Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH3:17])[CH2:16][C:4]2([CH2:7][CH:6]([NH:8]C(=O)OC(C)(C)C)[CH2:5]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:6]1[CH2:7][C:4]2([CH2:16][C:2]([CH3:17])([OH:1])[CH2:3]2)[CH2:5]1
Reactant: CC1(O)CC2(CC(NC(=O)OC(C)(C)C)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CC2(CC(N)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
To a solution of tert-butyl (6-hydroxy-6-methylspiro[3.3]heptan-2-yl)carbamate (760 mg, crude) in DCM (7 mL) was added TFA (3.5 mL) at ˜0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the crude product (500 mg, crude) as a brown oil, which was used in the next step without further purification. MS (ESI) m/z 142.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](=O)[CH3:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:4](=[N:11][C:27]([CH3:28])=[C:26]([C:21]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=3)[N:9]=2)[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2nc(N)nc(N)c2nc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A stirred solution of 1.0 gram (0.007 mole) of 2,4,6-triamino-5nitrosopyrimidine and 2.7 grams (0.020 mole) of potassium carbonate in 30 mL of N,N-dimethylformamide was heated to 95°-100° C., and 2.0 grams (0.010 mole) of (3,4-dichlorophenyl)acetone was added in one portion. Upon completion of addition, the reaction mixture was allowed to cool to ambient temperature, where it was allowed to stir for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure. The residue was triturated with 250 mL of water, and the remaining solid was collected by filtration. The solid was further triturated with 50 mL of 20% methanol in methylene chloride. The remaining solid was collected by filtration, yielding 0.5 gram of 2,4-diamino-6-(3,4-dichlorophenyl)-7-methylpteridine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([CH2:9][CH:10]([OH:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(Cl)Cl.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24](=[O:25])([O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)[O:16][CH:10]([CH2:9][N:6]1[C:5]2[CH:17]=[C:18]([Cl:19])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=[CH:7]1)[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(O)Cn1cnc2cc(Cl)c(Cl)cc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)CC(Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
The product from step B (445 mg, 1.48 mmol) was dissolved in pyridine (4 mL) and CH2Cl2 (2 mL) and treated with 4-nitrophenyl chloroformate (328 mg, 1.62 mmol). The reaction vessel was sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was diluted with ethyl acetate and extracted with water twice, 1 M aqueous HCl 3 times, water once and saturated aqueous NaCl once. The organics were then dried over MgSO4 and the solvent was removed. The residue was treated with ether, heated to reflux and put in the refrigerator overnight at −10° C. The resulting solid was collected, washed with cold ether and dried to afford 531 mg (77%) of the product as a slightly colored solid: 1H NMR (DMSO, 400 MHz) δ 1.01 (s, 9H), 1.66-1.79 (m, 2H), 4.62 (dd, 1H, J=8.2, J2=14.9), 4.70 (dd, 1H, J=3.4, J2=14.9), 5.23-5.32 (m, 1H), 7.11-7.17 (m, 2H), 8.03 (s, 1H), 8.21 (s, 1H), 8.28-8.33 (m, 2H), 8.51 (s, 1H); HPLC-MS calcd. for C21H22Cl2N4O2 (M+H+) 466.1, found 466.3.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[C:20]([C:28]1[C:32]2[CH:33]=[C:34]([OH:37])[CH:35]=[CH:36][C:31]=2[O:30][CH:29]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:37][C:34]1[CH:35]=[CH:36][C:31]2[O:30][CH:29]=[C:28]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:32]=2[CH:33]=1)(=[O:3])[CH3:2]
Reactant: O=C(c1ccccc1)c1coc2ccc(O)cc12
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc2occ(C(=O)c3ccccc3)c2c1
Yield: 20 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 3-benzoyl-5-hydroxybenzofuran, the desired product is obtained in the form of a white solid with a yield of 20%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH2:14].O>CCO>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([NH:14][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Solvent: O
Solvent: CCO
Product: CNc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 83 %

Procedure:
1,3,5-Trifluoro-2-nitrobenzene (3.0 g, 16.90 mmol) was dissolved in EtOH (29.7 mL) and Methylamine 40% in Water (1.44 mL, 17.80 mmol) was added dropwise at 0° C. The color went from bright yellow to an orange precipitate within 20 min After 4 h at RT. 0.66 mL of Methylamine was added (9 mmol). To complete the reaction, an additional 0.26 ml (3.6 mmol) of Methylamine was added after 2 h at RT. The completion was achieved within 20 min Water (75 mL) was added to the reaction mixture and the solid was isolated by filtration, washed with water (2*10 mL) and dried over high vacuum to afford 2.64 g of 3,5-difluoro-N-methyl-2-nitrobenzenamine (Yield: 83%) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].ClCCCl.[N+:13]([O-:16])([OH:15])=[O:14]>O>[N+:13]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])([O-:15])=[O:14].[N+:13]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][CH:5]=1)([O-:16])=[O:14]
Reactant: Cc1ccccc1C
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1C
Product: Cc1cccc([N+](=O)[O-])c1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
A 250 mL three-necked round bottom flask fitted with reverse dean-stark apparatus was charged with 10.62 g o-xylene (0.1 mol), 60 mL 1,2 dichloro ethane, and 2.12 g of catalyst as prepared in example 5. The reaction flask was flushed with nitrogen. The reaction mixture was refluxed at 110° C. for 1 h followed by the dropwise addition of 11.35 mL (0.2 mol) 70% HNO3. The water formed during the reaction was removed using the reverse dean-stark apparatus. The reaction was carried out for 16 h. The reaction was monitored by GC analysis. In this reaction 94.9% conversion of o-xylene was obtained with 48.0% and 51.1% 3-nitro o-xylene (3NOx) and 4-nitro o-xylene (4NOx), respectively. Other unidentified products were 0.9%.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][C:19](O)=O)=[CH:16][C:3]1=2.S(Cl)([Cl:24])=O>CN(C)C=O.C(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][Cl:24])=[CH:16][C:3]1=2
Reactant: O=C(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1c2ccccc2COc2ccc(CCCCl)cc21
Reaction time: 8 h

Procedure:
To a flask was added a few drops of N,N-dimethylformamide and 32.25 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propanoic acid in 500 ml of dry methylene chloride. The chilled stirring suspension was treated dropwise over several minutes with 11.0 ml of thionyl chloride. The suspension was warmed intermittently on a steam bath until all gas evolution ceased. The resulting solution was then allowed to reflux of 15 minutes and was allowed to stand at room temperature under nitrogen atmosphere overnight. The solution was concentrated in vacuo to an oil. The oil was dissolved in 500 ml of methylene chloride and was treated with another 11.0 ml of thionyl chloride. The solution was allowed to reflux for 3 hours and was again concentrated to an oil in vacuo. The oil still contained a significant amount of crystalline impurity, which was filtered away after triturating with a hexane/ether solution the supernatant was concentrated to an oil in vacuo which solidified overnight in refrigeration. The purified solids were recrystallized from three portions of cyclohexene to give 25.03 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propanyl chloride, m.p. 69°-72° C.
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:27]([NH:29]N)=[O:28])[CH2:25][OH:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4].Cl.C(ON=O)(C)(C)C.N[C@H:47]([C:51]([NH:53][C@H:54]([C:62]([NH:64][C@H:65]([C:69]([NH:71][C@H:72]([C:77]([OH:79])=[O:78])[CH2:73][CH:74]([CH3:76])[CH3:75])=[O:70])[CH:66]([CH3:68])[CH3:67])=[O:63])[CH2:55][S:56][CH2:57][NH:58][C:59]([CH3:61])=[O:60])=[O:52])[C@@H:48]([CH3:50])[OH:49]>CN(C)C=O.O1CCOCC1.C(N(CC)CC)C>[NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:27]([NH:29][C@H:47]([C:51]([NH:53][C@H:54]([C:62]([NH:64][C@H:65]([C:69]([NH:71][C@H:72]([C:77]([OH:79])=[O:78])[CH2:73][CH:74]([CH3:76])[CH3:75])=[O:70])[CH:66]([CH3:68])[CH3:67])=[O:63])[CH2:55][S:56][CH2:57][NH:58][C:59]([CH3:61])=[O:60])=[O:52])[C@@H:48]([CH3:50])[OH:49])=[O:28])[CH2:25][OH:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)NN
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)C
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)NCSC[C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)C
Reaction time: 0.17 h

Procedure:
13.6 g of Boc-Ser-Asn-Leu-Ser-NHNH2 are dissolved in 150 ml of dimethylformamide, cooled to -20°, then 40 ml of an anhydrous solution of HCl (2N) in dioxane are added, followed by 3.6 ml of tert.-butylnitrite. After 10 minutes at -20°, 16 ml of triethylamine and 13.0 g of H-Thr-Cys(Acm)-Val-Leu-OH are added, and the solution stirred for 16 hours at 25°. The mixture is filtered, the filtrate is evaporated to dryness, the residue is suspended repeatedly in 1N acetic acid and in water, filtered and dried to give the title compound.
Reaction SMILES: OCCCCCCCCCCCCCCC[C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CCCCCCCCCO)C)=[O:18].N1C=CC=CC=1.C(OCCCCCCCCCCCCCCCC([Cl:82])=O)(=O)CCCCCCCCCCCCCCC>C1COCC1>[Cl:82][C:17]([O:19][CH2:20][O:22][C:23](=[O:40])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:18]
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cl)OCOC(=O)c1ccccc1
Reaction time: 2 h
Yield: 145.8 %

Procedure:
Ethylidene bis (16-hydroxyhexadecanoate) (4.38 g, 7.67 mmol) was dissolved in THF (80 ml) and pyridine (0.61 g, 7.71 mmol) was added. 16-hexadecanoyloxyhexadecanoyl chloride (4.18 g, 7.90 mmol) was dissolved in THF (20 ml) and added dropwise. After 3 days at room temperature the mixture was filtered and the filtrate was left at -20° C. for 2 hours. The precipitated product was filtered and purified by flash chromatography (silicagel, chloroform) to give 2.4 g (29%) of the title compound. 1H NMR (300 MHz, CDCl3): δ0.85 (t, 3H, CH3), 1.2-1.4 (s, 90H, --CH2 --), 1.45 (d, 3H, --O--CH(CH3)--O--), 1.5-1.7 (m, 14H, --CH2 --), 2.25 (m, 8H, --CH2 --C(O)--O--), 3.60 (t, 2H, --CH2 --OH), 4.05 (t, 4H, --C(O)--O--CH2 --), 6.85 (q, 1H, --O--CH(CH3)--O--). 13C NMR (75 MHz, CDCl3): δ13.7, 19.1, 22.2, 24.2, 24.6, 25.2, 25.5, 28.2, 28.5, 28.7, 28.8, 29.0, 29.2, 31.5, 32.3, 33.7, 34.0, 62.5, 64.0, 88.0, 171.5, 173.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2.Cl[CH2:29][CH2:30][CH2:31][OH:32].Cl>>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:19]=[C:18]([N:20]4[CH2:26][CH2:25][CH2:24][N:23]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:22][CH2:21]4)[CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: OCCCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCNCC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCN(CCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS301 starting from 66 mg (0.18 mmol) of 1-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-pyridin-2-yl]-1,4-diazepane and 18 μl of 3-chloro-1-propanol. The product is the hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2([CH2:24][C:25]([O:27][CH3:28])=[O:26])[NH:17]S(C(C)(C)C)=O.Cl.O1CCOCC1>CO>[NH2:17][C:5]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:4]2[C:14](=[CH:15][CH:16]=[C:2]([Br:1])[CH:3]=2)[O:13][C:7]2([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:6]1
Reactant: COC(=O)CC1(NS(=O)C(C)(C)C)CC2(CCCCC2)Oc2ccc(Br)cc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CC1(N)CC2(CCCCC2)Oc2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)spiro[chroman-2,1′-cyclohexane]-4-yl)acetate (200 mg, 0.42 mmol) in MeOH (2 mL) was added 4 N HCl/1,4-dioxane (2 mL). After stirring for 30 minutes, the mixture was concentrated. The residue was dissolved in MeOH (1 mL) stirring for 5 minutes and evaporated again to afford methyl 2-(4-amino-6-bromospiro[chroman-2,1′-cyclohexane]-4-yl)acetate (140 mg, 90%). 1H NMR (CDCl3): 1.22-1.38 (m, 1H), 1.39-1.52 (m, 6H), 1.72-1.88 (m, 3H), 1.93-2.02 (d, 2H), 2.13-2.24 (t, 1H), 2.59 (d, 1H), 2.86 (d, 1H), 3.65 (s, 3H), 6.74 (d, 1H), 7.24 (s, 1H), 7.52 (s. 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)[N:17]=1)[C:12]([OH:14])=O.[O-:25][N+:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[C:28]([C@H:36]([NH2:38])[CH3:37])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)[N:17]=1)[C:12]([NH:38][C@@H:36]([C:28]1[CH:27]=[N+:26]([O-:25])[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=1)[CH3:37])=[O:14]
Reactant: Cc1ncc(-c2cc(C(=O)O)cc(-c3ccc(F)cc3F)n2)cn1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(-c2cc(C(=O)N[C@H](C)c3ccc(C(F)(F)F)[n+]([O-])c3)cc(-c3ccc(F)cc3F)n2)cn1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 2-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)isonicotinic acid (21.3 mg, 0.05 mmol) in DMF (0.5 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (27.0 mg, 0.07 mmol), HATU (0.5 M in DMF; 0.16 mL, 0.08 mmol) and diisopropylethylamine (65 μL, 0.37 mmol). The mixture was stirred at ambient temperature. After 25 min, the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound, which was converted to hydrochloride salt using 2.0 M HCl in ether (31 mg). HRMS 516.1453 (M+1). 1H NMR (400 MHz, CDCl3): δ 9.34 (s, 2H), 8.42 (s, 1H), 8.24-8.15 (m, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.11-7.04 (m, 1H), 6.97 (t, J=9.8 Hz, 1H), 6.85 (d, J=7.0 Hz, 1H), 5.37-5.30 (m, 1H), 2.83 (s, 3H), 1.69 (d, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(N(CC)CC)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:9]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:10])[CH:12]=1
Reactant: CC(Nc1ccc(Cl)cc1)c1cccnc1
Reactant: CCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)N(c1ccc(Cl)cc1)C(C)c1cccnc1

Procedure:
To a stirred solution of 7.5 g. of N-(4-chlorophenyl)-[1-(3-pyridyl)ethyl]amine in 200 ml. of toluene containing 5.0 g. of triethylamine were added dropwise over thirty minutes 4.5 g. of hexanoyl chloride. Following the complete addition, the solid precipitate which had formed was removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure. The product thus formed was chromatographed over a silica gel column to provide, after removal of the solvent from the appropriate factions, 650 mg. of N-[1-(3-pyridyl)ethyl]-N-(4-chlorophenyl)hexanamide. Oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:6][CH:7]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CN(CCN1CCCC1)c1ccc(I)cn1
Product: CN(CCN1CCCC1)c1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1

Procedure:
Prepared according to general working method I from (5-iodo-pyridin-2-yl)-methyl-(2-pyrrolidin-1-yl-ethyl)-amine (100 mg, 0.30 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (65 mg, 0.30 mmol).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]B(O)O)=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)[CH3:6].O.OO.S([O-])(O)=O.[Na+]>C1COCC1>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:9]=1)[CH3:6]
Reactant: CCOc1ccc(OB(O)O)c(C(F)(F)F)c1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOc1ccc(O)c(C(F)(F)F)c1
Temperature: 0 °C
Yield: 97.7 %

Procedure:
Acetic acid (21.3 g) was added to a mixture of THF (200 mL) and Compound (d) (8.28 g) at room temperature, and the mixture was stirred at 0° C. under a nitrogen atmosphere. After adding 30% hydrogen peroxide water (40.1 g) dropwise, the resulting reaction mixture was carefully heated and stirred at 50° C. for 4 hours. Saturated aqueous sodium hydrogen sulfite (200 mL) was then slowly added dropwise at 0° C., and the reaction mixture was extracted three times with ether. The organic layers were combined, washed with aqueous saturated sodium hydrogen sulfite, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.67 g of Compound (e).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH:20]1([CH2:25][NH:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)C>ClCCl.CO>[ClH:1].[CH:20]1([CH2:25][NH:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C1CCC(CNCCC2CCCNC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: O=C1Nc2cccnc2N(C(=O)N2CCCC(CCNCC3CCCC3)C2)c2ccccc21
Yield: 54 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-[(cyclopentyl)methylamino]ethyl]piperidine in a yield of 54% of theory. Colourless crystals, m.p. 244°-246° C. (ethanol), Rf 0.31 (Merck DC ready made TLC plates, silica gel 60 F254 ; eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.CC[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23].[CH3:26][C:27]#N>>[N:21]1[C:22]2[C:23](=[CH:13][CH:15]=[CH:16][CH:17]=2)[C:26]([CH2:27][O:8][C:9](=[O:10])[O:11][N:12]2[C:13](=[O:14])[CH2:15][CH2:16][C:17]2=[O:18])=[CH:25][CH:24]=1
Reactant: CCN(CC)CC
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC#N
Product: O=C(OCc1ccnc2ccccc12)ON1C(=O)CCC1=O
Yield: 58 %

Procedure:
The alcohol (50 mg, 0.31 mmol), N,N′-disuccinimidyl carbonate (1128 mg, 0.5 mmol), and Et3N (63 mg, 0.63 mmol) in CH3CN (2 mL) were stirred for 12 hours. After dilution with EtOAc (10 mL) and washing several times with brine (3×10 mL), the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain compound 31 (52 mg, 58%) as solid. M.P.: 94° C. 1H NMR (CDCl3, 400 MHz): δ 8.9 (d, 1H, J=4.4 Hz), 8.1 (d, 1H, J=8.5 Hz), 7.9 (d, 1H, J=8.3 Hz), 7.74 (m, 1H) 7.63 (m, 1H), 7.49 (d, 1H, J=4.3 Hz), 2.84 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([NH:29][C:30]([C:32]3[N:33]=[C:34]([CH2:37][N:38]4[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]4)[S:35][CH:36]=3)=[O:31])[CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[NH:46]1[CH:50]=[C:49]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[N:47]1.Cl.C(Cl)Cl>N1C=CC=CC=1>[CH3:45][C@H:40]1[O:41][C@@H:42]([CH3:44])[CH2:43][N:38]([CH2:37][C:34]2[S:35][CH:36]=[C:32]([C:30]([NH:29][C:12]3[CH:11]=[C:10]([C:4]4[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][S:51]([C:49]5[CH:50]=[N:46][NH:47][CH:48]=5)(=[O:53])=[O:52])[CH:3]=4)[CH:18]=[C:17]4[C:13]=3[CH:14]=[N:15][NH:16]4)=[O:31])[N:33]=2)[CH2:39]1
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1N
Reactant: O=S(=O)(Cl)c1cn[nH]c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{6-[5-Amino-6-(methyloxy)-3-pyridinyl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (65 mg) was dissolved in pyridine (2 ml) and 1H-pyrazole-4-sulfonyl chloride (25 mg) was added. The reaction was stirred at RT overnight. 2M HCl (aq) (12 ml) and DCM (12 ml) were added and the reaction was vigorously stirred. The solvent was passed through a hydrophobic frit then removed under nitrogen blow down. IPA (2 ml) and 2M NaOH (aq) (1 ml) were added and the reaction was stirred at RT. The reaction was evaporated to dryness and water (1 ml) and DCM (3 ml) were added, followed by 2M HCl (aq) (1 ml). A precipitate was observed. The mixture was evaporated to dryness. The residue was purified by MDAP using the following method: