Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:16]3[CH:24]=[C:23]4[C:19]([CH:20]=[CH:21][N:22]4[CH3:25])=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.ClS([N:31]=[C:32]=O)(=O)=O.CN(C=O)C>C(#N)C>[C:32]([C:20]1[C:19]2[C:23](=[CH:24][C:16]([C:14]([NH:13][C:11]3[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:2][CH2:3]4)[CH:8]=[CH:9][C:10]=3[CH3:26])=[O:15])=[CH:17][CH:18]=2)[N:22]([CH3:25])[CH:21]=1)#[N:31]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc2ccn(C)c2c1
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc2c(C#N)cn(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
To N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-1-methyl-1H-indole-6-carboxamide (0.045 g, 0.129 mmol, example 97, table 5) in anhydrous acetonitrile (2 mL) was added chlorosulfonyl isocyanate (11 μL, 0.129 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. and DMF (11 μL, 0.141 mmol) is added. After another 30 min. at room temperature, the reaction mixture was quenched with methanol (2 mL), concentrated under reduced pressure and subjected to reverse phase preparative HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were collected, and concentrated using speedVac® Plus (SC250DDA) to yield the title compound (Example 223, 0.005 g). HPLC retention time (YMC S5 Combiscreen ODS; 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; solvent B=90% MeOH, 10% H2O, 0.2% H3PO4): 2.6 min. LCMS [M+H]+ 373.2.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][NH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[CH3:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:8]([CH3:7])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CNc1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1N(C)Cc1ccccc1

Procedure:
K2CO3 (270 mg) is added to a solution of N,2-dimethyl-5-nitro-aniline (214.5 mg, 1.29 mmol) and benzyl bromide (0.2 mL, 1.7 mmol) in DMF (4 mL). The mixture is heated for 12 h to 70° C. under stirring. Volatiles are evaporated at reduced pressure. Chromatography of the residue (silica gel, hexane/EtOAc 4:1) yields N-Benzyl-N,2-dimethyl-5-nitro-aniline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[O:24][C:25]=1[CH3:26].COC1C=CC=CC=1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: COc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3OC)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 144 a], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole (prepared from 2-methoxy-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH:17]=[O:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.[Cu]>[O:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH2:10][CH2:9][N:8]2[CH:17]=[O:18])=[CH:19][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CN1CCC2=C(CCCC2)C1Cc1ccc(O)cc1
Reactant: Brc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=CN1CCC2=C(CCCC2)C1Cc1ccc(Oc2ccccc2)cc1
Yield: 69 %

Procedure:
A solution of 29.0 g (0.106 mol) of (±)-1-(p-hydroxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline in 530 ml of freshly distilled pyridine was refluxed with stirring under nitrogen with 12.88 ml of bromobenzene, 51.5 g of copper (granular) and 22.55 g of potassium carbonate for 14 days. The reaction mixture after cooling was diluted with ether 1 1. and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in ether (300 ml). The ether solution was washed with 4N aqueous sodium hydroxide (200 ml) then with water and dried. Removal of the solvent under reduced pressure gave 25.8 g (69%) of crude (±)-1(p-phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For analysis, a sample of this compound was distilled, bp 220°-230° (0.05 mm Hq).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([O:11]CC)=[O:10])[CH2:6][C:5]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3]1.[OH-].[Na+].O=C1NCC2(CCCCC2)N(C2C=CC=CC=2)C1CC(O)=O>O1CCCC1>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([OH:11])=[O:10])[CH2:6][C:5]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3]1
Reactant: CCOC(=O)CN1CC2(CCCCC2)N(c2ccccc2)CC1=O
Agent: O=C(O)CC1C(=O)NCC2(CCCCC2)N1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CN1CC2(CCCCC2)N(c2ccccc2)CC1=O
Yield: 89 %

Procedure:
In an analogous manner to Example 2(e), by reaction of 220 mg (0.66 mmol) of ethyl (3-oxo-1-phenyl-1,4-diazaspiro[5.5]undec-4-yl)acetate with 130 mg (3.25 mmol) of sodium hydroxide in 10 ml of tetrahydrofuran, 180 mg of (3-oxo-1-phenyl-1,4-diazaspiro[5.5]undecyl)acetic acid are obtained in the form of a beige solid. M.p. 167-9° C., yield=89%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[NH:17]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])[N:19]=[N:18]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[NH:17]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25]([NH:1][CH:2]2[CH2:3][CH:4]3[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]3)[CH2:8]2)=[O:26])[N:19]=[N:18]1
Reactant: O=C(O)CCCc1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(N)C2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(NC(=O)CCCc1c[nH]nn1)C2

Procedure:
A reaction mixture comprising of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (250 mg, 1.105 mmol), 4-(1H-1,2,3-triazol-4-yl)butanoic acid (Example 17, step 4) (171 mg, 1.105 mmol), T3P® 50% DMF (1.29 ml, 2.209 mmol) and TEA (462 μl, 3.31 mmol) in DMF (3.6 ml) was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting oil was diluted with DCM and washed with water. The organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. The material was taken crude to the next step.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][P+:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])=O)(C)(C)C.[Cl-:36].Cl.C(OCC)C.N>C(Cl)Cl.CO>[CH3:6][NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][P+:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].[Cl-:36]
Reactant: CN(CC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CNCC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of N2-(tert-butoxycarbonyl)-N2-methyl-N-[3-(triphenylphosphonio)propyl]glycinamide chloride (7.6 g, 14 mol) in methylene chloride (38 mL) and methanol (4.2 mL) was added 2.0 M HCl in diethyl ether (16 mL, 32 mmol), and the mixture was stirred overnight at room temperature. The solution was cooled to 0° C. and treated with 7 M ammonia in methanol (6.0 mL, 42 mmol), giving an immediate white precipitate. After 30 minutes, the slurry was filtered and the flask and filter cake were rinsed with methylene chloride (68 mL). The filtrate was concentrated to give the title compound (6.2 g, 100%) as a crude white solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][N:12]=[CH:13]2)=[C:8]([Cl:23])[CH:7]=1)[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1.O>[Cl:23][C:8]1[CH:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2
Reactant: CC(N=[N+]=[N-])c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 7-(1-azidoethyl)-5-chloro-8-(3-fluorophenyl)isoquinoline (0.105 g, 0.321 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL) was added 1.0 M trimethylphosphine in THF (0.39 mL, 0.39 mmol). The mixture was stirred at room temperature for 1 hour. After nitrogen was passed through the reaction solution, the reaction mixture was extracted with dichloromethane. The extracts were washed with brine, dried over magnesium sulfate and evaporated to dryness. The crude residue was used directly in the next step (75 mg, 78%). LCMS calculated for C17H15ClFN2 (M+H)+: m/z=301.1; Found: 301.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.C(N)(=[S:18])C.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[S:18])=[CH:10][N:9]=1
Reactant: N#Cc1ccc(-c2ccccc2F)nc1
Reactant: CC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=S)c1ccc(-c2ccccc2F)nc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A mixture of 6-(2-Fluoro-phenyl)-nicotinonitrile (9.8 g, 49.4 mmol) and thioacetamide (5.94 g, 79.1 mmol) in 4.0 M HCl in dioxane (200 mL) is heated at 100° C. for 3 days, cooled to room temperature. The raction mixture is poured into old saturated sodium bicarbonate and stirred for 30 min. Solid product is collected by filtration and dried under vacuum giving the title compound (11.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]CC)=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:22]([C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:27][O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=[CH:20][CH:19]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1cccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: Cl
Product: O=C(O)c1cccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1
Yield: 109.9 %

Procedure:
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(pyridin-3-yloxy)propanamide (41.7 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (23.3 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:25][CH3:26])(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:19]([C:18]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cccc(F)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
1,3-Difluoro-2-nitrobenzene (2.83 g, 17.79 mmol) was dissolved in N,N-dimethylformamide (25 mL). Potassium carbonate (2.49 g, 18.02 mmol) was added to the mixture followed by dimethyl malonate (2.033 ml, 17.79 mmol). Mixture was warmed to 65° C. and held for 24 hours. Mixture was cooled to room temperature. Reaction was quenched with 1N hydrochloric acid. Material was extracted three times with diethyl ether and the aqueous phase was discarded. Material was washed twice with water and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Residue was crystallized with hexanes. Solids were filtered off and washed with hexanes. Title compound was obtained as yellow crystals in 52% yield. MS (M−H)−=270.1.
Reaction SMILES: BrC1C=CC=CC=1[C:8]1[C:9]2[C:14]([C:15](C3C=CC=CC=3Br)=[C:16]3[C:21]=1C=CC=C3)=[CH:13][CH:12]=[CH:11][CH:10]=2.BrC1C2C(=CC=CC=2)C(C2C3C(=CC=CC=3)C(C3C4C(C(Br)=C5C=3C=CC=C5)=CC=CC=4)=CC=2)=C2C=1C=CC=C2>>[CH:13]1[C:14]2[C:9](=[CH:8][CH:21]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1ccccc1-c1c2ccccc2c(-c2ccccc2Br)c2ccccc12
Agent: Brc1c2ccccc2c(-c2ccc(-c3c4ccccc4c(Br)c4ccccc34)c3ccccc23)c2ccccc12
Product: c1ccc2ccccc2c1

Procedure:
Preparation analogous to Example 3b. Instead of 19.5 g (40 mmol) of 9,10-bis(2-bromophenyl)anthracene, 25.5 g (40 mmol) of 1,4-bis(10-bromoanthracen-9-yl)naphthalene are used. Sublimation at p=1×10−5 mbar, T=300° C. Yield: 12.1 g (16.5 mmol), 41.3% of theory; purity: 99.8% according to 1H-NMR.
Reaction SMILES: [F:1][C:2]1([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.ClC1C(C2(F)CCC3(OCCO3)CC2)=NC=CC=1>>[F:1][C:2]1([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: Cc1cccnc1C1(F)CCC2(CC1)OCCO2
Agent: FC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Product: Cc1cccnc1C1(F)CCC(=O)CC1

Procedure:
The title compound was prepared using the procedure as described in Example 1C, except for substituting the product of Example 10B for the product of Example 1B. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (d, J=4.4 Hz, 1 H) 7.66 (d, J=6.8 Hz, 1 H) 7.29 (dd, J=6.8, 4.4 Hz, 1 H), 2.54-2.93 (m, 4 H), 2.51 (s, 3 H), 2.18-2.46 (m, 4 H). MS (DCI) m/e 208 (M+H)+.
Reaction SMILES: IC1C2N=CN=C(N)C=2NN=1.FC1C=CC([N+]([O-])=O)=CC=1.[I:22][C:23]1[C:27]2[N:28]=[CH:29][N:30]=[C:31]([NH2:32])[C:26]=2[N:25]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35](OC)[CH:34]=2)[N:24]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[I:22][C:23]1[C:27]2[N:28]=[CH:29][N:30]=[C:31]([NH2:32])[C:26]=2[N:25]([C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)[N:24]=1
Reactant: COc1cc(-n2nc(I)c3ncnc(N)c32)ccc1[N+](=O)[O-]
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Nc1ncnc2c(I)n[nH]c12
Agent: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC#N
Product: Nc1ncnc2c(I)nn(-c3ccc([N+](=O)[O-])cc3)c12

Procedure:
The title compound was prepared from 3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine and 1-fluoro-4-nitrobenzene as described for the preparation of 3-iodo-1-(3-methoxy-4-nitrophenyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine 1H NMR (DMSO-d6, 400 MHz) δ 8.40-8.50 (m, 3H), 7.79 (d, 2H), 7.11 (bs, 2H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 15.98 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH2:13][CH2:14][CH3:15])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CCCNCCCCNC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(CCCCNC(=O)OC(C)(C)C)CC(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (339.0 mg) obtained in Example 84-1 was dissolved in chloroform (5.1 ml) and added with triethylamine (0.41 ml). Ethyl bromoacetate (0.20 ml) was dropped to the solution and the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (273.9 mg) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:8]([CH2:10][CH3:11])[CH3:9])=[O:6].[Cl:19]C1C=C(C=C(Cl)C=1)C(N(C(CC)C)C(CC)C)=O.ClC1C=CC(C(N(C(CC)C)C(CC)C)=O)=CC=1.ClC1C=C(C=CC=1Cl)C(N(C(CC)C)C(CC)C)=O.ClC1C=C(C=CC=1Cl)C(N(C(CC)C)CCCC)=O.ClC1C=C(Cl)C=CC=1C(N(C(CC)C)C(CC)C)=O.ClC1C=CC=C(Cl)C=1C(N(C(CC)C)C(CC)C)=O.IC1C=C(C=CC=1)C(N(C(CC)C)C(CC)C)=O.CC1C=C(C=CC=1)C(N(C(CC)C)C(CC)C)=O.ClC1C(Cl)=CC(Cl)=CC=1C(N(C(CC)C)C(CC)C)=O>>[Cl:19][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:8]([CH2:10][CH3:11])[CH3:9])=[O:6]
Reactant: CCC(C)N(C(=O)c1cccc(Br)c1)C(C)CC
Reactant: CCC(C)N(C(=O)c1cc(Cl)cc(Cl)c1)C(C)CC
Agent: CCC(C)N(C(=O)c1c(Cl)cccc1Cl)C(C)CC
Agent: CCC(C)N(C(=O)c1cc(Cl)cc(Cl)c1Cl)C(C)CC
Agent: CCC(C)N(C(=O)c1ccc(Cl)c(Cl)c1)C(C)CC
Product: CCC(C)N(C(=O)c1cccc(Cl)c1)C(C)CC

Procedure:
3-bromo-N,N-di-sec.butyl-benzamide; 3,5-dichloro-N,N-di-sec.butyl-benzamide; 3-bromo, 4-chloro-N,N-di-sec.butyl-benzamide; 3,4-dichloro-N,N-di-sec.butylbenzamide; 3,4-dichloro-N-sec.butyl-N-n-butyl-benzamide; 2,4-dichloro-N,N-di-sec.butyl-benzamide; 2,6-dichloro-N,N-di-sec.butylbenzamide; N,N-di-sec.butyl-amides from a mixture of mono-chlorobenzoic acids (about m.chloro = 83%; o.chloro = 15%; p.chloro = 2%); N,N-di-sec.butylamides from a mixture of trichlorobenzoic acids (about 2,3,6-trichloro = 75%, 2,3,5-trichloro = 25%); 3-iodo-N,N-di-sec.butyl-benzamide; 3-methyl-N,N-di-sec.butyl-benzamide; and 2,3,5-trichloro-N,N-di-sec.butyl-benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)(C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 2-amino-2-methyl-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+]539.2447, observed 539.2449.
Reaction SMILES: [NH:1]([C:27]([O:29][CH2:30][CH:31]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C@H:2]([C:24]([OH:26])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:45]>CO.C1C=CC=CC=1>[NH:1]([C:27]([O:29][CH2:30][CH:31]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C@H:2]([C:24]([O:26][CH3:45])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
To a stirred solution of Fmoc-L-Cys(Trt)-OH (2.34 g, 4.00 mmol) in methanol (4.0 mL) and benzene (16 mL) was added TMS-diazomethane (2.40 mL, 4.80 mmol). After 1 hour, the mixture was concentrated in vacuo to afford Fmoc-L-Cys(Trt)-OMe which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:68]([OH:80])[C@@H:69]([OH:79])[C@@H:70]([OH:78])[C@H:71]([OH:77])[C@@H:72]([NH2:76])[C:73]([OH:75])=[O:74]>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:76][C@@H:72]([C:73]([OH:75])=[O:74])[C@@H:71]([OH:77])[C@H:70]([OH:78])[C@H:69]([OH:79])[CH2:68][OH:80])=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: N[C@@H](C(=O)O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](C(=O)O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 1 h
Yield: 15.1 %

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.025 g, 0.046 mmol) was dissolved in DMSO (2 ml) at 30° C. N-Methylmorpholine (0.014 g, 0.139 mmol) and TBTU (0.018 g, 0.056 mmol) were added. After 1 h, D-glucosaminic acid (0.018 g, 0.092 mmol) and tetrabutylammoniumbromide (0.001 g, 0.005 mmol) were added. The mixture was stirred for 15 minutes. Additional TBTU (18 mg, 0.056 mmol) was added. After 30 minutes, approximately 30% amide formation had occurred. The reaction was quenched by the addition of 0.1M NH4OAc buffer (2 ml). The intermediate ketone was purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M NH4OAc buffer and freeze-dried. MeOH (3 ml) and NABH4 (0.005 g, 0.139 mmol) were added. After 5 minutes, the reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml). Concentration of the mixture and purification by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M NH4OAc buffer gave the title compound (0.005 g, 16%) as a colourless solid. M/z: 718.0 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 2.82-2.94 (m, 2H), 3.34-3.56 (m, 4H), 3.76-3.80 (m, 2H), 3.87-3.90 (m, 1H), 4.07-4.11 (m, 1H), 4.27-4.32 (m, 1H), 4.52 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.05 (m, 1H), 6.97-7.39 (m, 12H), 7.63-7.70 (m, 1H), 8.28-8.35 (m, 1H).