Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=O.[CH-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl.C1CCCCC1>[C:2]([C:3]1[CH2:4][CH2:5][CH2:6][C:7]=1[C-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1)(=[O:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(Cl)CCCCC(=O)c1ccccc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: O=C(C1=C([c-]2cccc2)CCC1)c1ccccc1
Reaction time: 2 h
Yield: 14.7 %

Procedure:
6-Oxo-6-phenylhexanoyl chloride (9.0g; 0.04 mole) and ferrocene (7.44g; 0.04 mole) in methylene chloride (150 ml) were stirred at 0° and aluminium chloride (5.34g; 0.04 mole) was added over 40 minutes at 0°. The mixture was stirred at 0° (2 hr.), and then at room temperature (90 min). More aluminium chloride (4g; 0.03 mole) was added and the reaction mixture was heated under reflux for 90 minutes. Water was added, the organic layer run off, and the aqueous layer extracted with methylene chloride (100 ml). The combined organic layers were washed with water (3 × 200 ml), and dried (sodium sulphate) to yield a brown oil. The portion of this oil which was insoluble in hot cyclohexane was discarded and the remainder (2.7g) was subjected to preparative thin layer chromatography to yield 2.1g (15%) of pure 1-benzoyl-2-ferrocenylcyclopentene as a brown solid mp 136°-7°.
Reaction SMILES: [F:1][C:2]1([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:20]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[F:1][C:2]1([C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:20])=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(C2(F)CC2c2ccccc2)cc1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C2(F)CC2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.35 g of 4-(1-fluoro 2-phenyl cyclopropyl) benzoic acid (mixture (B)), obtained according to Preparation 1, and 20 cm3 of dichloromethane are mixed together under an inert gas atmosphere, the mixture is cooled down to 0° C., 0.207 g of commercial oxalyl chloride and 0.01 cm3 of dimethylformamide are added, the whole is agitated for 3 hours at 20-250° C. and brought to dryness in order to collect the acid chloride.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1C(=O)C2=CC=CC=C2C1=O>CN(C=O)C>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCCCCCCCCSc1nc2ccccc2o1
Temperature: 60 °C

Procedure:
To a round bottom flask with 2-mercaptobenzoxazole (2.14 g, 14.2 mmol) and DMF (100 mL) at room temperature was added K2CO3 (2.61 g, 18.9 mmol) followed by N-(8-bromooctyl)phthalimide (4.00 g, 11.8 mmol). The resulting solution was heated to 60° C. for 0.5 h and then cooled back to room temperature. At this point, the reaction mixture was quenched with H2O (100 mL) and then diluted with EtOAc (600 mL). The organic layer was washed with 1 N HCl (60 mL), sat. aq. NaHCO3 (60 mL), and brine (60 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc/petroleum ether gradient) to afford the thioether intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4](I)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][C:17]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:16]=[CH2:17])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C=Cc1c(C)c(Cl)cc(C(C)=O)c1OCC
Temperature: 80 °C
Yield: 83.8 %

Procedure:
A mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (1.1 g, 3.2 mmol, from Example 14, Step 1), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.66 mL, 3.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.26 g, 0.32 mmol) and potassium carbonate (1.3 g, 9.4 mmol) in 1,4-dioxane (10 mL)/water (5 mL) was degassed with N2 and heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated and purified on silica gel (eluting with 0 to 10% EtOAc in hexanes) to give the desired product (0.64 g, 82%). LCMS calculated for C13H16ClO2 (M+H)+: m/z=239.1; Found: 239.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.CN(C=O)C.C(N(CC)C(C)C)(C)C.Br[CH2:34][C:35]([NH2:37])=[O:36]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:6]([CH2:34][C:35]([NH2:37])=[O:36])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Br)cn2)cc1
Reactant: NC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Br)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.6 %

Procedure:
To a 250 mL round-bottomed flask was added N-(5-bromopyridin-2-yl)-4-methylbenzenesulfonamide (10.0 g, 31 mmol), DMF (60 mL), N,N-diisopropylethylamine (6.4 mL, 37 mmol) and 2-bromoacetamide (5.1 g, 37 mmol, Aldrich, St. Louis, Mo.). The mixture was stirred at 25° C. for 1 day. The mixture was poured into water (600 mL) and the solution was stirred for 1 h. The solution was filtered and the filtercake was washed with water and then dried in vacuo to afford the title compound as a white solid (10.2 g, 87%). MS (ESI, positive ion) m/z: 384 (M(79Br)+1).
Reaction SMILES: O=[C:2]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+:23].CCCCCC>CO.C(OCC)(=O)C>[NH2:23][C:2]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CCOC(=O)C=C(N)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
Ethyl 3-oxo-4-(2,4,5-trifluoro-phenyl)-butyrate 1c (24.6 g, 94.5 mmol) was dissolved in 240 mL of methanol, and ammonium acetate (36.4 g, 473 mmol) was added to the solution. The reaction mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and then 100 mL of water was added to the residues. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a light yellow solid. The resulting solid was dissolved in 50 mL of ethyl acetate at 80° C., and then 50 mL of n-hexane and seed-crystal were added to the solution. The mixture was cooled to room temperature, and half an hour later, 100 mL of n-hexane was added. The mixture was stored in refrigerator for 12 hours and then filtered to obtain the title compound ethyl 3-amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoate 1d (19.5 g, yield 80%) as a white solid. MS m/z (ESI): 260.1 [M+1].
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH:33]([CH3:35])[CH3:34])=[C:29]([CH:32]=1)[CH:30]=[O:31]>C1COCC1>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH:30]([C:29]3[CH:32]=[C:25]([Br:24])[CH:26]=[CH:27][C:28]=3[CH:33]([CH3:35])[CH3:34])[OH:31])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(Br)cc1C=O
Reactant: Brc1ccc2c(c1)N(Cc1ccccc1)CCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccc(Br)cc1C(O)c1ccc2c(c1)N(Cc1ccccc1)CCO2
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 4-Benzyl-6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (1.5 g, 4.93 mmol) in THF (20 mL) was added 1.6 M n-butyl lithium in hexanes (3.0 mL, 74.93 mmol) at −78° C. The reaction was stirred for 30 min. then transferred to a stirred solution of 5-bromo-2-isopropylbenzaldehyde (1.12 g, 4.93 mmol) in THF (15 mL) at −78° C. After stirring for 30 min, the reaction was quenched by the addition of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with water (25 mL) and brine (25 mL), then dried over sodium sulfate, concentrated and purified using neutral alumina column chromatography to give (4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-(5-bromo-2-isopropyl-phenyl)-methanol (1.3 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[OH2:22]>OP(O)(O)=O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C:3]=1[C:20]([NH2:21])=[O:22]
Reactant: O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=P(O)(O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Yield: 77.5 %

Procedure:
A solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.0 g, 3.6 mmol) in H3PO4 (20 mL) was heated to 120° C. for 4 hr. The mixture was then poured into water (100 mL), extracted with EA (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to give the product (850 mg, 77.5%) as yellow solid. MS (ESI, m/e) [M+1]+ 295.1.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:22])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].[Cl:23][P:24]([O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[CH:32]=[CH:31]2)(Cl)=[O:25]>C(Cl)Cl>[Cl:23][P:24]([O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[CH:32]=[CH:31]2)([NH:12][C@@H:13]([CH3:22])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])=[O:25]
Reactant: C[C@H](N)C(=O)OCC(C)(C)C
Reactant: COC(=O)[C@@H](C)c1ccc2cc(OP(=O)(Cl)Cl)ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)c1ccc2cc(OP(=O)(Cl)N[C@@H](C)C(=O)OCC(C)(C)C)ccc2c1
Yield: 85.9 %

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates and tosylate salt of (S)-neopentyl 2-aminopropanoate (1.0 g, 2.8 mmol), (S)-methyl 2-(6-(dichlorophosphoryloxy)naphthalen-2-yl)propanoate (990 mg, 2.8 mmol), TEA (0.8 mL, 5.6 mmol) and DCM (20 mL) were combined to give 1.13 g of desired (2S)-methyl 2-(6-(chloro((S)-1-(neopentyloxy)-1-oxopropan-2-ylamino)phosphoryloxy)naphthalen-2-yl)propanoate in 83% yield as a gummy syrup.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)ccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of 4-bromopyridine-2-carboxylic acid (0.5 g, 2.5 mmol, Apollo Scientific) in a mixture of ethyl acetate (15 mL) and methanol (1.5 mL), was added dropwise a solution of trimethylsilyldiazomethane (3.7 mL, 2 M in diethyl ether, 7.4 mmol), at about 0° C. After the addition was complete the temperature was raised to rt and the mixture stirred for about another 1.5 h at rt. The resulting mixture was concentrated in vacuo and diethyl ether (25 mL) was added to the residue. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:1) to give methyl 4-bromopyridine-2-carboxylate (0.39 g, 1.8 mmol, 73%) as a pale yellow solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 4.03 (3H, s), 7.67 (1H, dd, J=5.0, 1.6 Hz), 8.31 (1H, d, J=1.6 Hz), 8.57 (1H, d, J=5.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5](=O)[CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[N+:18]([O-])=O)[CH3:2].O.CCOC(C)=O>C(O)(=O)C.[Zn]>[NH:18]1[C:8]2[C:7](=[CH:17][CH:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:6]=[C:5]1[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)C(=O)Cc1ccc(C(=O)OCC)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Temperature: 75 °C
Yield: 58.9 %

Procedure:
Ethyl 4-(3-ethoxy-2,3-dioxopropyl)-3-nitrobenzoate (91 g, 0.29 mol) is suspended in 800 mL of acetic acid and it is heated with stirring to 75° C. Once the solid is dissolved, water (600 mL) is added. Zinc dust (189 g, 2.9 mol) is added carefully in small portions and the reaction temperature is kept below 85° C. The mixture is then stirred vigorously for 1 hour after the addition. EtOAc (1500 mL) is added and the mixture was filtered through Celite. The solid is washed with more EtOAc (1500 mL) and the filtrates are combined, washed twice with water (1500 mL), four times with saturated NaHCO3 (1000 mL), and once with brine (1000 mL). The filtrate is dried (Na2SO4), filtered, and concentrated to afford the crude compound which was recrystallized from toluene to afford the title compound (44.6 g, 58%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23]O>>[CH3:23][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -10 °C

Procedure:
5.1 g of the product from step C are dissolved in methanol (50 ml). The solution is cooled to −10° C. and treated with thionyl chloride (3 ml) and subsequently heated under reflux for 1 hour. The reaction mixture is evaporated and the residue dissolved in ether. The ether phase is washed with water, dried and evaporated to yield 5.1 g of a reddish brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH:24]([CH:28]([N:32]2[CH2:43][CH2:42][N:41]([CH2:44][C:45]([OH:47])=[O:46])[CH2:40][CH2:39][N:38]([CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[CH2:37][CH2:36][N:35]([CH2:55][C:56]([OH:58])=[O:57])[CH2:34][CH2:33]2)[C:29]([OH:31])=[O:30])[C:25]([OH:27])=[O:26])[CH2:13][CH2:12][N:11]([CH2:59][C:60]([OH:62])=[O:61])[CH2:10][CH2:9]1.C([O-])(=O)C.[Gd+3:67].C([O-])(=O)C.C([O-])(=O)C.[OH-].[NH4+]>O>[CH3:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][N:38]1[CH2:39][CH2:40][N:41]([CH2:44][C:45]([OH:47])=[O:46])[CH2:42][CH2:43][N:32]([CH:28]([CH:24]([N:14]2[CH2:13][CH2:12][N:11]([CH2:59][C:60]([OH:62])=[O:61])[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15]2)[C:25]([OH:27])=[O:26])[C:29]([OH:31])=[O:30])[CH2:33][CH2:34][N:35]([CH2:55][C:56]([OH:58])=[O:57])[CH2:36][CH2:37]1.[Gd:67].[Gd:67]
Reactant: [Gd+3]
Agent: CC(=O)[O-]
Agent: COCCOCCN1CCN(CC(=O)O)CCN(C(C(=O)O)C(C(=O)O)N2CCN(CC(=O)O)CCN(CCOCCOC)CCN(CC(=O)O)CC2)CCN(CC(=O)O)CC1
Agent: [NH4+]
Solvent: O
Product: [Gd]
Reaction time: 120 h

Procedure:
A solution of the compound of Example 15 (300 mg, 0.25 mmol) in DI water (10 mL) is treated with gadolinium acetate (212 mg, 0.52 mmol) at ambient temperature, while the pH is maintained at 5.6-6.0 using 1N ammonium hydroxide solution. When the pH becomes steady, the temperature is elevated to 50° C., and the mixture is stirred for 5 days. The solvent is removed by rotary evaporation, and the residue reconcentrated from DI water (5×200 mL). The crude complex is desalted using preparative HPLC to yield the title compound as a white solid after lyophilization.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([Cl:16])[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Cl-:16].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([S:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCNc1cc(N)[n+](CCCC)c(Cl)c1C#N
Reactant: SCc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNc1cc(N)[n+](CCCC)c(SCc2ccccc2)c1C#N
Temperature: 100 °C
Yield: 49.4 %

Procedure:
3.15 gms (0.01 mole) of 2-amino-1-n-butyl-4-n-butylamino-6-chloro-5-cyano pyridinium chloride (compound 6 - Table 1), 1.24 gms (0.01 mole) of benzyl mercaptan and 1.0 gm (0.01 mole) of triethylamine was dissolved in dimethylformamide and heated at 100°C for 1 hour. The dimethylformamide was evaporated off, ethanol added and 2.0 gms (50% yield) of 2-amino-6-benzylmercapto-1-n-butyl-4-n-butylamino-5-cyano pyridinium chloride (compound 75 - Table 5) crystallised out and was recrystallised from ethanol (MPt 145° - 147°C).
Reaction SMILES: [ClH:1].FC(F)(F)C1C=CC=CC=1O[C@H]1CCNC1.[OH:18][C@@H:19]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1O>>[ClH:1].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[O:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1cc(F)ccc1Br
Agent: Cl
Agent: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Product: Fc1ccc(Br)c(O[C@H]2CCNC2)c1

Procedure:
The title compound was prepared in the same manner as described for (3S)-3-[2-(trifluoromethyl)phenoxy]pyrrolidine hydrochloride from tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate and 2-bromo-5-fluorophenol. 1H NMR (300 MHz, DMSO-d6): δ 7.62 (m, 1H), 7.19 (m, 1H), 6.84 (m, 1H), 5.22 (s, 1H), 3.53 (s, 1H), 3.32 (m, 3H), 2.14 (m, 2H).
Reaction SMILES: CI.C[N:4]([CH:6]=O)[CH3:5].[I:8][C:9]1[C:17]2C(=[CH:13][C:14]([C:18]([O:20][CH2:21]C)=[O:19])=[CH:15][CH:16]=2)N[N:10]=1.C([O-])([O-])=O.[K+].[K+]>CCCCCC.C(OCC)(=O)C.CO>[I:8][C:9]1[C:17]2[C:6](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=2)[N:4]([CH3:5])[N:10]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc2c(I)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(I)nn(C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100-mL egg plant-type flask, MeI (381 mL, 6 mmol) was added to a DMF solution (10 ml) of ethyl 3-iodo-1H-indazole-6-carboxylate (948 mg, 3 mmol) and K2CO3 (830 mg, 6 mmol), and stirred overnight at room temperature. Further, and K2CO3 (830 mg, 6 mmol) and methyl iodide (381 μL, 6 mmol) were added to it, and stirred at 50° C. for 1 hour. After the starting materials disappeared, methanol was added to the reaction solution and stirred at that temperature for 30 minutes. This was diluted with a mixed solvent of hexane and ethyl acetate, and washed with water and saturated saline water in that order, dried with sodium sulfate, filtered, concentrated and purified through silica gel column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:31])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:32]([NH:39][CH2:40][C:41](O)=[O:42])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N(C(C)C)CC)(C)C.CCCP(=O)=O>C(Cl)Cl.CCOC(C)=O>[C:35]([O:34][C:32](=[O:33])[NH:39][CH2:40][C:41](=[O:42])[NH:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:31])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(N)c2)cc1C(F)(F)F
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NC(=O)CNC(=O)OC(C)(C)C)c2)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide (800 mg, 1.69 mmol), Boc-glycine (742 mg, 4.24 mmol), diisopropylethylamine (1.9 mL, 10.14 mmol) in methylene chloride (4 mL) was added propylphosphonic anhydride (2.68 mL, 50% solution in EtOAc, 4.24 mmol) was added slowly. The resultant heterogeneous solution was allowed to stir overnight at 45° C. The following day, the reaction was diluted with EtOAc, the organics were washed with saturated sodium bicarbonate, aqueous saturated NH4Cl and dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to provide ({4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-ylcarbamoyl}-methyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7](=O)C=CC1C=CC=C(Cl)C=1)=[O:6])[CH3:3].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]O)=O)[CH:20]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>C(Cl)CCl>[CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[O:27]1)=[O:6])[CH3:3]
Reactant: CC(C)NC(=O)C(=O)C=Cc1cccc(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: CC(C)NC(=O)C1OC1c1cccc(Cl)c1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-chlorocinnamoylcarboxamide (22.4 g.), m-chloroperbenzoic acid (23.6 g.), 4,4'-thiobis(6-tert-butyl-m-cresol) (0.3 g.), and ethylene dichloride as described in Example 7, and purified by recrystallization from ether. The compound melted at 131°-133°, and weighed 14.5 g.