Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:29])=O)C=CC=CC=1>CN(C=O)C>[NH2:29][N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C:13]1=[O:17]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
4-(Benzyloxycarbonyl)-2-piperazinone (4.685 g) was dissolved in DMF (170 ml) and combined with sodium hydride (800 mg, in oil) with cooling on ice. After stirring at room temperature for 30 minutes, O-diphenylphosphinyl hydroxylamine (4.896 g) was added and the mixture was stirred at 50° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was combined with aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried and concentrated to obtain the title compound 1-amino-4-benzyloxycarbonyl-2-piperazinone (4.8 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(NC3CCOCC3)nc2)o1
Yield: 49 %

Procedure:
As described for example 136b, 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) was converted using 4-aminotetrahydropyran instead of morpholine to the title compound (117 mg, 49%) which was obtained as a light yellow solid. MS: m/e=404.4 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH3:31])=[C:6]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:7]([O:23][CH3:24])=[C:8]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:9]=1.[CH2:32]=O>>[Cl:3][C:4]1[C:5]([CH3:31])=[C:6]([CH:25]2[CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30]2)[C:7]([O:23][CH3:24])=[C:8]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:9]=1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CCNCC1
Reactant: C=O
Agent: Cl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CCN(C)CC1

Procedure:
This compound was prepared according to the procedure of Example 139 step 7, using of 1-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride and formaldehyde as the starting materials. The product was isolated as a racemic mixture. LCMS calculated for C22H30ClN6O (M+H)+: m/z=429.2; Found: 429.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(Cl)Cl.[Pd]>[O:14]1[C:13]2([CH2:18][CH2:19][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[O:17][CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A mixture of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (Synthesis, 606, 1981) (3.5 g, 13.3 mmol) and 10% Pd/C (0.5 g) in 100 mL of ethanol/methylene chloride (2:1) was pressurized with 30 psi hydrogen and shaken over 1 hours. The catalyst was then removed by filtering through a short pad of silica gel to give the title compound (2.8 g, 90%) as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.85–2.00 (m, 4 H), 3.00–3.10 (m, 4 H), 3.93 (s, 4 H), 6.60 (d, J=6.0 Hz, 2 H), 6.80 (d, J=6.0 Hz, 2 H); MS (ES) m/z: 235.2 (MH+); HRMS Calcd. for C13H18N2O2: 234.1380. Found: 234.1371.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].FC(F)(F)S(O[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])(=O)=O.CC1C=CC=C(C)N=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH2:11][O:12][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc([N+](=O)[O-])c(F)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a 3-L round-bottomed flask was added (3-fluoro-4-nitrophenyl)methanol (4.7 g, 27.5 mmol) and DCM (47 mL). To the mixture was added triisopropylsilyl trifluoromethanesulfonate (9.26 g, 30.2 mmol) and 2,6-dimethylpyridine (3.53 g, 33.0 mmol). The resulting mixture was stirred for 3 hours at RT, and washed with NH4Cl (5-250 mL) and H2O (5-250 mL). The organic layer was collected and dried over sodium sulfate and concentrated to afford (3-fluoro-4-nitrobenzyloxy)triisopropylsilane (8.9 g, 99% yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([OH:11])=O.[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:9]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:13])[F:12])=[O:11])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cnccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 4-trifluoromethylpyridine-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (69% yield). 1H NMR (300 MHz, CDCl3) δ 8.87, 8.69, 8.05, 7.82, 7.62, 7.00, 4.10-3.69, 3.51-3.44, 3.38-3.35, 1.75-1.61, 1.52-1.45, 0.90. MS (ES+) m/z 451.3 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1)[CH2:11][CH3:12]>C(Cl)(Cl)Cl>[Br:1][C:19]1[N:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:21]2[C:17]([N:18]=1)=[C:16]([NH2:29])[N:15]=[C:14]([O:13][C@@H:10]([CH3:9])[CH2:11][CH3:12])[N:22]=2
Reactant: CC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
N-Bromosuccinimide (1.182 g, 6.64 mmol) was added portionwise to a solution of 2-{[(1S)-1-methylpropyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.935 g, 6.64 mmol) in chloroform (50 ml) at 0-5° C. The resulting green solution was stirred at 0-5° C. for 1 hour during which time it turned red and the mixture was then allowed to warm to room temperature and stirred overnight. The resulting green solution was washed with water (2×20 ml), separated using a hydrophobic frit and concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (100 g cartridge) using a Flashmaster II apparatus and a 0-100% ethyl acetate-cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (1.79 g).
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)CC(OC(C)=O)C(Cl)(Cl)Cl
Yield: 91 %

Procedure:
A solution of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene (65 g) in pyridine (100 ml) was heated with acetic anhydride (65 ml) at 100° C. for 3 hours. The reaction mixture was poured into water (600 ml) and the resulting solution extracted with ether (3×200 ml). The combined other phases were dried over MgSO4 and the ether was evaporated. Distillation and re-distillation yielded 71.4 g (91%) of 1,1,1-trichloro-2-acetoxy-4-methyl-4-pentene. B.p. 92°-96° C./11 mm Hg.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Yield: 55 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (1.92 g, 6.97 mmol) and 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline from the previous step (2.0 g, 6.97 mmol) were reacted in the manner described in Example 16C to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (2.00 g, 3.8 mmol, 55%). 1H NMR (300 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.98 (s, 1H), 8.54 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.38 (t, 1H), 7.33 (s, 1H), 7.26 (d, 1H), 6.96 (d, 1H), 6.47 (s, 1H), 4.27 (t, 2H), 3.98 (s, 3H), 3.82 (t, 2H), 2.30-2.24 (m, 2H), 1.29 (s, 9H); LC-MS (ESI) m/z 526 (M+H)+.
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[C:6]([O:10][CH3:11])(=[O:9])[C:7]#[CH:8].[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH2:24]/[C:25]/2=[CH:26]/[CH3:27])[CH2:17]1)(=[O:14])[CH3:13].O>C(Cl)Cl>[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH:24]=[C:25]2[C@H:26]([CH3:27])/[CH:8]=[CH:7]/[C:6]([O:10][CH3:11])=[O:9])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Reactant: C#CC(=O)OC
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)/C=C/[C@@H](C)C1=CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
Ethyl aluminum dichloride (104.5 mL, 192 mmol, 1.8 M in toluene) was added to a solution of methyl propiolate (13.58 mL, 153 mmol) in DCM (100 mL) at 0° C. under inert atmosphere. The resulting solution was stirred for 15 min and then compound 1.6a (22 g, 64.3 mmol) was added. After stirring for an additional 20 min at 0° C., the temperature was raised to 25° C. and held there for a further 18 h. At this point the reaction was determined to be complete by TLC, and the mixture was poured into cold (0° C.) water (200 mL). The phases were separated and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined and washed sequentially with water (200 mL) and saturated brine solution (100 mL). It was then dried over anhydrous Na2SO4 (40 g) and filtered. The filtrate was concentrated under vacuum and the resulting solid was purified by slurring in methanol (280 mL) to provide compound 1.7a (17.5 g 68%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])[S:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([C:19]#[N:20])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2N=C(C(O)=O)SC=2C2C=CC(F)=C(C#N)C=2)C=CC=1[F:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])[S:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([C:19]#[N:20])[CH:18]=2)[CH:5]=[CH:6][C:7]=1[F:37]
Reactant: N#Cc1cc(-c2sc(C(=O)N3CNC(=O)C3)nc2-c2cccc(Cl)c2)ccc1F
Reactant: N#Cc1cc(-c2sc(C(=O)O)nc2-c2ccc(F)c(Cl)c2)ccc1F
Product: N#Cc1cc(-c2sc(C(=O)N3CNC(=O)C3)nc2-c2ccc(F)c(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 5 starting with the compound from Example 15A. 17.3 mg (35% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)Oc1cc(Cl)cc(Cl)c1
Reactant: C=C(Br)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Yield: 88.2 %

Procedure:
In a solution of 25.0 g of 3,5-dichlorophenyl boric acid in 200 ml of tetrahydrofuran and 100 ml of water, 27.5 g of 2-bromo-3,3,3-trifluoropropene, 38.0 g of potassium carbonate and 1.84 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 3 hours. After the completion of the reaction and cooling to room temperature, 500 ml of ice water was added, and extracted with ethyl acetate (500 ml×1). The organic phase was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane, and 25.7 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[C:24]([O:25][CH3:26])=[CH:23][C:9]([C:10]([C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[O:11])=[C:8]([CH3:27])[CH:7]=1.O>C1(C)C=CC=CC=1>[CH3:4][O:5][C:6]1[C:24]([O:25][CH3:26])=[CH:23][C:9]([C:10]([C:12]2[C:13]([O:2][CH3:1])=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[O:11])=[C:8]([CH3:27])[CH:7]=1
Reactant: C[O-]
Reactant: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2Cl)cc1OC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2OC)cc1OC
Yield: 100.5 %

Procedure:
0.9 g (16 mmol) of sodium methoxide was added to a solution having 1.5 g (4.2 mmol) of 3-(4,5-dimethoxy-2-methylbenzoyl)-2-chloro-4-trifluoromethylpyridine synthesized in accordance with a process in Synthesis Example 1 dissolved in 20 ml of toluene, followed by stirring under reflux by heating for 4 hours. The mixture was cooled, and then 20 ml of water was added thereto to terminate the reaction, the aqueous solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and subjected to filtration by using a silica gel cake. The solvent was distilled off under reduced pressure to obtain 1.5 g (yield 99%) of 3-(4,5-dimethoxy-2-methylbenzoyl)-2-methoxy-4-trifluoromethylpyridine (compound No. 32; m.p. 125-127° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[N:7][CH:8]=1)[CH3:2].[N+](C1C=CC=CC=1C=CC1C=CC=CN=1)([O-])=O>>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: CCc1ccc(C=Cc2ccccc2[N+](=O)[O-])nc1
Agent: O=[N+]([O-])c1ccccc1C=Cc1ccccn1
Product: CCc1ccc(CCc2ccccc2N)nc1

Procedure:
Reduction of 5-ethyl-2-(o-nitrostyryl)pyridine as described in Example 2 (a) for 2-(o-nitrostyryl)pyridine provides 2-(o-aminophenethyl)-5-ethylpyridine having a melting point of 52.5°-53.5° C. (corr.) when crystallized from isopropyl ether-heptane.
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:21]3[C:26]([N:27]=[C:28]4[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=1.ClC(OCC)=O.O[N:55]1[C:59](=[O:60])[CH2:58][CH2:57][C:56]1=[O:61]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][C:45]([O:47][N:55]3[C:59](=[O:60])[CH2:58][CH2:57][C:56]3=[O:61])=[O:46])=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:33]3[C:28]([N:27]=[C:26]4[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]4)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:19])=[CH:13][CH:12]=1
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)O)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Agent: Br
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
1.41 ml of triethylamine are added to 3.1 g of (4) in 50 ml of tetrahydrofuran, the mixture is cooled to -20° C., and 0.474 ml of ethyl chloroformate is added. After stirring for 20 min, 575 mg of N-hydroxysuccinimide are added, and the mixture is stirred at -20° C. for 3 hours and left to reach room temperature overnight while stirring. The precipitate is filtered off with suction, the filtrate is concentrated, the residue is taken up in dichloromethane or ethyl acetate, and the resulting solution is washed with water, NaHCO3 solution and water and dried over MgSO4. The organic phase is concentrated, and the residue is recrystallized from toluene.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=1)[C:8]([O-:10])=O)([O-:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>N1C=CC=CC=1.C1COCC1>[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=1)[C:8]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:10])([O-:4])=[O:3]
Reactant: O=C([O-])c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1
Reactant: NCCCCCC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(CCCCCNC(=O)c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1)OCc1ccccc1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
14.6 g of 3-nitro-5-sulfobenzoic acid monosodium salt were dissolved in 300 ml of pyridine and stirred for 2 hours, after which 2.2 ml of oxalyl chloride were added dropwise. After 1 hour, 16.6 g of benzyl ε-aminocaproate as a solution in 100 ml of THF were added dropwise and the mixture was stirred overnight. The mixture was concentrated on a rotary evaporator and then stirred with 100 g of strongly acid ion exchanger in 100 ml water for 50 hours. The mixture was filtered and washed with water, and the filtrate was concentrated. The residue was dissolved in 30% methanol/water, treated with 21 g of tetraethylammonium bromide and adjusted to pH 6.5 with sodium hydroxide solution. The resulting solution was chromatographed on 500 g of silanized silica gel (RP2) with 30% methanol. 8.6 g of benzyl ε-(3-nitro-5-sulfobenzoylamino)caproate were obtained in the form of the tetraethylammonium salt, which was stirred with 100 g of cation exchanger in water, filtered off and washed with water. The filtrate was concentrated and gave the corresponding free sulfonic acid. TLC (silica gel: HOAc/EtOAc=20%) Rf=0.7 (educt=0.4); TLC (silica gel: NH3/EtOH=1%) Rf=0.8 (educt=0.7); TLC (RP18: EtOH/Et4N+ (0.01M) phosphate buffer (0.1M; pH 6.5)=60% Rf=0.4 (educt=0.8). HPLC (RP18: MeCN/Et4N+ (0.01M) phosphate buffer (0.1M; pH 6.5)=30%) tR =5.9 min. (educt=1.3 min). 1.32 g of benzyl 6-(3-nitro-5-sulfobenzoylamino)hexanoate were dissolved in 30 ml ethanol/water=60%, 100 mg of Pd/C 10% were added and the mixture was hydrogenated while stirring (magnetic stirrer). The total absorption of hydrogen (1.5 hours) was 235 ml. TLC control showed that starting material was no longer present. In the TLC the amine is present practically at the start. The catalyst was filtered off and the solution was concentrated to dryness on a rotary evaporator. The IR control of the substance showed the complete absence of the original nitro group and of the benzyl group. The resulting 6-(3-amino-5-sulfobenzoylamino)hexanoic acid was used directly for the preparation of the azide.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][OH:5].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:5][CH2:4][CH:3]([NH:6][C:7]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[C:2]([F:17])([F:18])[F:1])(=[O:29])=[O:28]
Reactant: O=C(NC(CO)C(F)(F)F)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(NC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of benzyl (1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate (300 g, 1.14 mol) in dichloromethane (2500 mL) were added triethylamine (128 g, 1.27 mol) and methanesulfonylchloride (144 g, 1.26 mol). After 2 hours, the reaction mixture was quenched with water (1000 mL) and extracted with dichloromethane (3×300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2-{[(benzyloxy)carbonyl]amino}-3,3,3-trifluoropropyl methanesulfonate. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](Cl)=[O:31].C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])[C@H:13]([CH3:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1C(=O)c1ccccn1
Temperature: 85 °C
Yield: 45.5 %

Procedure:
To a solution of (3R)-1-[(4-chlorophenyl)sulfonyl]-3-methylpiperazine (0.15 g, 0.55 mmol) in dry acetonitrile (5 mL) was added potassium carbonate (90 mg, 0.66 mmol) and 2-pyridinecarbonyl chloride (106 mg, 0.60 mmol) and the reaction mixture heated at 85° C. for 24 h. To the mixture was added ethyl acetate (30 mL) and the organic phase washed with 10% aqueous sodium bicarbonate (50 mL) before it was dried (MgSO4), filtered and the solvent evaporated. The crude product was purified by Biotage SP4 (12+M silica column) eluting 0-4% MeOH in DCM to give the title compound as an off-white solid (95 mg).
Reaction SMILES: CC([O-])(C)C.[K+].[CH:7]([O:9][CH3:10])=[O:8].[N:11]1[CH:16]=[C:15]([CH2:17][CH2:18][C:19](OC)=[O:20])[CH:14]=[N:13][CH:12]=1>C1COCC1>[CH:19]([CH:18]([CH2:17][C:15]1[CH:16]=[N:11][CH:12]=[N:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:20]
Reactant: COC(=O)CCc1cncnc1
Reactant: COC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C=O)Cc1cncnc1
Temperature: 0 °C
Yield: 60.6 %

Procedure:
To an ice-cooled solution of KOtBu (43.0 g, 384 mmol) in anhydrous THF (300 ml) stirred under nitrogen was added methyl formate (18.43 g, 307 mmol) and methyl 3-(pyrimidin-5-yl)propanoate (25.5 g, 153 mmol) in anhydrous THF (10 mL) dropwise for 1 h. The mixture was stirred for 3 hr. The solvent was removed, and the residue was dissolved in water (150 mL). The aqueous phase was washed with ether (200 mL×3), and then to the aqueous solution was added AcOH to adjust the pH=5. The solid was collected and dried to give the target compound. The filtrate was extracted with DCM (200 mL×2), and the combined organic phase was dried over sodium sulfate, filtered and concentrated. The two crops were combined to give the title product as a yellow solid (18 g, 57.4% yield). LCMS: rt=0.96 min, [M+H+]=195