Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]=[C:20]([NH2:22])[NH2:21])=[O:18])=[CH:14][CH:15]=2)[C:10]([CH:23]=[O:24])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]=[C:20]([NH2:22])[NH2:21])=[O:18])=[CH:14][CH:15]=2)[C:10]([CH2:23][OH:24])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(N)=NC(=O)c1ccc2c(c1)c(C=O)cn2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(N)=NC(=O)c1ccc2c(c1)c(CO)cn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 415 mg portion of 1-benzyl-N-(diaminomethylene)-3-formyl-1H-indole-5-carboxamide was suspended in 15 ml of methanol, 98 mg of sodium borohydride was added at 0° C., followed by stirring at room temperature for 1.5 hours. After evaporation of the solvent and subsequent addition of water, the thus precipitated solid was purified by silica gel column chromatography (Clomatorex (registered trademark), methanol:chloroform:water=50:1:0.1 to 30:1:0.1 to 20:1:0.1 to 10:1:0.1). The thus obtained product was crystallized from methanol/water to obtain 325 mg of 1-benzyl-N-(diaminomethylene)-3-hydroxymethyl-1H-indole-5-carboxamide as a pale pink solid.
Reaction SMILES: C1C=CC(O[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][C:10]#[N:11])=CC=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24].C(N(CC)CC)C>ClCCl>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([NH:24][C:8](=[N:9][C:10]#[N:11])[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of diphenylcyanocarbonimidate (2 mmol, 476 mg), 3,5-bis(trifluoromethyl)aniline (2 mmol, 458 mg) and triethylamine (2 mmol, 202 mg) in dichloromethane (15 ml) was stirred under nitrogen for 12 h. After concentration the residue was stirred with toluene (5 ml) for 2 h and the solid was collected by filtration giving 550 mg of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (73.6%);
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH2:18][C:19]1([CH3:24])OCC[O:20]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.Cl>>[NH2:17][C:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:3][C:2]([CH3:25])([CH3:1])[CH2:18][C:19](=[O:20])[CH3:24])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)(Cn1cnc2c(N)nc3ccccc3c21)CC1(C)OCCO1
Agent: Cl
Product: CC(=O)CC(C)(C)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
By the general method of Example 11, 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-1H-imidazo[4,5-c]quinolin-4-amine was hydrolyzed with aqueous hydrochloric acid to provide 5-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one as a light yellow solid after recrystallization from aqueous methanol, mp 214-216° C.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[F:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([CH3:13])=[C:2]3[CH3:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)n(Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c2cnn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (354 mg) in DMF (30 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-fluorobenzoyl)benzyl bromide (645 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 2 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (628 mg, yield 81%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:15]([O:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
Dissolve (R)-(+)-2-(tert-butoxycarbonylamino)-1-propanol (875 mg, 5 mmol) in anhydrous THF (50 mL). Add sodium hydride (60% in mineral oil, 210 mg, 5.2 mmol) and stir at 0° C. for 30 min. Add benzyl bromide (620 μL, 5.2 mmol) followed by tetrabutylammonium iodide (20 mg, 0.05 mmol) and stir for 3 h at ambient temperature. Pour the mixture into water (200 mL), extract with DCM (3×50 mL), wash with brine, dry over MgSO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1) to give the desired intermediate as a colorless oil (800 mg, 60%).
Reaction SMILES: [CH2:1]([N:8]1[C@H:17]([CH3:18])[CH2:16][C:15]2[C:10](=[C:11]([O:21]C)[CH:12]=[C:13]([O:19]C)[CH:14]=2)[C@H:9]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[BrH:26]>C(O)(=O)C>[BrH:26].[CH2:1]([N:8]1[C@H:17]([CH3:18])[CH2:16][C:15]2[C:10](=[C:11]([OH:21])[CH:12]=[C:13]([OH:19])[CH:14]=2)[C@H:9]1[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(c(OC)c1)[C@@H](C)N(Cc1ccccc1)[C@H](C)C2
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1Cc2cc(O)cc(O)c2[C@@H](C)N1Cc1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
Into a 15 mL culture tube was placed N-benzyl-(1R, 3R)-1,2,3,4-tetrahydro-6,8-dimethoxy-1,3-dimethylisoquinoline (62 mg, 0.2 mmol) dissolved in acetic acid (1 mL). To this solution were added sodium iodide (120 mg, 0.8 mmol) and concentrated aqueous hydrobromic acid (49%, 2 mL). The mixture was heated at 100° C. for 3 hours and then cooled to 0° C., at which time light yellow crystals precipitated out of solution. Vacuum filtration with a glass fritted Buchner funnel gave the N-benzyl-(1R, 3R)-1,2,3,4-tetrahydro-6,8-dihydroxy-1,3-dimethyl-isoquinoline hydrobromide salt [105] (48 mg, 66%) as light yellow crystals.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7]O)[CH2:2][CH2:3][CH3:4].[C:9]([OH:16])(=[O:15])[CH2:10][CH2:11][C:12]([CH3:14])=[O:13].CCCCCCCC(O[Sn](OC(CCCCCCC)=O)(CCCC)CCCC)=O>C1(C)C(C)=CC=CC=1>[C:9]([O:16][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:15])[CH2:10][CH2:11][C:12]([CH3:14])=[O:13]
Reactant: CCCCOCCO
Reactant: CC(=O)CCC(=O)O
Agent: CCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCOCCOC(=O)CCC(C)=O

Procedure:
2 -Butoxyethanol (Butyl Cellosolve) 354g (3 mol), 232g (2 mol) levulinic acid and 1.5g dibutyl tin dioctoate were heated with a xylene azeotrope for 24 hours 151°-177° to AN 2.3 while collecting 42g water. Product was washed with sat. NaHCO3 and water, dried with anhy. MgSO4 and distilled. Ester product was collected in fr 2 and 3 120°-131° 1 mm. Yield was 349g, 81%, 96% ester product by gc.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[CH3:8][O:9][C:10]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:11]=1[CH2:12][NH:13][C:14]([C:16]1[C:20]([N+:21]([O-])=O)=[CH:19][NH:18][N:17]=1)=[O:15].C(Cl)Cl.CO.C(=O)([O-])O.[Na+]>C(O)C>[CH3:8][O:9][C:10]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:11]=1[CH2:12][NH:13][C:14]([C:16]1[C:20]([NH2:21])=[CH:19][NH:18][N:17]=1)=[O:15]
Reactant: COc1ccc(CNC(=O)c2n[nH]cc2[N+](=O)[O-])c(OC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNC(=O)c2n[nH]cc2N)c(OC)c1
Temperature: 20 °C
Reaction time: 48 h
Yield: 88.2 %

Procedure:
27.64 g of tin chloride dihydrate are added portionwise to a suspension of 10.72 g of 4-nitro-1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide in 600 ml of absolute ethanol. The reaction medium is stirred for 48 hours at 20° C. The clear brown solution obtained is brought to dryness on a rotary evaporator. The clear brown foam obtained is taken up in 700 ml of a 90/10 by volume a mixture of methylene chloride/methanol. 700 ml of saturated aqueous sodium hydrogen carbonate solution are added to the brown solution obtained. The cream-colored suspension obtained is stirred for 1 hour at room temperature. 30 g of Clarcel Flo are added to the suspension and the mixture is then stirred for 10 minutes at room temperature. The resulting mixture is filtered and the filter cake is washed with twice 250 ml of a 90/10 by volume a mixture of methylene chloride/methanol. The solid is drained by suction and the filtrate is recovered and then transferred into a separating funnel. The chloromethylene phase is separated out by settling and the aqueous phase is then re-extracted with twice 250 ml of dichloromethane. The organic phases are combined and then dried over magnesium sulfate, filtered through paper and then brought to dryness on a rotary evaporator. 8.53 g of 4-amino-1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide are obtained in the form of a pale pink solid. ([M+H]+): 277). RT: 2.36 min (Method A).
Reaction SMILES: [OH-].[Na+].[CH2:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:18][C:5]1=2>CO>[CH2:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([CH2:19][C:20]([OH:22])=[O:21])=[CH:18][C:5]1=2
Reactant: C=C1c2ccccc2COc2ccc(CC(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C1c2ccccc2COc2ccc(CC(=O)O)cc21
Yield: 98 %

Procedure:
To a mixed solvent of 200 ml of methanol and 50 ml of 2N-aqueous sodium hydroxide solution is added 2.9 g of methyl 11-methylene-6,11-dihydrodibenz[b,e]oxepin-2-acetate (raw material 7, Reference example 7) and the mixture is heated at reflux for two hours. After allowing the mixture to stand for cooling, the mixture is concentrated under reduced pressure, and the pH of the mixture is adjusted to 1.0 with aqueous 4N-hydrochloric acid solution. The mixture is extracted with 500 ml of ethyl acetate, washed with aqueous 1N-hydrochloric acid solution and saturated aqueous sodium chloride solution in order and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant crude product is crystallized from hexane to obtain 2.7 g of the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:24][C:21]=2[CH:22]=[O:23])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Temperature: 90 °C
Yield: 48.2 %

Procedure:
(3-Hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (2.0 g, 9.5 mmol), 5-bromo-2-fluorobenzaldehyde (2.0 g, 9.5 mmol), and potassium carbonate (2.0 g, 14.3 mmol) were combined in 1,4-dioxane and heated to 90° C. overnight. After work-up, the crude material was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give the desired product (1.8 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][C:6]=1[CH3:15])([O:3][CH3:4])=[O:2].[OH:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:18][NH2:19]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:19][CH2:18][CH:17]([OH:16])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[CH3:13])=[CH:7][C:6]=1[CH3:15])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)=O)cc1C
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1C

Procedure:
The title compound was prepared as in Example 1b from 1-(4-carbomethoxy-3-methylphenyl)propan-2-one (2.0 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.0 g), the compound crystallised from hexane m.p. 88°-92° as a 41:59 mixture of diastereoisomers. τ(CDCl3) 8.9 (3H,d,J=6 Hz), 7.4 (3H,s), 6.8-7.8 (5H,m,=2H, replaceable by D2O), 6.1 (3H,s), 5.3 (1H,m), 2.9 (2H,m), 2.3-2.6 (4H,m), 2.1 (1H,dd,J=8 Hz, J=2 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[N:6].[N-:7]=[N+:8]=[N-:9].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].Cl.N=[N+]=[N-]>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[N:7][N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: ClCCCc1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of 4-chlorobutyronitrile, (0.05 mol) sodium azide (0.20 mol) and anhydrous aluminum chloride (0.05 mol) in 100 ml of dry tetrahydrofuran is refluxed for 24 hours. After cooling to ambient temperature the reaction is acidified with 75 ml of 15% hydrochloric acid while the hydrazoic acid generated is removed by means of an aspirator. The organic and aqueous layers are then separated and the aqueous layer extracted with ethylacetate. The combined organic extracts are dried (magnesium sulfate) and evaporated to give 5-(3-chloropropyl)tetrazole which is used directly in the next step.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([N+]([O-])=O)[CH:14]=1.O>CN(C)C=O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(Cl)ccc1C#N
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
In 75 ml of dry N,N-dimethylformamide was dissolved acetone oxime (1.21 g), followed by potassium tertiary butoxide (1.85 g) and stirred under nitrogen. After 30 minutes, 4-chloro-2-nitro-benzonitrile (2.00 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of the product, m.p. 83-84° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:20]=1[C:21](O)=[O:22]>>[CH3:29][O:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[C:20]=1[C:21]([N:13]1[CH2:14][CH:15]2[CH:11]([CH2:10][N:9]([C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16]2)[CH2:12]1)=[O:22]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Product: COc1cccc(OC)c1C(=O)N1CC2CN(c3nc(C)cc(C)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing in a manner analogous to Example 15, utilizing Intermediate 23 and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. C21H26N4O3, 382.47; m/z found 383.1 [M+H]+. 1H NMR (CD3OD): 7.38 (t, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.81-6.70 (m, 2H), 4.04-3.89 (m, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.76-3.55 (m, 4H), 3.27-3.13 (m, 3H), 2.53 (s, 6H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:14]O>>[F:1][CH:2]([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:14])=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(C(F)F)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(difluoromethyl)benzoic acid (5.47 g, 31.8 mmol) in MeOH (100 mL) was treated with concentrated aq HCl (0.5 mL, 6.0 mmol), and the reaction mixture was heated to reflux. After 24 hr the solution was cooled to ambient temperature and concentrated in vacuo. The residue was taken up in Et2O and washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated in vacuo. The result was 5.82 g (98%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.13-8.06 (m, 2H), 7.76-7.69 (m, 2H), 7.14 (t, J=55.5, 1H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[N:8]=[CH:7][C:6]([C:15]#[N:16])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([Cl:32])[CH:19]=1.C(N(C(C)C)CC)(C)C.[Cl:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][C:48](Cl)=[O:49]>O1CCCC1>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH3:14])=[C:2]([NH:1][C:48](=[O:49])[CH:47]=[CH:46][CH2:45][CH2:44][CH2:43][Cl:42])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:15]#[N:16])=[CH:19][C:20]=1[Cl:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Cl)C=CCCCCl
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)C=CCCCCl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 6-amino-4-[4-(benzyloxy)-3-chloroanilino]-7-ethoxy-3-quinolinecarbonitrile (0.89 g, 2.0 mmol) and diisopropylethylamine (0.47 ml, 2.7 mmol) in 16 ml of tetrahydrofuran at 0° C. was added a freshly-prepared solution of 6-chloro-2-hexenoyl chloride in 4 ml of tetrahydrofuran during 30 s. The mixture was then stirred at 25° C. for 2.5 h and partitioned between ethyl acetate and water. The organic layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel with methylene chloride-ethyl acetate to give 0.83 g of amber solid; mass spectrum (electrospray, m/e) 574.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12](=[O:24])[CH2:11]1.[Cl:25][CH2:26][C:27](OCC)(OCC)OCC>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH:10]3[CH2:14][N:13]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:12](=[O:24])[CH2:11]3)[C:27]([CH2:26][Cl:25])=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: COc1ccc(CN2CC(Nc3ccc(Cl)cc3N)CC2=O)cc1
Product: COc1ccc(CN2CC(n3c(CCl)nc4cc(Cl)ccc43)CC2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 4-[(2-amino-4-chlorophenyl)amino]-1-(4-methoxybenzyl)pyrrolidin-2-one (1.35 g, 3.91 mmol) and 2-chloro-1,1,1-triethoxyethane (10 mL) was stirred at 80° C. for 1 hour. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography (DCM: MeOH=20:1) to afford 4-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]-1-(4-methoxybenzyl)pyrrolidin-2-one.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)O1.N.[C:36]([C:40]([OH:42])=[O:41])([F:39])([F:38])[F:37]>>[F:37][C:36]([F:39])([F:38])[C:40]([OH:42])=[O:41].[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([C:2]3[N:7]=[N:6][C:5]([O:8][C@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: Clc1ccc(O[C@@H]2CN3CCC2CC3)nn1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: c1cc2[nH]ncc2cc1-c1ccc(O[C@@H]2CN3CCC2CC3)nn1

Procedure:
The product of Example 30A (132 mg, 0.549 mmol) was the product of Example 49A (325 mg, 1.33 mmol) according to the procedure of Example 26B. The title product was purified by preparative HPLC (column: Xterra™, RP-18, 5 μm, 30×100 mm; eluting solvent, MeCN/H2O (with 0.1% v. TFA), (v. 90/10 to 10/90 over 20 min.); flow rate, 40 mL/min.; uv, 254 nm) to provide a solid (115.3 mg, yield, 45.8%). 1H NMR (300 MHz, CD3OD) δ 1.92-2.25 (m, 3H) 2.34-2.49 (m, 1H) 2.63-2.72 (m, 1H) 3.34-3.57 (m, 5H) 3.99 (dd, J=13.90, 8.14 Hz, 1H) 5.54-5.61 (m, 1H) 7.36 (d, J=9.49 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 8.08 (dd, J=8.82, 1.70 Hz, 1H) 8.16-8.23 (m, 2H) 8.38 (dd, J=1.53, 0.85 Hz, 1H) ppm. MS (DCI/NH3) m/z 322 (M+H)+. Anal. Calculated for C18H19N5O.1.2 CF3CO2H: C, 53.47; H, 4.44; N, 15.28. Found: C, 53.67; H, 3.99; N, 15.40.
Reaction SMILES: C(OC([N:8]([C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]2[C:26]=1[CH:27]1[CH2:29][CH2:28]1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:27]1([C:26]2[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][C:18]=2[NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N(c1nc2ccccn2c1C1CC1)S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nc2ccccn2c1C1CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound 12-E (0.083 g, 0.2 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (1 mL) and the resulting mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo and the crude product, isolated as a light yellow oil, was used in the next step without further purification; MS m/z (M+H+) 314.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:41][C:42]([OH:44])=[O:43])[CH2:6][CH2:7][N:8]([CH2:30][CH2:31][N:32]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][C:34]([OH:36])=[O:35])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[C:13]([Br:26])[CH:12]=1)([OH:3])=[O:2].[I:45]I>>[C:1]([CH2:4][N:5]([CH2:41][C:42]([OH:44])=[O:43])[CH2:6][CH2:7][N:8]([CH2:30][CH2:31][N:32]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][C:34]([OH:36])=[O:35])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([I:45])[CH:20]=2)=[C:13]([Br:26])[CH:12]=1)([OH:3])=[O:2]
Reactant: O=C(O)CN(CCN(CCN(CC(=O)O)CC(=O)O)[C@@H](Cc1cc(Br)c(Oc2ccc(O)cc2)c(Br)c1)C(=O)O)CC(=O)O
Reactant: II
Product: O=C(O)CN(CCN(CCN(CC(=O)O)CC(=O)O)[C@@H](Cc1cc(Br)c(Oc2cccc(I)c2)c(Br)c1)C(=O)O)CC(=O)O
Yield: 61 %

Procedure:
N,N-Bis[2-[bis(carboxymethyl)amino]ethyl]-3,5-dibromo-O-(4-hydroxyphenyl)-L-tyrosine, prepared according to Example 13 Step A, was monoiodinated in the outer ring with I2/KI at room temperature. The solution was concentrated, then acidified to pH 1 with 37% HCl and purified by preparative HPLC. Yield 61%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([NH2:10])=O)[O:5][N:4]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]#[N:10])[O:5][N:4]=1
Reactant: COc1cc(C(N)=O)on1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C#N)on1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 79.4 %

Procedure:
3-Methoxy-5-isoxazolecarboxamide (J. Chem Soc. 1968, 172) (1.0 g, 7.0 mmol) was dissolved in dichloromethane (20 mL), cooled to 0° C. then pyridine (1.1 mL, 14 mmol) and trifluoroacetic anhydride (1.0 mL, 7.4 mmol) were added and the reaction was stirred at 0° C. for 40 minutes. The mixture was diluted with dichloromethane (10 mL) and then washed with 5% aqueous citric acid solution (3×20 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed in vacuo to give the title compound as a yellow oil (0.69 g).