Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:23])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:2][CH2:3][CH3:4].[C:24]1([S:30][CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)Cl>B(F)(F)F.CCOCC.CCCCCC>[CH2:1]([O:5][C:6](=[O:23])[CH:7]([C:27]1[CH:28]=[CH:29][C:24]([S:30][CH3:31])=[CH:25][CH:26]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OC(C)=O
Reactant: CSc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OCc1ccccc1)c1ccc(SC)cc1

Procedure:
A solution of 1.6 g. (5.0 mmol.) of N-benzyloxycarbonyl-2-acetoxyglycine n-butyl ester, 1.0 g. (8.0 mmol.) of thioanisole and 10 drops of boron trifluoride etherate in 10 ml. of methylene chloride was stirred at 25° for 2 hours. The reaction mixture was diluted with hexane and chromatographed on silica gel with hexane followed by 1:1 chloroform-hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:16]=[C:15]([N:17]([S:18]([CH3:21])(=[O:19])=[O:20])[CH3:25])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1

Procedure:
Mix 5-methanesulfonylamino-N-methyl-N-propyl-isophthalamic acid methyl ester (2.09 g, 6.36 mmol), iodomethane (1.35 g, 9.55 mmol), potassium carbonate (1.38 g, 10 mmol), and tetrabutylammonium bromide (206 mg, 0.64 mmol) in DMF (10 mL) at room temperature for 30 min. Dilute with ethyl acetate and wash with 10% aqueous potassium carbonate, 1 N lithium chloride and saturated aqueous sodium chloride. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 40:60 ethyl acetate:dichloromethane) to give the title compound as an oil.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][C:18](=[O:23])[C:19]#[C:20][CH2:21][CH3:22])[CH3:16]>CN(C)C=O>[CH2:15]([O:17][C:18]([C:19]1[C:20]([CH2:21][CH3:22])=[N:2][N:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=12)=[O:23])[CH3:16]
Reactant: N[n+]1ccccc1
Reactant: CCC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)nn2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a solution of amino-pyridinium iodide (22 g, 99 mmol) and anhydrous potassium carbonate (17.8 g, 128.7 mmol) in dimethylformamide (225 mL) was added ethyl-2-pentynoate (24.98 g, 198 mmol). The solution was stirred at room temperature for 24 h. The reaction mixture was poured into 1.2 L of ice water. The resulting light brown precipitate was collected by vacuum filtration and air-dried for 16 h to yield crude product (11.9 g, 55%), which was used without further purification.
Reaction SMILES: [SnH4].C(OC([N:8]1[CH2:12][C@@H:11]([S:13]C(OC(C)(C)C)=O)[CH2:10][C@H:9]1[CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[O:43])[NH:33][C@H:34]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][CH2:36][S:37][CH3:38])[CH:27]=1)(=[O:25])=[O:24])=O)C=C.COC(=O)C(NC(=O)C1C=CC=C(S(=O)(=O)NC[C@@H]2C[C@H](SC(OC(C)(C)C)=O)CN2)C=1)CCSC>O.C(Cl)Cl>[CH3:42][O:41][C:39](=[O:40])[C@@H:34]([NH:33][C:32](=[O:43])[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([S:23](=[O:24])(=[O:25])[NH:22][CH2:21][C@@H:9]2[CH2:10][C@H:11]([SH:13])[CH2:12][NH:8]2)[CH:27]=1)[CH2:35][CH2:36][S:37][CH3:38]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNS(=O)(=O)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Agent: COC(=O)C(CCSC)NC(=O)c1cccc(S(=O)(=O)NC[C@@H]2C[C@H](SC(=O)OC(C)(C)C)CN2)c1
Agent: [SnH4]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(S(=O)(=O)NC[C@@H]2C[C@H](S)CN2)c1
Reaction time: 0.17 h

Procedure:
Tri-nButyl tin hydride (565 mL, 2.1 mmol) was added to a stirred solution of (15(c)) (1.18 g, 1.8 mmol) and (PPh)3PdCl2 (13 mg. 0.018 mmol) in a mixture of water (0.5 mL) and CH2Cl2 (100 mL). The reaction mixture was left to stir for 10 minutes. dried over MgSO4, filtered and concentrated to a brown oil. This was then purified by flash chromatography on 9385 SiO2, elutins with a gradient of 0-10% EtOAc/i-Hexane to give the desired starting material 15(d) as a white foam: 751 mg (73%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][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.[CH2:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(N(CC)CC)C>[CH2:20]([N:19]([CH2:17][CH3:18])[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCNCc1ccccc1
Reactant: COc1ccc(-c2oncc2C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: CCN(Cc1ccccc1)C(=O)c1cnoc1-c1ccc(OC)cc1

Procedure:
The title compound was prepared from 5-(4-methoxyphenyl)isoxazole-4-carboxylic acid (11.0 mg, 0.050 mmol) and N-ethylbenzylamine (8.1 mg, 0.060 mmol) as described in synthetic method A (using 21 μL of triethylamine and 45 μL of 1-propanephosphonic acid cyclic anhydride) and thereafter purified by preparative HPLC method B (without the extraction step) to give a solid (10.5 mg). MS (pos) m/z 337.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[CH2:10]([N:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([C:21]#N)[CH2:15]1)[CH2:11][CH2:12][CH3:13].Cl.CC[O:26]CC>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15]2)=[O:26])=[CH:3][CH:4]=1
Reactant: CCCCN1CCCCC(C#N)C1
Reactant: CCOCC
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Product: CCCCN1CCCCC(C(=O)c2ccc(F)cc2)C1
Reaction time: 1 h

Procedure:
To 25 mL of dry ether under N2 add 2 g (11 mmol) of 1-bromo-4-fluorobenzene and 0.25 g (0.10 mmol) of magnesium turnings. Initiate the reaction by standard procedures. When the magnesium filings are gone add 1 g (8.0 mmol) of 1-butyl-hexahydro-1H-azepine-3-carbonitrile and reflux the reaction mixture. Monitor the reaction by thin-layer chromatography. Upon completion add 50 mL 1M HCl and stir for one hr. The layers are separated and the aqueous layer is extracted with methylene chloride (25 mL). Add 4N NaOH to the aqueous layer until basic and extract with methylene chloride. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH:11]([CH3:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O)=[O:6])[CH:2]=[CH2:3].[N:16]1(O)[C:20]2[CH:21]=CC=C[C:19]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N)(C)C>ClCCl>[CH:20]([NH:16][C:13]([C@H:8]1[CH2:9][CH2:10][CH:11]([CH3:12])[N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:15])([CH3:21])[CH3:19]
Reactant: On1nnc2ccccc21
Reactant: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)N
Product: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)NC(C)C
Reaction time: 16 h

Procedure:
(R)-1-(allyloxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (0.92 g, 4.3 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.70 g, 5.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol), and isopropylamine (0.44 mL, 5.2 mmol) were dissolved in dichloromethane (2 mL) and stirred at ambient for 16 h before being diluted with dichloromethane (100 mL), washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography to obtain the title compound. MS (ES+): 255 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A solution of 6-bromonaphthalen-2-ol (12.0 g, 53.7 mmol) and imidazole (6.0 g, 79.5 mmol) in DMF (12.0 mL) was added t-butyldimethylsilyl chloride (TBDMSCl) (9.0 g, 59.0 mmol) in one portion at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was partitioned between EtOAc (500 mL) and water (300 mL). The aqueous layer was separated and extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes) to afford (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (81, 18.0 g, 98%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=1.8 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.48 (dd, J=8.7, 1.8 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.09 (dd, J=9.0, 2.4 Hz, 1H), 1.01 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[CH2:21]([C:24]#[N:25])[C:22]#[N:23].C([O-])([O-])=O.[K+].[K+].Cl>CC#N.O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:21]([C:24]#[N:25])[C:22]#[N:23]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Reactant: N#CCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CCCCCCCCCCCCCCCC(C#N)C#N
Temperature: 80 °C
Reaction time: 18.5 h
Yield: 139.8 %

Procedure:
To 16-bromohexadecanoic acid methyl ester (1.40 g, 4.0 mmol) in MeCN (20 ml) were added malonodinitrile (1.01 g, 15.3 mmol) and K2CO3 (0.92 g, 6.64 mmol). The mixture was stirred at 80° C. for 18.5 h. Water (50 ml) and 1N HCl (50 ml) were added, and the product was extracted with AcOEt. The combined extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. 1.87 g (100%) of an oil was obtained which crystallized completely after some hours.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](N)=[O:13])[CH:8]=[C:7]([NH:15][C:16](N)=[O:17])[CH:6]=1)[C:2](N)=[O:3]>CCOCC>[N:1]([C:5]1[CH:6]=[C:7]([N:15]=[C:16]=[O:17])[CH:8]=[C:9]([N:11]=[C:12]=[O:13])[CH:10]=1)=[C:2]=[O:3].[NH3:1]
Reactant: NC(=O)Nc1cc(NC(N)=O)cc(NC(N)=O)c1
Solvent: CCOCC
Product: N
Product: O=C=Nc1cc(N=C=O)cc(N=C=O)c1

Procedure:
Like the triamide, 1,3,5-triureido benzene is also known. It is obtained from 1,3,5-triisocyanato-benzene with ammonia in ether (Gill et al., Soc. 1949, 1753; WG P 815 486). With the process according to the invention it is formed by treatment of benzene tricarboxylic acid-(1,3,5)-tri-N-chloramide with ammonia. Expediently, tri-N-chloramide is suspended in water, reacted with ammonia in the presence of cooling, followed by vigorous mixing of the reaction mixture. The reaction mixture should thereby never exceed a temperature of 25° C. Once the sediment is fully dissolved, the solution is quickly heated to the boil and kept at this temperature for about 15 to 30 min. After cooling, the precipitated 1,3,5-triuredio-benzene is filtered off, washed and dried. At least stoichiometric quantities of ammonia are used hereby, i.e. one mole benzene tricarboxylic acid-(1,3,5)-tri-N-chloramide requires 6 moles of ammonia. It is advantageous to use up to 10 mole % excess ammonia and after separation of 1,3,5-triureido-benzene to use the filtrate for the reaction of additional tri-N-chloramide. The yield in this process step exceeds 97% of the theory.
Reaction SMILES: O.[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[C:4]=1[C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:11][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=2)[CH:6]=[C:5]([OH:10])[C:4]=1[C:11](=[O:13])[CH3:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(O)cc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′,4′,6′-trihydroxyacetophenone monohydrate (5 g) and potassium carbonate (7.42 g) in N,N-dimethylformamide (100 mL) was added benzyl bromide (6.39 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1-5/1) to give 2′,4′-dibenzyloxy-6′-hydroxyacetophenone (5.71 g). This material was suspended in ethanol (45 mL)-water (15 mL). To the suspension was added potassium hydroxide (11.0 g), and the mixture was stirred at room temperature for 10 minutes. Benzaldehyde (2.51 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was acidified by addition of concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 2′,4′-dibenzyloxy-6′-hydroxychalcone (4.85 g). This material was dissolved in N,N-dimethylformamide (40 mL)-acetone (12 mL). To the solution were added potassium carbonate (2.3 g) and methyl bromoacetate (1.1 mL), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (30 mL). To the solution was added 10% palladium-carbon powder (0.5 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-2/1) to give the title compound (2.26 g).
Reaction SMILES: N1C=CN=C1N[C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][S:56]([C:59]1[CH:66]=[CH:65][C:62]([CH2:63][NH2:64])=[CH:61][CH:60]=1)(=[O:58])=[O:57]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:55][S:56]([C:59]1[CH:66]=[CH:65][C:62]([CH2:63][NH:64][C:7]([C:9]2[C:17]3[N:16]=[C:15]([NH:18][C:19]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:20])[NH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:61][CH:60]=1)(=[O:57])=[O:58]
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc3[nH]c(NC(=O)c4cc5ccccc5cn4)nc23)cc1
Yield: 33.4 %

Procedure:
100 mg (0.3 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (from Example 58) was reacted with 130 mg (0.33 mmol) of HBTU and 55 mg (0.3 mmol) 4-methanesulfonyl-benzylamine in 3.0 mL of DMF and 1.0 mL of DIEA as described in general procedure A. After the usual work up as described in general procedure A, 50 mg (33%) of isoquinoline-3-carboxylic acid [4-(4-methanesulfonyl-benzylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was isolated. LCMS: 500 (M+1)+.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=[CH:22][C:21]=1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:25]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:22]=[CH:23][CH:24]=3)[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)cccc1C1CCNCC1
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
To a solution of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (548 mg, 1.643 mmol), 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (544 mg, 1.725 mmol) and Pd(Ph3P)4 (190 mg, 0.164 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (1.000 mL) was added tripotassium phosphate (1395 mg, 6.57 mmol), The solution was sealed and irritated in Biotage MW at 120° C. for 20 min. The mixture was directly dried with silica gel and purified by column chromatography to afford 4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]piperidine (D122) (169 mg). MS (ES): C24H28ClN3OS requires 441.2. found 442.2 (M+H+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][N:23]1[C:27]([CH3:28])=[N:26][N:25]=[N:24]1.OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH3:28][C:27]1[N:23]([CH2:22][C@@H:7]2[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:10])[NH:6]2)[N:24]=[N:25][N:26]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nnnc2C)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nnnn1C[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((5-methyl-1H-tetrazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (221 mg, 0.474 mmol), K2S2O8 (179 mg, 0.663 mmol) and K2HPO4 (107 mg, 0.616 mmol) in ACN:water (2:1, 7.9 mL) at 90° C. for 1.5 h. More K2S2O8 (38.4 mg, 0.142 mmol) and K2HPO4 (21.5 mg, 0.123 mmol) were added and it was heated for an additional 30 min then cooled to rt then concentrated in vacuo. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%), to afford the title compound (97 mg, 65%). LCMS: Rt=1.00 min, m/z=317.3 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[O:14][C:13]([CH2:15][CH:16]([CH:24]([NH:26][CH2:27]/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:40][C:41]([CH:43]1[CH2:47][C:46](=[O:48])[O:45][CH:44]1[C:49](O)=[O:50])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)(Cl)Cl.O>[C:20]([O:19][C:17]([CH:16]([CH2:15][C:13]1[O:14][C:10]([C:8](=[O:9])[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH:24]([N:26]([CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:49]([CH:44]1[CH:43]([C:41]([O:40][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:42])[CH2:47][C:46](=[O:48])[O:45]1)=[O:50])[CH3:25])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(NC/C=C/c1ccccc1)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C)N(C/C=C/c1ccccc1)C(=O)C1OC(=O)CC1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
86 mg of tert-butyl (2RS,3RS)-2-{5-(phenylcarbamoyl)-2-furylmethyl}-3-{(E)-3-phenyl-2-propenylamino}butanoate prepared in Reference Example 3, 46 mg of (2RS,3RS)-3-(tert-butoxycarbonyl)-5-oxotetrahydrofuran-2-carboxylic acid prepared in Reference Example 6 and 140 μl of triethylamine were dissolved in 2 ml of chloroform and stirred with 41 mg of 2-chloro-1,3-dimethylimidazolinium chloride in 1 ml of chloroform under cooling with ice for 10 minutes and then at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=10/1→2/1] to give 124 mg (stoichiometric yield) of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([CH:15]=[O:16])[C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[C:8]([CH3:21])([CH3:20])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Mg]Cl)[CH3:23]>C1COCC1.CN1CCCN(C)C1=O>[C:1]([C:5]1[C:14]2[CH:13]=[C:12]([CH:15]([OH:16])[CH2:22][CH3:23])[C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=2[C:8]([CH3:20])([CH3:21])[CH2:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Mg]Cl
Reactant: CCOc1cc2c(cc1C=O)C(C(C)(C)C)=CCC2(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOc1cc2c(cc1C(O)CC)C(C(C)(C)C)=CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalene-2-carbaldehyde (Compound A-27, 450 mg, 1.57 mmol) in THF (7 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 0.3 mL) was added ethylmagnesium chloride (2 M in THF, 1.6 mL, 3.1 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with 1N HCl. The resulting mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexane).