Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].[BrH:17]>CO.CC(C)=O.O>[Br:17][CH:6]([CH2:5][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Br
Reactant: COC(=O)c1cc(N)ccc1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(CC(Br)C(=O)OC)ccc1F
Yield: 45 %

Procedure:
To a solution of methyl 5-amino-2-fluorobenzoate (4.12 g) in 47% hydrobromic acid (11.4 ml), methanol (20 ml) and acetone (50 ml), a solution of sodium nitrite (1.88 g) in water (3 ml) was slowly added dropwise under cooling with salt-ice and stirring so as to keep an internal temperature of not higher than -5° C. After stirred for 30 minutes as it was, ice bath was removed, methyl acrylate (13.3 ml) was added, and cuprous oxide (225 mg) was added little by little while stirring vigorously. After no nitrogen became to generate, the reaction liquor was concentrated under reduced pressure. The residue was dissolved into ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=10:1) to obtain 3.48 g (45%) of aimed compound as an oily material.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[N:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.O.ClCCl.[Cu]I>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: c1cn[nH]c1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ncccc3c2ncn1[C@H]1CCCC[C@@H]1O
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=c1c2cc(Cc3ccc(-n4cccn4)nc3)c3ncccc3c2ncn1[C@H]1CCCC[C@@H]1O
Temperature: 120 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[2,3-h]quinazolin-4(3H)-one (0.063 g, 0.15 mmol) and pyrazole (0.015 g, 0.22 mmol) in 1 mL of DMSO and 0.2 mL of water under an atmosphere of nitrogen was added potassium phosphate (0.095 g, 0.45 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (21.3 mg, 0.150 mmol), and copper(I) iodide (8.6 mg, 0.045 mmol). The mixture was heated at 120° C. for 30 h, cooled to rt, and diluted with dichloromethane. The organic solution was washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 453.2034 for [M+H]+ [Calc'd for C26H25N6O2, [M+H]+=453.2034]: 1H NMR (400 MHz, CDCl3) δ 9.24-9.22 (m, 1H), 9.10-9.08 (m, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 8.27-8.26 (m, 2H), 7.85-7.77 (m, 2H), 7.68 (s, 1H), 7.62-7.59 (m, 1H), 6.42 (s, 1H), 4.68 (s, 2H), 4.66-4.64 (m, 1H), 4.02 (br s, 1H), 2.27-2.25 (m, 1H), 2.06-2.03 (m, 1H), 1.90 (br s, 3H), 1.56-1.44 (m, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:41])([F:40])[C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[CH2:17][NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[C:30](F)[CH:29]=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])[CH:21]=1>CN(C)C=O.O>[F:40][C:13]([F:12])([F:41])[C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[CH2:17][NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[C:30]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:29]=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])[CH:21]=1
Reactant: C1CCNC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCC3)ccc2[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 118.1 %

Procedure:
Into a 10-mL vial, was placed a solution of pyrrolidine (152.5 mg, 2.15 mmol, 3.00 equiv) in N,N-dimethylformamide (5 mL), potassium carbonate (296.2 mg, 2.15 mmol, 3.00 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (300 mg, 0.72 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at 90° C. in an oil bath. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 400 mg of crude product as a yellow to green oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39]>CC(C)=O>[CH3:41][O:40][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][N:15]([C:10]1[N:9]=[C:8]2[O:7][C:6]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[C:13]2=[CH:12][C:11]=1[I:14])[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(CCCCC(=O)OC)S(C)(=O)=O)c(I)cc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (300 mg, 0.613 mmol), K2CO3 (169 mg, 1.226 mmol), KI (1018 mg, 6.13 mmol), and methyl 5-bromopentanoate (250 μl, 1.747 mmol) is added acetone (3066 μl) and the reaction mixture is stirred at 60° C. overnight. The acetone is removed under N2 and the mixture is taken up in 2 mL 1:1:1 DMF/H2O/ACN and filtered with a 0.45μ PTFE filter. Purification is achieved by reverse phase HPLC with a C8 column with 40-80% MeOH (0.1% TFA)/H2O (0.1% TFA). MS (ESI) m/z 604.0 (M+1). Retention time=1.48 min, Method A. 1H NMR (400 MHz, CDCl3 d ppm 8.77 (s, 1H), 7.96 (t, 2H), 7.19-7.36 (m, 2H), 5.80 (br s, 1H), 3.68 (t, 2H), 3.54 (s, 3H), 3.14 (s, 3H), 2.97 (d, 3H), 2.29 (t, 2H), 1.69-1.79 (m, 2H), 1.42 (s, 2H)
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]1>CO>[OH:22][CH2:21][CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[OH:4])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(CO)C2)c(OCOC)c1
Solvent: CO
Product: OCC1CCCC(c2ccc(O)cc2O)C1
Reaction time: 6 h
Yield: 8 %

Procedure:
(±)-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}methanol (35 mg) was heated at 50° C. in methanol (3.5 ml) containing acidic ion exchange resin (350 mg). After 6 hr, the mixture was filtered, the resin was washed with ethyl acetate, and the combined filtrate and washings were evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish a mixture of diastereoisomers of the title compound as a white solid (2 mg, 8%). δH (d4-MeOH) 0.9-1.9 (9H, overlapping m), 2.80 (0.5H, m), 2.90 (0.5H, m), 3.20-3.40 (2H, overlapping m), 6.15 (2H, m), 6.80 (0.5H, d), 6.85 (0.5H, d); m/z (ES−) 221 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=[O:4].[OH-].[K+]>CO.O>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1ccc(C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
A solution of methyl 2-methyl-2-(4-(trifluoromethyl)phenyl)propanoate (1528 mg, 6206 μmol) in MeOH (60 mL) and water (15 mL), was treated with KOH (1741 mg, 31028 μmol). The reaction was heated to reflux. After 18 hours, the reaction was cooled to 23° C. and concentrated in vacuo. The crude mixture was partitioned between water/diethyl ether (100 mL each). The aqueous layer was separated and washed with diethyl ether (100 mL). The combined ether layers were extracted with a 1N NaOH solution (25 mL). The combined aqueous washes were acidified with concentrated HCl to pH=2 and were then extracted with EtOAc (3×100 mL). The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo to afford 1323 mg of the title compound. MS m/e=233.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:29][CH2:30][CH3:31])=[N:22][C:23]([O:26][CH2:27][CH3:28])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:32](Cl)([Cl:34])=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:32]([Cl:34])=[O:33])[C:10]([C:20]3[C:21]([O:29][CH2:30][CH3:31])=[N:22][C:23]([O:26][CH2:27][CH3:28])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1ncc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2)c(OCC)n1
Product: CCOc1ncc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC)n1

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C28H29N6O4Cl2 [(M+H)+] 583.1622, observed 583.1621.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:5][O:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
40 g of finely powdered aluminium chloride are added in portions to a stirred solution of 20.6 g of 6-methoxy-indane-1-carboxylic acid methyl ester and 15.5 g of benzoyl chloride in 200 ml of absolute methylene chloride at 20° C., in an anhydrous atmosphere, stirring is continued overnight at room temperature and the reaction solution is then poured onto 500 g of ice and extracted with 3 times 100 ml of methylene chloride. The organic phases are washed successively with 500 ml of saturated sodium bicarbonate solution, 500 ml of 2 N hydrochloric acid and 500 ml of water, dried over anhydrous sodium sulphate and evaporated in vacuo. The evaporation residue, when crystallised from ether-petroleum ether after treatment with active charcoal, gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid methyl ester of melting point 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[C:14](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 2-chloro-5-nitroisonicotinic acid (Intermediate 25A) (0.64 g, 3.17 mmol) in DMF (15 mL) under nitrogen was added sodium carbonate (1.0 g, 9.51 mmol). Reaction cooled in an ice bath and methyliodide (1.35 g, 9.51 mmol) was added dropwise. After complete addition, reaction allowed to warm to room temperature and stirred overnight under nitrogen. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 20 g silica column eluting with 40% ethylacetate in hexane to afford methyl 2-chloro-5-nitroisonicotinate (0.62 g, 2.86 mmol).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:14]([NH2:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[NH:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:18]([C:29]([OH:31])=O)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[NH:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:18]([C:29]([NH:2][C@@H:3]([C:14]([NH2:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(N)=O
Reaction time: 1 h
Yield: 99.8 %

Procedure:
In 10 ml of DMF, HCl, H-D-Trp-NH2 (8.9 mmol; 1 eq.), Boc-D-Trp-OH (2.98 g; 9.8 mmol; 1.1 eq.), NMM (2.26 ml; 2.1 eq.) and BOP (4.33 g; 1.1 eq.) were added successively. After 1 hr, the mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (200 ml), aqueous potassium hydrogen sulfate (200 ml, 1M), and saturated aqueous sodium chloride (100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford 4.35 g of Boc-D-Trp-D-Trp-NH2 as a white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[C:44]([N+:48]([O-:50])=[O:49])[CH:45]=3)[C:40]2=[O:51])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[C:44]([N+:48]([O-:50])=[O:49])[CH:45]=3)[C:40]2=[O:51])[C:36]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cc([N+](=O)[O-])ccc2C1=O
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nccs1)C(CC1CCCCC1)N1Cc2cc([N+](=O)[O-])ccc2C1=O
Yield: 34.7 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Step C; 301 mg; 0.91 mmol) and 2-aminothiazole (116 mg; 1.12 mol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (as outlined in Example 1, Step B) provided after chromatography (Biotage 40M, eluent: 30% ethyl acetate/hexanes) 131 mg of 3-Cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C20H22N4O4S (M+) 414.1362, found 414.1362 and 121 mg of regioisomeric 3-Cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C20H22N4O4S (M+) 414.1362, found 414.1368.
Reaction SMILES: [ClH:1].Cl.C([O:10][C:11]1[CH:35]=[CH:34][C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][N:21](C=O)[CH2:20][CH:19]3[CH2:26][O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[S:17][C:13]=2[CH:12]=1)C1C=CC=CC=1.Cl.O>CCO>[ClH:1].[ClH:1].[ClH:1].[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH2:26][CH:19]2[CH2:20][NH:21][CH2:22][CH2:23][N:18]2[C:16]2[S:17][C:13]3[CH:12]=[C:11]([OH:10])[CH:35]=[CH:34][C:14]=3[N:15]=2)[CH:29]=1
Reactant: O=CN1CCN(c2nc3ccc(OCc4ccccc4)cc3s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1ccc2nc(N3CCNCC3COc3cccnc3)sc2c1
Temperature: 25 °C
Yield: 200.8 %

Procedure:
4-(6-(Benzyloxy)benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carbaldehyde dihydrochloride (130 mg, 0.244 mmol) and HCl (conc., 1.0 mL) were heated to 100° C. in EtOH (1 mL) and water (1 mL) for 2 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 73.8 mg (67%) of the title compound as a white solid. LC-MS: RT=3.45 min, [M+H]+=343.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClCc1ccccc1OCc1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccccc3OCc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-benzyloxybenzylchloride as described for component 78. Purified by chromatography [ethyl acetate/petroleum ether (60°-80° C.), 1:3]. M.p. colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([Cl:32])=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:32].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12a) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 653.4 [(M+H)+]
Reaction SMILES: C1COCC1.C([O:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[NH:20])[N:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)C.[OH-].[Li+]>O>[CH3:18][N:17]([CH3:19])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:21])=[O:8])=[CH:11][CH:12]=1)=[NH:20]
Reactant: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=N)c1ccc(C(=O)O)cc1
Reaction time: 6 h

Procedure:
To a THF solution of ethyl-4(N,N-dimethylcarbamimidoyl)benzoate (G) was added an aqueous solution of lithium hydroxide (2 eq.) and the reaction mixture was stirred for 6 hr. The completion of the reaction was confirmed by HPLC. To the reaction mixture was added water, followed by extraction with ethyl acetate. The aqueous layer was acidified with 6N HCl to pH between 3-4 at which point the desired 4-(N,N-dimethylcarbamimidoyl)benzoic acid precipitated as the white solid. The white solid isolated was washed with hexane to afford 4-(N,N-dimethylcarbamimidoyl)benzoic acid as an hydrochloride salt (A).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]2[C:24]([C:25]([NH:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:26])=[C:23]([O:34][CH3:35])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-].OS([O-])(=O)=O.[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH2:14][C:15]2[C:24]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[C:23]([O:34][CH3:35])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1c(CC(=O)N2CCN(C(=O)OCC)CC2)nc2ccccc2c1OC
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)Cc2nc3ccccc3c(OC)c2C(=O)NCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl](ethoxycarbonylmethyl)aminocarbonyl-4-methoxyquinoline (30 mg, 0.06 mmol) in ethanol (1.0 mL), was added a solution of LiOH (6 mg, 0.12 mmol) in water (1.0 mL). The resulting reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was acidified to pH 3 by 2N NaHSO4, extracted by ethyl acetate (3×20 mL), dried over sodium sulfate, and concentrated in vacuo to afford 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl](carboxymethyl)aminocarbonyl-4-methoxyquinoline (25 mg) as a solid; NMR (DMSO-d6), 1.20 (m, 3), 3.20–3.60 (m, 8), 4.00–4.14 (m, 5), 4.20 (s, 1), 4.35 (s, 1), 4.50 (s, 1), 4.70 (s, 1), 7.23 (d, 1), 7.65 (m, 1), 7.80–7.94 (m, 2), 8.17 (m, 1) ppm.
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1>C(#N)C>[CH:21]1[C:20]([CH2:23][N:6]2[CH2:7][CH2:8][NH:9]/[C:5]/2=[N:4]\[N+:1]([O-:3])=[O:2])=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])/N=C1\NCCN1Cc1ccc(Cl)nc1

Procedure:
7.8 g (60 mmol) of 2-nitroiminoimidazolidine and 12.1 g (87.5 mmol) of potassium carbonate were dissolved in 60 ml of acetonitrile in a reflux flask. The mixture is heated to a temperature sufficient for achieving reflux operating condition. 8.1 g (50.0 mole) of 2-chloro-5-chloromethyl pyridine is dissolved in 40 ml of acetonitrile, and is dropwisely and continuously added into the flask under the reflux condition for a period of 0.5 hr, i.e. the addition rate is about 1.5 ml/minute (the addition rate at the onset of the reaction corresponds to 0.0278 equivalent of 2-chloro-5-chloromethyl pyridine per equivalent of 2-nitroiminoimidazolidine per minute) After completion of the reaction, the mixture is subjected to filtration. The filtrate is concentrated, and is further purified.