Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([OH:17])=O)[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:24][C@H:25]1[O:30][C@@H:29]([CH3:31])[CH2:28][NH:27][CH2:26]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([N:27]2[CH2:26][C@H:25]([CH3:24])[O:30][C@H:29]([CH3:31])[CH2:28]2)=[O:17])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2ccccc2C3)C[C@H](C)O1

Procedure:
A suspension of 2.0 g of 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylic acid in 25 ml of N,N-dimethylformamide was treated under argon with 0.91 ml of cis-2,6-dimethylmorpholine and then with 0.81 ml of N-methylmorpholine and 2.8 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and stirred at room temperature for a further 4.5 hours. The reaction mixture was then poured into a mixture of 50 ml of saturated sodium hydrogen carbonate solution and 250 ml of water. The crystallized-out crude product was filtered under suction and dried. After chromatography on silica gel with toluene and toluene/acetone (9:1) recrystallization was carried out twice from ethyl acetate. There was obtained 1.19 g of cis-4-[(4,6-dihydro-4-oxo-3-phenylpyrido-[2,1-a]isoindol-1-yl)carbonyl]-2,6-dimethylmorpholine as yellow crystals with a m.p. of 226°-228°.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CN(C)c1ccc(CNc2ccc(Cl)c(Cl)c2)cc1
Yield: 61.7 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (1.5 g) and 3,4-dichloroaniline (1.6 g) as starting materials, (3,4-dichlorophenyl)[(4-dimethylaminophenyl)methyl]amine (1.8 g) was obtained. melting point: 117° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
4'-Hydroxybiphenyl-4-carboxylic acid (3.5 g) and triethylamine (2.4 g) were dissolved in dichloromethane (30 ml). Nonanoyl chloride (4.3 g) and dimethylaminopyridine (0.2 g) were added to the solution, and the mixture was stirred at room temperature for about 20 hours. Dilute hydrochloric acid was added thereto, and the organic layer was separated in a separating funnel. The solvent was removed by evaportaion, and the residue was dried after washing with n-hexane to give the titled compound (5 g).
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14].O.Cl>CCOCC>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]([OH:14])[CH3:1]
Reactant: C[Mg]I
Reactant: CCCCC(C=O)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCCC(c1ccc(Cl)cc1Cl)C(C)O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To 14.3 g (0.088 mole) of methylmagnesium iodide in 75 ml of ether is slowly added at less than 10°, 14.5 g (0.059 mole) of the α-(2,4-dichlorophenyl) hexanal. When the addition is complete, the reaction is stirred for 1 hour then heated up to reflux for 2 hours. The reaction is cooled and poured into water. The mixture is acidified with hydrochloric acid and the oil which separates is extracted out with water. The ether solution is dried and concentrated to give 11.7 g (76%) of the crude product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[C:6]([O:17][CH3:18])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([O-:13])=O)=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]>ClCCl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][C:22]=1[O:27][CH3:28])[C:11]([C:10]1[CH:9]=[CH:8][C:7]([C:6]([O:17][CH3:18])=[O:16])=[CH:15][CH:14]=1)=[O:13]
Reactant: COc1ccccc1OC
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1
Reaction time: 8 h

Procedure:
2.1 g (15.72 mmol) of aluminum chloride, a solution of 2.39 g (12.02 mmol) of monomethyl terephthalate chloride dissolved in 2 ml of dichloromethane and 1.2 ml (9.25 mmol) of 1,2-dimethoxybenzene dissolved in 2 ml of dichloromethane were added to 10 ml of dichloromethane, and they were stirred overnight. The reaction solution was poured into 5 g of 1 N hydrochloric acid/ice. After the treatment with chloromethane as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was washed with ethyl acetate and dichloromethane to obtain-the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CON(C)C(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(NC(C)=O)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Amino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (1.2 g) was dissolved in methylene chloride (15 ml), and triethylamine (0.7 ml) followed by acetic anhydride (1.75 ml) were added while stirring with exclusion of moisture. After stirring at RT for 3 h, water and saturated sodium hydrogencarbonate solution were added, the phases were separated and the methylene chloride phase was washed three times more with water, dried over magnesium sulfate, filtered and concentrated. The resulting product (1.3 g) was used in the next stage without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH3:10][CH2:11]OCC.C1(C)C=CC=CC=1.C([Mg]Cl)C>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CCOCC
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Br)nc1
Reaction time: 4 h

Procedure:
To a chilled (ice bath) solution of 6-bromo-pyridine-3-carbaldehyde (15.0 g, 80.64 mmol) in a 1:1 mixture of ether:toluene (400 mL) was added a 2 M solution of ethylmagnesium chloride (40.0 mL, 80.0 mmol) in THF over a 15 minute period. The reaction was monitored by TLC (ethyl acetate-hexanes 3:7). After 4 hours, the mixture was diluted with saturated aqueous ammonium chloride (300 mL) and the organic phase separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was passed through a pad of silica gel eluting with dichloromethane-hexanes (0-100%). The material from the pad was purified by silica gel chromatography eluting with ethyl acetate-hexanes (2:98, then 4:96, then 6:94, then 8:92, then 1:9, then 12:88, then 15:85) to afford 1-(6-bromo-pyridin-3-yl)-propan-1-ol as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]2=[CH:14][CH:15]=1)([O-:3])=[O:2].[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[CH2:19][CH2:20][NH2:21].CN(C=O)C>C(Cl)Cl>[NH2:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=1[C:8]([NH:21][CH2:20][CH2:19][C:18]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:17]=1[Cl:16])=[O:10]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Reactant: NCCc1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)NCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a stirred solution of 4-nitro-isatoic anhydride (10.0 g, 0.048 mol) in CH2Cl2 (100 mL) was added 2,4-dichlorophenethylamine (10.08 g, 0.053 mol) followed by DMF (10 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was then dissolved in 1.0 L CH2Cl2 and washed with 1.0 M NaOH. The combined organic layers were concentrated under reduced pressure and purified by silica gel flash chromatography (0-100% EtOAc/hexanes eluent) to give the product (16.5 g, 97% yield) as a yellow solid. HPLC retention time: 3.04 min; Method A; LRMS (ESI) m/z 354 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].O>CS(C)=O>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:14](=[O:15])[NH:13][CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)N=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)NC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
13.0g (0.1 mole) of 5-fluorouracil was dissolved in 100ml of dimethyl sulfoxide, then 9.4g (0.11mole) of isopropyl isocyanate was added thereto at room temperature and stirred at the same temperature for 15 hours. The reaction mixture was poured into 800ml of water. The resultant precipitate was filtered off, washed with water and dried to give 14.7g (68.5% yield) of 5-fluoro-1-(iso-propylcarbamoyl)-uracil melting at 275°-285° C (decomposition).
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:29]5[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: CCN1CCNCC1
Solvent: c1ccncc1
Product: CCN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 27.2 %

Procedure:
1-Cyclopropyl-8-(4-ethyl-1-piperazinyl)-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 5 but starting from 2 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.74 g of 1-ethyl-piperazine in 20 cm3 of pyridine. The pure product is isolated after a first recrystallization from 105 cm3 of ethanol containing 25% of dimethylformamide followed by a second recrystallization from 75 cm3 of ethanol containing 50% of dimethylformamide. 0.67 g of 1-cyclopropyl-8-(4-ethyl-1-piperazinyl)-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow-green solid melting at 254° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]=[CH:33][N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1>CC#N>[Cl:17][C:18]1[CH:19]=[CH:20][C:21](=[O:55])[N:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[N:32]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=4)[CH:33]=[N:34][CH:35]=3)=[CH:26][N:25]=2)[CH:23]=1
Reactant: N#Cc1ccc(CBr)cc1-c1ccccc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1-c1ccccc1
Temperature: 60 °C

Procedure:
5-Bromomethyl-biphenyl-2-carbonitrile from step 4 (51 mg, 0.19 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (100 mg, 0.19 mmol) were dissolved in CH3CN (950 μl) and heated to 60° C. for 14 hours. The solvent was removed in vacuo and th ressidue dissolved in MeOH (950 μl). The reaction mixture was heated to 60° C. for 4 hours. Solvent was removed in vacuo and the residue was purified by flash chromatography [15% MeOH(5 % NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[N:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:23])CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[N:13]=[C:12]([CH2:14][F:23])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nccc(CO)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nccc(CF)n1
Reaction time: 0.17 h
Yield: 31.7 %

Procedure:
A solution of (4-hydroxymethylpyrimidin-2-yl)carbamic acid tert-butyl ester (450 mg, 2.0 mmol) in DCM (10 mL) at 0° C. was treated with DAST (396 μL, 3.0 mmol) and stirred for 10 minutes. The reaction mixture was partitioned between DCM and sodium bicarbonate (sat. aq.). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (144 mg, 32% yield). 1H NMR (300 MHz, CDCl3): δ 8.64 (d, J=5.1 Hz, 1H), 7.53 (s, 1H), 7.15-7.12 (m, 1H), 5.45-5.44 (m, 1H), 5.33-5.32 (m, 1H), 1.54 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[S:32]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1)(=[O:35])(=[O:34])[NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:44][CH2:43][CH2:42][C:39]3[CH:38]=[CH:37][C:36]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:41][CH:40]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(CCNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(4-sulfamoylphenyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=629.94 (M+H+); retention time=0.77 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O.[OH-].[Na+]>[C:15]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2)(=[O:17])[CH3:16]
Reactant: Cn1c(=O)c(=O)[nH]c2cc(N)ccc21
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)[nH]c(=O)c(=O)n2C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 0.3 g (1.3 mmol) 6-amino-1-methylquinoxaline-2,3(1H,4H)-dione in a mixture of 15 ml water and 0,6 ml 4N sodium hydroxide was added 5 ml acetic acid anhydride. Stirring was continued at 25° C. for 2 h. The precipitate was filtered off and washed with water to give 0.21 g (68%) of 6-acetamido-1-methylquinoxaline-2,3(1H,4H)-dione. M.p. 390° C. NMR (DMSO-d6): 10.1 (1H, broad s), 9.7 (1H, broad s), 7.5-7.0 (3H), 3.43 (3H, s), 2.0 (3H, s).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH:19]C(OC(C)(C)C)=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].Cl>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccc(OCC(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](N)c1ccc(OCC(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.8 %

Procedure:
To a solution of ethyl 3-(4-isobutyloxyphenyl)-3-(S)-tert-butyloxycarbonylamino-propionate (0.42 g) in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at 0° C. After stirring for 2.5 hours at ambient temperature, the mixture was partitioned between a mixture of ethyl acetate and a saturated aqueous NaHCO3 solution. The separated organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography eluting with chloroform and methanol (19:1 to 4:1) to give ethyl 3-(4-isobutyloxyphenyl)-3-(S)-amino-propionate(100 mg, 33.7%).
Reaction SMILES: C([O:4][CH:5]([CH2:43][O:44]C(=O)C)[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:21][CH2:20][CH:19]([O:22]C(=O)C)[C:18]2=[O:26])[C:13]([I:27])=[C:12]([C:28]([NH:30][CH2:31][CH:32]([O:38]C(=O)C)[CH2:33][O:34]C(=O)C)=[O:29])[C:11]=1[I:42])=[O:9])(=O)C.C[O-].[Na+].CO.CCC1(C2C=CC(N)=CC=2)C(=O)NC(=O)CC1>O>[OH:4][CH:5]([CH2:43][OH:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[C:18]2=[O:26])[C:13]([I:27])=[C:12]([C:28]([NH:30][CH2:31][CH:32]([OH:38])[CH2:33][OH:34])=[O:29])[C:11]=1[I:42])=[O:9]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCC(OC(C)=O)C2=O)c1I)OC(C)=O
Agent: CCC1(c2ccc(N)cc2)CCC(=O)NC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N2CCC(O)C2=O)c1I
Yield: 71.2 %

Procedure:
N,N'-Bis-[2,3-diacetyloxypropyl]-5-[3-acetyloxy-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 5b (4.20 g, 4.20 mmol) was treated with a 0.105 M solution of methanolic sodium methoxide [prepared by the addition of Na metal (48 mg, 2.10 mmol) to dry methanol (20 ml)] under a nitrogen atmosphere for 2.5 hours. The pH was then adjusted to 6.70 using Dowex-50 resin (H+ form) and AG-1 (OH- form) as necessary. The resin was removed and the solvents evaporated to give a yellow oil. This product was dissolved in 20 ml of deionized water and the pH adjusted to 6.98 by the addition of AG-1 (OH- 1 form) resin. The resin was filtered off and the filtrate containing the crude product was purified by low pressure reverse phase column chromatography using a CHP-20 resin to obtain N,N'-bis-[2,3-dihydroxypropyl]-5-[3-hydroxy-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white foam (2.36 g, 71% yield).
Reaction SMILES: O([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)S(C(F)(F)F)(=O)=O.[C:18]1([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1>[C:18]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
Table 1, Entry 11. In the reaction tube were mixed 4-acetylphenyl triflate (0.268 g, 1.0 mmol), phenyltributyltin (0.441 g, 1.2 mmol), Pd2 dba3 (0.00916 g, 0.010 mmol), triphenylarsine (0.0245 g, 0.080 mmol), lithium chloride (0.127 g, 3.0 mmol) and 1.0 ml NMP.under nitrogen. The contents of the flask were irradiated for 2.50 min with an effect of 50 W. After cooling, addition of 1 M aqueous KF (4 ml) with stirring for 120 min, were followed by dilution (DCM) and filtration through a pad of celite. The filtrate was washed with water (25 ml). Additional extraction of the aqueous phase was performed with DCM (2×25 ml). The combined extracts were washed with 25 ml saline and concentrated to an oil. The crude product was purified by column chromatography on silica gel using i-hexane/ethyl acetate (10/1) as the eluent. The yield was 68% (white solid).
Reaction SMILES: [Br:1]Br.[O:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[CH2:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.BrBr.O1C2C(=CC=CC=2)C(=O)CC1C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:11]1[CH:12]=[C:13]2[C:8]([C:6](=[O:7])[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:3]2)=[CH:9][CH:10]=1
Reactant: BrBr
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2ccccc2)oc2cc(Br)ccc12
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Bromine was added to a solution of flavanone in carbon tetrachloride at 0° C. The ratio of bromine/flavanone was 1.3 in molar terms. The temperature of the solution was raised to 30° C. and kept there for 1 hour. The temperature of the solution was then raised to 65° C. and kept there for 45 minutes.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Br.[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>>[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[CH:27]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: Br
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3cccc(-c4ccccc4)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,1′-biphenyl-3-ylmethylamine hydrobromide gave the title compound as an oil. M+(LC/MS(ESI)): 496.5. HPLC (Condition A), Rt: 4.99 min (HPLC purity: 90.9%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16](Br)[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:15]=1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(N2CCC3(CC2)OCCO3)c1

Procedure:
A mixture of 2,2′-Bis(diphenylphosphino)1,1′-binaphthyl[BINAP] (54.35 mg, 0.085 mmol) and Palladium(II)acetate[Pd(OAc)2] (6.95 mg, 0.028 mmol) in dry toluene (3 ml) was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. To this, 1,4-Dioxa-8-aza-spiro[4.5]-decane (100 mg, 0.699 mmol), 3-Bromo-4-methyl-benzoic acid methyl ester (192.1 mg, 0.839 mmol) and dry Cesium Carbonate (683.5 mg, 2.09 mmol) was added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to reflux overnight. The mixture was cooled, diluted with ethylacetate, water was added and the layers separated. The aqueous layer was extracted with ethyl acetate) and the two organic extracts were combined. The organics were washed with brine, then dried (sodium sulfate), filtered and concentrated. Further purification by silica gel chromatography using 5-10% ethyl acetate/Hexane as eluent provided 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-benzoic acid methyl ester [11] as a yellow solid [150.5 mg, 61.7%]