Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][N+:10]2[N-:11][O:12][C:13](=[O:15])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[K+].C(O)(=O)C.[Br:25]Br>O>[CH:1]1([S:7][CH2:8][CH2:9][N+:10]2[N-:11][O:12][C:13](=[O:15])[C:14]=2[Br:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrBr
Reactant: O=c1c[n+](CCSC2CCCCC2)[n-]o1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1o[n-][n+](CCSC2CCCCC2)c1Br
Reaction time: 0.5 h

Procedure:
4 Parts of 3-[2-(cyclohexylthio)ethyl]sydnone is stirred with 4 parts of potassium acetate in 40 parts by volume of acetic acid while 2.8 parts of bromine in 10 parts by volume of acetic acid is added dropwise. Stirring is continued for 30 minutes and then the reaction mixture is poured into water, filtered and washed with water to give 3-[2-(cyclohexylthio)ethyl]-4-bromosydnone.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NC(C)(C)C[C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.O>C(O)(=O)C.CO>[OH:1][C@@H:2]([CH2:3][N:11]([C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31](=[O:32])[NH2:33])=[CH:34][CH:35]=2)=[CH:36][CH:37]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccc(C(N)=O)cc2)cc1
Temperature: 60 °C
Yield: 174.6 %

Procedure:
A stirred mixture of (S)-(+)-4-(oxiranylmethoxy)carbazole (7.50 g, 31.3 mmol), 4-(4-(2-amino-2-methylpropyl)-phenoxy)benzamide (17.82 g, 62.67 mmol), acetic acid (0.10 g, 1.7 mmol), water (10 mL) and methanol (260 mL) was heated to 60° C. for 22.7 hrs. The mixture was cooled and concentrated in vacuo to an oil. The concentrate was taken up in ethyl acetate (250 mL) and partitioned with water (100 mL). The organic layer was then extracted with a solution of 25 mL 1N HCl (25 mL) in water (35 mL). A white precipitate formed during the extraction was mostly 4-(4-(2-amino-2-methylpropyl)-phenoxy)benzamide and was removed by filtration of the two phase mixture. The organic layer was extracted two times with a solution of 1N HCl (3 mL) in water (50 mL). The ethyl acetate layer was stripped to an oily residue. The crude product was purified by flash chromatography with 416 g 230–400 silica gel and eluting with ethyl acetate then 10:1–3 ethyl acetate:ethanol gradient. Concentration of the appropriate fractions and drying under vacuum gave 14.31 g (87.2%) of the desired product as a foamy white solid. 1H NMR was consistent with the desired compound.
Reaction SMILES: N(CCC1C=CC(C(O)=O)=CC=1)C(C)=O.N(CC[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[N+:31]([O-])=O)C(C)=O>CO>[NH2:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:22]=1)[C:26]([OH:28])=[O:27]
Reactant: CC(=O)NCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(=O)NCCc1ccc(C(=O)O)cc1
Solvent: CO
Product: Nc1cccc(C(=O)O)c1

Procedure:
4-(2-Acetaminoethyl)-benzoic acid was reacted with nitrating acid to 4-(2-acetaminoethyl)-3-nitro-benzoic acid, M.p. 189° C. (from methanol). The following catalytical hydrogenation yielded the 4-(2-acetaminoethyl)-3-aminoethyl)-3-amino-benzoic acid with a melting point of 143° C. (from ethanol/petroleum ether). From this compound, there was obtained by diazotation and Sandmeyer-reaction the 4-(2-acetamino-ethyl)-3-chloro-benzoic acid having a melting point of 150° C. or by boiling up the diazo solution, the 4-(2-acetaminoethyl)-3-chloro-benzoic acid M.p. 222°-223° C. From 4-(2-acetaminoethyl)-3-hydroxy-benzoic acid, there were obtained with dimethyl sulfate or diethyl sulfate, the corresponding 4-(2-acetaminoethyl)-3-methoxy-benzoic acid methyl ester and the 4-(2-acetaminoethyl)-3-ethoxy-benzoic acid ethyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[CH:11][C:12]([CH3:20])(O[Si](C)(C)C)[CH:13]=[CH2:14])=[C:4]([CH3:21])[C:3]1=[O:22].[C:23]1([S:29]([OH:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na]>C(O)(=O)C>[OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[CH:11][C:12]([CH3:20])=[CH:13][CH2:14][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])=[C:4]([CH3:21])[C:3]1=[O:22]
Reactant: O=S(O)c1ccccc1
Reactant: C=CC(C)(C=CC1=C(C)C(=O)C(O)CC1(C)C)O[Si](C)(C)C
Agent: [Na]
Solvent: CC(=O)O
Product: CC(C=CC1=C(C)C(=O)C(O)CC1(C)C)=CCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-hydroxy-3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-3-trimethylsiloxy-1,4-pentadiene (200 mg, 0.62 mmol) in 1 ml glacial acetic acid is added benzenesulfinic acid, sodium salt (153 mg, 0.93 mmoles) and the mixture is stirred overnight at ambient temperature. The mixture is concentrated in vacuo and the remanecens is taken up in 10 ml diethylether and 10 ml 1M sodium hydroxide. The aqueous layer is separated and extracted twice with 10 ml diethylether. The combined ether phases are dried and concentrated in vacuo yielding the title compound as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.O>C(O)=O.C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: C=O
Solvent: O
Solvent: O=CO
Product: CN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
Tert-butyl 3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate (160 mg, 394 μmol, Eq: 1.00) was dissolved in a solvent mixture of formic acid (6.0 ml) and formaldehyde, 37% (12.0 ml). The solution stirred at 70° C. for 18 h. The solution was cooled to room temperature. Water was added. The reaction mixture was extracted once with DCM. Solid K2CO3 was slowly added to the aqueous layer until the pH=14. A solid formed that was subsequently filtered. The solid was dried to give 6-chloro-2-methyl-4-(5-(1-methylpyrrolidin-3-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (70 mg, 55%). LC/MS-ESI observed [M+H]+ 320.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]1[C:26]2[CH:27]=[CH:28][C:29](Br)=[CH:30][C:25]=2[CH2:24][CH2:23][O:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:39]=[O:40]>C1COCC1>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH:39]=[O:40])=[CH:30][C:25]=2[CH2:24][CH2:23][O:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(Br)ccc21)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(C=O)ccc21)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl tert-butyl(diphenyl)silyl ether (2.5 g, 5.05 mmol) in dry THF (60 mL), cooled to −78° C. under nitrogen, was slowly added n-butyllithium (2.5M in THF) (5.4 mL, 13.5 mmol). After 30 min stirring at −78° C., dry dimethylformamide (3.5 mL, 45 mmol) was added and the reaction allowed to warm to room temperature overnight. The reaction was quenched by addition of water and extracted into ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The resultant yellow oil was purified by flash chromatography on silica, eluting with ethyl acetate/hexane (0:4 to 1:3), to yield the title compound as a colourless oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CN1CCN(C(=O)Cc2csc(-c3cnn(C(C)(C)C)c3-c3ccc(F)cc3)n2)CC1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 1-methylpiperazine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S-:13][C:14]#[N:15].[Na+].[Br-].[Na+].BrBr.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([S:13][C:14]#[N:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: N#C[S-]
Reactant: COC(=O)c1cccc(N)c1C
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CO
Product: COC(=O)c1c(SC#N)ccc(N)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
While maintaining a solution comprising 27.7 g of methyl 3-amino-2-methylbenzoate, 41.5 g of sodium thiocyanate and 250 ml of methanol at a temperature of not higher than 0° C., 100 ml of sodium bromide-saturated methanol with 28.1 g of bromine was slowly dropwise added thereto. The mixture was stirred at room temperature for 3 hours and then poured into 1 liter of ice water. The solution was neutralized with sodium carbonate and then extracted with chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 34.0 g of the desired product as an oily substance.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([CH:7]=O)=[C:4]([C:9]([O:11]C)=O)[CH:3]=1.O.[NH2:14][NH2:15].CO.C(Cl)Cl>CCO>[Br:1][C:2]1[NH:6][C:5]2[CH:7]=[N:14][NH:15][C:9](=[O:11])[C:4]=2[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cc(Br)[nH]c1C=O
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=c1[nH]ncc2[nH]c(Br)cc12
Temperature: 75 °C
Reaction time: 16 h
Yield: 39.5 %

Procedure:
A solution of methyl 5-bromo-2-formyl-1H-pyrrole-3-carboxylate (245 mg, 1.056 mmol) and hydrazine hydrate (50-60 wt % in water; Aldrich; 0.14 mL, 1.58 mmol) in EtOH (5.0 mL) was stirred under argon at 75° C. for 1.5 h. Additional hydrazine hydrate (50-60 wt % in water; 0.33 mL, 3.70 mmol) was added, and the resulting mixture was stirred at 75° C. for 16 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographic purified (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-bromo-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (89.3 mg, 0.417 mmol, 40% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.69-13.17 (1H, m), 12.34 (1H, s), 8.06 (1H, d, J=0.6 Hz), 6.72 (1H, d, J=0.6 Hz) (2.5:1 mixture of pyridazinone tautomers; only major tautomer peaks reported). m/z (ESI, +ve) 213.8/215.9 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][Cl:24])=[N:21][C:20]([C:25]([NH2:27])=[O:26])=[N:19]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1.CO>[OH:10][CH:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][Cl:24])=[N:21][C:20]([C:25]([NH2:27])=[O:26])=[N:19]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(O)c2ccccc2)n1
Temperature: 25 °C

Procedure:
0.57 g (0.015 mole) of sodium borohydride is added all at once at 0°, with stirring, to the solution of 5.6 g (0.015 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide [see Example 1(a)] in 250 ml of tetrahydrofuran and 25 ml of methanol, and the whole is subsequently stirred for a further hour at room temperature. There is then slowly added dropwise, with ice-water cooling, 1 N hydrochloric acid solution until the pH-value of the reaction mixture has reached 4. The mixture obtained is concentrated in vacuo to dryness. Water is added to the residue, and extraction is performed twice with ethyl acetate. The organic phase is washed once with saturated potassium bicarbonate solution, twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. There is obtained amorphous 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide, which can be used directly in the next stage. On the silica gel plate, the compound has an Rf value of 0.61 in the system ethyl acetate/methanol (95:5).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]([CH3:30])=[CH:28][S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[C:29]([CH3:30])=[CH:28][S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][O:2][N:3](C)[C:4](=O)C1C=CC(OCC2C=CC3C(=CC=CC=3)N=2)=CC=1.[F:25][C:26]1[C:34]([F:35])=[C:33]([O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=2)[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O>>[F:25][C:26]1[C:34]([F:35])=[C:33]([O:36][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=2)[CH:32]=[CH:31][C:27]=1[C:28]([N:3]([O:2][CH3:1])[CH3:4])=[O:30]
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1F
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1F

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting 2,3-Difluoro-4-(quinolin-2-ylmethoxy)-benzoic acid provided the title compound. MS: (M+H m/z=359.1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C.[Pd]>[N:10]1([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1cccc(O)c1
Reactant: C1CCNCC1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(CN2CCCCC2)c1

Procedure:
3-Hydroxybenzaldehyde (15 g) and piperidine (15 ml) in ethanol (500 ml) were hydrogenated over 10% palladium/carbon catalyst. The catalyst was removed by filtration and the solvent was evaporated off. The residue was triturated with light petroleum (b.p. 60°-80°) and the resulting solid was recrystallised from acetonitrile to give the title compound as a buff coloured solid (8.7 g) m.p. 134°-7°. TLC silica, methanol, Rf 0.56.
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][C:6]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:8])[CH3:7])C.[OH-].[Na+]>CO.O>[SH:3][CH2:4][CH2:5][C:6]([NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:8])[CH3:7]
Reactant: CC(=O)SCCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CCS)NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of S-3-(benzyloxycarbonylamino)-3-methylbutyl ethanethioate (45.0 g, 152 mmol, prepared as described in WO 2008/083347) in methanol (300 ml) was added 5.0 M NaOH in H2O (60.0 ml, 300. mmol). The solution was stirred for 1 hour, concentrated in vacuo, diluted with saturated NaHSO4 (200 ml), filtered through a coarse glass funnel, and extracted with 5×100 ml ethyl acetate. The organic layers were combined, washed with 100 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. The residue was used without further purification (24.10 g, 95.1 mmol, 63%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reaction time: 14 h
Yield: 102.8 %

Procedure:
To a solution of tert-butyl [(3S)-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (411.2 mg, 1.128 mmol) in MeOH (5.00 mL) under a nitrogen atmosphere was added 10% Pd on carbon (108.7 mg, 0.1021 mmol). The reaction mixture was hydrogenated at 1 atm. for 14 h. The mixture was then filtered through a pad of diatomaceous earth (eluted with MeOH). The filtrate was concentrated under reduced pressure to give the sub-title compound as an off-white solid (387.9 mg) which was used directly in the next step without further purification. LCMS calc. for C17H27N4O3 (M+H)+: m/z=335.2. found 335.2.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25][OH:26])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:40]([O:47][CH2:48][CH2:49]Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>[Cl-].[Na+].O>[CH2:40]([O:47][CH2:48][CH2:49][O:39][C:36]1[CH:37]=[CH:38][C:33](/[C:22](/[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:17][CH:18]=2)=[C:23](\[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH2:24][CH2:25][OH:26])=[CH:34][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: OCCC(=C(c1ccc(O)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Reactant: BrCCOCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC/C(=C(/c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Reaction time: 4 h

Procedure:
The reaction vessel was charged with sodium hydride (0.43 g, 0.0178 mol) and dimethyl formamide (34 ml). 4-[1-(4-Benzyloxyphenyl)-4-hydroxy-2-phenyl-but-1-enyl]phenol (5 g, 0.0118 mol) prepared by the method of U.S. Pat. No. 4,996,225 was dissolved to dimethyl formamide (6 ml), added to the mixture at room temperature and stirring was continued for half an hour. Then benzyl-(2-bromoethyl)ether (3.06 g, 0.014 mol) was added dropwise during 20 minutes to the reaction mixture and stirring was continued for additional 4 hours. The reaction mixture was poured into brine and extracted with ethyl acetate. Organic layer was washed with 2 N hydrogen chloride solution and twice with water, dried and evaporated to dryness. The product was purified by flash chromatography (toluene: methanol, 9.8:0.2). Yield 2.8 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:10]=1)[C:5]([NH:26][CH2:25][C:22]1[CH:23]=[N:24][C:19]([CH3:18])=[CH:20][CH:21]=1)=[O:7]
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)nc1
Reactant: Cc1ccc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3ccc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 3-bromo-5-(5-methylpyridin-2-yl)benzoic acid (450.00 mg, 1.5404 mmol), (6-methylpyridin-3-yl)methanamine (225.83 mg, 1.8485 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1171.4 mg, 3.0808 mmol), N,N-diisopropylethylamine (0.93910 mL, 5.3915 mmol) and N,N-dimethylformamide (5.00 mL, 64.6 mmol) and the reaction stirred at room temperature for 1 hour. The reaction was poured into brine and extracted with ethyl acetate to get the product as brown solid
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14](=[CH:15]N(C)C)[C:13](=[O:19])[C@@H:12]2[C@H:10]1[C@H:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14](=[CH2:15])[C:13](=[O:19])[C@@H:12]2[C@H:10]1[C@H:11]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 98.6 %

Procedure:
To a solution of di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-(dimethylaminomethylene)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (15.7 g, 33.8 mmol) in tetrahydrofuran (340 ml) is added triethylamine (6.6 mL, 47.32 mmol). The mixture is cooled to −78° C. Diisobutylaluminium hydride (1N in toluene, 50 mL, 50 mmol) is added over one hour. The mixture is stirred for two additional hours. Then add 30 mL of saturated aqueous ammonium chloride. The mixture is allowed to warm to ambient temperature. The mixture is transferred to a separatory funnel and washed with brine. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (0 to 50% ethyl acetate/hexanes) to give the title compound (12 g, 33.34 mmol, 83.8% yield). MS (m/z): 422 (M−H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([NH:17][C:18]3([C:22]([O:24]CC)=[O:23])[CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([NH:27][C:28]([NH2:30])=[NH:29])=[N:6][CH:5]=1.Cl>CO>[ClH:3].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([NH:17][C:18]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19]3)(=[O:15])=[O:16])=[CH:11][CH:12]=2)[C:7]([NH:27][C:28]([NH2:30])=[NH:29])=[N:6][CH:5]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCC3)cc12
Temperature: 55 °C
Yield: 28.7 %

Procedure:
A solution of NaOH (5 mL, 2 M, 10 mmol) was added to a solution of ethyl 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino)cyclobutanecarboxylate (100 mg, 0.23 mmol) in MeOH (5 mL) and the mixture was heated at 55° C. for 6 h. The cooled mixture was neutrilised with dilute HCl (5 mL, 2 M) to give a precipitate and the MeOH was evaporated in vacuo. The solid was collected by filtration, with copious water washing, and dried under high vacuum to give 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclobutanecarboxylic acid hydrochloride (15 mg, 0.033 mmol).