Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([C:28]2[S:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=2)[O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.[C:45]([OH:50])(=[O:49])[C:46]([OH:48])=[O:47]>ClCCl.CC(C)=O>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH:19]([O:20][CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)[C:15]1[CH:14]=[C:13]([S:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])[CH:18]=[CH:17][CH:16]=1.[C:45]([O-:50])(=[O:49])[C:46]([O-:48])=[O:47]
Reactant: O=C(O)C(=O)O
Reactant: CN1CCC(OC(c2cccc(SCCCCNC(=O)OC(C)(C)C)c2)c2nc3ccccc3s2)CC1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(OC(c2cccc(SCCCCN)c2)c2nc3ccccc3s2)CC1
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-{3-[Benzothiazol-2-yl-(1-methyl-piperidin-4-yloxy)-methyl]-phenylsulfanyl}-butyl)-carbamic acid tert-butyl ester (140 mg) is dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.4 mL) is added. The reaction mixture is stirred at room temperature for 1 hour. The mixture is evaporated to dryness. The residue is basified by adding a solution of saturated sodium carbonate to pH 10 and the aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 90/10/1). The residue is added to oxalic acid (1 equivalent) in acetone (0.5 ml), and the precipitate is filtered and dry to give 4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine, oxalate melting at 108° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1ccccc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
The procedure of Zahler et al. was followed with minor modification (Zahler, R.; Koster, W. H.; Slusarchyk, W. A. EP 0138407). To a solution of benzyl bromoacetate (18.0 g, 12.5 mL, 79.6 mmol) and o-fluoroaniline (8.8 g, 7.7 mL, 100 mol %), in anhydrous DMF (60 mL) was added anhydrous K2CO3 (11 g, 100 mol %), and the mixture was stirred at rt overnight. The reaction mixture was diluted with water (120 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with water, dried, and then concentrated. Purification by LPLC (5% EtOAc- hexane) provided 18.0 g (88%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ7.39-7.35 (m, 5H), 7.03-6.97 (m, 2H), 6.72-6.67 (m, 1H), 6.59 (dt, J=8.4, J=1.2, 1H), 5.23 (s, 2H), 4.01 (s, 2H); 13C (CDCl3) δ170.59, 151.66 (d, J=240), 135.24, 128.64 (2 carbons), 128.52, 128.39 (2 carbons), 124.55 (d, J=3.5), 117.79 (d, J=7.1), 114.71 (d, J=17.7), 112.28 (d, J=3.5), 67.11, 45.54; MS (EI, m/z)259 (M+).
Reaction SMILES: [N:1]([CH:4]1[CH2:16][N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([O:14]C)=[O:13])[N:6]2[C:5]1=[O:17])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[NH2:1][CH:4]1[CH2:16][N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17]
Reactant: COC(=O)C1CCCN2CC(N=[N+]=[N-])C(=O)N12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NC1CN2CCCC(C(=O)O)N2C1=O
Yield: 76.3 %

Procedure:
1.19 g of methyl 2-azido-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (racemate A) and 1.31 g of triphenylphosphine in 25 ml of dioxane were stirred at room temperature for 1 hour and the mixture was then evaporated. The residue was treated with 40 ml of 2N aqueous ammonia at 50° C. for 2.5 hours and the precipitated triphenyl phosphine oxide was removed by filtration. Evaporation then yielded 0.756 g (76%) of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate A) in the form of a white solid which, after recrystallization from aqueous methanol, melted at 245°-246° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[N:11]=[N:12][C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:14][C:15]=1[C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.[I:31]N1C(=O)CCC1=O>CC(C)=O>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[I:31][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][C:16]=1[C:15]1[CH:14]=[C:13]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:12]=[N:11][C:10]=1[O:9][CH3:8]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 2 g 2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole trifluoroacetate and 1.3 g N-Iodosuccinimide (NIS) in acetone is stirred for 4 h at ambient temperature. The product is isolated by filtration, washed with acetone and used without further purification
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=1)=[O:8].[CH3:29]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[Cl:28][C:26]1[CH:25]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:27]=1)[CH2:5][N:6]([CH3:29])[C:7]([C:9]1[C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=1)=[O:8]
Reactant: CN(C)C=O
Reactant: CSc1ncc(C(=O)NCc2cc(Cl)cc(Cl)c2)c(Oc2ccccc2C)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: O
Product: CSc1ncc(C(=O)N(C)Cc2cc(Cl)cc(Cl)c2)c(Oc2ccccc2C)n1
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 0.6 g (1.8 mmol) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid 3,5-dichloro-benzylamide in 20 ml N,N-dimethylformamide 0.096 g (2.4 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the mixture stirred for 1 h. After the addition of 0.18 ml (2.9 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated, and the aqueous layer extracted twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 0.5 g (61%) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide as a light yellow oil, MS (EI): 447.1 (M+).
Reaction SMILES: C1(N)C=CC=C(N)C=1.NC1C=CC=CC=1.[C:16]1([C:28](Cl)=[O:29])[CH:21]=[C:20]([C:22](Cl)=[O:23])[CH:19]=[C:18](C(Cl)=O)[CH:17]=1.[C:31](Cl)(=[O:34])C=C>CN1CCCC1=O.O>[C:28](=[C:16]1[CH2:17][CH:18]=[CH:19][C:20](=[C:22]=[O:23])[C:21]1=[C:31]=[O:34])=[O:29]
Reactant: C=CC(=O)Cl
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: Nc1cccc(N)c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Nc1ccccc1
Product: O=C=C1C=CCC(=C=O)C1=C=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, a 1,000 mL four-neck flask was charged with 20.37 g (188.3 mmol) of 1,3-phenylenediamine (DuPont K.K.), 28.06 g (301.3 mmol) of aniline (Junsei Chemical Co., Ltd.) and 250.4 g of N-methyl-2-pyrrolidone (Junsei Chemical Co., Ltd.), after which the flask contents were cooled to 5° C. Separately, in a 500 mL four-neck flask and under a nitrogen atmosphere, 40 g (150.7 mmol) of 1,3,5-benzenetricarbonyl trichloride (Wako Pure Chemical Industries, Ltd.) was dissolved in 250.4 g of N-methyl-2-pyrrolidone (Junsei Chemical Co., Ltd.), after which the solution was cooled to −20° C. and subsequently added dropwise to the amine solution at an internal temperature of 5 to 10° C. over a period of 30 minutes, thereby effecting polymerization. Following dropwise addition, the mixture was stirred for 1 hour at 10° C. or below. To this was added dropwise 27.27 g (301.3 mmol) of acryloyl chloride (Tokyo Chemical Industry) at an internal temperature of 5 to 10° C. over a period of 20 minutes, after which the mixture was stirred for 2 hours at 45° C. The reaction mixture was added to 2,000 g of pure water and re-precipitated, and the precipitate thus obtained was collected by filtration then dried at 150° C. for 3 hours in a vacuum desiccator. The resulting moist product was again dissolved in 240 g of DMAc and stirred at 45° C. for 1 hour. The DMAc solution was allowed to cool to 30° C., then added to 2,000 g of pure water and re-precipitated. The resulting precipitate was collected by filtration and dried at 150° C. for 10 hours in a vacuum desiccator, giving 52.7 g of the target tricarbonylbenzene-based hyperbranched polymer (abbreviated below as “HPmDA-Acry”). FIG. 8 shows the measured 1H-NMR spectrum for HPmDA-Acry.
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH2:18])[CH2:7][N:6]1[CH2:19][CH2:20][CH3:21].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].N>N1C=CC=CC=1>[CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH2:7][N:6]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCN1C[C@@H](N)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Reactant: COCC(=O)Cl
Agent: N
Solvent: c1ccncc1
Product: CCCN1C[C@@H](NC(=O)COC)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Reaction time: 0.25 h

Procedure:
849 mg of 2-methyl6n-propyl-8alpha-ergolinylamine (3 mmol) is dissolved in 20 ml of pyridine and stirred with 2.28 ml of methoxy acetyl chloride (30 mmol) for 30 minutes at room temperature. Then it is poured onto ice, stirred for 15 minutes, make alkaline with ammonia and extracted with dichloromethane. The organic phases are dried and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/methanol and crystallized from ethyl acetate. Yield 420 mg (40% of theory), [α]D =+24° (0.5% in chloroform).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:12])[N:3]=1.[BrH:13].BrBr>C(O)(=O)C>[Br:13][CH:9]([CH3:10])[C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:12])=[CH:5][CH:6]=1)=[O:11]
Reactant: CCC(=O)c1ccc(C)nc1C
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)C(C)Br)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution 1-(2,6-dimethl-pyridine-3-yl)-propan-1-one (0.3 g, 1.8 mmol) in 30% by weight solution of hydrogen bromide in acetic acid (3 ml) was added dropwise (0.29 g, 1.8 mmol) of Bromine. The reaction was allowed to warm to room temperature with stirring for 2h. The mixture was then concentrated in vacuo and the resulting crude material neutralized using saturated sodium carbonate solution. The mixture was extracted twice with dichloromethane and the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Yield: 400 mg (92%). 1H NMR (300 MHz, CDCl3), •1.88 (d, CH3, 3H), 2.64 (s, CH3, 3H), 2.76 (s, CH3, 3H), 5.12 (q, CH, 1H), 7.14 (d, Ar, 1 H,), 7.93 (d, Ar, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:39])[NH:34][CH2:35][CH2:36][CH2:37][NH2:38])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:39])[NH:34][CH2:35][CH2:36][CH2:37][NH:38][C:10]([C:9]1[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=2)=[N:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCN
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(C#N)cc1
Yield: 62.1 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-Cyano phenoxy)-nicotinic acid 0.335 g (0.94 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (0.163 g, 0.94 mmol) were used to afford 0.3 g of the required product. Percentage purity (LCMS): 78.7%, (M+1)=513.5+1.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19]([CH2:22][CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)([OH:21])=[O:20].B(F)(F)F.CCOCC>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:28]3[N:24]([CH2:23][CH2:22][C:19]([OH:21])=[O:20])[N:25]=[N:26][N:27]=3)[CH2:15][S:14][C@H:9]12
Reactant: O=C(O)CCn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12
Yield: 80.1 %

Procedure:
7-aminocephalosporanic acid (38.4 g) and 1-(2-carboxyethyl)-1H-tetrazole-5-thiol (20.0 g) were reacted in the presence of boron trifluoride etherate (80.0 g) and dry acetonitrile (200 ml) to give 7-amino-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (35.52 g).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19]>C(Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([O:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C=CC(=O)Cl)cc1
Reactant: CN(C)CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)CCOC(=O)C=Cc1ccc(N=[N+]=[N-])cc1

Procedure:
In carbon tetrachloride was dissolved 14 g (70 millimoles) of the p-azidocinnamic acid chloride obtained in Example 16, and 6 g (70 millimoles) of 2-dimethylaminoethanol was added dropwise to the resulting solution at 10° to 20° C., after which the resulting mixture was allowed to react for 1 hour. The deposited precipitate was collected by filtration, and 100 ml of water was added thereto.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][N:36]([C:39](=O)C)[CH2:35][CH2:34]4)=[C:29]4[C:25]=3[C:26](=[O:43])[N:27]([CH3:42])[CH2:28]4)[C:20]([C:44]([F:47])([F:46])[F:45])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(OP(CC1C=CC(NC2N=C(NC3C=CC(Br)=C4C=3C(=O)N(C)C4)C(C(F)(F)F)=CN=2)=CC=1)(=O)OCC)C.CN1CCNCC1>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)=[C:29]4[C:25]=3[C:26](=[O:43])[N:27]([CH3:42])[CH2:28]4)[C:20]([C:44]([F:45])([F:47])[F:46])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C(C)=O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: CN1CCNCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Diethyl(4-{[4-{[7-(4-acetylpiperazin-1-yl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 199) using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and the commerically available N-methylpiperazine. MS (ES+): m/z 648.35 (100) [MH+]; HPLC: tR=0.70 min (UPLC, purity).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:41])[C@H:4]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9](=[O:24])[CH:10]([S:14]CC1C=CC(OC)=CC=1)[CH2:11][CH2:12][CH3:13].C1(OC)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:1][NH:2][C:3](=[O:41])[C@H:4]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:8][C:9](=[O:24])[CH:10]([SH:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NC
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CCCC(S)C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NC
Reaction time: 3 h
Yield: 80.5 %

Procedure:
Combine 2-(4-methoxybenzylthio)-pentanoyl-(L)-homophenylalanyl-(L)-phenylalanine N-methyl amide (0.26 g, 0.45 mmol), mercury (II) acetate (0.156 g, 0.49 mmol), and anisole (0.49 mL, 4.5 mmol) in dichloromethane (10 mL). Cool in an ice bath and degas by repeatedly applying vacuum and filling the vessel with nitrogen. Add trifluoroacetic acid (2 mL). After 3 hours, filter and evaporate in vacuo to give a residue. Repeatedly, combine the residue and carbon tetrachloride and evaporate in vacuo to give a residue. Triturate the residue with hexane to give the title compound as a solid (165 mg, 80.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[C:16]([NH2:17])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].O>CN(C=O)C>[NH2:17][C:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:33]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=4[Cl:25])(=[O:35])=[O:34])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[NH:14][N:15]=1
Reactant: Nc1ccc(-c2ccc3c(N)n[nH]c3n2)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.44 mmol) of 6-(4-aminophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine are dissolved in 3 ml of anhydrous DMF. The solution is then degassed for 15 minutes with argon. 123.8 μl (89.9 mg, 0.89 mmol, 2 eq.) of triethylamine are subsequently added. The solution is once again degassed for 15 minutes. Finally, 0.109 g (0.444 mmol, 1 eq.) of 2,3-dichlorophenylsulphonyl chloride is added. The solution is stirred at ambient temperature under argon overnight. At the end of the reaction, 10 ml of water are added. A yellow-brown precipitate forms. The mixture is filtered. The solid is dried and purified on a column of 4 g of silica with an eluent gradient of 0 to 10% of methanol in dichloromethane. A beige solid is isolated (11 mg).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:26])=[N:6][C:7]2[N:8]([CH:18]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:20]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])(=O)[NH2:2].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([C:4]1[C:5]([CH3:26])=[N:6][C:7]2[N:8]([CH:18]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:20]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])#[N:2]
Reactant: COC(=O)Cc1cn2c(-c3ccc(Cl)cc3Cl)c(C(N)=O)c(C)nc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cn2c(-c3ccc(Cl)cc3Cl)c(C#N)c(C)nc2n1
Yield: 79.7 %

Procedure:
To a suspension of methyl 2-(6-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetate (766 mg, 1.95 mmol) in CH2Cl2 (20 mL) was added Et3N (592 mg, 5.85 mmol) and trifluoroacetic anhydride (819 mg, 3.90 mmol). The reaction mixture became a dark brown-green solution within 2 min. Satd aq NH4Cl (20 mL) was added after 30 min. The organic layer was washed with 20 mL each of satd aq NaHCO3 and water, followed by drying with MgSO4, filtration, and concentration under reduced pressure. The residue was purified by silica gel chromatography eluting product through a 40 mm i.d. by 150 mm column with 1.5% MeOH in CH2Cl2. Concentration of the fractions containing product gave methyl 2-(6-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)acetate (583 mg, 80%) as a yellow foam.
Reaction SMILES: [C:1]([C:5]1([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([O:3]C)=[O:2].[OH-].[K+]>C(O)C.O.O1CCCC1>[C:1]([C:5]1([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(SCc2ccc(OC)cc2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CSC2(C(=O)O)Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Dissolve 2-(carbomethoxy)-2-(4-methoxybenzylthio)indan (2.20 g, 3.55 mmol) in 95% ethanol (25 mL), water (12 mL) and tetrahydrofuran (15 mL). Treat with potassium hydroxide (1.3 g, 23 mmol) and stir at room temperature for 1 hour. Filter and evaporate the solvent in vacuo. Partition between water (125 mL) and ether (75 mL). Separate the aqueous phase and acidify with cold concentrated hydrochloric acid. Extract with methylene chloride (75 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (2:1 hexane/ethylacetate) to give 2-carboxy-2-(4-methoxybenzylthio)indan as a yellow solid (0.48 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH:11]([O:19][C:20](=O)[CH3:21])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])(=O)C.[NH4+:28]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:28]=[C:20]([CH3:21])[O:19][C:11]=3[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)OC(C(=O)c1ccc2c(c1)OCO2)c1cccc(C)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cccc(-c2oc(C)nc2-c2ccc3c(c2)OCO3)n1
Yield: 20.8 %

Procedure:
A solution of acetic acid 2-benzo[1,3]dioxol-5-yl-1-(6-methyl-pyridin-2-yl)-2-oxo-ethyl ester (80 mg, 0.26 mmol), ammonium acetate (200 mg, 2.6 mmol, 10 equiv) in acetic acid (4 mL) was heated to 105° C. for 3 hours. The resulting reaction mixture was concentrated in vacuo, and reverse phase high pressure liquid chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provided 2-(4-Benzo[1,3]dioxol-5-yl-2-methyl-oxazol-5-yl)-6-methyl-pyridine (15.9 mg, 21%).[LCMS: Rt=2.10 min; M+H=295.2]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)OC)c1
Temperature: 60 °C

Procedure:
To 3.3 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester (example B13c)) and 3.3 mmol potassium carbonate in 50 ml acetone was added dropwise 4.9 mmol 2,2,2-trifluoro-ethyl trifluoromethanesulfonate and the mixture was heated at 60° C. for 16 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 3:7) to afford the title compound. MS (m/e): 328.0 (M+H+, 100%)