Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cn1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cn1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.2) (1.31 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure Ia. Obtained as a light brown solid (1.84 g, 95%). MS (ISP) 486.9 [(M+H)+]; mp 179° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:27](Cl)(=O)[C:28](Cl)=O.C(O)C.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:27][CH3:28])=[O:13])(=[O:7])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(COC(C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 506.8 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (14) (0.5 g, 1.2 mmol) dissolved in 5 mL of anhydrous dichloromethane (DCM) was reacted with 0.14 mL (0.2 g, 0.14 mmol) of oxalyl chloride. After the reaction was complete, a solution of 5 mL of ethanol (EtOH) and 0.16 mL of pyridine (0.15 g, 1.9 mmol) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.31 g (58% yield) of the title compound (23a) as a colorless oil. Rf=0.59 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.05 (s, 3H), 1.06 (s, 3H), 1.33 (t, J=6.8 Hz, 3H), 2.25-2.33 (m, 2H), 3.22-3.26 (m, 2H), 3.65-3.68 (m, 2H), 3.81 (s, 1H), 3.82 (s, 3H), 3.97 (d, J=9.2 Hz, 1H), 4.19-4.31 (m, 4H), 4.56 (d, J=11.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.26 (d, J=9.2 Hz, 2H) ppm. MS (ESI) m/z 458.97 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].N#N>CN1CCCC1=O.CN(C1C=CN=CC=1)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: Cc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CN1CCCC1=O
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1F
Temperature: 150 °C
Yield: 46.1 %

Procedure:
To a solution of 6-chloro-4-(5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide (109 mg, 387 μmol) in N-methyl-2-pyrrolidinone (2.4 mL) was added DMAP (50.7 mg, 406 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (166 mg, 774 μmol) and the mixture was heated to 150° C. for 1.5 d. A steam of N2 was blown into the mixture while still heating at 140° C. to evaporate the NMP, then the reaction mixture was purified by chromatography (silica, 50 μm, 40 g, Analogix, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min) to provide tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-fluoro-6-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (82 mg, 23%) as a brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.43 (s, 1H) 8.24 (s, 1H) 8.08 (br. s., 2H) 7.22-7.37 (m, 1H) 6.66-6.77 (m, 1H) 5.64 (d, J=3.28 Hz, 1H) 4.02 (br. s., 2H) 2.49 (d, J=3.03 Hz, 3H) 1.67-1.92 (m, 2H) 1.35-1.65 (m, 8H). LCMS (EI/CI) m/z: 460 [M+H].
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:12]1([N:18]2[NH:19][C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]n(-c2ccccc2)c(=O)c2ccccc12
Yield: 58 %

Procedure:
A mixture of phthalic anhydride (0.02 mol) and phenyl hydrazine (0.04 mol) in 95 percent acetic acid (70 ml.) was heated to reflux for 24 hours in the presence of a catalytic amount of sodium acetate (0.4 g). Water was added to the mixture and the precipitate collected. The precipitate was washed with water, agitated with 2 percent aqueous solution of sodium hydroxide and filtered. The filtrate was acidified with concentrated hydrogen chloride. The precipitate was collected and recrystallized from ethyl acetate to produce the product, 2-phenyl-2,3-dihydrophthalazine-1,4-dione.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CC[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:25]1[CH2:26][C:30]2[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28]1)=[O:6]
Reactant: CCN(CC)Cc1ccccc1
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1Cl)N1Cc2ccccc2C1
Reaction time: 16 h
Yield: 65.2 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D36) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.0 g) in DCM (10 ml) at rt was treated with isoindoline (0.08 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound as a white solid (0.08 g). MS electrospray (+ion) 411/413 (MH+). 1H NMR δ (DMSO-d6): 10.55 (1H, s), 7.45 (2H, m), 7.27 (4H, m), 7.11 (1H, m), 4.89-4.68 (3H, m), 4.52 (2H, m), 3.67 (1H, m), 3.46-3.18 (2H, m), 2.90 (2H, m), 2.40-1.63 (10H, m).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:33]2[O:32][C:31]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:30][C:29](=[O:39])[C:28]=2[CH:27]=[CH:26][CH:25]=1>>[O:39]=[C:29]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:23][C:20]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[O:11][CH:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:19][CH2:18]4)=[O:22])[C:33]=2[O:32][C:31]([C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[CH:30]1.[CH3:1][OH:8]
Reactant: Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12
Reactant: O=C(O)c1ccc2c(c1)CCC(COCc1ccccc1)O2
Product: CO
Product: O=C(Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12)c1ccc2c(c1)CCC(COCc1ccccc1)O2
Yield: 57 %

Procedure:
Following the process described in example 1 (point K), starting from 2-(benzyloxymethyl)-6-chromanecarboxylic acid and 8-amino-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran, the title compound was prepared as a white solid with melting point 214-216° C., which was purified by crystallization in methanol (57% yield).
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.[Br-].[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N+:23]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:29][CH2:28][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:9]2[C:7](=[O:8])[CH2:6][C:4]3([CH2:5][CH2:1][CH2:2][CH2:3]3)[CH2:12][C:10]2=[O:11])[CH2:22][CH2:21]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture 3,3-tetramethyleneglutarimide (16.7 g., 0.1 mole), 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane bromide (29.9 g., 0.1 mole) and potassium carbonate (16.6 g., 0.12 mole) in 190 ml. of dimethylformamide is maintained at 150°-155° C. for a reaction period of 24 hours and then evaporated to dryness under reduced pressure. The resulting solid is triturated with 90 ml. of water, taken up in 10% hydrochloric acid and filtered. The acid filtrate is made basic with 10% aqueous sodium hydroxide and precipitated free base collected and dried to provide 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione.
Reaction SMILES: [OH-].[Li+].[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9]C)=[O:8].Cl>C1COCC1.CO.O.O>[I:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(OC)c(I)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)O)cc1I
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Lithium hydroxide (72 mg, 1.71 mmol) was added to a mixture of methyl 3-iodo-4-methoxybenzoate (100 mg, 0.342 mmol) in 3.0 mL of a 3:1:1 THF-MeOH-water solution at room temperature. The mixture was stirred for eight hours in the dark and than diluted with H2O (2 mL). The solution was acidified to pH=2 by the dropwise addition of concentrated HCl. The solution was extracted twice with EtOAc (10 mL portions) and the combined organic layers dried (Na2SO4), filtered, and concentrated to afford acid 26 (95 mg, 100%) as a yellow solid that was suitable for use without further purification: 1H NMR (400 MHz, DMSO) δ 8.24 (d, J=2.0 Hz, 1H), 7.92 (dd, J=2.0, 8.7 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8](O)([CH3:23])[CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2([CH3:23])[CH2:9][N@:10]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH:7]=1
Reactant: C[C@@](O)(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Agent: CC1(c2cc(Br)ccc2F)C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(c2cc(Br)ccc2F)C[N@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N—[(S)-2-(5-bromo-2-fluoro-phenyl)-2-hydroxy-propyl]-2-nitro-benzenesulfon-amide (20.8 g, 48 mmol) in CH2Cl2 (400 ml) was added PPh3 (19.2 g, 72.4 mmol) at 0-5° C. and diethyl azodicarboxylate (11.6 ml, 72.4 mmol). The reaction mixture was stirred for 24 h at 25° C. and concentrated. The title compound was obtained after chromatographic purification over silica gel (hexane-EtOAc 20:1 to 2:1) as yellow crystals: TLC (toluene-EtOAc 3:1): Rf=0.69; UPLC RtH5=1.308 min; 1H NMR (360 MHz, CDCl3): δ 8.31 (m, 1H), 7.28 (m, 3H), 7.60 (dd, 1H), 7.42 (m, 1H), 6.91 (dd, 1H), 3.24 (s, 1H), 2.81 (s, 1H), 2.06 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](O)=[C:12]([F:17])[C:11]=2[F:18])=[C:6]([F:19])[C:5]=1[F:20])[CH3:2].[CH:21]([CH:23]1[CH2:28][CH2:27][CH:26]([CH:29]2[CH2:34][CH2:33][CH:32](CC3C=C(S(O)(=O)=O)C=CC=3C)[CH2:31][CH2:30]2)[CH2:25][CH2:24]1)=[CH2:22].[OH-].[K+].CN(C)[CH:51]=[O:52]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:52][CH2:51][CH:32]3[CH2:33][CH2:34][CH:29]([CH:26]4[CH2:25][CH2:24][CH:23]([CH:21]=[CH2:22])[CH2:28][CH2:27]4)[CH2:30][CH2:31]3)=[C:12]([F:17])[C:11]=2[F:18])=[C:6]([F:19])[C:5]=1[F:20])[CH3:2]
Reactant: C=CC1CCC(C2CCC(Cc3cc(S(=O)(=O)O)ccc3C)CC2)CC1
Reactant: CCOc1ccc(-c2ccc(O)c(F)c2F)c(F)c1F
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC1CCC(C2CCC(COc3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)CC2)CC1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
In a reactor under nitrogen atmosphere, 4.0 g of compound (a4), 5.3 g of compound (a6) and 1.2 g of potassium hydroxide (KOH) were added into 30 ml of N,N-dimethylformamide (DMF), followed by stirring at 60° C. for 14 hours. The reaction solution was cooled to 30° C., to which 100 ml of water and 100 ml of toluene were added. The mixture was separated into organic layer and aqueous layer and the organic layer was extracted. The resulting organic layer was separated and washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide the residue. The resulting residue was purified by column chromatography (silica gel; toluene), further purified by recrystallization from (volume ratio Solmix A-11: toluene=1:2), dried to provide 2.5 g of 4′-ethoxy-2,3,2′,3′-tetrafluoro-4-(4′-vinylbicyclohexyl-4-ylmetoxy)-biphenyl (a7).
Reaction SMILES: Cl.[N:2]1[CH:3]=[C:4]2[N:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=13)[S:7][C:6]([C:14]([OH:16])=O)=[CH:5]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:39][CH2:40][C:41]1[CH:60]=[CH:59][C:44]([CH2:45][N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:48][CH2:47]2)=[CH:43][CH:42]=1>C(#N)C.C(N(CC)CC)C>[CH2:52]([CH:49]1[CH2:50][CH2:51][N:46]([CH2:45][C:44]2[CH:43]=[CH:42][C:41]([CH2:40][NH:39][C:14]([C:6]3[S:7][C:8]4[N:13]5[C:4](=[CH:3][N:2]=[C:12]5[CH:11]=[CH:10][CH:9]=4)[CH:5]=3)=[O:16])=[CH:60][CH:59]=2)[CH2:47][CH2:48]1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: NCc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCc1ccc(CN2CCC(Cc3ccccc3)CC2)cc1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid hydrochloride and 0.90 g (7.82 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.51 g (7.88 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature, and the mixture was stirred for 2 hours. To this reaction mixture was added a solution of 1.88 g (5.12 mM) of 1-[4-(aminomethyl)benzyl]-4-benzylpiperidine dihydrochloride and 0.55 ml (3.95 mM) of triethylamine in acetonitrile (20 ml) and the mixture was further stirred for 4 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (a small amount of ethanol was additionally used). The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 20%) to provide the title compound as red amorphous substance.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][O:7][CH2:8][C:9](O)=O.P(Cl)(Cl)(Cl)=O.[Na]>O1CCOCC1.O>[CH3:6][O:7][CH2:8][C:9]1[S:4][C:3]([NH2:5])=[N:2][N:1]=1
Reactant: COCC(=O)O
Reactant: NNC(N)=S
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nnc(N)s1
Temperature: 80 °C
Yield: 81 %

Procedure:
To a suspension of thiosemicarbazide a24 (40 g, 0.44 mol, 1 eq) in dioxane (400 ml) at room temperature is added methoxyacetic acid (39.56 g, 0.44 mol, 1 eq) in one portion, and the reaction mixture is heated at 80° C. then phosphorous oxychloride (67.54 g, 0.44 mol, 1 eq) is carefully added over 1.5 hours. After reaction completion (4 hours), water is added and the solution is neutralised to pH=6-7 with sodium hydroxyde pellets. After extraction EtOAc/iPrOH (9/1) and evaporation under vacuum, the residue is recrystallized from MeTHF/iPrOH to afford 51 g of pure 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine a25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:13]I)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:39]1[C:48]([CH2:49][P:50]([O:55][CH2:56][CH3:57])([O:52][CH2:53][CH3:54])=[O:51])=[CH:47][C:46]2[C:41](=[CH:42][C:43]([Cl:59])=[C:44]([CH3:58])[CH:45]=2)[N:40]=1>C1(C)C=CC=CC=1.CC(N(C)C)=O.C(OCC)(=O)C.[Cu].Cl[Pd]Cl>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:13][C:39]1[C:48]([CH2:49][P:50]([O:52][CH2:53][CH3:54])([O:55][CH2:56][CH3:57])=[O:51])=[CH:47][C:46]2[C:41](=[CH:42][C:43]([Cl:59])=[C:44]([CH3:58])[CH:45]=2)[N:40]=1)[C:3]([O:2][CH3:1])=[O:15])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Reactant: CCOP(=O)(Cc1cc2cc(C)c(Cl)cc2nc1Br)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cc2cc(C)c(Cl)cc2nc1C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)OCC
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester (0.81 g, 2.46 mmol) in dry toluene (12 ml) and dry dimethylacetamide (0.8 ml) was added to a nitrogen purged flask charged with zink-copper couple (0.32 g, 4.92 mmol). The mixture was treated in an ultrasonic bath for 1 h until no starting material remained (as judged by TLC). A mixture of PdCl2 (23 mg, 0.13 mmol) and tri-o-tolylphosphine (79 mg, 0.26 mmol) was added followed by 2-bromo-7-chloro-3-diethylphosphonomethyl-6-methylquinoline (0.5 g, 1.23 mmol) and sonication was continued for 3 hours at 50°-60° C. After cooling the reaction mixture was diluted with ethyl acetate, extracted with saturated sodium hydrogen carbonate solution, dried over MgSO4 and evaporated. The crude product was subjected to chromatography on silica gel with ethyl acetate as eluant to yield 0.49 g of methyl (R)-α-t-butoxycarbonylamino-7-chloro-3-diethylphosphonomethyl-6-methyl-2-quinolinepropionate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24].I.[NH2:27][C:28]1[C:29]([C:36]([NH:38][C:39](=[NH:42])SC)=[O:37])=[N:30][C:31]([Cl:35])=[C:32]([NH2:34])[N:33]=1>C(O)C>[NH2:27][C:28]1[C:29]([C:36]([N:38]=[C:39]([NH2:42])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24])=[O:37])=[N:30][C:31]([Cl:35])=[C:32]([NH2:34])[N:33]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCCCCCCCCC(N)=O
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=O)CCCCCCCCCCCNC(N)=NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
Diisopropylethylamine (0.24 mL, 1.38 mmol) was added to a suspension of 12-amino-dodecanoic acid amide hydrochloride (8) (0.068 g, 0.27 mmol) in absolute ethanol (5 mL). The resulting solution was stirred at 70° C. (oil bath) for 5 min, after which time 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (115 mg, 0.30 mmol) was added in one portion. The reaction mixture was then stirred at this temperature for 3 hours then cooled to room temperature. After removal of the solvent by rotary evaporation the resulting residue was dissolved in small volume of methanol, and the solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution concentrated in vacuo to a yellow residue. This residue was stirred in a minimal volume of methanol and the resulting solid was collected by suction filtration and washed with a small amount of methanol to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-dodecanoic acid amide 9 (0.065 g, 56%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) 1.23 (m, 14H), 1.49 (m, 4H), 2.01 (t, 2H), 3.11 (m, 2H), 6.65 (m, 4H), 7.21 (br, 1H), 9.06 (br, 1H). m/z (ESI) 427 [C18H31ClN8O2+H]+. mp 192-194° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2C(OC(C)(C)C)=O)=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cnc(OCC2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(OCC2CCCN2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a stirred solution of methyl 3-chloro-2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (235.6 mg, 0.635 mmol) in CH2Cl2 (5.0 mL) was added TFA (1.0 mL) at 0° C., and the reaction mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure. The residue was made basic by the addition of 1N NaOH and extracted with CHCl3. The extract was dried over Na2SO4, concentrated under a reduced pressure to afford 172.3 mg (q.y.) methyl 3-chloro-2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ 1.55–1.63 (m, 1H), 1.76–1.99 (m, 3H), 2.93–2.99 (m, 1H), 3.02–3.08 (m, 1H), 3.57–3.62 (m, 1H), 3.92 (s, 3H), 4.33 (dd, J=7.3, 10.7 Hz, 1H), 4.44 (dd, J=4.4, 10.7 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H); MS (FAB) m/z 271 (M++1).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([C:9]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[CH:27][C:10]=1[O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:12]([O:11][C:10]1[CH:27]=[C:28]([O:31][CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[CH:29]=[CH:30][C:9]=1[C:6]([CH3:7])=[CH2:1])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [Li]CCCC
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)=O)c1ccccc1C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OCc2ccsc2)cc1OC(CCC(=O)OCC)c1ccccc1C
Reaction time: 2 h

Procedure:
A stirred suspension of methyltriphenylphosphonium bromide (2.4 g) in tetrahydrofuran (50 mL) at ambient temperature is treated with a solution of butyllithium in hexanes (2.6 mL; 2.5 M). After two hours, the reaction mixture is treated with a solution of ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)-butanoate (1 g) in tetrahydrofuran (2 mL) and stirred for a further two hours. It is then partitioned between hydrochloric acid (50 mL; 1 N) and ethyl acetate (100 mL). The organic layer is washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 v/v) to give ethyl (RS)-4-(2-methylphenyl)-4-[2-(propen-2-yl)-5-(3-thienylmethoxy)phenoxyl]butanoate (0.7 g), in the form of a colourless oil.