Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br.[OH:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[CH2:22][CH2:23][NH2:24]>CN(C)C=O>[OH:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[CH2:22][CH2:23][NH:24][C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: NCCc1ccccc1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cccnc1)NCCc1ccccc1O
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 62.1 %

Procedure:
Trans-3-(3-pyridyl)acrylic acid (22.35 g) and N,N′-carbonyldiimidazole (24.54 g) were dissolved in dimethylformamide (300 ml) and stirred at 40° C. for 40 minutes. Then, potassium carbonate (41.4 g) and 2-hydroxyphenethylamine hydrobromide (32.70 g) were added under room temperature and stirred for 1 hour. Insoluble materials were filtered out and the filtrate was concentrated under reduced pressure. Dilute hydrochloric acid was added to the residue under ice-cooling and stirring. The precipitated crystal was filtered out, washed with water, purified by silica gel column chromatography (chloroform:methanol=20:1) and then recrystallized in methanol to yield the titled compound (24.98 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CO>[NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([F:23])[CH:25]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(-c2nc(Br)cc(C(=O)OC)c2N)cc1
Reactant: COc1ccc(B(O)O)cc1F
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: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC)c(F)c3)cc(C(=O)OC)c2N)cc1
Temperature: 125 °C
Yield: 80 %

Procedure:
A mixture of methyl 3-amino-6-bromo-2-(4-(methoxycarbonyl)phenyl)-isonicotinate (2.00 g, 5.48 mmol), 3-fluoro-4-methoxyphenylboronic acid (0.931 g, 5.48 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.316 g, 0.274 mmol) in a flask was flushed with nitrogen. Toluene (25 mL), MeOH (5 mL) and a 2 N aqueous solution of sodium carbonate (6.2 mL, 12.4 mmol) was added and the reaction was heated in a 125° C. oil bath for 2 hr. The reaction was partitioned between EtOAc and a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine. It was dried with sodium sulfate and the solvents removed. Flash silica gel chromatography (elution with hexane containing 10% EtOAc) afforded methyl 3-amino-6-(3-fluoro-4-methoxyphenyl)-2-(4-(methoxycarbonyl)phenyl)isonicotinate (1.8 g). MS (ESI) m/z 411.2 (M+H). 1H NMR (CDCl3) δ ppm 8.18 (2H, d, J=8.24 Hz), 8.06 (1H, s), 7.81 (2H, d, J=8.24 Hz), 7.74 (1H, dd, J=12.97, 1.98 Hz), 7.68 (1H, d, J=8.85 Hz), 6.99 (1H, t, J=8.70 Hz), 5.98 (2H, br. s.), 3.97 (3H, s), 3.96 (3H, s), 3.92 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]1C=C(NC2C=CC=CC=2)C=CC=1.N1C=CC=CC=1C=O>>[CH2:19]([C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1)[CH3:20]
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Cc1cccc(Nc2ccccc2)c1
Agent: O=Cc1ccccn1
Product: CCc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-methylphenylaniline (32.1 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(3-ethylphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:18][CH2:17][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A cold solution (0° C.) of N-Boc-D-phenylalaninol (0.53 g, 2.09 mmol) in anhydrous methylene chloride (20 mL) was treated sequentially with methanesulfonyl chloride (360 mg, 3.14 mmol) and triethylamine (0.32 g, 3.14 mmol). The reaction was stirred at 0° C. for 2 hr, quenched with 1M hydrochloric acid (2×25 mL) and extracted with methylene chloride. The combined extract was washed with saturated sodium bicarbonate (1×25 mL), and brine (1×25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate adsorbed onto silica gel and applied to a column prepacked with silica gel. The title compound was eluted from the column with hexane:ethyl acetate (60:40, v:v) to furnish titled compound (352 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CC(C)(O)C1(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)C1(Nc2nc(Cl)nc3c2SCC3)CC1
Temperature: 160 °C

Procedure:
2.7 g (II) are placed in 30 ml dioxane, then 6.8 ml diisopropyl-ethylamine and 1.8 g 2-(1-aminocyclopropyl)-propan-2-ol (cf. Liebigs Ann. Chem. 1978.1194) are added. The reaction mixture is heated to 160° C. until there is no further reaction and after cooling it is evaporated to dryness. The residue is mixed with ice water. The product is extracted with dichloromethane and purified by chromatography. 125 mg (III-8) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.08 min.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7](N(OC)C)=[O:8])[CH2:3]1.[CH3:14][Mg]Br.C(OCC)C>C1COCC1>[F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7](=[O:8])[CH3:14])[CH2:3]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCC(F)(F)C1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1CCC(F)(F)C1
Reaction time: 1.5 h

Procedure:
To a solution of (rac)-3,3-difluoro-N-methoxy-N-methylcyclopentane-carboxamide (1.90 g, 9.83 mmol) in 20 mL THF at 0° C. was added methylmagnesium bromide 3.0 m in diethyl ether (6.56 mL, 19.67 mmol) slowly dropwise. The reaction mixture became white and cloudy. After 1.5 h, the reaction mixture was quenched carefully with ice and 1N HCl, and diluted with Et2O. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give (rac)-1-(3,3-difluorocyclopentyl)ethanone as a light yellow oil. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.03-3.19 (m, 1 H), 2.22-2.48 (m, 2 H), 2.20 (s, 3 H), 2.03-2.16 (m, 3 H), 1.90-1.99 (m, 1 H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[N:37]1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[NH2:43]>ClCCl>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:43][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][N:37]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cnccn1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cnccn1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (50 mg, 0.16 mmol) in dichloromethane (5 mL) was added oxalylchloride (0.02 mL, 0.25 mmol) at 0° C. and the reaction mixture was stirred at 25° C. for 3 h. Solvent was removed in vacuo and the residue was dissolved in dry dichloromethane. To this was added DIPEA (0.2 mL, 0.99 mmol) followed by 2-pyrazinamine (CAN 5049-61-6, 19 mg, 0.21 mmol) at 25° C. and the reaction mixture was stirred for 12 hours at that temperature. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to give 5-cyclohexyl-N-pyrazin-2-yl-6-(2,2,2-trifluoro-ethoxy)-nicotinamide as off white solid (10 mg, 15.9%); MS (ESI): 381.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39](O)=[O:40])[CH:37]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][N:20]([C:39]([C:38]5[CH:37]=[C:36]([CH:44]=[CH:43][CH:42]=5)[C:35]([O:34][CH3:33])=[O:45])=[O:40])[CH2:21][CH2:22]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole IIa (300 mg, 0.7 mmol) in dichloromethane (10 mL) was added isophthalic acid monomethyl ester (138.9 mg, 0.77 mmol) and triethyl amine (107 μL, 0.77 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (146.7 mg, 0.77 mmol) and 4-dimethylaminopyridine (8.5 mg. 0.07 mmole). After being stirred for 4 hours at ambient temperature, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3×40 mL). The combined organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate 10 as amorphous solid (297 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 8.13-8.08 (m, 2H), 7.70 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.45-7.40 (m, 2H), 7.35-7.30 (m, 4H), 7.20-7.15 (m, 2H), 4.68 (br, 1H), 4.2 (br, 1H), 3.96 (s, 3H), 3.57 (br, 1H), 3.43-4.31 (m, 4H), 2.60 (s, 3H), 2.42 (br, 3H), 2.19 (br, 1H), 1.99-1.92 (m, 10H), 1.69 (br, 2H). HRMS m/z (M+H)+ calcd 591.33335; obsd 591.3325.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]([CH3:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH3:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH:21][C:33]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])=[O:9])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCNC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 4-nitro-N-methyl-N-[2-(3-aminoprop-1-yloxy)phenyl]benzamide (422 mg) and triethylamine (130 mg) in dichloromethane (10 ml) was added phenyl chloroformate (201 mg) and the solution was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with dichloromethane and then the organic solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; 1% methanol in chloroform) to give 4-nitro-N-methyl-N-[2-(3-phenoxycarbonylaminoprop-1-yloxy)phenyl]benzamide (383 mg) as a slightly yellow oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C:16]([CH:19]=O)([CH3:18])[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:50]([F:55])([F:54])C([O-])=O.[Na+]>COCCOCCOC>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C:16]([CH:19]=[C:50]([F:55])[F:54])([CH3:18])[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CC1(C=O)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Product: CC1(C=C(F)F)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 21.7 %

Procedure:
To 2.0 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-formyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (5 mmole), was added 4 g of triphenylphosphine (15 mmole), 3 g of sodium chlorodifluoroacetate (20 mmole) and 15 ml of diglyme. The mixture was heated slowly to reflux over 1 hour. Gas evolved. After refluxing for 20 minutes the mixture was colled, partitioned between ether and water, dried, rotovaped and chromatographed (ether/hexane) to yield 0.5 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-(2,2-difluorovinyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide mp 142°-8° C. NMR data was consistent with the structure.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(C)=O>[O:27]=[C:20]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To an ice-cooled solution of 3-(trifluoromethyl)aniline (64.5 g, 0.40 mol) and triethylamine (60 ml) in acetone (700 ml) was added dropwise, ethyl 3-chloro-3-oxopropanoate (63.6 g, 0.42 mol) in acetone (50 ml). After the addition was complete (approx. 30 minutes), stirring was continued at RT overnight. The solvents were removed and water (1200 ml) was added. The resulting precipitate was filtered off, thoroughly washed twice with water and then dried to afford ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate as a yellow powder (109 g, 99%).
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([N:11]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]1[C:20]1[O:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:32]([CH:34]1[O:36][CH2:35]1)Cl>O1CCOCC1>[O:36]1[CH2:35][CH:34]1[CH2:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[O:21][C:20]([C:12]3[N:11]([CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=3)=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: Oc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3Cc3ccccc3)o2)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1cn(Cc2ccccc2)c(-c2ccc(-c3ccc(OCC4CO4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 48.1 ml of 1N sodium hydroxide solution and 18.5 ml of water is added to a solution of 18.5 g of 2-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-5-(4-hydroxyphenyl)-furan in 160 ml of dioxan and the mixture is stirred for 10 minutes at room temperature. After the addition of 13.3 g of epichlorohydrin, the mixture is stirred for a further 48 hours at room temperature, then filtered and the filter residue is washed with dioxan/water 1:1 and then with ether. After drying, 2-[4-(2,3-epoxypropoxy)-phenyl]-5-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-furan is obtained in the form of a white crystallisate.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])[NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])[N:16]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=P(N=Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 39.6 %

Procedure:
P,P-diphenyl-N-phenylmethylene phosphinic amide was prepared following the method of Jennings (ibid) by adding titanium tetrachloride (635 ml; 5.78 mmol) in dry dichloromethane (10 ml) to a stirred solution of benzaldehyde (1.17 ml; 11.59 mmol), P,P-diphenylphosphinic amide (2.52 g; 11.59 mmol) and anhydrous triethylamine (4.84 ml; 34.78 mmol) in dry dichloromethane (50 ml) at 0° C. Upon completion of the addition, the stirring was maintained at 0° C. for a further 4 hours. Subsequent work-up gave P,P-diphenyl-N-phenylmethylene phosphinic amide (1.4 g; 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([O:12]/[C:13](/[C:23](OC)=[O:24])=[C:14](/OC(=O)C)\[C:15]([O:17][CH3:18])=[O:16])(=O)C>C(O)(=O)C.CO>[CH3:18][O:17][C:15]([C:14]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]2[C:23](=[O:24])[C:13]=1[OH:12])=[O:16]
Reactant: COC(=O)/C(OC(C)=O)=C(\OC(C)=O)C(=O)OC
Reactant: Nc1ccc(Br)cn1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1nc2ccc(Br)cn2c(=O)c1O
Temperature: 25 °C
Yield: 2.1 %

Procedure:
2-Amino-5-bromo-pyridine (664 mg, 3.85 mmol), dimethyl diacetoxyfumarate (1.00 g, 3.84 mmol) and glacial acetic acid (10 drops) in dry methanol (10 mL) were combined and heated to reflux. After 48 h the reaction was cooled to room temperature and concentrated in vacuo. Ethyl acetate (2 mL) was added to the residue which was sonicated for 2 min and the resulting precipitate collected by filtration and washed with cold ethyl acetate (1 mL) and dried on the pump to afford 7-bromo-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester as a yellow solid (24 mg, 2%): 1H NMR (300 MHz, CDCl3) δ 4.19 (3H, s, OCH3), 7.53 (2H, d, J=1.4 Hz, H8 and H9), 9.00 (1H, d, J=1.4 Hz, H6), 10.53 (1H, br s, OH).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[CH2:46][C:47](=[O:49])[OH:48])=[O:43])[CH2:38][CH2:39][S:40][CH3:41])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:3].CCOCC>FC(F)(F)C(O)=O.C(S)(S)C>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:51])[CH2:46][C:47](=[O:48])[OH:49])=[O:43])[CH2:38][CH2:39][S:40][CH3:41])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:3]
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: CC(S)S
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 4 °C
Yield: 76.1 %

Procedure:
1.00 g of Boc-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (m.p. 197°-200° C. Anal. Calcd. (%) for C48H61N9O12S: C, 58.35; H, 6.22; N, 12.75. Found (%): C, 58.35; H, 6.43; N, 12.61) was dissolved in 5 ml of trifluoroacetic acid containing 0.2 ml of ethanedithiol and reacted at room temperature for 30 minutes. Then 100 ml of anhydrous ether was added to the reaction mixture, and the resulting precipitate was filtered and dried. This deprotected heptapeptide was dissolved in 20 ml of DMF containing 0.14 ml of triethylamine, and 0.40 g of glutaric anhydride was added under cooling with ice. After 17-hour stirring at 4° C., the reaction mixture was distilled in vacuo to remove the solvent, and 1N citric acid was added to the residue to form a precipitate. It was washed with water and recrystallized from 20 ml of methanol, giving 0.77 g of Glt-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ; yield 76.1%, m.p. 167°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:32](=[O:33])[C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:31]2[C:32](=[O:33])[N:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A, 1.00 g, 2.59 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.728 g, 3.11 mmol, example 104, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.596 g, 3.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.420 g, 3.11 mmol), N-ethyl-N-isopropylpropan-2-amine (0.669 g, 5.178 mmol) and DMF (50 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (200 mL) and H2O (200 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (1.34 g, 85.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 603 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.85 (s, 1H), 8.43 (m, 2H), 8.24 (d, 1H), 7.96 (dd, 1H), 7.77 (s, 1H), 7.60 (m, 2H), 7.40 (m, 1H), 7.21-7.28 (m, 3H), 6.48 (m, 1H).