Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)N2CC(Oc3ccc(Br)cc3)C2)CC1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 2.9 g (0.01 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1 g (0.01 mole) of 1-methylpiperazine and stirred for 2 hr. The paste-like slurry was diluted with water and the solid was collected by filtration (4 g, wet). Recrystallization from benzene/ligroin yielded 3.0 g of white crystalline product, m.p. 91°-95° C. The solid and 1.16 g of fumaric were dissolved in isopropanol by boiling until a clear solution was obtained. Upon cooling, the precipitated salt was collected by filtration to yield 3 g (63.8%) of fine white crystals, m.p. 197°-198° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
A mixture of 91.7 parts of 4-(1-piperazinyl)phenol, 71.0 parts of 1-fluoro-4-nitrobenzene, 60.0 parts of potassium carbonate and 450 parts of N,N-dimethylacetamide was stirred over weekend at room temperature. Water was added and after standing for 5 hours, the product was filtered off. It was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 114.4 parts (76%) of 4-[4-(4-nitrophenyl)-1-piperazinyl]phenol; mp. 260.0° C. (intermediate 9).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:13]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1>O>[CH2:1]([NH:3][C:22](=[O:23])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]2[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:12]=2[Cl:11])[CH:16]=1)[CH3:2]
Reactant: O=C(Cl)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CCN
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 1 h
Yield: 97.6 %

Procedure:
0.7 g of ethylamine and 1.5 g of triethylamine were dissolved in 20 ml of N,N'-dimethylacetamide at 0° C., followed by addition of 3.5 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetyl chloride. The reaction was allowed to proceed at 0° C. for 1 hour and then at room temperature for further 3 hours to complete the reaction. After completion of the reaction, 50 ml of water was added to the liquid reaction mixture, followed by extraction twice with 30 ml portions of ether. The ether layer was washed with dilute hydrochloric acid and water and dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure. As a result, there was obtained 3.5 g of N-ethyl-3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:7][N:6]=1)=N.O[Li].O.P(=O)(O)(O)[OH:35].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:35])=[N:6][CH:7]=3)=[N:12][C@H:13]3[C@@H:18]2[CH2:17][C@H:16]([OH:30])[CH2:15][CH2:14]3)=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: O=P(O)(O)O
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=N)OC)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Agent: O=P([O-])([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
In a second step, 443 mg (1.08 mmol) of 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester are dissolved in 3 ml of THF. A solution of 51 mg (2.16 mmol) LiOH.H2O is added and the solution stirred at 60° C. for 18 hrs. The pH is adjusted to 5 using phosphoric acid and Disodiumhydrogenphosphate. The solvent is removed and the solid residue extracted with chloroform/methanol. After filtering off and removing the volatiles 350 mg (82%) of the title compound are obtained.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:15]N>C(O)C>[C:7]1([C:5]2[CH:4]=[CH:3][NH:2][N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cc[nH]n2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2.63 g, 15 mmol) in ethanol (40 ml) was added hydrazine hydrate (1.459 ml, 30.0 mmol). The reaction was heated to 100° C. for 2 hours. Whereupon was cooled to room temperature and ethanol was removed by vacuum. The residue was partitioned between DCM and water. The organic phase was dried over MgSO4 and filtered. After evaporation the crude product was purified by triturating with a mixture of petroleumether and ethyl acetate. (Yield: 1.59 g, 73%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[CH2:5].C12BC(CCC1)CCC2.C[O-].[Na+].Br[C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C=CCOC
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: B1C2CCCC1CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(CCCOC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a THF solution (0.1 M) of allyl methyl ether (1.4 eq.) was added, at 0° C., 9-borabicyclo[3.3.1]nonane (2.4 eq.) over a period of 30 min. The solution was stirred at 0° C. for 1 h and then warmed slowly to RT over 16 h. To the resulting clear solution was then added sodium methoxide (2.4 eq.), Cl2Pd(dppf)-dichloromethane complex (5% loading) and ethyl 3-bromobenzoate (1 eq.). The now brown suspension was heated to reflux for 16 h. The reaction mixture was cooled to RT, quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→4:1 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)([O-])=O.CO.[H][H]>C1(C)C=CC=CC=1.[Pd]>[N:35]1[CH:36]=[CH:37][C:32]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[N:9]([C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:33][CH:34]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 105.8 %

Procedure:
To a 500 ml round bottom flask equipped with a magnetic stir bar was added 5-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazole (1332 g, 27.6 mmol) and dissolved in a mixture of toluene:MeOH (120 ml: 40 ml). While stirring, Pd/C (1.5 g, 10% wet) was added. The mixture was then subjected to a hydrogen balloon and stirred overnight. Upon completion of the reaction, which was determined by LC/MS, the mixture was filtered through celite and concentrated under vacuum to give 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (13.21 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc2c(Cl)ccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(Cl)ccnc2n1[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (0.85 g) in N,N-dimethylformamide (8.5 ml) was added 60% oil-suspended NaH (245 mg) under nitrogen atmosphere while being cooled in an ice water bath. The reaction solution was stirred at ambient temperature for 1 hour and cooled again in the ice water bath. To the reaction solution was added triisopropylsilyl chloride (1.3 ml) slowly dropwise for 10 or more minutes. The reaction solution was stirred for 3 hours at ambient temperature and diluted with ethyl acetate (30 ml). The solution was washed with saturated aqueous sodium hydrogencarbonate (30 ml) and brine (20 ml). The solution was dehydrated with anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain 4-chloro-2-methyl-1-(triisopropylsilyl)-pyrrolo[2,3-b]pyridine (1.45 g) as a colorless transparent liquid.
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl.CN(C=O)C>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Thionyl chloride (36.0 g, 302 mmol) was added to a suspension of 4-iodobenzoic acid (50.0 g, 202 mmol) in anhydrous DCM (300 ml) followed by a few drops of DMF and the reaction mixture was stirred overnight at r.t. Upon completion, reaction flask was concentrated under reduced pressure to yield 51.6 g (96.0% yield) of crude 4-iodobenzoyl chloride that was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1[N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[SH:38].O>C(O)(C)C>[CH3:9][C:8]1[C:3]([CH:2]([S:38][C:34]2[NH:35][CH:36]=[CH:37][N:33]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: Sc1nccn1-c1ccccn1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Solvent: CC(C)O
Solvent: O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1C(Sc1ncc[nH]1)c1ccccn1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
2.3 g (5.6 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine and 1.0 g (5.6 mmol) of 1-pyridin-2-yl-1H-imidazole-2-thiol in 100 ml of isopropanol are heated under reflux for 2 h under a nitrogen atmosphere. The mixture is then cooled to room temperature, treated with 1 l of water and extracted with 4×200 ml of ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia=19:1:0.6). The fractions of Rf =0.35 are concentrated and crystallized from methanol. 0.45 g of the title compound is isolated as a pale beige solid. M.p. 146-149° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]1[C:18]([O:25][CH3:26])=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:24][C:23]1[CH:22]=[C:21]2[C:19](=[C:18]([O:25][CH3:26])[C:17]=1[F:16])[N:20]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: COc1c(N)ccc(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(OC)c(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
2.84 g (0.013 mole) of diethyl ethoxymethylenemalonate were added to 1.74 g (0.011 mole) of 3,4-difluoro-2-methoxyaniline (VIII) (prepared as described in Preparation 13). The mixture was then stirred at 140°-150° C. for 3 hours, after which 20 ml of diphenyl ether were added, and the mixture was stirred at 240°-250° C. for 1 hour. At the end of this time, the mixture was allowed to cool to room temperature, and then hexane was added to precipitate crystals, which were collected by filtration. 1.60 g of ethyl 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylate (IX) were obtained as colorless crystals.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1.[Br:21]N1C(=O)CCC1=O.C(OO)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:21][CH2:20][C:1]1[CH:2]=[C:3]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc2nc(-c3cccc(C)c3)oc12
Agent: O=C(OO)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3cccc(CBr)c3)oc12
Yield: 30 %

Procedure:
Methyl 2-m-tolylbenzo[d]oxazole-7-carboxylate (500 mg, 1.87 mmol), 1-bromopyrrolidine-2,5-dione (367 mg, 2.06 mmol) and benzoperoxoic acid (25.81 mg, 0.187 mmol) were added to toluene (30 mL) and the mixture was stirred at reflux overnight. The resulting mixture was evaporated, extracted with ethyl acetate (100 mL×4) and concentrated to obtain methyl 2-(3-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate as a solid (194 mg, yield 30%). LC-MS (ESI) m/z 347 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH:13](O)[CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>C(#N)C.ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH:13]([Cl:40])[CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1C=C2C(CC(O)CN2Cc2ccc(Cl)nc2)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: O=C1C=C2C(CC(Cl)CN2Cc2ccc(Cl)nc2)O1
Temperature: 25 °C

Procedure:
At 70° C., 146.0 mg (0.52 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-6-hydroxy-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one (cf. I-16) and 274.2 mg (1.05 mmol) of triphenylphosphine are stirred in a mixture of 2.5 ml of acetonitrile and 2.5 ml of carbon tetrachloride. After cooling to room temperature, the mixture is diluted with dichloromethane and washed successively with dilute aqueous ammonium hydroxide solution and saturated sodium chloride solution: the organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 063 m) using the mobile phase ethyl acetate and subsequent preparative HPLC gives both possible diastereomers of 4-[(6-chloropyridin-3-yl)methyl]-6-chloro-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one: (a) 4 mg of diastereomer A (3% of theory) and (b) 15 mg of diastereomer B (9% of theory). In addition, (c) 10 mg (7% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-7,7a-dihydrofuro[3,2-b]pyridin-2(4H)-one are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[N:10]([CH:13]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[N+:11]=[N-:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N:10]([CH:13]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[O:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:2][CH2:3][CH2:4][CH:5]2[O:9][CH2:8][CH2:7][O:6]2)=[O:24])=[CH:21][CH:20]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Reactant: ClCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)OCCCC3OCCO3)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a stirred solution of 3-chloropropyl-1,3-dioxolane (0.2 g, 1.35 mmol) in dimethyl formamide (14 mL), was added 4-((3-(azido(phenyl)methyl)phenoxy)-methyl)benzoic acid (Example 51 Step 3) (0.5 g, 1.39 mmol) and potassium carbonate (0.38 g, 2.78 mmol). The reaction was allowed to stir at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (×3). The organic extracts were washed with brine, dried (sodium sulphate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (0.63 g, 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[C:39]([NH:41][CH:42]3[CH2:44][CH2:43]3)[N:38]=[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:36]=2)[CH:32]=[N:33][CH:34]=1>COCCOC.CCOC(C)=O>[CH:42]1([NH:41][C:39]2[N:38]=[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:36]=[C:35]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH:7]=4)[CH:30]=3)[CH:40]=2)[CH2:44][CH2:43]1
Reactant: CN(C)CCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CN(C)CCOc1cccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)c1

Procedure:
To a solution of Dimethyl-(2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl)-amine (2 eq, 0.272 mmol, 0.079 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (3 eq, 0.408 mmol, 0.204 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 50 mg) and PdCl2dppf (0.1 eq, 0.014 mmol, 11 mg). The reaction mixture is heated using microwave radiation at 90° C. for 90 minutes. The reaction mixture is dissolved in EtOAc and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 452.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][NH2:7].C([O-])(=O)C.[Na+].[CH3:19][O:20][C:21]([NH:23][C:24](=N)SC)=[O:22]>CO>[CH3:3][N:4]1[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:7]=[C:24]1[NH:23][C:21]([O:20][CH3:19])=[O:22]
Reactant: CNC(CN)c1ccccc1
Reactant: COC(=O)NC(=N)SC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)NC1=NCC(c2ccccc2)N1C

Procedure:
This example illustrates the process of the invention wherein 1-(mono)-alkoxycarbonyl-S-methylisothiourea is used in place of a mixture of the mono- and bis-alkoxycarbonyl-reagents. In this example, a solution containing 2.1 g. of β-methylamino-β-phenylethylamine dihydrochloride, 1.64 g. of sodium acetate and 2.4 g. of 1-methoxycarbonyl-S-methylisothiourea in 20 ml. of 50%, wt., aqueous methanol is gently refluxed for two hours. The resulting heavy slurry is cooled, filtered and the collected solid product then washed with methanol affording 1-methyl-4,5-dihydro-5-phenyl-2-methoxycarbonylaminoimidazole.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1.[C:27]([O:31][C:32](=[O:46])[CH:33]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][C:35](O)=[O:36])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:46])[C@@H:33]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][C:35]([O:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[CH:5]=[C:4]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH2:25][CH3:26])[N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:10][CH:11]=1)=[O:36])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(N)n1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)nc(N)n1

Procedure:
(S)-2-tert-Butoxycarbonylamino-succinic acid 4-{4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl} ester 1-tert-butyl ester was prepared according to the method described for Example 64 by using the title compound of Example 44 and 2-tert-butoxycarbonylamino-succinic acid 1-tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([S:14](=[O:19])(=[O:18])[N:15]([CH3:17])[CH3:16])[CH:13]=1.C([Li])CCC.CN(C)[CH:27]=[O:28].Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:27]=[O:28])[N:12]([S:14](=[O:18])(=[O:19])[N:15]([CH3:16])[CH3:17])[CH:13]=1
Reactant: CN(C)C=O
Reactant: CN(C)S(=O)(=O)n1cnc(-c2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(-c2ccc(Cl)cc2Cl)nc1C=O
Temperature: 25 °C

Procedure:
To 4-(2,4-Dichlorophenyl)-1-(dimethylsulphamoyl)imidazole, (8.0 g) in tetrahydrofuran (125ml), maintained under a dry nitrogen atmosphere at -60° was added 2.6M butyllithium in hexane (10.57 ml). The solution was stirred and after a short time dimethylformamide (2.9 ml) was added. The mixture was warmed slowly to room temperature and then added to dilute hydrochloric acid. The product was extracted with ethyl acetate and the extract washed with water, dried the solvent evaporated and the solid residue recrystallised from toluene to give 4-(2,4-dichlorophenyl)-1-(dimethylsulphamoyl)-2-formylimidazole, m.p. 148°-157° (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.CC[O:13][C:14]([CH:16]([C:20]([CH3:22])=O)[C:17]([CH3:19])=O)=[O:15]>C(O)(=O)C>[C:7]([C:5]1[CH:6]=[C:2]2[N:1]=[C:17]([CH3:19])[C:16]([C:14]([OH:15])=[O:13])=[C:20]([CH3:22])[N:3]2[N:4]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2cc(C(C)(C)C)nn2c(C)c1C(=O)O
Temperature: 120 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
3-Amino-5-t-butylpyrazole (1.6 g) and ethyl diacetoacetate (1.7 g) were dissolved in acetic acid (5 ml) and stirred for 3 hours at 120° C. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (10 ml) and 5 N sodium hydroxide solution (3 ml) were added to the residue and then stirred for 1 hour at 70° C. The mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give the title compound (2.1 g, Y.:78%) as white crystals.