Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[C:38]([N:16]1[CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]([CH3:31])[N:12]=[C:11]1[S:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cold solution (5°) of 2.0 g. (0.0045 mole) of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester in 25 ml. of dichloromethane containing 0.72 g. (0.0091 mole) of pyridine is treated slowly with a solution of 0.76 g. (0.0054 mole) of benzoyl chloride in 3 ml. of dichloromethane. After stirring at room temperature for 16 hours, the solution is diluted with dichloromethane and washed with water, 1N hydrochloric acid, sodium bicarbonate and brine. The dried solution is evaporated to give 2.37 g. of a viscous oil which is not purified.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=3)=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[C-]#[N:38].[Na+].N>CO>[CH3:26][S:23]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([N:9]3[CH:10]=[C:6]([C:4]([NH2:38])=[O:5])[N:7]=[C:8]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:34])([F:36])[F:35])=[CH:16][CH:15]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:25])=[O:24]
Reactant: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Reactant: [C-]#N
Agent: N
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(N)=O)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 60 °C
Yield: 316.4 %

Procedure:
Ethyl-1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H imidazole-4-carboxylate (500 mg, 0.971 mmol), NaCN (10 mg, 0.194 mmol) and 6 mL 2M NH3 in MeOH were added to a 15 mL sealed tube and heated at 60° C. for 72 h. The reaction was cooled and the compound was absorbed on to silica purified by column chromatography using hexanes:ethyl acetate as eluents to afford 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide (298 mgs, 63%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 8.14-8.13 (m, 2H), 8.04-8.01 (m, 1H), 7.92-7.89 (m 1H), 7.85-7.80 (m, 3H), 7.74-7.65 (m, 4H), 7.45 (s, 1H), 7.37-7.35 (m, 2H), 7.27 (s, 1H), 3.28 (s, 3H); MS (ES): 486.1 [M+H]+ and 508.3 [M+Na]+.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[S:8].[CH3:15]I.CO>[OH-].[Na+]>[CH3:15][S:8][CH:7]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])[NH:6][C:2]1[S:1][CH:5]=[N:4][N:3]=1
Reactant: CI
Reactant: CCOC(=O)NC(=S)Nc1nncs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)NC(Nc1nncs1)SC
Temperature: 40 °C

Procedure:
A mixture of 6.96 g (30 mM) of [(1,3,4-thiadiazol-2-ylamino)thioxomethyl]carbamic acid, ethyl ester (prepared as described in Preparation 1) in 45 ml of 1N sodium hydroxide containing 9.0 g (4 ml) of methyl iodide and 15 ml of methanol was heated at 40° C. for ten minutes. The reaction mixture was cooled to 5' C. and filtered. The filter cake was washed with water and air dried to provide 4.72 g of [(methylthio)(1,3,4-thiadiazol-2-ylamino)methyl]carbamic acid, ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Brc1ccc2c(c1)NCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(CN2CCc3ccc(Br)cc32)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 6-bromoindoline (750 mg, 3.79 mmol), 1-(bromomethyl)-3-fluorobenzene (697 pt, 5.68 mmol) and cesium carbonate (1.851 g, 5.68 mmol) in N,N-dimethylformamide (7.573 mL) was stirred at 110° C. for 2 hours. The mixture was cooled, diluted with 100 mL ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column), eluting with a gradient of 2-50% ethyl acetate/hexane, afforded the title compound. LCMS: 306 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[N:12]3[C:13](=[O:25])[C:14]4[NH:15][CH:16]=[N:17][C:18]=4[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]3=[N:10][N:9]=2)=[CH:5][CH:4]=1.[Br:28]N1C(=O)CCC1=O>C1COCC1>[Br:28][C:16]1[NH:15][C:14]2[C:13](=[O:25])[N:12]3[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=4)=[N:9][N:10]=[C:11]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]=2[N:17]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(Cc3ccc(OC)cc3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To the solution of 3-(4-methoxybenzyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (0.40 g, 1.1 mmol) in THF was added N-Bromosuccinimide (0.29 g, 1.6 mol). The mixture was stirred at 70° C. for 1 hour. The mixture was concentrated and purified by preparative LCMS to yield the desired product (290 mg, 60%). 1HNMR (300 MHz, d6-DMSO): δ 7.16 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.46 (s, 3H), 4.20 (t, J=7.2 Hz, 2H), 3.67 (s, 2H), 1.79 (m, 2H), 1.28 (m, 4H), 0.83 (m, 3H). LCMS calculated for C19H21BrN6O2 (M+H): 445.1. Found: 445.0, 447.0.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C(=O)=O.CC(C)=O.C([Li])CCC.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:24])[CH3:21].C(I)C=C>C1COCC1.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C>[CH2:20]([O:22][C:23]([C:25]1([CH2:3][CH:1]=[CH2:2])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=CCI
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.9 %

Procedure:
In a 250 mL round bottom flask was weighed 6.1 g (60 mmol) of diisopropylamine and dissolved in THF (100 mL). This solution was cooled to −78° C. (dry ice/acetone bath). To this solution was added 24 mL of 2.5 M (60 mmol) of butyllithium in hexane and stirred for 15 min, warmed up to 0° C. for 20 min, re-cooled to −78° C. To this mixture was added piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (12.87 g, 50 mmol) in THF (10 mL). There was almost no color change. This was stirred at −78° C. for 45 min. Then, a mixture of 5 g of HMPA and 10.92 g of allyl iodide was added via cannula. The solution was still clear, light yellow color. This mixture was stirred at −78° C. for 20 min, then the dry ice bath was removed and the stirring was continued to allow the reaction mixture warm to r.t. over 40 min. The reaction mixture was poured into ice (˜50 g), saturated NH4Cl aq. (50 mL) and ether (50 mL). The two layers were separated; the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried (K2CO3), filtered, and concentrated in vacuo to obtain 15 g (100%) of the title compound as a yellow liquid,
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:20][C:21]1[C:25]([C:26]([O:28]C)=O)=[CH:24][S:23][CH:22]=1)=[O:19])=[C:14]([CH3:30])[C:13]([C:31]([F:34])([F:33])[F:32])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([C:8]1[N:9]([C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[C:10]2[C:15]([C:16]=1[N:17]1[C:26](=[O:28])[C:25]3=[CH:24][S:23][CH:22]=[C:21]3[NH:20][C:18]1=[O:19])=[C:14]([CH3:30])[C:13]([C:31]([F:34])([F:32])[F:33])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(-c2ccsc2)c2ccc(C(F)(F)F)c(C)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C(F)(F)F)ccc2c1c(-n1c(=O)[nH]c3cscc3c1=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Temperature: 100 °C

Procedure:
To a solution of 3-[3-(4-methoxycarbonyl-thiophen-3-yl)-ureido]-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1H (1.50 g, 2.59 mmol) in anhydrous methanol (10 mL) was added a 0.5 M solution of sodium methoxide (7.8 mL, 3.90 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 20 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 3-(2,4-dioxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1J which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:3][CH2:2]1.[H][H]>CO.O.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CN(CCC(=O)N1CCOCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN(CCC(=O)N1CCOCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Yield: 98.4 %

Procedure:
A solution of benzyl 2(S)-[N-(2-morpholinocarbonyl-ethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (726 mg) in methanol (150 ml) and water (10 ml) was hydrogenated over 10% palladium on carbon (80 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give 2(S)-[N-(2-morpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionic acid (573 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:26]1([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:29]3[CH2:30][CH2:31][N:26]([C:32]4[O:33][C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=4)[CH2:27][CH2:28]3)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 49, step 2) was coupled with 2-piperazin-1-yl-benzooxazole (CAS [111628-39-8]) to give the title compound as a colorless solid. MS: 566.3 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]([C:7]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[O:8])[C@@H:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][C:3]1=[O:26].[Li+].[BH4-].O>C1COCC1>[OH:8][C@@H:7]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[C@@H:6]1[N:2]([CH3:1])[C:3](=[O:26])[CH2:4][C@@H:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C(=O)c1ccc(-c2ccccc2)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@@H](O)c1ccc(-c2ccccc2)s1
Temperature: 50 °C
Yield: 69.6 %

Procedure:
To a solution of (4R,5R)-1-methyl-4-phenyl-5-[(5-phenyl(2-thienyl))-carbonyl]pyrrolidin-2-one (60 mg, 0.17 mmol) in THF (2 mL) was added a solution of LiBH4 (2M in THF, 0.1 mL, 0.2 mmol) and the reaction mixture was heated at 50° C. for 2 h. The resulting pale yellow suspension was treated with water and a saturated NH4Cl solution, extracted with EtOAc, dried (Na2SO4), concentrated onto silica gel and purified by flash chromatography to give (4R,5R)-5-[(1R)-hydroxy(5-phenyl(2-thienyl))methyl]-1-methyl-4-phenylpyrrolidin-2-one (43 mg, 71%) as a yellow solid: TLC (EtOAc) Rf 0.36; HPLC ES-MS m/z 364 (MH+).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.O(C(C)(C)C)[K].[I-].[K+].[CH2:19]([OH:22])[CH2:20][OH:21]>[Cu]=O>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([O:21][CH2:20][CH2:19][OH:22])=[CH:3]1
Reactant: Brc1csc2ccccc12
Reactant: OCCO
Agent: O=[Cu]
Agent: CC(C)(C)O[K]
Agent: [I-]
Product: OCCOc1csc2ccccc12
Temperature: 140 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of 3-bromobenzothiophene (3.00 g, 14.1 mmol), KO-t-Bu (4.74 g, 42.2 mmol), copper (II) oxide (0.56 g, 7.0 mmol) and potassium iodide (2.34 g, 14.1 mmol) in ethylene glycol (10 mL) was stirred at 140° C. for 24 h. The reaction was quenched with water (100 mL) and filtered through a pad of Celite. The water phase was extracted with EtOAc (3×50 mL). The organic phase was treated with MgSO4 and silica, filtered through Celite and concentrated. The remaining oil was purified by column chromatography on silica using isohexane/EtOAc (6:4) as eluent. The product crystallized on standing to give 1.63 g (60%) of the title product: mp 55-56° C. Anal. (C10H10O2S) C, H.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:27](=[O:28])[CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCc1noc(-c2sc(NC(=O)Cc3ccccc3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and phenyl-acetyl chloride.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:23]2)=[CH:18][C:17]=1[S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:26](=[O:31])[C:27]([F:29])([F:28])[F:30])[CH2:23]2)=[CH:18][C:17]=1[S:32]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([F:7])=[CH:9][CH:10]=1)(=[O:33])=[O:34]
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)c(Br)cc2C1)C(F)(F)F
Reactant: Nc1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(N1CCc2cc(S(=O)(=O)Nc3ccc(F)cc3)c(Br)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 94.2 %

Procedure:
Pyridine (3.09 mL, 38.4 mmol) was added to a solution of 4-fluoroaniline (3.73 g, 33.6 mmol) in chloroform (107 mL), and 7-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonyl chloride (13.0 g, 32.0 mmol) was added thereto while cooling in ice. The mixture was warmed to room temperature and stirred for 13 hr. To the mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure and the concentrate was powdered with hexane and ethyl acetate (4:1) and then collected by filtration to afford 7-bromo-N-(4-fluorophenyl)-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an orange powder (14.5 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:22])[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)([OH:3])=[O:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27].Cl>CN(C)C=O>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:13](=[O:22])[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:25][N:26]([CH3:28])[CH3:27])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCc1ccc(CC(=O)C(=O)c2ccccc2)cc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of 4.44 g of 3-[4-(2-carboxyethyl)phenyl]-1-phenyl-1,2-propanedione in 25 ml of dry dimethylformamide, cooled in an ice-bath, was added 11 ml of dimethylformamide dimethyl acetal. After stirring at room temperature for 15 min., the reaction mixture was poured onto 300 ml of crushed ice and the reaction mixture was acidified with 25 ml of 1 N hydrochloric acid. The mixture was extracted with methylene chloride. The layers were separated and the organic phase was washed with water, dried, filtered and evaporated under vacuum. Recrystallization of the residue from methylene chloride-ether gave 3.95 g (75%) of 2-[4-(2-carboxyethyl)phenyl]-1-dimethylamino-4-phenyl-1-butene-3,4-dione as yellow crystals after drying at 50° C. for 3 hrs.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:27]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>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]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:27]=[C:2]([C:32]5[CH:33]=[N:28][CH:29]=[N:30][CH:31]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1
Reactant: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1cc(-c3cncnc3)ccc1OCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 128.1 %

Procedure:
A mixture of 10-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.5 mmol), pyrimidin-5-ylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 565 (283 mg, 64.2%). 1H NMR (CDCl3, 400 MHz): δ 9.25 (s, 1H), 8.81(s, 2H), 8.09-8.01 (m, 2H), 7.54 (s, 1H), 7.19-7.47 (m, 3H), 7.43-7.41 (dd, J=8 Hz, 2H), 7.11-7.09 (d, J=8 Hz, 1H), 4.47-4.45 (d, J=8 Hz, 4H), MS (ESI) m/z 442.11 [M+H+]
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][CH:7]=[CH:6]1)(=O)C>[PH5].[Cl-].[Na+].O>[C:5]([O:11][C@@H:10]1[C@@H:9]([CH2:12][O:13][C:9](=[O:8])[CH3:10])[O:8][CH:7]=[CH:6][C@H:5]1[OH:4])(=[O:4])[CH3:6]
Reactant: CC(=O)O[C@@H]1C=CO[C@H](CO)[C@H]1O
Agent: [Cl-]
Agent: [Na+]
Agent: [PH5]
Solvent: O
Product: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 189.1 %

Procedure:
Per-O-acetyl glucal (27.5 mmol) was dissolved in phosphorane buffer (80 mL). Amano lipase (4.0 g) was added and the reaction mixture was stirred at room temperature for 24 hr. Brine (200 mL) was added and the obtained mixture was extracted with ethyl acetate (3×150 mL). Combined organic extracts were filtered trough Celite, and dried over anhydrous sodium sulfate. Drying agent and solvent were removed and product was purified by column chromatography (SilicaGel 60) using hexanes:ethyl acetate as eluents. 4,6-Di-O-Acetyl-D-glucal (26 mmol, yield 96%) was obtained.
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:9]=1)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][C:10]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: COCCOc1cc(OC(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc(O)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a methylene dichloride (3 ml) solution of tert-butyl 4-tert-butyl-3-(2-methoxyethoxy)phenyl carbonate (792 mg, 2.4 mmol) was added trifluoroacetic acid (TFA) (3 ml) and the mixture was stirred for 1 hour at ambient temperature. The solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=⅓ to furnish 0.32 g (59% yield) of the title compound as a white solid.
Reaction SMILES: OC(CO)CN(CCC[N:12]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16][N:15]([CH2:25][C:26]([OH:28])=[O:27])[CH2:14][CH2:13]1)CC(O)=O.[O-2].[Gd+3].[O-2].[O-2].[Gd+3]>O>[C:22]([CH2:21][N:18]1[CH2:17][CH2:16][N:15]([CH2:25][C:26]([OH:28])=[O:27])[CH2:14][CH2:13][NH:12][CH2:20][CH2:19]1)([OH:24])=[O:23]
Reactant: O=C(O)CN1CCN(CCCN(CC(=O)O)CC(O)CO)CCN(CC(=O)O)CC1
Agent: [Gd+3]
Agent: [O-2]
Solvent: O
Product: O=C(O)CN1CCNCCN(CC(=O)O)CC1
Reaction time: 15 h

Procedure:
To a solution of 1-[3-[N-(2,3-dihydroxypropyl)-N-(carboxymethyl)amino]propyl]4,7-bis(carboxymethyl)-1,4,7-triazacyclononane (5.0 g, 0.010 mol) in 50 mL of deionized water is added gadolinium oxide (1.8 g, 0.005 mol). The slurry is heated at 80 C. under argon atmosphere for 15 hours. The resulting solution is cooled at 25 C., filtered and the filtrate is evaporated under reduced pressure to give 1-[3-[N-2,3-dihydroxypropyl)-N-(carboxymethyl)amino]propyl]-4,7-bis-(carboxymethyl)-1,4,7-triazacyclononane, gadolinium(III) complex.
Reaction SMILES: NC1C=CC(S(C(C)C)(=O)=O)=C([C@@H]2CCCN2C(OC(C)(C)C)=O)C=1.[ClH:26].[CH3:27][N:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])=[C:34]([C@H:44]2[CH2:48][CH2:47][CH2:46][NH:45]2)[CH:33]=1)[C:29](=[O:31])[OH:30]>>[ClH:26].[CH3:27][N:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])=[C:34]([C@@H:44]2[CH2:48][CH2:47][CH2:46][NH:45]2)[CH:33]=1)[C:29](=[O:30])[OH:31]
Reactant: CC(C)S(=O)(=O)c1ccc(N(C)C(=O)O)cc1[C@H]1CCCN1
Agent: CC(C)S(=O)(=O)c1ccc(N)cc1[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)S(=O)(=O)c1ccc(N(C)C(=O)O)cc1[C@@H]1CCCN1

Procedure:
44B was prepared from 40B following a procedure similar to that used in the preparation of 44A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.24 (d, J=6.85 Hz, 3H) 1.35 (d, J=6.85 Hz, 3H) 2.14-2.29 (m, 1H) 2.29-2.45 (m, 2H) 2.45-2.62 (m, 1H) 3.36-3.56 (m, 3H) 3.79 (s, 3H) 7.68 (dd, J=8.56, 1.96 Hz, 1H) 7.95 (d, J=8.56 Hz, 1H) 8.08 (d, J=2.20 Hz, 1H) 8.10-8.19 (m, 2H) 8.60-8.77 (m, 1H) 8.89 (d, J=5.14 Hz, 2H) 9.96 (s, 1H).