Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:27][C:28]1[CH:29]=[C:30]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:39]2[CH2:38][CH2:37][N:36]([C:30]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([OH:27])[CH:29]=3)[CH2:41][CH2:40]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Reactant: COc1ccc(N2CCNCC2)cc1O
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(O)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-hydroxy-4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:33]([F:36])([F:35])[F:34])[C:17]=2[N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)[NH:12][CH:11]=1)=[O:8].C(O)(C(F)(F)F)=O.C(Cl)[Cl:45]>>[ClH:45].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:17]2[C:16]([C:33]([F:35])([F:36])[F:34])=[CH:15][N:14]=[C:13]3[NH:12][CH:11]=[C:10]([NH:9][C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:8])[C:18]=23)[CH2:20]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(C(F)(F)F)cnc3[nH]cc(NC(=O)c4cnccn4)c23)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(C(F)(F)F)cnc3[nH]cc(NC(=O)c4cnccn4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
(R)-tert-Butyl 1-(3-(pyrazine-2-carboxamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.120 g, 0.237 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness to give the crude product, which was purified C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-50% CH3CN/water gradient; 25 CV). The purified product was then dissolved in DCM (with minimal MeOH to aid solubility) and added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, dried and collected to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide hydrochloride (0.071 g, 62% yield). 1H NMR (400 MHz, D2O) δ 8.84 (s, 1H), 8.59-8.59 (m, 1H), 8.52-8.52 (m, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 3.62-3.54 (m, 1H), 3.37-3.33 (m, 1H), 3.00-2.92 (m, 3H), 2.04-2.01 (m, 1H), 1.85-1.72 (m, 1H), 1.71-1.66 (m, 1H), 1.50-1.40 (m, 1H); LCMS (APCI+) m/z 406 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[S:18]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1cnccn1
Product: CN(C)CCNC(=S)NCCNCc1cnccn1

Procedure:
By the procedure of Example 40 (a), treating N-(2-pyrazinylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate gives the title compound.
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)C)=[CH:19][CH:18]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:6](=[O:8])[CH:7]=1.[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O.C(O)(=O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:4]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:5][C:6](=[O:8])[C:7]([S:40][C:32]3[CH:33]=[C:34]([CH3:39])[C:35]([CH2:37][OH:38])=[CH:36][C:31]=3[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:2]([OH:1])[CH2:3]2)=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1ccc(CCC2(c3ccccc3)CC(O)=CC(=O)O2)cc1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(N)cc3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 0.23 g (0.65 mmol) of N-{4-[2-(4-hydroxy-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl)-ethyl]-phenyl}-acetamide (prepared in Example RR), 0.33 g (0.90 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.54 g (3.9 mmol) of K2CO3, and 5 mL of DMF. The solution was stirred overnight at room temperature and then poured into glacial acetic acid (5 mL) and EtOAc (20 mL). After standard work-up, the residue was triturated with Et2O, and the solids were filtered. The penultimate intermediate was dissolved in H2 0 (30 mL), 50% NaOH (4 mL), and MeOH (5 mL) and was refluxed for 18 hours. The mixture was cooled to room temperature, concentrated, and suspended in phosphate buffer (pH 7.5). Acidification to pH 6.8 with phosphoric acid was followed by extraction with CH2Cl2. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound, m.p. 218-221° C. 1H NMR (DMSO-d6) δ 1.44 (s, 9 H), 1.76 (s, 3 H), 2.05-2.22 (m, 3 H), 2.40 (m, 1 H), 3.40 (m, partially obscured by H2O, 2 H), 4.32 (s, 2 H), 4.90 (br s, 1 H), 6.17 (s, 1 H), 6.47 (d, 2 H), 6.75 (d, 2 H), 7.21 (s, 1 H), 7.38-7.43 (m, 5 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:26])[CH2:24][CH2:25][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: C=CC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reactant: C1COCCN1
Product: O=C(CCN1CCOCC1)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 105 °C

Procedure:
A mixture of 4-[4-(3-indolyl)piperidinomethyl]-2-acryloylaminothiazole (360 mg) and morpholine (870 mg) was heated at 105° C. After the reaction finished, excess morpholine was distilled off, and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1 V/V) to give 4-[4-(3-indolyl)piperidinomethyl]2-(3-morpholinopropionylamino)thiazole, which was treated with an ethanol solution of hydrogen chloride to give dihydrochloride thereof.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:19]1[N:23]=[N:22][C:21]([C:24]([F:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([OH:27])=O)=[N:20]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:35]([C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[C:39]=1[NH2:40])([CH3:37])[CH3:36].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:47][CH:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:38]([CH:35]([CH3:37])[CH3:36])[C:39]=1[NH:40][C:25](=[O:27])[C:24]([F:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]1[N:22]=[N:23][N:19]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:20]=1)[CH3:46]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCCCCCCCCCCCn1nnc(C(F)(C(=O)O)c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Oxalyl chloride (0.08 mL, 0.92 mmole) was added to a stirred solution of 2-dodecyl-α-fluoro-α-phenyl-2H-tetrazole-5-acetic acid (0.24 g, 0.61 mole) in 5 mL of CH2Cl2 at room temperature. The mixture was stirred 60 minutes, the one drop of DMF was added (immediate gas evolution). The solution was stirred overnight, concentrated (rotovap), toluene was added, and the solution concentrated again. The residue was dissolved in CH2Cl2 (3 mL) and added to a stirred solution of 2,6-diisopropylaniline (0.12 mL, 0.61 mole) and Et3N (0.14 mL, 1.0 mole) in CH2Cl2 (2 mL) cooled to 0° C. under dry nitrogen. After 20 minutes, the ice bath was removed and the solution allowed to warm to room temperature and stirred for 3 days. The mixture was then diluted with ethyl acetate (150 mL) and washed with dilute HCl (50 mL), bicarbonate (50 mL), brine (50 mL), and dried. Filtration and concentration afforded an oil which was flash chromatographed (silica gel, 10: 1 hexanes-ethyl acetate) to produce 150 mg of the title compound as an oil which solidified on standing.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:24][C:25]1[S:29][N:28]=[C:27]([CH3:30])[CH:26]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:37])=[C:4]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:5]=1)[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3c[nH]c4ccccc34)C(N)=O)ccc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3c[nH]c4ccccc34)C(N)=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-(1H-indol-3-yl)propanamide (100 mg, 0.240 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 1 h. HOAc (1 mL) was added. The mixture was purified by HPLC to give the titled compound (51 mg). MS 435.2 (M+H); UV 221.7, 292.8 nm.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:3]1=[O:19].[O:20]=[C:21]1[N:30]([CH:31]2[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1>>[CH:16]1([CH2:15][N:4]2[CH2:5][C@@H:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][CH2:8][C@H:2]([NH:1][C:37]([N:34]3[CH2:35][CH2:36][CH:31]([N:30]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][C:21]4=[O:20])[CH2:32][CH2:33]3)=[O:38])[C:3]2=[O:19])[CH2:18][CH2:17]1
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: N[C@H]1CC[C@H](c2ccccc2)CN(CC2CC2)C1=O
Product: O=C(N[C@H]1CC[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

Procedure:
The title compound was prepared with (3S,6R)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 4. MS 516 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C[N:11](C=O)C.S(Cl)(Cl)=O.[OH-].[NH4+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:11])=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 2-bromo-1,3-thiazole-4-carboxylic acid (3.82 g, 18.4 mmol) and a catalytic amount of DMF in CH2Cl2 (100 mL) at 0° C. was slowly added thionyl chloride (14 mL of a 2M solution in CH2Cl2). The resulting mixture was stirred for 12 h at the room temperature and then heated to reflux for 1 h. The mixture was concentrated to dryness in vacuo. The white solid obtained was taken up in ethyl acetate, added to a pre-cooled (0° C.) 9-10% aqueous ammonium hydroxide solution (90 ml) and stirred for 1 h at 0° C. The organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo, affording the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.60 (s, 1H), 7.82 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][SH:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccc(F)cc2)C1
Yield: 100.2 %

Procedure:
Using a similar method to that described in Example 93, step 1, (3R)-1-(tert-butoxycarbonyl)-3-[(methanesulfonyloxy)methyl]pyrrolidine (1.5000 g, 5.37 mmol) was reacted with 4-fluorobenzyl mercaptan (1.5511 g, 10.91 mmol) and potassium carbonate (1.1132 g, 8.05 mmol) in DMF (30 ml) at room temperature for 24 h to give 1.7507 g (100%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.45 (9H, s), 1.60 (1H, m), 2.00 (1H, m), 2.44 (2H, m), 2.97 (1H, m), 3.28 (1H, m), 3.46 (2H, m), 3.69 (2H, s), 7.00 (2H, t, J=8.6 Hz), 7.25-7.29 (2H, m). m/e (ES+) 348 (M+Na)+, 326 M+H)+, 270 (M-CMe3 +2H)+.
Reaction SMILES: [Cl:1]C1C=C(C=C(I)C=1)C(N)=N.F[C:13]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16].IC1C=C(C=CC=1)C(N)=N>>[Cl:1][C:13]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16]
Reactant: N=C(N)c1cc(Cl)cc(I)c1
Reactant: N=C(N)c1cc(I)ccc1F
Agent: N=C(N)c1cccc(I)c1
Product: N=C(N)c1cc(I)ccc1Cl

Procedure:
3-Chloro-5-iodo-benzamidine, 2-fluoro-5-iodo-benzamidine as well as 3-iodo-benzamidine may be prepared analogously.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:10]=2)=[N:7][CH:8]=1.[C:32](Cl)(=[O:37])[O:33][CH2:34][CH:35]=[CH2:36]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([N:25]([C:32]([O:33][CH2:34][CH:35]=[CH2:36])=[O:37])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[N:10]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2nn(C(=O)OC(C)(C)C)c3ccccc23)nc1Nc1ccncc1
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Product: C=CCOC(=O)N(c1ccncc1)c1nc(-c2nn(C(=O)OC(C)(C)C)c3ccccc23)ncc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
96.3 mg of tert-butyl 3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazole-1-carboxylate (1-8-1, 0.23 mmol, 1 eq.) was suspended in 7 ml of pyridine. 27.7 mg of prop-2-en-1-yl carbonochloridate (0.23 mmol, 1 eq.) were added and stirred for two hours at room temperature. Twice 27.7 mg of prop-2-en-1-yl carbonochloridate (0.23 mmol, 1 eq.) were added again and stirred the first time for 24 hours and the second time for three days at room temperature. The reaction mixture was concentrated in vacuo. To the residue was added water and acidified with 1M aq. hydrogen chloride solution. This aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over a silicone filter and concentrated under vacuo. Purification by flash chromatography (ethyl acetate/methanol 0-50%) provided 50.8 mg (0.09 mmol, 39.97%) of the analytically pure target compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.C(OCC)C>[ClH:23].[CH3:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[CH2:21][CH2:20]1
Reactant: CN1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1CCN(C(=O)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 4-(4-methyl-piperazine-1-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (25.8 g, 82.8 mmol), dry dioxane (500 mL) and 6.5 N hydrogen chloride in dioxane (275 mL) was stirred at room temperature overnight, then diluted with diethyl ether and stirred at 0° C. for 1 h. The precipitated crystals were filtered off, washed with diethyl ether and dried to yield 12.44 g (54%) of the title compound. Mp: 305-307° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Cl-].[NH4+].O.C(O)C>[Fe].COCCO>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=3)[CH2:13][CH2:12]2)=[O:24])=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCO
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCC(C(=O)c3ccc(F)cc3)CC2)cc1
Yield: 82.8 %

Procedure:
4-(4-Fluorobenzoyl)-1-(4-nitrobenzoyl)piperidine (4.75 g) was added slowly to a stirred mixture of iron powder (4.75 g), ammonium chloride (0.57 g), water (28.5 ml), ethanol (38 ml) and methyl cellosolve (76 ml) under reflux. The resulting mixture was stirred under reflux for 30 minutes and filtered. The filtrate was concentrated in vacuo. The residue was diluted with saturated sodium bicarbonate solution and extracted twice with methylene chloride. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was recrystallized from ethanol to give 1-(4-aminobenzoyl)-4-(4-fluorobenzoyl)piperidine (3.6 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[N:4][O:5][N:6]=1.Cl[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].[ClH:35]>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:32][C:31]([Cl:34])([Cl:33])[CH2:30][O:29][C:27]([N:1]([C:27]([O:29][CH2:30][C:31]([Cl:33])([Cl:32])[Cl:35])=[O:28])[C:2]1[C:3]([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)=[N:4][O:5][N:6]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3N)cc2)CC1
Reactant: Cl
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To tert-butyl 4-[4-(4-amino-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate (700 mg, 2.03 mmol) and DMAP (820 mg, 6.7 mmol) in 1,2-dichloroethane (50 mL) under dry nitrogen was added 2,2,2-trichloroethyl chloroformate (0.62 mL, 4.5 mmol) dropwise and the reaction was refluxed for ½ hour. An additional aliquot of DMAP (820 mg, 6.7 mmol) and 2,2,2-trichloroethyl chloroformate (0.62 mL, 4.5 mmol) were added and the reaction mixture was refluxed for 1 hour. Further aliquots of DMAP (820 mg, 6.7 mmol) and 2,2,2-trichloroethyl chloroformate (0.62 mL, 4.5 mmol) were added and the reaction mixture was refluxed for a total of 4 hours. After cooling to rt, the reaction was poured into aqueous 10% HCl and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7, then 1/1) to afford tert-butyl 4-[4-(4-{bis[(2,2,2-trichloroethoxy)carbonyl]amino}-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][OH:19].O.Cl>N1C=CC=CC=1>[CH3:12][O:13][CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(C)CCCCO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(C)CCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.83 g (9.6 mmol) of p-toluenesulfonic acid chloride in 5 ml of pyridine was added dropwise to a solution of 1.06 g (8.0 mmol) of 5-methoxyhexanol in 5 ml of pyridine below 5° C. on an iced water bath. After stirring for 6 hours at room temperature, the reaction mixture was injected into 100 ml of cold water and, after being acidified with 6N-hydrochloric acid, was extracted with isopropyl ether. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to obtain 5-methoxyhexyl-p-toluenesulfonate.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c[nH]c(-c2cccnc2F)c1Cl
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 44.4 %

Procedure:
5-(2-Fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (610 mg) was dissolved in N,N-dimethylformamide (20 mL), N-chlorosuccinimide (641 mg) was added, and the mixture was stirred at 80° C. for 40 min. After cooling the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2→1:1) to give the title compound as colorless crystals (yield 320 mg, 44%).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].C[Si](C)(C)[NH:15][Si](C)(C)C.CO.O>CN(C=O)C>[I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([NH:15][C:8](=[O:7])[C:3]=12)=[O:6]
Reactant: O=C1OC(=O)c2c(I)cccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(I)cccc21
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 67.7 %

Procedure:
3-Iodophthalic anhydride (598 mg, 2.18 mmol) was dissolved in DMF (14 mL), and the solution was added with an aqueous solution (10 mL) of hexamethyldisilazane (HMDS) (4.6 mL, 22 mmol) and methanol (0.44 mL, 11 mmol), followed by stirring at room temperature for 18.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure a and the residue was purified by slurry using chloroform to obtain 3-iodophtalimide (403 mg, yield 68%).
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=3[C:16]=2[CH3:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:14]2[O:13][C:12]([S:9]([C:6]3[NH:5][NH:4][CH:3]=[CH:8][CH:7]=3)(=[O:10])=[O:11])=[C:16]([CH3:17])[C:15]=2[CH:18]=1.[N:5]1[NH:4][C:3](=[O:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1ccc(S(=O)(=O)c2oc3ccc(Cl)cc3c2C)nn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(S(=O)(=O)C2=CC=CNN2)oc2ccc(Cl)cc12
Product: O=c1cccn[nH]1
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-pyridazine (22.2 mmol, 7.5 g), conc. HCl (5 mL), and dioxane (50 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (20 mL) was added to the residue. The resulting precipitate was collected and crystallized from ethanol to obtain the desired product: 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-2H-pyridazin-3-one (89%, 6.42 g).