Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:20][C:21]1[CH:22]=[C:23]([C@H:28]([NH2:30])[CH3:29])[CH:24]=[C:25]([F:27])[CH:26]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:30][C@@H:28]([C:23]2[CH:24]=[C:25]([F:27])[CH:26]=[C:21]([F:20])[CH:22]=2)[CH3:29])=[CH:13][CH:14]=1
Reactant: C[C@@H](N)c1cc(F)cc(F)c1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Yield: 94.2 %

Procedure:
Following a similar procedure to that described in Example (1a), 1.0 g of 4-chlorophenyl 3-nitrophenyl ketone, 1.11 g of (R)-1-(3,5-difluorophenyl)ethylamine hydrochloride, 2.93 ml of triethylamine, 0.50 ml of titanium tetrachloride, 1.01 g of sodium cyanoborohydride and 0.33 ml of acetic acid were reacted, to obtain 1.45 g of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][NH:28][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=3)[CH2:11][N:12]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)N(CCc1ccncc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(CCc1ccncc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 21 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 504. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 2H) 8.3 (d, 1H) 8.0 (s, 1H) 7.9 (m, 1H) 7.5 (m, 2H) 7.0 (m, 4H) 6.9 (d, 1H) 6.7 (d, 2H) 5.5 (m, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.5 (, 2H) 2.8 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([I:8])=[CH:6][N:7]=1.[CH:12]([N:15](C(C)C)[CH2:16]C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.C1COCC1.ClCCl>[CH3:12][N:15]([CH3:16])[C:9]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([I:8])[N:4]=1)=[O:11]
Reactant: Nc1ncc(I)nc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1nc(I)cnc1N
Reaction time: 23 h
Yield: 62 %

Procedure:
534 mg (2.02 mmol) of 3-amino-6-iodo-pyrazine-2-carboxylic acid were dissolved in 20 mL of 50% v/v acetonitrile in dichloromethane containing 350 μL (2.01 mmol) of di-iso-propyl-ethylamine. 818 mg (2.18 mmol) of N,N,N′,N′,-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate were added. Upon stirring for 3 minutes at ambient temperature 2.5 mL (5 mmol) of 2.0 M dimethylamine in anhydrous THF was added and stirring was continued for 23 h. The resulting solution was distributed between dichloromethane and 10% w/v aqueous citric acid solution. The organic phase was dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate and hexanes to afford 363 mg (1.24 mmol, 62%) of 3-amino-6-iodo-pyrazine-2-carboxylic acid dimethylamide as a pale yellow crystalline solid. 1H-NMR [500 MHz, d6-DMSO] δ: 8.25 (s, 1H), 6.71 (s, hr., 2H), 2.98 (s, 3H), 2.92 (s, 3H); MS [MH+] m/z: 293.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[C:13]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:14]=4[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[C:10]([CH3:33])[C:9]([N+:34]([O-])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:34][C:9]1[C:10]([CH3:33])=[C:11]([C:12]2[C:13]3[CH:22]=[CH:21][N:20]([S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=4)(=[O:25])=[O:24])[C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(OCC5CC5)ccc([N+](=O)[O-])c4C)cn(C)c(=O)c32)cc1
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(OCC5CC5)ccc(N)c4C)cn(C)c(=O)c32)cc1

Procedure:
Example 251c was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 251b for the product of Example 2b to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:5]2[N:6]=[C:7]3[C:12]([C:11]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)=[CH:10][CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:2]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][N:5]4[N:6]=[C:7]5[C:12]([C:11]([C:13]6[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=6)=[CH:10][CH:9]=[CH:8]5)=[C:4]4[N:3]=3)=[CH:44][CH:45]=2)[CH2:37][CH2:38][CH2:39]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: N#Cc1ccc(-c2cccc3nn4cc(-c5ccccc5)c(Cl)nc4c23)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5c(-c6ccc(C#N)cc6)cccc5nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
114 mg (0.3 mmol) 4-(2-Chloro-3-phenylpyrimido[1,2-b]indazol-10-yl)benzonitrile, 122.9 g (0.3 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester, 34.6 mg (0.03 mmol) tetrakistriphenylphosphinepalladium(0) and 95 mg (0.90 mmol) sodium carbonate in 3.2 mL dioxane and 0.45 mL water were heated in a microwave vial which had been sealed with a microwave cap over night at 105° C. (heating block). After the usual work up, the crude mixture (235 mg) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=2[CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35]([N:13]3[C:14](=[O:15])[C:9]([CH2:8][C:6]4[CH:5]=[CH:4][C:3]([C:20]5[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=5)=[C:2]([F:1])[CH:7]=4)=[C:10]([CH2:17][CH2:18][CH3:19])[N:11]=[C:12]3[CH3:16])[CH:36]=[CH:37][C:31]=2[O:30]1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)c(F)c1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
A mixture of 2′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.53 g), copper acetate (0.5 g), pyridine (1.1 mL), triethylamine (1.9 mL), molecular sieves 4 A (2.0 g) and methylene chloride (10 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.98 g, 69%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:26][CH3:27])[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([O:28][CH3:29])[CH:10]=1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>ClCCl>[CH3:29][O:28][C:11]1[CH:12]=[C:13]2[O:17][C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:26][CH3:27])[S:21]4)=[CH:15][C:14]2=[C:9]([OH:8])[CH:10]=1
Reactant: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: ClCCl
Product: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A mixture of 6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (Example 1G, 1.250 g, 3.06 mmol) and pentamethylbenzene (3.17 g, 21.4 mmol) in dichloromethane (200 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated immediately (to avoid crystallization) with 8 mL (8 mmol) of a 1 M solution of boron trichloride in dichloromethane added dropwise over 3 min. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was then quenched by the addition of a solution of sodium bicarbonate (6 g) in water (100 mL) added in one portion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 h. The solid formed was filtered, washed successively with water (50 m) and dichloromethane (50 mL). The filter cake was allowed to soak with anhydrous ethanol (15 ml) and then sucked dry. The white solid obtained was then dried under vacuum for 24 h to give 0.788 g (80% yield) of pure title material (>95% by hplc). The combined filtrate and washings were diluted with dichloromethane (600 mL) and stirred in a warm water bath till the organic phase was clear with no apparent solid in suspension. The organic phase was collected, dried over anhydrous magnesium sulfate and rapidly filtered while still warm. The filtrate was evaporated and the residue (product and hexamethylbenzene) was triturated with toluene (20 mL), the solid collected and washed with toluene (20 mL) to give 0.186 g (19% yield, 99% combined yield) of title material as a tan solid (>95% by hplc). LC (Method E): 1.444 min. HRMS (ESI) calcd for C14H12N3O4S [M+H]+ m/z 318.0543. found 318.0578. 1H NMR (DMSO-d6, 600 MHz) δ 3.71 (s, 3H), 4.16 (s, 3H), 6.21 (d, J=1.87 Hz, 1H), 6.61 (broad s, 1H), 6.95 (s, 1H), 8.29 (s, 1H), 9.96 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([NH:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:3]1[N:2]([CH3:1])[C:6]2[C:7]([NH:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2cccc(Nc3ccc(C#N)cc3)c21
Product: Cn1c(Cl)nc2cccc(Nc3ccc(C#N)cc3)c21
Yield: 45 %

Procedure:
A mixture of 4-[(1-methyl-2-oxo-1,3-dihydro-2H-benzimidazol-7-yl)amino]benzonitrile (137 mg, 0.518 mmol), prepared in a similar manner as described in Example 154, and phosphorous oxychloride (1.5 ml) was refluxed for 3 h. The mixture was concentrated in vacuo and quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was flash chromatographed eluting with a solution of 25% ethyl acetate/hexane to give 66 mg (45%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8](O)=[N:7][C:6]=2[NH:5][N:4]=1)[CH3:2].P(Br)(Br)([Br:20])=O>C(#N)C>[Br:20][C:8]1[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:11]2[C:3]([CH2:1][CH3:2])=[N:4][NH:5][C:6]=2[N:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1cc(O)nc2[nH]nc(CC)c12
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2[nH]nc(CC)c12
Yield: 68.3 %

Procedure:
Ethyl 3-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.52 g, 2.21 mmol) was suspended in acetonitrile (6 mL) and POBr3 (1.27 g, 4.42 mmol) was added to it. The reaction mixture was refluxed for 6 h. On completion of reaction, acetonitrile was removed under reduced pressure and residue neutralized with saturated NaHCO3. Extraction was carried out using EtOAc; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired intermediate (0.45 g, 68.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[CH:26]12[NH:33][C:30]([C:34]([OH:36])=[O:35])([CH2:31][CH2:32]1)[CH2:29][O:28][CH2:27]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:33]2[C@@:30]3([C:34]([OH:36])=[O:35])[CH2:31][CH2:32][C@@H:26]2[CH2:27][O:28][CH2:29]3)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C(O)C12CCC(COC1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(CN2[C@@H]3CC[C@@]2(C(=O)O)COC3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (compound C, 61 mg, 0.138 mmol), 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a (20 mg, 0.127 mmol) and DIPEA (0.07 mL, 0.4 mmol) in DCM (5 mL) was stirred at 25° C. for 16 h. Then the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford a pair of diastereomers, Example 81 and Example 82.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Cl[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].Cl>CN(C=O)C.C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: COCCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
10 g (43.8 mmol) of 4′-hydroxybiphenyl-4-carboxylic acid methyl ester, 100 ml of THF and 150 ml of DMF are introduced in order and under a nitrogen stream into a 500 ml three-necked flask. 1.93 g (48.2 mmol) of NaH at 60% in oil are added in small portions and the mixture is stirred at room temperature for 15 hours. 5.75 ml of 1-chloromethoxy-2-methoxyethane are added dropwise, and the mixture is stirred at room temperature for 30 minutes. The reaction medium is poured over a 1N HCl solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. After filtration and evaporation 12 g of 4′-(2-methoxyethoxymethoxy)biphenyi-4-carboxylic acid methyl ester are obtained in the form of a beige powder after filtration and evaporation (yield=87%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH2:14][C:15](=[O:17])N)=[C:9]([OH:18])[CH:8]=[CH:7]2)(=[NH:3])[NH2:2].Cl.C(=O)(O)[O-:21].[Na+]>O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH2:14][C:15]([OH:21])=[O:17])=[C:9]([OH:18])[CH:8]=[CH:7]2)(=[NH:3])[NH2:2]
Reactant: O=C([O-])O
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(N)c1ccc2c(CC(=O)O)c(O)ccc2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 98.8 %

Procedure:
To 12.4 g of 6-amidino-1-carbamoylmethyl-2-naphthol was added 370 g of 25% hydrochloric acid, followed by stirring at 70° C. for 2.5 hours. After cooling with water, the precipitate was collected by filtration and washed with 80 g of 15% hydrochloric acid. The collected precipitate was added to a solution prepared by adding 200 ml of water to 10 g of sodium bicarbonate, followed by stirring for 1 hour at room temperature, and the resulting precipitate was collected by filtration and washed with water. This collected precipitate was added to a solution of 13 ml of methanesulfonic acid in 180 ml of water to dissolve the precipitate at 50° C. Furthermore, 1.0 g of active carbon was added to the solution, followed by stirring for 1 hour at room temperature. Thereafter, insoluble matter was filtered off and the filtrate was concentrated to 90 ml under reduced pressure. This solution was stirred for 24 hours under cooling with water. Then, the precipitate was collected by filtration and washed with a small amount of acetone and ether to obtain 12.3 g of the desired product.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 6 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[4-(methylsulfonyl)phenyl]pyridazin-4(1H)-one (crude 615 mg, 1.77 mmol) in 20 mL of methanol was added phenylhydrazine (765 mg, 7.08 mmol). The mixture was, refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-[4-(methylsulfonyl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (42 mg, 6% for two steps) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]4[N:22](CC5C=CC(OC)=CC=5)[CH:21]=[N:20][C:19]=4[C:13]3=[N:12][C:11]2=[O:32])=[CH:5][CH:4]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:36]=1[O:43][CH3:44]>C(O)(C(F)(F)F)=O>[CH3:33][O:34][C:35]1[C:36]([O:43][CH3:44])=[C:37]([O:41][CH3:42])[CH:38]=[CH:39][C:40]=1[C:13]12[NH:12][C:11](=[O:32])[N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:14]1=[N:15][CH:16]=[N:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=12
Reactant: COc1ccc(Cn2c3ncnc4c(ncn4Cc4ccc(OC)cc4)c-3nc2=O)cc1
Reactant: COc1cccc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)NC3(c4ccc(OC)c(OC)c4OC)C2=NC=Nc2[nH]cnc23)cc1
Temperature: 60 °C
Yield: 80 %

Procedure:
To a stirred suspension of 3 (0.43 g, 1 mmol) in 1,2,3-trimethoxybenzene (5 mL), TFA (10 mL, dropwsie) was added. The reaction mixture was heated at 60° C. for 3 h. TFA was evaporated on rotary evaporator after the disappearance of starting material (TLC) and excess of sodium bicarbonate was added. The reaction mixture was extracted with EtOAc (30×3 mL), washed with brine, dried (anhyd. Na2SO4) and adsorbed over silica and purified through column chromatography to afford 14 as yellowish white solid (0.38 g, 80%); mp: decomposed >225° C. IR: 1734 (C═O str.), 1620, 1514, 1247 (C—O str.) cm−1. 1H NMR (400 MHz, d6-DMSO): δ=3.52 (s, 3H, OCH3), 3.69 (s, 6H, OCH3), 4.60 (dd, J=15.1, 18.3 Hz, 2H, CH2), 5.80 (J=8.7 Hz, 1H, Ar—H), 6.50 (J=8.7 Hz, 1H, Ar—H), 6.85 (d, J=8.7 Hz, 2H, Ar—H), 7.22 (d, J=8.7 Hz, 2H, Ar—H), 7.50 (s, 1H, Ar—CH═N—), 7:85 (s, 1H, Imid-H), 9.40 (brs, 1H, D2O-exchangable NH). 13C NMR (100 MHz, d6-DMSO): δ=42.9, 55.6, 56.3, 60.7, 60.8, 63.4, 106.7, 114.2, 120.0, 122.0, 122.8, 129.1, 129.9, 134.9, 137.2, 142.0, 146.0, 152.6, 154.2, 154.7, 156.6, 159.1. HRMS (FAB) Calcd for C24H24N6O5, 476.1808 (M+); observed m/z 477.1875 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[C:26]2[C:21](=[CH:22][C:23]([N:27]=[C:28]=[O:29])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>>[CH2:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:28](=[O:29])[O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]4)=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: O=C=Nc1ccc2c(c1)CCC2
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1ccc2c(c1)CCC2)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with 5-indanylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a solid (14.3 mg, 75%) having the following characteristics.
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH3:20])[CH:14]=[CH:13][C:12]=1[CH2:21][CH3:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH3:20])[C:14]([I:1])=[CH:13][C:12]=1[CH2:21][CH3:22])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCOc1ccc(CC)c(OCc2ccccc2)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCOc1cc(OCc2ccccc2)c(CC)cc1I
Reaction time: 1 h

Procedure:
A solution of iodine (2.82 g, 11.1 mmol) dissolved in CHCl3 (80 mL) was added dropwise to a stirred mixture of 2-benzyloxy-1-ethyl-4-propoxy-benzene (3 g, 11.1 mmol), silver trifluoroacetate (2.45 g, 11.1 mmol) in CHCl3 (20 mL). After the addition was complete the reaction mixture was stirred for 1 hour. The mixture was filtered through a pad of celite washing with CH2Cl2. The filtrate was washed with satd Na2S2O3, brine, dried over Na2SO4 and concentrated to a pale yellow solid (4.04 g, 92%). 1H NMR (400 MHz, CDCl3): δ 1.07 (t, J=7.3 Hz, 3H), 1.17 (t, J=7.6 Hz, 3H), 1.81 (m, 2H), 2.59 (q, J=7.6 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 5.05 (s, 2H), 6.43 (s, 1H), 7.31-7.45 (m, 5H), 7.49 9s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12]Cl>C(Cl)(Cl)Cl>[Cl:12][C:7]1[CH:8]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(N)c([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 25 %

Procedure:
To a stirred solution of 4-methyl-2-nitroaniline (19.69 g, 129.4 mM) in chloroform (200 mL) under a nitrogen atmosphere was added dropwise a solution of chlorine (10.15 g, 285.9 mM) in chloroform (100 mL) while maintaining the reaction mixture temperature below 30° C. The reaction mixture was stirred for 3 days and then washed with aqueous sodium bicarbonate. The organic phase was then concentrated and the residue chromatographed (eluant: hexane/diethyl ether; 9/1) over silica gel to provide (6.03 g, 25%) the title compound as an orange crystalline solid, mp 68.5°-69.5° C.; MS(CI): 187 (M+H).
Reaction SMILES: [C:1]1(Cl)[C:7](=[O:8])[C:6]([Cl:9])=[C:5]([Cl:10])[C:3](=[O:4])[C:2]=1[Cl:11].C(=O)([O-])O.[Na+].[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(C(C)=O)C>[Cl:9][C:6]1[C:7](=[O:8])[C:1]([O:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:2]([Cl:11])[C:3](=[O:4])[C:5]=1[Cl:10]
Reactant: OC1CCCCC1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C1C(Cl)=C(Cl)C(=O)C(OC2CCCCC2)=C1Cl
Temperature: 55 °C
Yield: 66.7 %

Procedure:
Chloranil (0.06 mole) and sodium hydrogen carbonate (0.075 mole) were added to 300 ml of methyl ethyl ketone (MEK). The mixture was heated to 55° C. before adding cyclohexanol (0.5 mole) dropwise with stirring. When the reaction was complete (as judged by HPLC) the MEK solvent was removed from the product mixture under vacuum. The resultant orange gum was recrystallised from petroleum ether to provide the bright orange crystalline title product (0.04 moles).