Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[N+:9]([C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:11])=[O:10].C(N(C(C)C)CC)(C)C>[Cl-].[Cl-].[Zn+2].C(#N)C>[N+:9]([C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14]([O:16][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1)=[O:15])([O-:11])=[O:10]
Reactant: O=C1C=C(Cl)CCC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c([N+](=O)[O-])c1
Temperature: 45 °C
Yield: 50.5 %

Procedure:
To a mixture of 157 mg (1.15 mmol) of 3-chlorocyclohex-2-en-1-one (prepared as described in Synthesis (1974), (1), 47-8), 16 mg (0.12 mmol) of ZnCl2, 297 mg (1.15 mmol) of 2-nitro-4-methylsulfonylbenzoic acid and 3 ml of anhydrous acetonitrile there are added dropwise, under a nitrogen atmosphere, over the course of 15 minutes, 166 mg (1.27 mmol) of diisopropylethylamine. A further 2 ml of acetonitrile are then added and the reaction mixture is maintained at a temperature of 45° C. for 18 hours in an oil bath, with stirring. The reaction mixture is then heated up again and maintained at reflux temperature for 40 hours. The reaction mixture is then brought to ambient temperature and the solvent is removed in vacuo. 25 ml of dichloromethane and 0.35 g of 36% hydrochloric acid in 5 ml of water are then added and the phases are separated. The organic phase is washed twice with 10 ml of water, dried using magnesium sulfate and concentrated in vacuo. 197 mg of 3-(2-nitro-4-methylsulfonyl-phenylcarbonyloxy)-cyclohex-2-en-1-one are obtained in the form of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H](NC(=O)c1ccccc1)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A solution of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [3.0 g, Reference Example 7(c)] in dimethylformamide (50 ml), was treated with benzoyl chloride (1.24 ml) and triethylamine (1.56 ml). After stirring at ambient temperature for 2.25 hours, the mixture was evaporated to dryness and the resultant solid washed with water before being fried in vacuo. The resulting white solid (3.8 g) was dissolved in dichloromethane (70 ml) and the solution was treated with trifluoracetic acid (20 ml). After stirring at ambient temperature for 45 minutes, the reaction mixture was evaporated. The residue was treated with toluene (70 ml), concentrated to dryness and the resultant material treated with dichloromethane (200 ml). The resultant suspension was treated with saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulphate, and then evaporated to give the title compound as a white foam (2.0 g).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19].[C:20](Cl)(=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>N1C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(=O)Cl
Reactant: CSCCCCCNc1c(N)cnc2ccccc12
Solvent: c1ccncc1
Product: CCCCCCC(=O)Nc1cnc2ccccc2c1NCCCCCSC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (3.17 g, 11.46 mmol) and anhydrous pyridine (46 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to 0° C. in an ice-water bath. To the cooled solution was added neat heptanoyl chloride (1.87 g, 12.61 mmol). The reaction was judged to be complete after stirring at ambient temperature for 1 hour. The volatiles were removed under reduced pressure and the resulting oil was partitioned between chloroform and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford N-(4-[{5-(methylthio)pentyl]amino}quinolin-3-yl)heptanamide (4.44 g, 11.46 mmol) which was isolated as a brown oil and used without further purification.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[C:2]=[S:3].[C:11]([NH2:19])([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]>>[C:11]([NH:19][C:2]([NH:1][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[S:3])([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]
Reactant: S=C=NCCc1cccs1
Reactant: CC(C)(C)CC(C)(C)N
Product: CC(C)(C)CC(C)(C)NC(=S)NCCc1cccs1
Yield: 82.1 %

Procedure:
The procedure of step (1-1) of Example 1 was repeated except for using the compound obtained in step (2-1) (2.5 g, 15.0 mmol) and t-octyl amine (1.6 mL, 10.2 mmol), to obtain the title compound (2.5 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CS(O[CH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:19]1([CH2:18][CH2:17][O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: CS(=O)(=O)OCCC1CC1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCC2CC2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 6 h
Yield: 84.2 %

Procedure:
A suspension of 4-methyl-3-nitrophenol (3 g), 2-cyclopropylethyl methanesulfonate (3.22 g) and potassium carbonate (2.71 g) in DMF (100 mL) was stirred at 80° C. for 6 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was extracted with ethyl acetate and water, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (NH, hexane/ethyl acetate) to give the title compound (3.65 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.BrCC1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:3]=1
Reactant: BrCc1ccncc1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1sc(Br)cc1NCc1ccncc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 4-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 50:50 hexane/EtOAc) to give the title compound (238 mg, 48%) as a yellow solid:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:18][N:19]([CH3:38])[C:20]1[CH:37]=[CH:36][C:23]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][C@H:28](OS(C)(=O)=O)[CH2:27]2)=[CH:22][CH:21]=1>CCCCCC.CS(C)=O>[CH3:38][N:19]([CH3:18])[C:20]1[CH:21]=[CH:22][C:23]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][C@@H:28]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:27]2)=[CH:36][CH:37]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: CN(C)c1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CN(C)c1ccc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (160 mg, 4.0 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (12 ml). After stirring at room temperature for 30 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (790 g, 4.0 mmol) was added to the obtained suspension. They were stirred at room temperature for 60 minutes and then at 50° C. for 60 minutes. A solution of (S)-1-(4-dimethylaminophenethyl)-3-methanesulfonyloxypyrrolidine (378 mg, 1.21 mmol) in dimethyl sulfoxide (7 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was poured into ice/water. After the extraction with ethyl acetate, the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1), then with hexane and ethyl acetate (3:1) and finally with a mixture of the same solvents (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-dimethylaminophenethyl)pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (196 mg, 39%).
Reaction SMILES: C([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[C:7](Br)[C:6]=1[O:16][CH3:17])(=O)C.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19]>>[CH:9]([C:8]1[C:7]([C:24]2[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[C:6]([O:16][CH3:17])[C:5]([OH:4])=[C:12]([O:13][CH3:14])[CH:11]=1)=[O:10]
Reactant: COc1cc(C=O)c(Br)c(OC)c1OC(C)=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: COc1cc(C=O)c(-c2ccc(C(=O)O)cc2)c(OC)c1O

Procedure:
6′-Formyl-3′-hydroxy-2′,4′-dimethoxy-biphenyl-4-carboxylic acid was prepared from 4-acetoxy-2-bromo-3,5-dimethoxybenzaldehyde (Example 162, step a) and 4-carboxyphenyl boronic acid using the protocol described in Example 145, step a. Mass Spectrum 288 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([F:20])=[C:18]([B:21]([OH:26])[OH:22])[CH:17]=[CH:16][N:15]=1
Reactant: Fc1cccnc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1ccnc(F)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of THF and hexanes (6 mL, 1:1 v:v), and diisopropyl amine (0.681 mL, 4.78 mmol) was cooled to −78° C. BuLi (2.5 M in hexanes, 2.00 mL, 5.00 mmol) was added to the cooled mixture, followed by addition of 2,3-difluoropyridine after about 15 minutes. The mixture was stirred for 1 hour at −78° C. before being transferred to a 3 mL THF solution of triisopropyl borate (1.11 mL, 4.78 mmol) at −78° C. via a cannula. The resulting solution was stirred at −78° C. for 1 hour, slowly warmed up to ambient temperature and then quenched with 2 M NaOH solution (20 mL). The two layers were separated and the aqueous phase was washed once with ether. The aqueous phase was then acidified with HCl to pH 5 and extracted three times with EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated to yield the product as a light yellow solid, which was used in the next step without purification. LCMS (m/z): 159.9 (M+H), retention time=0.35 min.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH2:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:13]1[O:15][CH2:14]1>C1COCC1>[CH2:17]([O:16][CH2:12][C@H:13]([OH:15])[CH2:14][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O[C@@H](COCc1ccccc1)CC1SCCCS1
Temperature: -30 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A solution containing 1,3-dithiane (11 g) in THF (190 mL) was cooled to −70° C. n-Butyllithium (2.64 M solution in hexane, 35 mL) was added to the reaction solution, and then the mixture was heated to −30° C. and stirred for one hour. The reaction solution was cooled to −70° C., and a solution containing benzyl(R)-(−)-glycidyl ether (16.5 g) in THF (18 mL) was added dropwise. The cooling bath was removed and the mixture was gradually warmed to room temperature. After stirring overnight, a saturated ammonium chloride solution, brine and t-butyl methyl ether were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography to obtain the title compound (22.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH3:14][S:15](Cl)(=[O:17])=[O:16].Cl>O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][S:15]([CH3:14])(=[O:17])=[O:16])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-hydroxybenzoic acid (3.45 g, 20 mmol) and sodium hydroxide (2.40 g, 60.0 mmol) in 30 ml of water is added, dropwise at 0°, methanesulfonyl chloride (2.57 ml, 3.80 g, 33.0 mmol). After addition is complete, the reaction mixture is stirred at RT for 30 min., after which it is poured into water, acidified with dil. HCl and extracted with ether. The combined organic extracts are washed with brine, dried and evaporated to give 2-chloro-4-methylsulfonyloxybenzoic acid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (8.00 g, 33.6 mmol) in CH2Cl2 (140 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-fluoro-4-((E)-2-nitro-vinyl)-benzene (5.12 g, 30.6 mmol) and trifluoroacetic acid (0.23 ml, 3.1 mmol) in CH2Cl2 (200 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 6.60 g (72%) of the title compound as a light yellow oil.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1ccc(F)cc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 41.6 %

Procedure:
A mixture of intermediate 59 (1.0 g, 0.0027 mol), 4-fluorobenzylamine (0.372 mL, 0.00321 mol) and MeOH (0.4 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and partitioned between dichloromethane and water. The organic solution is separated, dried (MgSO4), and concentrated in vacuo. The residue is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (80:20-40:60) gives 0.50 g of the product 85. 1H NMR (CDCl3) δ 7.60-7.35 (m, 3H), 7.15-6.90 (m, 10H), 6.85-6.70 (m, 2H), 5.50-5.30 (m, 2H), 5.75-5.55 (m, 2H), 1.12 (s, 9H); MS: m/z 446 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]([NH2:16])=[S:15])[CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=1.BrBr.N>C(Cl)Cl.O>[Br:1][C:2]1[C:3]2[S:15][C:14]([NH2:16])=[N:13][C:4]=2[CH:5]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=1
Reactant: NC(=S)Nc1cc(Br)cc(-n2cccn2)c1
Agent: BrBr
Agent: N
Solvent: ClCCl
Solvent: O
Product: Nc1nc2cc(-n3cccn3)cc(Br)c2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a solution of (3-bromo-5-pyrazol-1-yl-phenyl)-thiourea (1.0 g, 3.0 mmol) in DCM (17.0 mL) at 0° C. was added dropwise a solution of Br2 (1.07 g, 6.0 mmol, in 3.0 ml of DCM) over a period of 15 min. The reaction mixture was stirred at 0° C. for 15 min followed by refluxing for 2 h. The reaction mixture was cooled to room temperature and filtered to get the crude residue that was washed with hexane and diethyl ether. The solid thus obtained was dissolved in H2O, basified with aqueous ammonia solution to pH 10-12 and extracted with ethyl acetate (×3). The combined organic was washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (230-400 M, 25% EtOAc-Hexane) to get the desired product (0.30 g, 30%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[CH3:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1)[CH2:27][O:26][CH3:25]
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Yield: 71.1 %

Procedure:
3 g (8.66 mmol) of 1,4,7-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecane is stirred in 50 ml of dimethylformamide for 10 hours with 1.57 g (11.29 mmol) of 2-methoxyethyl bromide and 4.15 g of potassium carbonate at 90° C. It is concentrated by evaporation in a vacuum and the residue is spread between 100 ml of water and 50 ml of diethyl ether. The aqueous phase is adjusted to pH 2 with 5 N hydrochloric acid and evaporated to dryness. The residue is refluxed with 200 ml of methanol, the undissolved material is filtered out, it is evaporated to dryness in a vacuum, the residue is dissolved in 50 ml of water, adjusted to pH 2 with 5 N hydrochloric acid and the solution is put on a column with 200 ml of cation exchanger IRC 50. It is eluted first with 0.5 l of water, which is discarded. Then, it is eluted with 0.5 l of 0.5 N ammonia solution. It is evaporated almost to dryness in a vacuum, mixed with 100 ml of water and enough cation exchanger IRC 50 is added with stirring until pH 3.5 is reached. The solution is then filtered and freeze-dried. 2.49 g of the title compound with a water content of 4.30% is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:17]([C:22]([CH3:26])([CH3:25])[C:23]#N)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1.C(OCC)(=[O:29])C.[OH-].[Na+]>O.S(=O)(=O)(O)O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@H:13]([N:15]2[C:16]3=[N:21][CH:20]=[CH:19][N:18]=[C:17]3[C:22]([CH3:26])([CH3:25])[C:23]2=[O:29])[CH2:14]1
Reactant: CCOC(C)=O
Reactant: CC(C)(C#N)c1nccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2nccnc21
Temperature: 100 °C
Reaction time: 0.58 h

Procedure:
2-(3-((Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)amino)pyrazin-2-yl)-2-methylpropanenitrile (0.067 g, 0.184 mmol) was dissolved in a mixture of water (3 mL) and concentrated sulfuric acid (2 mL) and heated at 100° C. After 35 minutes the heat was turned off and the reaction allowed to cool in the oil bath over 90 minutes. Water (100 mL), ice (about 100 mL), and ethyl acetate (200 mL) were added followed by 5 N sodium hydroxide (15 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 5-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.061 g, 0.167 mmol, 91% yield) as a white solid. M+1: 366.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 6 H) 2.42-2.58 (m, 2 H) 3.45 (s, 2 H) 4.53-4.68 (m, 1 H) 5.31 (quin, J=8.46 Hz, 1 H) 6.53 (br. s, 1 H) 7.04-7.15 (m, 1 H) 7.30 (t, J=7.24 Hz, 1 H) 7.59 (d, J=8.22 Hz, 1 H) 7.61 (d, J=8.02 Hz, 1 H) 8.09 (d, J=3.33 Hz, 1 H) 8.13 (d, J=3.30 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[O:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1.BrC[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH2:10][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7](=[CH:14][CH:15]=1)[C:8]([OH:9])=[O:13]
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CNc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (80% in oil; 1.2 g) was added slowly to a stirred suspension of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (7 g). Effervescence occurred and a clear solution was produced. Ethyl bromoacetate (4.5 ml) was added and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was diluted with water. The solid (9.5 g) was filtered off and washed with water and hexane and dried. This solid (5.4 g) was added to a solution of sodium carbonate (5.3 g) in water (60 ml). After stirring for 6 hours the undissolved solid was filtered off. The filtrate was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The solid was purified by flash chromatography and recrystallised from diisopropyl ether to give 4-fluoro-N-(ethoxycarbonylmethyl)- anthranilic acid, mp. 123°-125°. (Compound 11).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:15]([N:18]([CH3:20])[CH3:19])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[N:10]=[CH:15][N:18]([CH3:20])[CH3:19])=[O:4]
Reactant: COC(=O)c1sc(C=O)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(C=O)cc1N=CN(C)C

Procedure:
3-Amino-5-formylthiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 308.40 (C15H20N2O3S) was obtained in this way; MS (ESI): 309 (M+H+).