Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:20]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([O:18]C)[CH:13]=3)=O)[N:4]2[N:3]=1.BrC1N2N=C(N)N=C2C=CC=1.[CH2:32]([Li])[CH2:33][CH2:34][CH3:35].CO[N:39]([CH3:50])[C:40](=[O:49])[C:41]1C=CN=C(OC)[CH:42]=1>O1CCCC1>[OH:18][C:14]1[CH:13]=[C:12]([CH2:10][C:9]2[N:4]3[N:3]=[C:2]([NH:1][C:33]4[CH:34]=[C:35]5[C:41](=[CH:42][CH:32]=4)[C:40](=[O:49])[NH:39][CH2:50]5)[N:20]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[CH:17]=[CH:16][N:15]=1
Reactant: [Li]CCCC
Reactant: COc1cc(C(=O)c2cccc3nc(N)nn23)ccn1
Reactant: COc1cc(C(=O)N(C)OC)ccn1
Agent: Nc1nc2cccc(Br)n2n1
Solvent: C1CCOC1
Product: O=C1NCc2cc(Nc3nc4cccc(Cc5ccnc(O)c5)n4n3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)(2-methoxypyridin-4-yl)methanone. 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (10 g, 46.9 mmol) was suspended in anhydrous tetrahydrofuran (300 mL) and cooled to −78° C. n-Butyl lithium (64.5 mL, 103 mmol) was added over 30 minutes and the solution was allowed to stir for 1 h (brown suspension). N,2-dimethoxy-N-methylisonicotinamide (9.21 g, 46.9 mmol) dissolved in tetrahydrofuran (50 mL, dried over molecular sieves) was added dropwise via syringe (brown suspension). The reaction was stirred for 1 h and allowed to slowly warm to room temperature for 3 h (reaction became a clear solution as it warmed up to room temperature). LCMS analysis showed the desired product. The reaction was quenched by dropwise addition of water (20 mL) and then neutralized with aqueous hydrochloric acid to pH=7. Flash chromatography (30-100% ethyl acetate in hexane) gave the desired product as a light yellow solid (6.5 g, 24.14 mmol, 51.4% yield). MS (ESI) m/z 270.2 [M+1]+.
Reaction SMILES: [C:1](C1C=CC(OCC(O)=O)=CC=1)(C)(C)C.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:16][O:17][C:18]([C:19]1[CH:24]=[CH:23][C:22]2[NH:25][CH:1]=[N:26][C:21]=2[CH:20]=1)=[O:27]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]cnc2c1
Temperature: 160 °C
Yield: 221.8 %

Procedure:
A mixture of (4-tert-butyl-phenoxy)acetic acid (300 mg, 1.4 mmol), 3,4-diaminobenzoic acid methyl ester (300 mg, 1.4 mmol) in PPSE (4.8 mL) was heated at 160° C. for 4 h. At the end of the reaction period, the mixture was taken to ethyl acetate and neutralized with aqueous sodium bicarbonate. The organic layer was separated and the aqueous solution extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (EtOAc:Hexane=1:9˜4:6) to afford 2-2,4-tert-butyl-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester as a colorless powder (547 mg, 80% yield).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([S:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][N:5]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])(=[O:3])[NH2:2].CO[CH:44](OC)[N:45](C)C>>[N+:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][O:31][C:29]([N:5]2[CH2:6][C@@H:7]([S:9][C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][C@H:4]2[C:1]2[O:3][N:45]=[CH:44][N:2]=2)=[O:30])=[CH:34][CH:35]=1)([O-:41])=[O:40]
Reactant: NC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(OC)N(C)C
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1c1ncno1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To (2S,4R)-2-Carbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-(tritylthio)pyrrolidine (2 g) was added N,N-dimethylformamide dimethyl acetal (1 ml) and the mixture was stirred at 70° C. for 1 hour, and evaporated in vacuo. The oily residue was dissolved in acetic acid (20 ml) and to this solution were added sodium acetate (0.43 g) and hydroxylamine hydrochloride (0.37 g) at room temperature. After stirring at 70° C. for 1 hour, the mixture was poured into water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine successively, and dried over magnesium sulfate. After the solvent was evaporated, the residue was subjected to a column chromatography on silica gel and eluted with a mixture of acetone and dichloromethane (1:20, V/V) to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(1,2,4-oxadiazol-5-yl)-4-(tritylthio)pyrrolidine (1.16 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:8]1[C:7]([OH:12])=[C:6]([CH3:13])[CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2
Reactant: Cc1ccc2cc(O)c(C)cc2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1ccc2c(Br)c(O)c(C)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,7-dimethylquinolin-6-ol (200 mg, 1.2 mmol) in acetic acid (10 mL) was added Br2 (0.062 mL, 1.21 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 0.5 hour. The solid formed was filtered and collected, washed with 2 mL acetic acid to give the product as an HBr salt. LCMS-ESI+: calc'd for C11H10BrNO: 252.0 (M+H+); Found: 252.2 (M+H+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[NH2:13][C:14]([NH2:16])=[S:15]>CO>[BrH:1].[NH2:16][C:14](=[NH:13])[S:15][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccccc1CBr
Reactant: NC(N)=S
Solvent: CO
Product: Br
Product: COC(=O)c1ccccc1CSC(=N)N
Temperature: 25 °C
Yield: 105697.8 %

Procedure:
A mixture of the crude bromide from Step 1 (7.2 g, 0.031 mmol) and thiourea (2.6 g, 35 mmol) in MeOH (40 mL) was heated to reflux for 4 h, cooled to room temperature, and concentrated to afford methyl 2-({[amino(imino)methyl]thio}methyl)benzoate hydrobromide (10 g, ca. 100%), which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][OH:23])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:24](O)(C)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][OH:23])[CH:14]=[CH:13][CH:12]=3)=[O:5])([CH3:24])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(CO)c3c2c1COC
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(CO)c3c12

Procedure:
5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester (7.27 g) is refluxed in isopropanol (1000 ml) with titanium tetraisopropylate (7.1 ml) for 5 hours. The solution is evaporated, the residue is dissolved in ethyl acetate. The complete solution is reached by addition of 1N hydrochloric acid. Then it is made alkaline by addition of 1N sodium hydroxide solution. A precipitate resulting thereby is suctioned off. The filtrate is evaporated and yields a residue of 6.0 g of the title compound.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]=1[CH:39]1[CH2:43][CH2:42][NH2+:41][CH2:40]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH:1]1([NH:7][C:8]([N:41]2[CH2:42][CH2:43][CH:39]([C:26]3[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:30][C:25]=3[O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:40]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(COc2ccc(C3CC[NH2+]C3)c(OCc3ccccc3)c2)cc1
Reactant: O=C=NC1CCCCC1
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
In a 10 ml round-bottomed flask, 0.25 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidinium trifluoroacetate is dissolved in 5 ml of tetrahydrofuran in the presence of 0.25 ml of N,N-diisopropylethylamine. 0.1 g of cyclohexyl isocyanate is added and the reaction mixture is stirred for 30 minutes at ambient temperature. The reaction mixture is extracted with ethyl acetate and the organic phases are then combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (7/3 heptane/ethyl acetate). 0.23 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid cyclohexylamide is obtained. Yield=66%.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[C:4]([CH:17]=O)=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.[S:20]1[CH2:26][C:24](=[O:25])[N:23]([CH2:27][C:28]([OH:30])=[O:29])[C:21]1=[S:22]>>[CH3:1][N:2]([CH3:19])[C:3]1[C:4]([C:17]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]=[C:4]([CH:17]=[C:26]2[S:20][C:21](=[S:22])[N:23]([CH2:27][C:28]([OH:30])=[O:29])[C:24]2=[O:25])[CH:3]=[CH:12]3)=[CH:5][C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1
Reactant: CN(C)c1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reactant: O=C(O)CN1C(=O)CSC1=S
Product: CN(C)c1cc2c(cc1-c1ccc3cc(C=C4SC(=S)N(CC(=O)O)C4=O)ccc3c1)C(C)(C)CCC2(C)C

Procedure:
{5-[6-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-naphthalen-2-yl methylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid was prepared in a similar manner as described in Example 1 using 6-(3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-carboxaldehyde and rhodanine acetic acid, mp 194–196° C., 1H NMR (300 MHz; DMSO-d6) 1.25 (s, 6 H), 1.30 (s, 6 H), 1.66 (s, 4 H), 2.47 (s, 6 H), 4.76 (s, 2 H); 6.99 (s, 1 H), 7.21 (s, 1 H), 7.74 (dd, J1=1.5 Hz, J2=8.4 Hz, 1 H), 7.87 (dd, J1=1.5 Hz, J2=8.4 Hz, 1 H), 8.05 (brs, 2 H), 8.07 (d, J=8.1 Hz, 1 H), 8.10 (d, J=8.1 Hz, 1 H), 8.28 (s, 1 H).
Reaction SMILES: [I-].[CH3:2][O:3][CH2:4][CH:5]1[NH+:9]([CH3:10])[C:8]([CH3:12])([CH3:11])[CH2:7][O:6]1.C(=O)([O-])[O-].[K+].[K+].[N:19]([C:21]1[C:30]([OH:31])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2)=O>C1C=CC=CC=1>[CH3:2][O:3][C:4]1[C:5]2([N:9]([CH3:10])[C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[O:31][C:30]2[CH:29]=[CH:28][C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]=2[N:19]=1
Reactant: COCC1OCC(C)(C)[NH+]1C
Reactant: O=Nc1c(O)ccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC1=Nc2c(ccc3ncccc23)OC12OCC(C)(C)N2C
Temperature: 70 °C
Yield: 4.2 %

Procedure:
Into a dry 250 ml three-necked flask kept under dry nitrogen and fitted with a reflux condenser and internal thermometer was added 2-methoxymethyl-3,4,4-trimethyl-1,3-oxazolidinium iodide (7.13 grams, 25 mmole), powdered potassium carbonate (8.97 grams, 65 mmole) and 125 ml dry benzene. The heterogeneous mixture was heated at 70° C. for 90 minutes before addition of 5-nitroso-6-quinolinol (5.44 grams, 25 mmole). The resulting reaction mixture was heated at 70° C. for 17 hours, cooled and filtered through Celite® diatomaceous earth powder. The solvent was removed in vacuo from the filtrate, and the resulting residue purified by flash chromatography to yield 0.33 grams of 2'-methoxy-3,4,4-trimethylspiro [oxazolidine-2,3'-[3H] pyrido [3,2-f] [1,4] benzoxazine].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>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>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)[CH:7]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(C)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of Example A5 (3.83 g, 13.79 mmol) in dioxane (50 mL) was sparged with argon, treated with a solution of K2CO3 (3.81 g, 27.6 mmol) in H2O (10 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.44 g, 16.55 mmol) and Pd(PPh3)4 (0.637 g, 0.552 mmol) and heated at 80° C. for 16 h. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics washed with H2O, then brine, dried over Na2SO4 and concentrated to dryness. The material was suspended in 3:2 EtOAc/Hex, sonicated and the resulting solid collected via filtration and dried. The filtrate was concentrated to dryness, purified via silica gel chromatography (MeOH/DCM) and combined with the isolated solid to afford N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (3.88 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 8.34 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.58 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 324.1 (M+H+).
Reaction SMILES: CC(C)([O-])C.[Li+].[OH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=1[C:18](=[O:20])[CH3:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>CN(C=O)C>[CH2:21]([O:17][C:12]1[CH:11]=[CH:10][C:9]([C:18](=[O:20])[CH3:19])=[C:8]([OH:7])[C:13]=1[N+:14]([O-:16])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Lithium tert-butoxide (4.06 g) was added to a stirred solution of 1-(2,4-dihydroxy-3-nitrophenyl)ethanone (10 g) in DMF (100 mL), under nitrogen, whilst maintaining the internal temperature below 30° C. After stirring for a further 10 min at ambient temperature, benzyl bromide (6.03 mL) was added and the mixture stirred for a further 20 h. Further benzyl bromide (3 mL) was added and the mixture stirred for 24 h. The reaction was quenched with water (300 mL), 1M aqueous sodium hydroxide (50 mL) was added and the mixture was washed with ether (2×300 mL), filtering through Celite to aid separation. The basic solution was cooled in ice/water, acidified with ice cold 2M hydrochloric acid (200 mL) and the resulting precipitate filtered off, washed with water and dried to afford a light brown solid. The solid was slurried with ethanol (100 mL) for 1 h and the solid filtered off, washed with cold ethanol (20 mL), and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid (6.8 g). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.45-7.32 (m, 5H), 7.01 (d, J=9.2 Hz, 1H), 5.42 (s, 2H), 2.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([N+:14]([O-])=O)[CH:6]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:14])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1N

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (2.1 g, 5.8 mmol) and ammonium chloride (6.2 g, 116.0 mmol) is heated in ethanol/water (40 ml/20 ml) to 70°. Iron powder (3.2 g, 58.0 mmol) is added in small portions over 15 minutes, and the mixture is then heated under reflux for 2 hours. The reaction is filtered through celite and stripped. The residue is taken up in ether, washed with water, dried and stripped to give 4-(2-chloro-4-trifluoromethylphenoxy)-2-aminoaniline.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[N:20][OH:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1C(=NO)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a suspension of 7.11 g of N-benzylisatin in 75 ml of ethanol was added a solution of 3.84 g of hydroxylamine hydrochloride and 3.84 g of sodium acetate in 500 ml of water. The mixture was stirred at room temperature for 1 hour, followed by concentration. The residue was washed with water and recrystallized from ethanol to give 6.11 g (81%) of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH:19]1[O:24][CH2:23][CH2:22][CH2:21][O:20]1>>[Br-:16].[O:20]1[CH2:21][CH2:22][CH2:23][O:24][CH:19]1[CH2:18][CH2:17][N+:11]1[CH:12]=[CH:13][C:8]([CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(C=Cc2ccncc2)cc1
Reactant: BrCCC1OCCCO1
Product: Cc1ccc(C=Cc2cc[n+](CCC3OCCCO3)cc2)cc1
Product: [Br-]

Procedure:
By the procedure described in Ex. 8, 4-(4-methylstyryl)pyridine and 2-(2-bromoethyl) 1,3-dioxane were reacted to obtain N-[2-(1,3 dioxane-2-yl)ethyl]-4-(4-methylstyryl)pyridinium bromide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:41])[CH2:39][NH2:40])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:48][O:49][C:50]([NH:52][C@H:53]([C:67](ON1C(=O)CCC1=O)=[O:68])[CH:54]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51]>C1COCC1.O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9](=[O:42])[N:10]([C@@H:16]([CH2:36][CH2:37][CH:38]([F:41])[CH2:39][NH:40][C:67](=[O:68])[C@H:53]([CH:54]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[NH:52][C:50]([O:49][CH3:48])=[O:51])[CH2:17][O:18][Si:19]([C:32]([CH3:35])([CH3:33])[CH3:34])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)ON1C(=O)CCC1=O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CCN(C(=O)OCc1ccccc1)[C@@H](CCC(F)CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)C(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of the material from Step 10 (86 mg, 0.145 mmol) in THF (1 mL) and water (333 μL) at 0° C. was added NaHCO3 (49 mg, 0.58 mmol) and followed by portionwise addition of 2,5-dioxopyrrolidin-1-yl N-(methoxycarbonyl)-β-phenyl-L-phenylalaninate (63 mg, 0.16 mmol). The reaction mixture was stirred at room temperature overnight, poured into brine, and extracted with EtOAc (2×). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 110 mg of the title compound. 1H NMR (DMSO-d6): δ 8.24-8.12 (m, 1H), 7.67-7.53 (m, 4H), 7.51-7.37 (m, 6H), 7.37-7.20 (m, 11H), 7.19-7.07 (m, 2H), 7.03-6.91 (m, 1H), 5.15-4.90 (m, 3H), 4.29-4.19 (m, 1H), 3.96-3.76 (m, 1H), 3.74-3.47 (m, 2H), 3.06 (s, 3H), 3.16-2.97 (m, 4H), 2.96-2.76 (m, 1H), 1.55-1.28 (m, 5H), 1.27-1.01 (m, 2H), 0.97 (s, 9H), 0.85 (d, J=4.2 Hz, 3H), 0.77 (d, J=4.20 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]=[O:11].CCO>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]([NH:9][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: CCOC(=O)CN=C=O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Nc1cccc(I)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 3-iodoaniline (9.39 g) in dichloromethane (75 ml) was treated with ethyl isocyanatoacetate (7.21 ml) at 0° C. and the mixture was stirred for 2 h and allowed to warm to 20° C. EtOH (10 ml) was added and the mixture was stirred for 15 h. The solvents were evaporated under reduced pressure and the residue was triturated in Et2O to give the title compound (12.9 g)LCMS RT=3.08 min.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1([F:22])[CH2:19][CH:18]([CH2:20]O)[CH2:17]1>>[F:15][C:16]1([F:22])[CH2:19][CH:18]([CH2:20][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH2:17]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCC1CC(F)(F)C1
Product: N#Cc1ccnc(-n2nccc2OCC2CC(F)(F)C2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3,3-difluorocyclobutyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.48-2.71 (5H, m), 5.14 (2H, d, J=4.4 Hz), 5.64 (1H, d, J=1.6 Hz), 7.34 (1H, dd, J=0.4 Hz, J=4.8 Hz), 7.51 (1H, d, J=2.0 Hz), 7.93 (1H, s), 8.61 (1H, d, J=4.8 Hz). [M+H] Calc'd for C14H12F2N4O, 291. Found, 291.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:13]=[C:12]([O:14]C)[C:11]([O:16][CH3:17])=[CH:10][C:7]=1[CH:8]=[O:9]>C(Cl)Cl>[F:5][C:6]1[CH:13]=[C:12]([OH:14])[C:11]([O:16][CH3:17])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C=O)c(F)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
AlCl3 (8.69 g, 65.2 mmol) was added to a solution of 2-fluoro-4,5-dimethoxy-benzaldehyde (2.00 g, 10.9 mmol) in DCM (100 mL) under an atmosphere of argon. The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was slowly quenched with water. The layers were separated and the aqueous layer was then extracted with ethyl acetate (3×). The combined organic layers were dried over sodium sulfate and then evaporated to dryness to yield 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.82 g, 98%) as an off white solid. ESI-MS m/z calc. 170.0, found 171.0 (M+1)+. Retention time: 0.84 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 7.22 (d, J=6.7 Hz, 1H), 6.73 (d, J=11.9 Hz, 1H), 3.81 (s, 3H).