Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5](C(OC(C)(C)C)=O)[CH2:4]1.O1CCOCC1.[N+:31]([O-])([O-:33])=[O:32].[K+].N>Cl.OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:31]([O-:33])=[O:32])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1ccc(C#N)cc21
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: N#Cc1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A solution of 196 (30 mg, 0.088 mmol) in HCl(g) saturated dioxane (3 mL) was stirred for 1 h. The solvent was evaporated to provide the crude amine hydrochloride (24 mg, 100%). This solid was cooled to 0° C. and treated with conc. H2SO4 (2 mL). A cooled (O OC) solution of KNO3 (9 mg, 0.088 mmol) in conc. H2SO4 (0.5 mL) was then added dropwise. After 15 min, the mixture was poured into ice water and conc. aqueous ammonia was carefully added until the pH of the mixture was 3-4. Solid KHCO3 was then carefully added until the pH of the mixture was 8. The mixture was partitioned between CH2Cl2 and water, and the aqueous layer was extracted with CH2Cl2 (×3). The combined organic extracts were washed with brine and dried. The CH2Cl2 was removed under reduced pressure and the residue was triturated with MeOH to give 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-8-carbonitrile (197) (18 mg, 72%) as red crystals: mp 231-234° C.; 1H NMR [(CD3)2SO] δ 8.54 (dd, J=1.5, 0.5 Hz, 1 H), 8.22 (dd, J=9.0, 0.4 Hz, 1H), 7.80 (s, 1H), 7.59 (dd, J=9.0, 1.6 Hz, 1H), 6.63 (d, J=1.3 Hz, 1H), 4.32-4.23 (m, 1H), 3.95 (dd, J=11.0, 3.8 Hz, 1H), 3.84 (td, J=10.3, 2.3 Hz, 1H), 3.79-3.70 (m, 2H); 13C NMR δ 151.8, 148.1, 130.6, 129.9, 126.8, 125.7, 125.0, 120.0, 119.6, 112.8, 111.4, 51.8, 47.5, 43.5. Anal. (C14H10ClN3O2) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[NH:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]2)=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=1
Reactant: O[C@H]1CCNC1
Reactant: FC(F)(F)c1cc(Cl)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O[C@H]1CCN(c2ccc(Cl)cc2C(F)(F)F)C1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 1-bromo-4-chloro-2-(trifluoromethyl)benzene (15.0 g), (3S)-pyrrolidin-3-ol (5.0 g), palladium(II) acetate (561 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.11 g) and cesium carbonate (37.8 g) in toluene (280 ml) was stirred under an argon gas atmosphere at 100° C. for 18 hr. After cooling to room temperature, water was added to 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 filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 95:5-80:20) to give the title compound (12.4 g, yield 81%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:7](=[O:23])[CH:6]=2.[C:24]1([CH2:30][C:31]#[CH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:23]=[C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:32]#[C:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=[CH:4]2)=[CH:9][N:8]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)c1ccc(Cn2cc3cc(Br)ncc3cc2=O)cc1
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ncc3cc2=O)cc1

Procedure:
The coupling of 4-(7-bromo-3-oxo-2H-6-azaisoquinolin-2-ylmethyl)benzenesulfonamide (0.71 g, 1.81 mmol) with 3-phenyl-1-propyne (0.56 mL, 4.51 mmol) using triethylamine (0.50 mL, 3.61 mmol), CuI (0.025 g, 0.13 mmol), and Pd(Ph3P)4 (0.084 g, 0.07 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). Purification is carried out on a silica gel column eluted with hexanes/ethyl acetate 3:1 to give the desired product.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>ClCCl>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][C:19](=[O:21])[NH:58][CH2:57][C:56]([F:60])([F:59])[F:55])([CH3:11])([CH3:12])[CH3:13]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)NCC(F)(F)F
Reaction time: 24 h

Procedure:
DIPEA (15 ml) is added to a solution of N-(tert-butoxycarbonyl)glycine (5.0 g), PYBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 16.3 g) and 2,2,2-trifluoroethylamine (2.47 ml) in dichloromethane (48 ml). After 24 hours at room temperature, the reaction is quenched with water and extracted three times with dichloromethane. The combined organic phases are washed with HOC (2M), Na2CO3 (1M) and a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified by column chromatography (450 g) eluting with a mixture of ethyl acetate and hexane (2:3 to 3:2) to yield [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (3.89 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C.Br[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[ClH:2].[Cl:2][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: BrCCCc1ccccc1
Reactant: Clc1ccc(N2CCNCC2)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1ccc(N2CCN(CCCc3ccccc3)CC2)nn1
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of 3.6 parts of 3-chloro-6-(1-piperazinyl)pyridazine monohydrochloride, 5.3 parts of sodium carbonate and 90 parts of N,N-dimethylacetamide was stirred for a while at 60° C. Then there were added 3 parts of (3-bromopropyl)benzene and the whole was stirred overnight at 60° C. The reaction mixture was poured into water. The product was filtered off and converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 3.2 parts (60%) of 3-chloro-6-[4-(3-phenylpropyl)-1-piperazinyl]pyridazine monohydrochloride; mp. 207.3° C. (compound 226) In a similar manner there were also prepared:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C(O)C.Cl[C:11]1[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=1.[OH:19][CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:17]([C:14]1[CH:13]=[N:12][C:11]([C:26]2[CH:27]=[CH:28][C:23](/[CH:22]=[CH:21]/[CH2:20][OH:19])=[CH:24][CH:25]=2)=[N:16][CH:15]=1)[CH3:18]
Reactant: OC/C=C/c1ccc(B(O)O)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cnc(-c2ccc(/C=C/CO)cc2)nc1
Yield: 45.3 %

Procedure:
1 M aq. Na2CO3 (2 mL), and ethanol (1 mL) were successively added to a mixture of 2-chloro-5-ethylpyrimidine (0.30 mL, 2.47 mmol), [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (61 mg, 0.10 mmol) and [4-[(1E)-3-hydroxy-1-propenyl]phenyl]boronic acid (360 mg, 2.02 mmol, prepared as described in Reference Example 238) in toluene (4 mL) and the resulting mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with ethyl acetate (10 mL) and the organic layer was separated, washed with brine (10 mL), dried (MgSO4) and concentrated. Purification by chromatography (SiO2, 3:2 hexane/ethyl acetate) provided 220 mg (45%) of the title compound as a yellow solid. MS 241 (M+H)+.
Reaction SMILES: [Br-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[NH2-].[Na+].O=[C:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:43][CH:42]([CH2:44][O:45][CH3:46])[O:41][C:40]3=[O:47])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.O>O1CCCC1>[CH3:46][O:45][CH2:44][CH:42]1[O:41][C:40](=[O:47])[N:39]([C:36]2[CH:37]=[CH:38][C:33]([CH:30]3[CH2:31][CH2:32][C:27](=[C:2]([CH3:4])[CH3:3])[CH2:28][CH2:29]3)=[CH:34][CH:35]=2)[CH2:43]1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CN(c2ccc(C3CCC(=C(C)C)CC3)cc2)C(=O)O1

Procedure:
1.60 g (3.3 mmol) of isopropyl-triphenylphosphonium bromide/sodium amide mixture in 30 ml of tetrahydrofuran were stirred at room temperature for 1 hour. Then, a solution of 1.0 g (3.3 mmol) of (RS)-3-[4-(4-oxo-cyclohexyl)-phenyl]-5-methoxymethyl-oxazolidin-2-one in 25 ml of tetrahydrofuran was added dropwise. After boiling at reflux over the weekend the mixture was poured into 100 ml of water and extracted three times with 50 ml of dichloromethane each time. After chromatography over silica gel with ethyl acetate/hexane 1:2 and recrystallization from n-hexane 120 mg (11%) were obtained as white crystals with m.p. 89°-91°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C@@H:25]([CH2:27][OH:28])[CH3:26].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[OH:28][CH2:27][C@@H:25]([NH:24][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][O:10][CH:11]=2)=[CH:20][N:19]=1)=[O:23])[CH3:26]
Reactant: C[C@@H](N)CO
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)NC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.8 %

Procedure:
To a solution of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (80 mg, 0.24 mmol) and D-alaninol (22.8 □L, 0.29 mmol) in THF (7 mL) was added 1-hydroxybenzotriazole hydrate (37.3 mg, 0.24 mmol), N-ethyldiisopropylamine (105.2 □L, 0.60 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (47.1 mg, 0.24 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 72 h. Then the reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1 to 2:3) afforded the title product (39 mg, 42%) which was obtained as white solid. MS: m/e=389.0 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:18]CC2C=CC(OC)=CC=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C[SiH](C)C.FC(F)(F)C([O-])=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si:14]([CH3:15])([CH3:17])[CH3:16])[C:9]([OH:18])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2C#C[Si](C)(C)C)cc1
Agent: C[SiH](C)C
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(=O)OCc1cc(C#C[Si](C)(C)C)c(O)cn1
Reaction time: 8 h
Yield: 52.7 %

Procedure:
(5-((4-Methoxybenzyl)oxy)-4-((trimethylsilyl)ethynyl)pyridin-2-yl)methyl acetate (5.38 g, 11.1 mmol) which is a crude product obtained in a-5) was dissolved in dichloromethane (55 mL), added trimethylsilane (1.9 mL, 35.1 mmol) and trifluoroacetate (5.5 mL) at room temperature, and the mixture was stirred overnight. The reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions (pH=8 was confirmed). The reaction solution was filtered through a pad of celite. The obtained filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (1.54 g (yield 53%)) was obtained as a yellow oil.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[C:30]([O:34][C:35]([NH:37][CH:38]([CH3:42])[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].C1(N=C=NC2CCCCC2)CCCCC1.O>O1CCCC1.C(OCC)(=O)C>[C:30]([O:34][C:35]([NH:37][CH:38]([CH3:42])[C:39]([NH:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
A solution of 5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzyl]thiazolidin-2,4-dione hydrochloride (2.3 g, 5.27 mmol) and 2-t-butoxycarbonylaminopropionic acid (0.997 g, 5.27 mmol) in tetrahydrofuran (20 ml) was stirred for 1 h at 0° C. N,N′-Dicyclohexylcarbodiimide (1.086 g, 5.27 mmol) was added to this solution and stirring was continued for 1.5 h at ambient temperature. Water (200 ml) was added to the reaction mixture, stirred for 15 minutes, ethyl acetate (250 ml) was added and stirring was continued for another 15 minutes. The organic layer was separated and washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated to give the title compound, which was purified by column chromatography (0.7 g, yield 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH:23]([OH:26])[CH2:24][CH3:25].C1CCN2C(=NCCC2)CC1.[Cl-].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 84.2 %

Procedure:
Under an argon atmosphere, 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-propanol (compound 9) (31.3 mg) was dissolved in methylene chloride (2 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (30.7 mg) was then added to the solution, followed by cooling to −78° C. N-Tert-butylbenzenesulfineimidoyl chloride (30.4 mg) was dissolved in methylene chloride to prepare a solution, the solution was added thereto, and the mixture was stirred at −78° C. for 50 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (26.2 mg, yield 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25](O)=[O:26].[Cl-].[NH4+].C([N:32](CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25]([NH2:32])=[O:26]
Reactant: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ncc(C(N)=O)c3cc(OC)c(OC)cc23)c1

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (30mg, 81.7 mmol), ammonium chloride (43.5 mg. 0.817 mM) and triethylamine (0.115 mL, 0.817 mM) in 2 mL of dimethylformamide was stirred with O-benzotriazol-1-yl-N,N,N,N-tetramethyluronium hexafluorophosphate (61.9 mg. 0.163 mM) at room temperature for 20 hours. Poured into 20 mL of water and 20 mL of ethyl acetate, extracted ethyl acetate layer with saturated sodium bicarbonate, dried ethyl acetate solution. over anhydrous magnesium sulfate and evaporated to give 5.4 mg of an off-white solid pure product: APCI-MS m/e calcd for C20H18N2O6 (M+H.) 367.4, found 367; H NMR (300 MHz) compatible.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N+]=[N-])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C.O1CCCC1>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([O:14][CH:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC=O)n1

Procedure:
To a solution of 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (65.9 g) in ethyl acetate (300 ml) and tetrahydrofuran (200 ml) was dropwise added a solution of diphenyldiazomethane in ethyl acetate (1 m mol/ml, 200 ml) at ambient temperature and the mixture was stirred for an hour. The resultant mixture was washed with saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The solution was evaporated to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.3 g). To the solution of benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.0 g) in methanol (500 ml) was added conc. hydrochloric acid (41.6 g) at ambient temperature and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into a solution of sodium bicarbonate (33.6 g) in water (2.5 l) and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was pulverized with ether to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (72.3 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[Cl:36][C:37]1[CH:42]=[N:41][CH:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[N:38]=1.[F-].[Cs+]>CN(C=O)C.C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:37]1[N:38]=[C:39]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:15][C:14]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)[CH:40]=[N:41][CH:42]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (1.50 g, 2.433 mmol) and 2-chloro-6-(tributylstannyl)pyrazine (1.473 g, 3.65 mmol) in DMF (20 mL) followed by cesium fluoride (555 mg, 3.65 mmol), CuI (46 mg, 0.243 mmol) and Pd(PPh3)4 (0.281 g, 0.243 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h, then the mixture was diluted with DCM and washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified silica gel chromatography (eluting with 20-60% EtOAc in Hex) to give 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (1.0 g, 68.2%) as a solid. MS (ESI, pos. ion) m/z: 603 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.C(=O)([O-])[O-].[K+].[K+].[C:17]([O-:25])(=[O:24])[CH:18]([CH2:20][C:21]([O-:23])=[O:22])[OH:19]>CN(C)C=O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:17]([O-:25])(=[O:24])[CH:18]([CH2:20][C:21]([O-:23])=[O:22])[OH:19]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: O=C([O-])CC(O)C(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN(C)C(=N)NC(=N)N
Temperature: 25 °C

Procedure:
9.97 g (2 molar equivalents) of metformin hydrochloride, 8.34 g (2 molar equivalents) of potassium carbonate and 4.05 g (1 molar equivalent) of malate were stirred in N,N-dimethylformamide (DMF) at 100° C., and then the produced inorganic salt was filtered. To the filtered solution, acetone was added dropwise and stirred at room temperature. The produced crystal was filtered and dried in hot air, thus obtaining 1.49 g (yield: 12.6%) of metformin malate.
Reaction SMILES: [OH-].[K+].O.Cl[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][N+:6]=1[O-:12].[CH2:13]([SH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([S:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N+:6]([O-:12])[CH:7]=1
Reactant: SCc1ccccc1
Reactant: [O-][n+]1cc(Cl)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: [O-][n+]1cc(Cl)ccc1SCc1ccccc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A solution consisting of 1.1 g (0.016 mole) of 85% KOH pellets, 50 ml of ethanol, and 0.5 ml of water was prepared. To this solution was added slowly, with stirring at room temperature, a mixture of 3.3 g (0.02 mole) of 2,5-dichloropyridine-N-oxide and 2.5 g (0.02 mole) of benzylmercaptan dissolved in 25 ml of ethanol. The reaction mixture was heated to about 60° C. for 2 hours and then evaporated to dryness. The residue was taken up in water and chloroform, the phases separated and the chloroform phase was dried over Na2SO4. The Na2SO4 was filtered off and the chloroform evaporated to leave a solid. The solid was recrystallized from ethanol to give 3.0 g of material, having a melting point of 130-133° C. Recovery was 2.2 g. The structure was confirmed by its IR spectrum.