and vacuum dried to give 4.88 g of 2-(methylamino)-N-[1,2-diphenyl-1-(trifluoromethyl)ethyl]acetamide maleate as a white solid, mp 179°-181° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)[CH3:15].Cl>CS(C)=O.CCOCC>[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[CH3:15]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCOC(CBr)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(COc1ccc(CC(=O)O)cc1)OCC
Yield: 93.9 %

Procedure:
To a solution of 4-hydroxyphenylacetic acid (50.0 gm, 0.33 mol) in DMSO (300 mL) was added 50% aqueous NaOH (57.0 gm, 0.71 mol) with stirring. After stirring for 10 min at room temperature bromoacetaldehyde diethyl acetal (66.0 gm, 0.33 mol) was added. The solution was heated at 100°-110° C. for 2 hr when an additional 2 gm of 50% NaOH was added. After heating for another hour the reaction mixture was cooled and poured into a mixture of aqueous HCl (30 mL of conc. HCl in 400 mL ice-H2O) and Et2O. The layers were separated and hexane was added to the Et2O layer. The organic layer was washed successively with H2O (twice) and saturated NaCl before being dried over Na2SO4, filtered and evaporated to dryness to give 83.7 gm (0.31 mol) of 4-[(2,2-diethoxy)ethoxy]phenylacetic acid which was suitable for use in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.[Cl:25][C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:25][C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:28]
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCCO)c2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCOC(=O)Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-(3-(6-hydroxyhexyloxy)phenyl)picolinate (13), (33 mg, 0.10 mmol, 1 eq.) in ethyl acetate (1 mL) was added triphosgene (14 mg, 0.047 mmol, 1.4 eq) dissolved in a minimum amount of ethyl acetate, followed immediately by DIEA (26 μL, 20 mg, 0.15 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min, the precipitated DIEA hydrochloride was filtered off, and the filtrate evaporated to dryness in vacuo. The oily residue of crude 14 was used directly for the next step.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:8][C@@H:9]([CH3:12])[CH2:10][O:11][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)N)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.4 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (1.02 g, 5.82 mmol), methyl 4-hydroxybenzoate (0.89 g, 5.85 mmol), and Ph3P (1.98 g, 7.55 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (1.49 mL, 7.57 mmol), and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo and the residue was treated with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHC3:MeOH (50:1, v/v) to give 480 mg (2 steps 39%) methyl (S)-4-(2-amino-1-propoxy)benzoate as a pale yellow oil. 1H-NMR (CDCl3) δ1.19 (d, 3 H, J=6.4 Hz), 3.35-3.39 (m, 1 H), 3.72-3.76 (m, 1 H), 3.89 (s, 3 H), 3.90-3.94 (m, 1 H), 6.92 (d, 2 H, J=8.8 Hz), 7.99 (d, 2 H, J=8.8 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18][C@H:19]1[NH:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:16][C:4]1[C:3]([CH3:17])=[C:2]([N:21]2[CH2:22][CH2:23][NH:24][C@H:19]([CH3:18])[CH2:20]2)[N:7]=[N:6][C:5]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: Cc1c(Cl)nnc(C(=O)c2cccnc2)c1C
Reactant: C[C@@H]1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cccnc2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 89.6 %

Procedure:
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-3-yl-methanone (1.2 g, 4.84 mmol) and (R)-2-methy 1-piperazine (485 mg, 4.84 mmol) are added to a microwave vial followed by NMP (17 mL) and triethylamine (2.01 mL, 14.49 mmol). The vial is sealed and irradiated in the microwave at 170° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2). The resulting oil is co-evaporated with CH2Cl2 and heptane to afford the title compound as a powder (1350 mg, 90%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:24]=1>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: ClCc1ccc2ccccc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(Cc3ccc4ccccc4c3)CC2)cc1

Procedure:
A mixture of 10.0 g. of β-chloromethylnapthalene, 6.0 g. of sodium carbonate and 9.0 g. of phenylpiperazine in 60 ml. of dimethylformamide is stirred under nitrogen on a steambath for five hours. The reaction mixture is then cooled and filtered. The filtrate is concentrated and stirred with ice water. The formed precipitate is filtered off, dissolved in isobutyl alcohol and treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(β-napthylmethyl)-4-(phenyl)piperazine having a melting point of 226°-228° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C@H:16]([CH2:20][CH3:21])[C@H:17]([OH:19])[CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[CH2:8]([N:15]([C@H:16]([CH2:20][CH3:21])[C@H:17]([OH:19])[CH3:18])[C:24](=[O:25])[CH2:23][Cl:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC[C@@H](NCc1ccccc1)[C@@H](C)O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]([C@@H](C)O)N(Cc1ccccc1)C(=O)CCl
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.43 mL, 3.4 mmol) was added to a −40° C. solution of (2R,3R)-3-(benzylamino)pentan-2-ol (220 mg, 1.1 mmol) in dichloromethane (100 mL), followed by the addition of 2-chloroacetyl chloride (0.10 mL, 1.1 mmol) dropwise. The reaction mixture was stirred at −40° C. for 1 hour and then quenched with saturated NaHCO3 solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded N-benzyl-2-chloro-N-((2R,3R)-2-hydroxypentan-3-yl)acetamide. MS APCI calc'd for C14H20ClNO2 [M+H]+ 270. found 270.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.C(N(CC)CC)C.[CH2:38]([N:40]([CH2:44][CH3:45])[C:41](Cl)=[O:42])[CH3:39]>O1CCCC1>[CH2:38]([N:40]([CH2:44][CH3:45])[C:41](=[O:42])[O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1)[CH3:39]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: CCN(CC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 100 °C

Procedure:
A mixture of dehydro-aripiprazole (1.50 g, 3.36 mmol), triethylamine (1.03 mL, 7.39 mmol), diethyl carbamoyl chloride (1.02 mL) were combined in tetrahydrofuran (30 mL). This was then heated to 100° C. for 6 hours by microwave. The reaction was quenched with water (50 mL) and extracted with dichloromethane (2×100 mL). The combined organics were dried (MgSO4) and concentrated. The crude product was purified by column chromatrography on silica eluting with ethyl acetate to 20% tetrahydrofuran/ethyl acetate to give the product. The product was then triturated with heptane to remove aliphatic impurities and then dried to give Compound-334 (1.54 g) as a light brown oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17]O)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH2:17][CH2:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: CCc1ccc(S(=O)(=O)CCO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)CCCl)cc1
Yield: 109.5 %

Procedure:
A solution of 1.0 ml (14.0 mmol) of thionyl chloride in toluene (15 ml) was added dropwise, while cooling with ice, to a solution of 1.0 g (4.67 mmol) of 2-(4-ethylphenylsulfonyl)-ethanol and 56 μl (0.70 mmol) of pyridine in toluene (20 ml). The mixture was then heated for 3 h under reflux. Quenching with ice and water was then carried out. The phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. There were obtained as crude product 1.19 g of slightly impure 1-(2-chloroethylsulfonyl)-4-ethylbenzene, which was reacted further without additional purification.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[ClH:10].[CH:11](O)([CH3:13])[CH3:12].N[C@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CCCNC(=N)N>>[ClH:10].[CH:11]([O:8][C:7](=[O:9])[C@H:2]([C@H:3]([CH2:5][CH3:6])[CH3:4])[NH2:1])([CH3:13])[CH3:12]
Reactant: CC(C)O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: Cl
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)OC(C)C

Procedure:
Isoleucine isopropyl ester-hydrochloride is prepared in a known manner from isoleucine and HCl/isopropanol. 2.1 g of this compound are reacted analogously to Example 5 (C) with 14.4 g of Adoc-Arg(Adoc)2 -Arg(Adoc)2 -Glu(OBut)-OH.2H2O and the product is worked up. Yield 6.2 g. Aminoacid analysis: Glu 1.00, Ile 0.95 and Arg 2.06.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[NH:8][C:9](=O)[N:10]([CH3:12])[CH3:11])#[N:2].P(Br)(Br)([Br:19])=O.C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9]([Br:19])[N:10]([CH3:12])[CH3:11])#[N:2]
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)c1nsc(NC(=O)N(C)C)c1C#N
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)c1nsc(N=C(Br)N(C)C)c1C#N
Yield: 47.9 %

Procedure:
To a solution of 22.8 g of N'-(4-cyano-3-isopropyl- 5-isothiazolyl)-N,N-dimethylurea in 300 ml of benzene was added 83.3 g of phosphorous oxybromide. The solution was cooled to 0° and 14 ml (9.7 g) of triethylamine was added. The ice-bath was removed and the reaction mixture was heated under reflux overnight. The following day the reaction mixture was filtered through sintered glass. The filtrate was washed with two 200 ml portions of cold water and two 200 ml portions of saturated sodium bicarbonate solution. Two hundred milliliters of chloroform was added to aid in separation of the organic phase from the final wash. The separated organic phase was dried, then concentrated under reduced pressure. The residue was passed over a column of 300 grams of silica gel with chloroform as the eluant. The first ten 250 ml fractions were evaporated to produce a yellow solid, mp 93°-97°. The combined residues were recrystallized from 175 ml of cyclohexane to yield 13.8 g of N'-(4 -cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylbromoformamidine mp 92°-96°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CN1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCN(C)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (4 mL), 1-methyl-1,4-diazepane (100.3 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 126.6 mg (77%) of methyl 3-(4-methyl-1,4-diazepan-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1.ClC1C=C(C=CC=1)C(O)=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]3)[C:10]3=[N+:11]([O-:33])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:27]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc[n+]([O-])c32)CC1
Reaction time: 1.58 h
Yield: 51.8 %

Procedure:
8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5 g, 13.06 mmol) was dissolved in CH2Cl2 at −10C. 3-Chlorobenzoic acid (4.9 g, 15.67 mmmol) was then added and the reaction mixture stirred for 95 minutes. The reaction mixture was taken up in CH2Cl2 and extracted with sodium bisulfite, 10% NaOH. The crude reaction product was purified on silica gel eluting first with 1% and then with 2% MeOH in CH2Cl2 to give the title compound (2.7 g, MH+ 399).
Reaction SMILES: CN(C=O)C.C[O:7][C:8](=O)[N:9]=[C:10](SC)[C:11]([C:25]1[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:39]([O:41][C:42]([C:44]1[S:48][CH:47]=[N:46][C:45]=1[NH:49][NH2:50])=[O:43])[CH3:40]>C(N(CC)CC)C>[CH2:39]([O:41][C:42]([C:44]1[S:48][CH:47]=[N:46][C:45]=1[N:49]1[C:8](=[O:7])[NH:9][C:10]([CH:11]([C:25]2[CH:26]=[N:27][C:28]([O:34][CH3:35])=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=2)[NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[N:50]1)=[O:43])[CH3:40]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cnc1OC
Reactant: CCOC(=O)c1scnc1NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cnc(OC)c(OCC)c2)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To 4 ml of a DMF solution containing 117 mg of {2-(5-ethoxy-6-methoxypyridin-3-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example 160a), 52 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester and 0.038 ml of triethylamine were added. The mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 10 ml of methanol and 0.05 ml of acetic acid, and then 125 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:3]=1.[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]=2[C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O.C(COC)OC>[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]=2[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[N:3]=2)=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2cccc(Cl)n2)c1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-6-(3-methoxyphenyl)pyridine (3.5 g, 16 mmol), dibenzothiophene-4-boronic acid (4 g, 17.5 mmol), potassium phosphate (10.2 g, 48 mmol), dimethoxyethane 500 mL and water 50 mL was prepared. Nitrogen was bubbled directly in the mixture for 15 minutes. Next tris dibenzylideneacetone dipalladium (147 mg, 0.16 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (263 mg, 0.64 mmol) were added, and then nitrogen was bubbled in the mixture for another 15 minutes. The reaction mixture was heated to reflux overnight under nitrogen. The next day the reaction mixture was cooled to room temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The mixture was purified by silica column with up to 10% ethyl acetate in hexanes to gain 3.8 g yellow solid (65%).
Reaction SMILES: CCl.[OH-].[K+].[C:5]1(C)C=CC=CC=1.[CH3:12][C:13]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH2:26])=[O:25]>O>[CH3:12][C:13]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[C:23](=[N:27]\[O:28][CH3:29])/[C:24]([NH:26][CH3:5])=[O:25]
Reactant: Cc1ccccc1
Reactant: CO/N=C(/C(N)=O)c1ccccc1COc1cc(C)ccc1C
Agent: CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Methyl chloride (0.45 g, 9.0 mmol), 85% potassium hydroxide (0.30 g, 4.5 mmol) and toluene (9 ml) were added to (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (0.94 g, 3.0 mmol). The mixture was stirred at 100° C. for 1 hour. After completion of the reaction, water (100 ml) was added. The mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.88 g, Yield: 90.2%) as colorless crystals. mp 136°-137° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=1)#[N:54]>CN(C=O)C>[C:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:62]=1)#[N:54]
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cccc(NC(=O)c2cc3cccc(OC(F)(F)F)c3oc2=O)c1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
DIEA (0.015 mL, 0.085 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.021 g, 0.077 mmol) and HATU (0.032 g, 0.085 mmol) in 0.45 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-cyano-biphenyl-3-ylamine (0.015 g, 0.077 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 63% yield: LCMS (ESI) m/z 451 (MH+).