Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:6].BrN1C(=O)CCC1=O.[NH2:25][C:26]([NH2:28])=[S:27].CCOC(C)=O>ClCCl>[NH2:28][C:26]1[S:27][C:4]([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[O:6])=[C:3]([C:2]([F:16])([F:15])[F:1])[N:25]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2sc(N)nc2C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
4,4,4-trifluoro-1-p-tolylbutane-1,3-dione (4 g, 17.4 mmol) in 100 mL dichloromethane at 0° C. under N2 was treated in portions with 3.09 g (17.4 mmol) N-bromosuccinimide. A white precipitate gradually formed. After 4.5 h solids were filtered off, the filtrate was washed with water and brine and dried over Na2SO4, then evaporated. The residue was taken up in 100 mL EtOH, treated with 1.32 g (17.4 mmol)thiourea and 1.04 g (17.4 mmol) silica and heated at 70° C. overnight. The reaction was cooled, filtered and evaporated. The crude was taken up in EtOAc, washed with NaHCO3 and brine, dried over Na2SO4 and evaporated. Trituration with Et2O: heptane provided 1.31 g desired as a yellow solid, still containing impurities. Chromatography (SiO2, EtOAc: dichloromethane) provided the title compound. The filtrate from the trituration also contained desired material and was similarly purified to provide the title compound. LCMS (method A) 287.1 (M+H), 285.2 (M−H). 1H-NMR (400 MHz, Chloroform-d) ppm 2.45 (s, 3H), 5.68 (br s, 2H), 7.29 (d, J=7.96 Hz, 2H), 7.77 (d, J−8.21 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:36]=[C:37]([NH:40][C:41](=[O:43])[CH3:42])[S:38][CH:39]=3)=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:36]=[C:37]([NH:40][C:41](=[O:43])[CH3:42])[S:38][CH:39]=2)=[CH:33][CH:34]=1
Reactant: Cc1cc(-c2c(O)c3cc(I)c(Cl)cc3[nH]c2=O)on1
Reactant: CC(=O)Nc1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cs1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(-c3cc4c(O)c(-c5cc(C)no5)c(=O)[nH]c4cc3Cl)cc2)cs1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
To a solution of 7-chloro-4-hydroxy-6-iodo-3-(3-methylisoxazol-5-yl)quinolin-2(1H)-one (Intermediate 99) (125 mg, 0.311 mmol) in 1,4-dioxane (4 mL) and water (2 mL) were added N-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)acetamide (Intermediate 31) (118 mg, 0.342 mmol), cesium carbonate (152 mg, 0.466 mmol) and tetrakis(triphenylphosphine)palladium (3.59 mg, 3.11 μmol). The reaction mixture was heated at 80° C. for 16 h. After cooling the reaction mixture was filtered, evaporated to dryness. The resulting residue was acidified with HCl 1N. The precipitate was filtered and dried to give the title compound N-(4-(4-(7-chloro-4-hydroxy-3-(3-methylisoxazol-5-yl)-2-oxo-1,2-dihydro quinolin-6-yl)phenyl)thiazol-2-yl)acetamide (130 mg, 0.264 mmol, 85% yield) as a grey solid. LCMS: (M+H)+=493; Rt=2.37 min.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]([NH:17][CH2:18][CH2:19][CH2:20][NH2:21])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:13]([O:12][C:10](=[O:11])[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 6.1 g (26.6 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 100 ml of acetonitrile is mixed successively with 5.0 g (28.7 mmol) of N-boc-1,3-diaminopropane and 4.5 ml (32.4 mmol) of triethylamine and stirred for 3.5 hours at room temperature. The batch is diluted with 200 ml of ethyl acetate. It is washed with saturated NaCl solution, citric acid (10%), saturated NaHCO3 solution as well as saturated NaCl solution. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 9.7 g (26.6 mmol, corresponding to 100% of theory) of the product is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:9]CCO1.[CH3:17][N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:19]1=[O:32].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][C:20]3([C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:18]([CH3:17])[C:19]3=[O:32])[CH2:21][CH2:22]2)=[O:9])=[CH:15][CH:14]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCN(CCCC(=O)c3ccc(F)cc3)CC2)c2ccccc21

Procedure:
A mixture of 3.0 g of 4-chloro-1-(4-fluorophenyl)-1,1-ethylenedioxybutane, 2.0 g of 1-methyl-2-oxo-indoline-3-spiro-4'-piperidine, 2.8 g of anhydrous potassium carbonate, 0.1 g of potassium iodide and 30 ml of dimethylformamide was refluxed for 2 hours. The resulting mixture was poured into water and was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. To the residual oil were added 60 ml of methanol, 20 ml of water and 10 ml of concentrated hydrochloric acid. The mixture was refluxed for 25 minutes and concentrated in vacuo. The residual oil was made alkaline with 28% aqueous ammonia and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residual oil was chromatographed over silica gel with ethyl acetate as an elueting agent to give 1'-[3-(4-fluorobenzoyl)propyl]-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine, M.P. 95°-96.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:15]([OH:17])=[O:16].[CH2:19]([N:22]1[CH2:26][C:25](=[O:27])[N:24]([CH2:28]O)[C:23]1=[O:30])[C:20]#[CH:21]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[C@H:3]1[C:15]([O:17][CH2:28][N:24]1[C:25](=[O:27])[CH2:26][N:22]([CH2:19][C:20]#[CH:21])[C:23]1=[O:30])=[O:16]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Reactant: C#CCN1CC(=O)N(CO)C1=O
Solvent: c1ccccc1
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C\C(=O)OCC(F)(F)F)C2(C)C)C1=O

Procedure:
Using the procedure of Step F of Example 9, the acid of Step D of Example 1 and (3-propargyl-2,5-dioxo-imidazolidinyl)-methanol were reacted to obtain [3-propargyl-2,5-dioxo-imidazolidinyl]-methyl (1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =-4°±1° (c=1% in benzene).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>CN(C)C=O.[Cu-]=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: C#CC(=O)OCC
Reactant: Oc1ccc(I)cc1
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: CCOC(=O)C#Cc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To a solution of 4-iodophenol (22.3 g) in dimethylformamide (200 ml) were added 19.5 ml of ethyl propiolate and 14.8 g of copper (I) oxide, and the reaction solution was stirred at 110° C. for 15 hours. The reaction solution was cooled and then filtered through Celite, and the filtrate was vacuum-concentrated. The residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (4:1)), followed by recrystallization of the purified residue with hexane/ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](F)[C:6]=1[N:15]1[CH:19]=[N:18][C:17]([CH3:20])=[N:16]1>C1COCC1>[F:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([O:2][CH3:1])[C:6]=1[N:15]1[CH:19]=[N:18][C:17]([CH3:20])=[N:16]1
Reactant: Cc1ncn(-c2c(F)cc([N+](=O)[O-])cc2F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])cc(F)c1-n1cnc(C)n1
Reaction time: 2 h
Yield: 82 %

Procedure:
Step S (1): A solution of sodium methanolate (0.5 M in methanol, 17.5 mL, 8.74 mmol) was added to a round bottom flask charged with a solution of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (2.1 g, 8.74 mmol, from preparation R, step R(1) in THF (25 mL). A slight pink color resulted. After 2 h, the reaction mixture was concentrated under reduced pressure. The white solid residue was triturated with ˜50 mL of 1 N HCl. The solid was collected by vacuum filtration and dried under high vacuum for several hours to afford 1-(2-fluoro-6-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.84 g, 7.15 mmol, 82% yield) as a white solid. LC-MS (M+H)+ 253.1.0. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.22 (s, 1 H), 7.80 (dd, J=9.0, 2.3 Hz, 1 H), 7.76 (t, J=2.0 Hz, 1 H), 3.99 (s, 3 H), 2.52 (s, 3 H).
Reaction SMILES: F[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.N[C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1N1N=CC=N1.[Br:53]C1C(Cl)=NC=C(C(F)(F)F)C=1>>[Br:53][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 105) from N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 100 mg, 0.33 mmol) and 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (CAS number 71701-92-3; 93 mg, 0.36 mmol) to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]4[C:30](=O)[O:29][C:28](=[O:32])[C:17]=4[CH:18]=[C:19]4[C:27]=3[C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=[CH:20]4)=[CH:14][C:9]=2[O:8][CH2:7]1.O>C1(C)C=CC=CC=1>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:27]4[C:19](=[CH:20][CH:21]=[C:22]5[O:26][CH2:25][O:24][C:23]5=4)[CH:18]=[C:17]4[C:28](=[O:32])[N:1]([CH2:2][CH2:3][CH2:4][OH:5])[C:30](=[O:29])[C:16]=34)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: NCCCO
Reactant: O=C1OC(=O)c2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2cc3ccc4c(c3c(-c3ccc5c(c3)OCO5)c2C(=O)N1CCCO)OCO4
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
3-Amino-1-propanol (27 mg, 0.36 mmol) in toluene (5 mL) at 0° C. was added dropwise to a stirred solution of anhydride 1 (109 mg, 0.3 mmol) in toluene (40 mL). The mixture was stirred at room temperature for 1 h and then heated under Dean-Stark trap for 3 h. After water ceased to distill, the reaction mixture was cooled, washed successively with water (2×50 mL), 5% aqueous NaHCO3 solution (2×50 mL), and water (2×50 mL), and then dried over MgSO4. The solvent was removed in vacuo, and the resulting product was purified by column chromatography on silica gel using CH2Cl2/acetone (3:1 to 1:1, v/v) to provide 29 (10 mg, 11%) as a pale yellow powder. mp 150-152° C.; 1H NMR (CDCl3) δ 8.27 (s, 1H, H4), 7.56 (d, 1H, H5, J=8.4 Hz), 7.26 (d, 1H, H6, J=8.4 Hz), 6.86-6.91 (m, 3H, H2′+H5′+H6′), 6.04 (s, 2H, 3′,4′-OCH2O—), 5.97 (s, 2H, 7,8-OCH2O—), 3.69-3.76 (m, 4H, NCH2CH2CH2OH), 1.83 (m, 2H, NCH2CH2CH2OH).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23](OC1C=CC=CC=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)Oc1ccccc1
Product: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)N1CCCC1
Yield: 50.1 %

Procedure:
3.12 g (7,5 mmol) of 1,4-dibenzyl-2-phenoxycarbonyloxymethylpiperazine are dissolved in 9.4 ml (15 equivalents; 112.8 mmol) of pyrrolidine in a 100 ml ground-necked conical flask on which is fitted a condenser. The mixture is refluxed in a thermostatically controlled oil bath for 60 hours. After cooling and evaporation of the excess amine, the residue is taken up in CH2Cl2 and washed with water until neutral. After drying the organic phase (MgSO4), filtration on paper and evaporation of the solvent, the product is chromatographed on a column of silica gel, eluting with an MeOH/CH2Cl2 mixture (0.5/99.5 v/v). 1.48 g of 1,4-dibenzyl-2-(1′-pyrrolidinocarbonyloxymethyl)piperazine are thus obtained in the form of a viscous product. Yield 50.2%. Rf=0.38 (5/95 v/v MeOH/CH2Cl2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1>O1CCCC1.C1CCCCC1>[F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][C:7]=1[C:19]1([OH:22])[CH2:20][CH2:21][S:17][CH2:18]1
Reactant: O=C1CCSC1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)CCSC2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 1.00 g) in dry tetrahydrofuran (16 mL) at −78° C. under N2 is treated with see-butyllthium (1.3 M in cyclohexane, 3.30 mL) dropwise over 2 mins, and the resulting mixture is stirred at −78° C. for 2 hrs. The mixture is then treated with a solution of tetrahydrothiophen-3-one (423 mg) in dry tetrahydrofuran (4.1 mL) dropwise over 2 mins and is stirred at −78° C., allowing the cooling bath to expire over 4 hrs. The mixture is then quenched with saturated aqueous ammonium chloride (25 mL), diluted with water (25 mL), the layers are separated, and the combined organic phase is washed with saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (16 mL) and treated with anhydrous potassium carbonate (1.09 g), and the mixture is stirred at ambient temperature for 30 mins, concentrated under reduced pressure, diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude 3-fluoro-4-[3-(hydroxy)tetrahydrothiophen-3-yl]benzenamine intermediate (Rf=0.37 by TLC, ethyl acetate/hexane (50/50)). A solution of this intermediate in tetrahydrofuran (16 mL) and water (8 mL) is then treated with sodium bicarbonate (662 mg) and benzyl chloroformate (0.56 mL), and the resulting mixture is stirred at ambient temperature for 4 hrs, diluted with water (8 mL), the layers are separated, and the organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf=0.19 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound, mp 134-135° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[S:9]1[CH:13]=[CH:12][C:11]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:10]1
Reactant: Oc1ccc(I)cc1
Reactant: OB(O)c1ccsc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Oc1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a 25 mL press resistant vial which contained a suspension of 4-iodo-phenol (220 mg, 1 mmol), thiophene-3-boronic acid (128 mg, 1 mmol), palladium(II) acetate (20 mg, 0.1 mmol) and triphenyl phosphine (60 mg, 0.25 mmol) in DME (10 mL) was added potassium carbonate (400 mg, 2.5 mmol), ethanol (0.25 mL) and water (0.25 mL) at rt. The tube was sealed and the mixture was allowed to stir at rt for 30 min and then was heated to 98° C. and stirred at 98° C. for 16 h. After cooling to rt, the mixture was poured onto 200 mL ice-water solution and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL) and brine (20 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (130 mg, 70%); 1H NMR (400 MHz, CDCl3); 4.70 (s, 1H), 6.65 (d, J=6.8 Hz, 2H), 7.31-7.3 (m, 3H), 7.48 (d, J=6.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])=[CH:14][C:10]=2[CH:11]=[N:12][N:13]=1.C(Cl)(=O)C(Cl)=O.[NH2:36][C:37]1[CH:41]=[CH:40][O:39][N:38]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([NH:36][C:37]3[CH:41]=[CH:40][O:39][N:38]=3)=[O:24])=[CH:14][C:10]=2[CH:11]=[N:12][N:13]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc2cnnc(-c3ccccc3Cl)c2n(C)c1=O
Reactant: Nc1ccon1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-c1cc2cnnc(-c3ccccc3Cl)c2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzoic acid (100 mg, 0.25 mmol; prepared by the general method shown in scheme 2) in DCM at 0° C. was added oxalyl chloride (43.7 μl, 0.49 mmol) followed by a drop of DMF. The reaction was stirred at 0° C. for 15 min then warmed to RT for 1 h. The volatile solvents were removed under reduced pressure and the residue was dissolved in DCM. To the reaction mixture was added 3-aminoisoxazole (54.6 μl, 0.74 mmol) and N,N-diisopropylethylamine (42.9 μl, 0.25 mmol). After the reaction mixture was stirred at RT for 3 h, the solvent was then removed in vacuo. The residual crude material was purified with Reverse phase-HPLC [elution gradient of 10-50% of (0.1% TFA in acetonitrile) in (0.1% of TFA) in water] and the fractions containing the product were combined and concentrated in vacuo. The remaining crude mixture was stirred with EtOAc and sat. Na2CO3. The organic layer was separated and washed with brine, separated, then dried with sodium sulfate and concentrated to give 3-(8-(2-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-N-(isoxazol-3-yl)-4-methylbenzamide (33.0 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 (1H, s), 9.48 (1H, s), 8.81 (1H, s), 8.24 (1H, s), 7.95-8.10 (2H, m), 7.76-7.86 (1H, m), 7.56-7.74 (3H, m), 7.46 (1H, d, J=8.0 Hz), 7.05 (1H, s), 3.12 (3H, s), 2.24 (3H, s); Mass Found: LC-MS (ESI): m/e=472/474
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[C:22]([C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=1)[NH2:29])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:29][C:28]2[CH:30]=[C:31]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH:32]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:27]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1cc(C(C)(C)C)cc(C(C)(C)C)c1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reaction time: 48 h

Procedure:
2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetylpyridine (1.3 g, 4.64 mmol), prepared according to the method disclosed in WO02/28805, and 3,5-di-tert-butylaniline (1 g, 4.87 mmol) were dissolved in 100 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 2 days the mixture was filtered. The solvent was removed in vacuo. The residue was washed with methanol and crystallised from ethanol. Yield 1.1 g (51%) of 2-[1-(2,4,6-trimethylphenylimino) ethyl]-6-[1-(3,5-di-tert-butylphenylimino)ethyl]pyridine. 1H-NMR (CDCl3) δ 8.43 (d, 1H, Py-Hm), 8.37 (d, 1H, Py-Hm), 7.87 (t, 1H, Py-Hp), 7.16 (t, 1H, ArH), 6.89 (s, 2H, ArH), 6.69 (d, 2H, ArH), 2.42 (s, 3H, Me), 2.29 (s, 3H, Me), 2.22 (s, 3H, Me), 2.01 (s, 6H, Me), 1.33 (s, 18H, But).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(O)C.C(CN)O>O>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: O
Solvent: CCO
Solvent: NCCO
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 70 °C
Yield: 91.3 %

Procedure:
Thebaine (142.86 g of 70 wt % material containing 30 wt % water, 100.00 g, 0.321 mol), p-toluene sulfonyl hydrazide (131.58 g, 0.706 mop and ethanol (400 ml) were stirred and heated to 70° C. Ethanol amine (43.16 g, 0.706 mol) was added to this solution over a 1 h period. The reaction was heated for a further 10 h at this temperature and then allowed to cool to room temperature. The reaction was diluted with water (400 ml) and the pH adjusted to >9.30 with concentrated (28.0-30.0%) ammonium hydroxide (30 ml) and cooled to <5° C. The product was isolated by filtration and washed with 1% v/v ammonium hydroxide in water (400 ml) to give 8,14-dihydro-thebaine as a white amorphous solid (91.94 g, 91.3% yield, 99.29 wt % by assay, with 0.16 wt % of the 6-β-parzone methyl ether impurity).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[NH:28][C:27]([NH2:30])=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:15]1[CH:16]=[CH:17][N:13]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[N:28]=[C:27]([NH:30][C:10]([C:8]3[CH:9]=[C:4]4[CH:3]=[CH:2][S:1][C:5]4=[CH:6][N:7]=3)=[O:12])[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=C(O)c1cc2ccsc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccsc2cn1
Yield: 2.6 %

Procedure:
2.6 mg (3%) of thieno[2,3-c]pyridine-5-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was prepared according to general procedure A using 54 mg (0.3 mmol) thieno[2,3-c]pyridine-5-carboxylic acid, 61 mg (0.25 mmol) intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 114 mg (0.3 mmol) of HBTU, 0.106 mL (0.6 mmol) of DIEA in 1 mL of DMF stirring at 85° C. for 1 h. LCMS: 404 (M+1)+.