Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[C:30]([O:33][CH2:34][C:35](Cl)=[O:36])(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[C:30]([O:33][CH2:34][C:35]([N:1]([C:35](=[O:36])[CH2:34][O:33][C:30](=[O:32])[CH3:31])[C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1)=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1cc(CSc2ncccc2C(=O)Nc2ccc(OC(F)(F)F)cc2)ccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)N(C(=O)COC(C)=O)c1cc(CSc2ncccc2C(=O)Nc2ccc(OC(F)(F)F)cc2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
2-(2-Aminopyridin-4-ylmethylthio)-N-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide (Compound No. 3-11, 800 mg, 1.9 mmol) was dissolved in pyridine (10 mL), and acetoxyacetyl chloride (0.66 mL, 6.1 mmol) was added thereto under ice-cooling, and the mixture was stirred for 18 hours at room temperature. The mixture was diluted with ethyl acetate (100 mL), and the whole was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) and 1 N hydrochloric acid (50 mL) twice successively. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) again and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from ethyl acetate-hexane to give 300 mg of the target compound as a colorless solid. (Yield 30%)
Reaction SMILES: [O:1]([C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=O)C1C=CC=CC=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.CN(C1C=CC=CN=1)C>>[CH2:17]([O:24][C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(CC(=O)Oc1ccccc1)NC(N)=O
Reactant: OCc1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: CN(C)c1ccccn1
Product: CC(CC(=O)OCc1ccccc1)NC(N)=O
Temperature: 100 °C

Procedure:
A mixture of phenoxycarbonylpropyleneurea of 1.0 g (4.5 mmol), benzyl alcohol of 2.4 g (22.2 mmol), dibutyltin dilaurate of 20 mg (0.6 wt %) and dimethylaminopyridine of 20 mg (0.6 wt %) was heated for 3 hours at 100° C. with stirring. After confirming the completion of the reaction by the thin layer chromatograpy, the reaction product was concentrated and the resulting crude substance was separated by the chromatography to obtain the aimed substance of 600 mg (56.4%).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])=[O:13])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C@@:16]2([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH2:18][N:14]([C:12]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:42])=[O:2])=[CH:5][CH:6]=3)=[O:13])[C@@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])=[C:27]([F:33])[CH:28]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2Cl)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a mixture of rac-4-({[(2S,3S,4S)-2-(2,3-dichloro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (44.2 mg, 0.07 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-({[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid (43.0 mg, 99.6%). LC-MS (ES+/−) m/z Calcd for C31H29Cl3FN3O3: 617; Found: 617.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8](=O)[CH2:7][O:6][CH2:5][C:4]1=[O:10].F[B-](F)(F)F.[C:16]([C:21]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([C:21]1[CH2:22][CH2:23][N:3]2[C:4](=[O:10])[CH2:5][O:6][CH2:7][C:8]=12)=[O:17])[CH3:20]
Reactant: O=C1COCC(=O)N1
Reactant: CCOC(=O)C1([P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: F[B-](F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C2COCC(=O)N2CC1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (480 mg, 60% in mineral oil, 12 mmol) in 10 ml of anhydrous THF is added morpholine-3,5-dione (1.2 g, 10 mmol) in 20 ml of THF under an argon athmosphere. After 10 min., 1-carbethoxycyclopropyltriphenylphosphonium tetrafluoroborate (Fuchs' reagent, 6.8 g, 11 mmol)) in 20 ml of THF are added and the mixture is refluxed for 21 hours. After cooling, the suspension is concentrated on a rotary evaporator, poured onto ice/sat. sodium bicarbonate solution, and extracted three times with ether. The combined organic phases are washed with brine, dried over anhydrous sodium sulphate, and evaporated. The residual yellow oil (3.04 g) is purified by chromatography (Silica gel 60, 0.063-0.2 mesh, cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]5[N:29]=[C:28]([NH2:30])[C:27]([N+:31]([O-])=O)=[CH:26][N:25]=5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.CO.[Pd]>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]5[N:29]=[C:28]([NH2:30])[C:27]([NH2:31])=[CH:26][N:25]=5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1nc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1N
Temperature: 25 °C
Reaction time: 28 h
Yield: 69.6 %

Procedure:
2-[1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidyl amino]-4-amino-5-nitropyrimidine (1.000 g, 2.3 mmol, prepared as described in Example 97), 0.2 weight equivalents of 10% Pd/C, and ammonium formate (1.000 g, 15.9 mmol) were combined in 20 mL 50% ethyl acetate/methanol and stirred under a nitrogen atmosphere at room temperature for 28 hours. The reaction mixture was filtered through celite and concentrated on a rotary evaporator to give the title compound as a tan glassy solid (0.643 g, 1.6 mmol, 69%), mp 138°-140°C.; MS(CI): 413 (M+H); NMR (250MHz, DMSO-d6): 7.29-7.18(m, 5H), 6.98-6.87(m, 4H), 6.33(s, 2H), 5.75-5.72(br m, 1H), 4.32(s, 1H), 3.56(br m, 1H), 3.36(br, m, 2H), 2.99-2.94(d, J=11.3Hz, 2H), 2.47(s, 2H), 2.32-2.23(m, 2H), 1.80-1.75(m, 2H), 1.41-1.37(m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](F)=[N:27][CH:26]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([C:25]1[CH:30]=[CH:29][C:28]([N:14]2[CH2:15][CH2:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:18])([CH3:17])[CH2:12][CH2:13]2)=[N:27][CH:26]=1)=[O:32])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)c1ccc(F)nc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Solvent: C1COCCO1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(C(=O)OC(C)(C)C)cn2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.31 g, 1.28 mmol, Example 30B) in dioxane (5.0 mL) at room temperature was added 6-fluoro-nicotinic acid tert-butyl ester (0.21 g, 1.07 mmol). The reaction mixture was stirred at 80° C. for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 10% to 30% ethyl acetate in hexane to provide 4-benzyloxycarbonylamino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylic acid tert-butyl ester. MS (CT) m/z 426 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.74 (d, 1H), 7.97 (dd, 1H), 7.35 (m, 5H), 7.26 (s, 1H), 5.07 (s, 2H), 4.68 (s, 1H), 3.97 (m, 2H), 3.37 (m, 2H), 2.08 (m, 2H), 1.66 (m, 2H), 1.56 (s, 9H), 1.42 (s, 3H).
Reaction SMILES: CN(C(C1C(I)=C(N[C:18]([CH2:20][O:21][CH3:22])=[O:19])C(I)=C(C(NCC(O)CO)=O)C=1I)=O)CC(O)CO.[NH2:33][C:34]1[C:35]([I:48])=[C:36]([C:45]([Cl:47])=[O:46])[C:37]([I:44])=[C:38]([C:42]=1[I:43])[C:39]([Cl:41])=[O:40].COCC(Cl)=O>CN(C)C=O>[CH3:22][O:21][CH2:20][C:18]([NH:33][C:34]1[C:42]([I:43])=[C:38]([C:39]([Cl:41])=[O:40])[C:37]([I:44])=[C:36]([C:35]=1[I:48])[C:45]([Cl:47])=[O:46])=[O:19]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: COCC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)N(C)CC(O)CO)c1I
Agent: COCC(=O)Cl
Solvent: CN(C)C=O
Product: COCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I

Procedure:
According to the above reaction scheme 1, iopromide of formula (1) is prepared through the steps of reacting 5-amino-2,4,6-triiodoisophthalic acid dichloride of formula (2) with methoxyacetyl chloride in dimethylformamide solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride of formula (3), and reacting the compound of formula (3) with 2,3-dihydroxypropylamine and in turn with 2,3-dihydroxy-N-methylpropylamine in dimethylformamide solvent in the presence of basic material.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:7]=2[NH:6][C:5]1=[O:24].[CH3:25]I>O1CCCC1>[F:3][CH:4]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:7]=2[N:6]([CH3:25])[C:5]1=[O:24]
Reactant: CI
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A slurry of 0.20 g (0.08 mole) of sodium hydride in 10 ml of tetrahydrofuran was added to a solution of 1.74 g (0.0058 mole) of 3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one and 10 ml methyl iodide in 100 ml of tetrahydrofuran at 25°. The reaction mixture was stirred for 3 hr at 25°, and then poured into 300 ml of ice water. The aqueous mixture was extracted with methylene chloride, and the extracts were dried (MgSO4) and then evaporated to dryness under reduced pressure. The residue was dissolved in hot benzene and then fractionally precipitated by the addition of hexane. The first dark fractions of solid were discarded. The remaining fractions were collected on a filter and dried in vacuum to give 1.10 g (60%) of 3-fluoro-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one as a light tan amorphous solid with no distinct melting point: 1H nmr (CDCl3) δ 3.53 ppm (s, 3H), 5.59 ppm (d, J = 57 Hz, 1H), 7.2-7.9 ppm (m, 6H) and 8.2-8.9 ppm (m, 2H); 19F nmr (CDCl3) δ -161.7 ppm (d, J = 57 Hz).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19].[O-]S([O-])(=O)=O.[Mg+2]>>[N:23]1[CH:24]=[CH:25][C:20](/[CH:18]=[CH:19]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:21][CH:22]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: C=Cc1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1ccncc1

Procedure:
The product of Example 1B (100 mg, 0.34 mmol), 4-vinylpyridine (144 mg, 1.37 mmol; Aldrich) and MgSO4 (83 mg, 0.69 mmol) were combined and processed as described in Example 1D to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.97-2.22 (m, 4 H), 3.03-3.12 (m, 2 H), 3.13-3.18 (m, 1 H), 3.21-3.29 (m, 2 H), 4.24 (s, 2 H), 7.04 (t, J=7.6 Hz, 1 H), 7.24 (d, J=16.5 Hz, 1 H), 7.31 (dd, J=7.8, 0.8 Hz, 1 H), 7.44 (d, J=7.6 Hz, 1 H), 7.59-7.69 (m, 2 H), 7.94 (d, J=16.5 Hz, 1 H), 8.46-8.50 (m, 2 H); MS (APCI) m/z 316 (M+H)+.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=O)[CH2:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].O.NN.C(O)CO>O>[NH:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][CH2:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1
Reactant: O=C1CCC2CN(C(=O)c3ccccc3)c3cccc1c32
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: c1cc2c3c(c1)NCC3CCC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A mixture of 5.0 g of 1-benzoyl-1,2,2a,3,4,5-hexahydrobenz[cd]indol-5-one, 2.7 g of potassium hydroxide, 2 ml of hydrazine hydrate and 20 ml of ethylene glycol was heated at 120° C. for 2 hours and then at 190° C. for 3 hours. After mixture cooling, water was added, and the reaction product was extracted with dichloromethane. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: dichloromethane-ethyl acetate=10:1 (v/v)) to yield 1.9 g of 1,2,2a,3,4,5-hexahydrobenz[cd]indole as a colorless crystal having a melting point of 58° to 59° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:19][C:20]#[N:21])=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:22]I.O>CN(C)C=O>[CH3:22][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:18]=2)[C:14]([CH2:19][C:20]#[N:21])=[CH:15]1
Reactant: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CC#N)c2ccc([N+](=O)[O-])cc21
Reaction time: 0.67 h
Yield: 98.8 %

Procedure:
65.5 g (0.474 mol) of powdered potassium carbonate was added to a solution of 28.9 g (0.143 mol) of (6-nitro-1H-indol-3,yl)-acetonitrile (13) from Step C above in 230 ml of dimethylformamide at room temperature. The suspension was stirred for 40 minutes then 25.48 g (0.179 mol) of methyl iodide was added dropwise over 65 minutes. After stirring at room temperature over night the reaction mixture was cooled and poured into a total of 600 ml of water. The precipitate was filtered, washed with a little water and dried on phosphor anhydride until reaching constant weight. The procedure yielded 30.4 g (95.4%) of (1-methyl-6-nitro-1H-indol-3-yl)acetonitrile (14), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][NH:15][C:16]2=[O:19])=[CH:12][C:11]=1[C:20]([OH:22])=O.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:20]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[C:16](=[O:19])[NH:15][CH2:14]2)=[O:22])=[CH2:24]
Reactant: C=COCCON
Reactant: O=C1NCc2cc(C(=O)O)c(Nc3ccc(I)cc3F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2c(cc1Nc1ccc(I)cc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
6-(2-Fluoro-4-iodo-phenylamino)-1-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (209 mg, 0.52 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (58 mg, 0.56 mmol), HOBt (77 mg, 0.56 mmol), EDCI hydrochloride (109 mg, 0.56 mmol) and DIPEA (96 μL, 0.56 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a brown solid (100 mg, 40%). LCMS (Method B): RT=3.32 min, 2M+H+=995.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8]C)=O.C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].C[O-].[Na+]>CO>[CH3:1][O:2][CH2:3][C:4]1[N:17]=[CH:15][N:16]=[C:6]([OH:8])[CH:5]=1
Reactant: COCC(=O)CC(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCc1cc(O)ncn1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
To a solution of methyl 4-methoxy-3-oxobutanoate (3.54 mL, 26.5 mmol) in methanol (30 ml) was added formamidine acetate (3.07 g, 29.2 mmol) and sodium methoxide (13 mL, 58.4 mmol). The mixture was then heated to reflux for 18 hours and cooled to ambient temperature, then concentrated. The residue was taken up in water and the pH adjusted to 7 with 1N HCl. The aqueous mixture was extracted with chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford 6-(methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85 mmol, 37.1% yield). MS (LC/MS) R.T.=0.19; [M+H]+=141.20.
Reaction SMILES: [C:1]1([P:7]([C:14]2C=C[CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].Cl.ClCC1C=C[NH:26][N:25]=1>O1CCCC1>[C:1]1([P:7]([CH2:14][C:15]2[CH:16]=[CH:17][NH:26][N:25]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1cc[nH]n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: c1ccc(P(Cc2cc[nH]n2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of tetrahydrofuran (100 ml) and triphenylphosphine (3.56 g, 13.6 mmol) at room temperature is added lithium (0.100 g, 14.5 mmol). The reaction mixture is stirred at room temperature for 2 hours at which time the lithium has dissolved. The bright red solution is cooled to 0° C., and 3-(chloromethyl)pyrazole hydrochloride (0.960 g, 6.8 mmol) is added at once. The ice bath is removed and the reaction solution is allowed to stir an additional 2 hours. Degassed ethanol (40 ml) is added to the reaction mixture followed by diethyl ether (100 ml). The organic phase is separated and the aqueous phase extracted with diethyl ether (2×25 ml). The organic phases are combined and dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by chromatography (SiO2, 50% ethyl acetate/petroleum ether) to give purified 3-(diphenylphosphinomethyl)pyrazole as a cloudy white oil in 77% yield (2.81 g, 10.6 mmol). This material is characterized as follows: 1H NMR (CDCl3, 500 MHz) δ7.43 (m,4H), 7.41 (d, J=2.0 Hz, 1H), 7.34 (m, 6H), 5.99 (d, J=2.0 Hz, 1H), 3.47 (s, 2H); 13C{1H} NMR (CDCl3, 125 MHz) δ138.16 (d, 14.3 Hz), 132.97 (d, J=18.6 Hz), 129.11, 128.73 (d, J=6.6 Hz), 105.18 (d, J=5.1 Hz), 27.14 (d, J=6.2 Hz) MS m/z 265.9, 182.9 (M—C4H3N2).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>C1COCC1>[Br:45][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CBr)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 77.1 %

Procedure:
To a solution of {4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-methanol (P-6; 5.033 g, 15.01 mmol) in THF (100 mL) was added triphenylphosphine (6.009 g, 22.91 mmol). Carbon tetrabromide (7.704 g, 23.23 mmol) dissolved in THF (20 mL) was then added dropwise at room temperature. The mixture was allowed to stir at room temperature for 23 h. It was then filtered through Celite, and the solvent was evaporated at room temperature under vacuum. The crude material was purified by silica gel chromatography, eluting with 50% EtOAc/hexane going to 70% EtOAc/hexane and then 100% EtOAc in a two-step gradient. The title product (4.61 g, 77%) was isolated as a beige solid: mp 124-126° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.25-8.13 (m, 2H), 7.89-7.72 (m, 2H), 7.60-7.47 (m, 2H), 7.47-7.34 (m, 2H), 4.57 (s, 2H); ESIMS m/z 400 (M+2H), 399 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([O-])=O.[Na+].O>Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)cc1F
Temperature: 25 °C

Procedure:
Alternatively, 4-chloro-2-fluorophenyl hydrazine is prepared by the following method. 43.7 parts of 4-chloro-2-fluoroaniline was dissolved in 735 parts of concentrated hydrochloric acid. The solution was cooled to 0°-5° C. and a solution of 22.8 parts of sodium nitrite in 187 parts water was added dropwise maintaining the temperature of the reaction between 0°-5°. The excess nitrite was destroyed by the addition of small amounts of sulfamic acid until a negative test with sulfone reagent was obtained. To the solution of the diazonium salt was added, as rapidly as possible, a solution of 170 parts stannous chloride dihydrate in 275 parts of concentrated hydrochloric acid, precooled to -50°. When the addition was complete, a heavy white precipitate formed. The reaction mixture was allowed to warm to ambient temperature over one hour. The precipitate was collected by filtration, then suspended in 750 parts ice-water. The pH of the solution was adjusted to 11 by the addition of 50% aqueous sodium hydroxide. The resulting aqueous suspension was extracted three times; 200 parts of methylene chloride was used for each extraction. The combined organic extracts were dried with anhydrous magnesium sulfate, and the solvent removed under reduced pressure of 300 mm Hg to leave 38.5 parts of pinkish-tan crystalline 4-chloro-2-fluoro-phenylhydrazine, mp 51°-63°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:29])[C:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH:27]=O)([CH3:18])[CH3:17])[CH3:13].N1CCCC1>CO>[CH2:12]([O:14][C:15](=[O:29])[C:16]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1/[CH:27]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:18])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 78.1 %

Procedure:
To the mixture of 6-chlorooxindole (5.3 g, 31.7 mmol) and 2-(4-fluoro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (8 g, 31.7 mmol) in methanol (30 mL) was added pyrrolidine (2.6 mL, 31.7 mmol) dropwise. Then the mixture was heated at 70° C. for 3 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (10 g).