Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:3][CH2:2]1.[OH-:19].[K+].OO>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]([C:17]([NH2:18])=[O:19])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCOCC2)c2cccnc12
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: NC(=O)c1ccc(N2CCOCC2)c2cccnc12
Yield: 55.8 %

Procedure:
To 0.8 g of 5-morpholino-8-quinolinecarbonitrile (Compound No. 13) 60 ml of methanol was added and the mixture was stirred at 0° C. with further addition of an aqueous solution of 0.47 g of potassium hydroxide and then 5 ml of 30% hydrogen peroxide aqueous solution. The mixture was heated at 40° to 50° C. for 16 hours with stirring. After evaporation of the solvent, saturated sodium chloride aqueous solution was added to the residue, which was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. Chloroform was evaporated, and the residue was refined by column chromatography on silica gel using chloroform as an eluent. The crystals thus obtained were recrystallized from ethanol to yield 0.48 g (yield: 56%) of 5-morpholino-8-quinolinecarboxamide (Compound No. 22).
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([O:11][CH2:12][CH2:13][O:14]CCOC(Cl)C)[CH3:10].C(OC([O-])=O)(OC(C)(C)C)=[O:22].[C:32]([O:35][CH2:36][CH3:37])(=[O:34])[CH3:33]>CN(C)C=O.O>[OH:34][CH:32]([O:35][CH2:36][CH2:37][O:14][CH2:13][CH2:12][O:11][CH:9]([OH:22])[CH3:10])[CH3:33]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCOC(C)=O
Reactant: CC(Cl)OCCOCCOC(C)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)OCCOCCOC(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The thus obtained partially hydroxycarbonylmethylated polyhydroxystyrene, 90 g, was dissolved in 180 g of N,N-dimethylformamide. With stirring under ice cooling, 30.0 g of triethylamine and then 2.0 g of diethylene glycol di(1-chloroethyl) ether were added. Reaction was carried out for 30 minutes under ice cooling, 35.0 g of tert-butyl dicarbonate was added, and reaction was carried out for a further 2 hours at 40° C. After the reaction mixture was allowed to cool down to room temperature, 500 g of ethyl acetate and 300 g of water were added thereto, followed by separation. The ethyl acetate layer was washed twice with 300 g of water and then concentrated in vacuum. The residue was dissolved in 300 g of methanol and added dropwise to 20 liters of water whereupon a powdery solid precipitated. The solid was collected by filtration, washed with 20 liters of water, and dried in vacuum at 40° C. for 24 hours. On 1H-NMR analysis, it was identified to be a polymer (Polym. 6) in which 18.0 mol % of the hydrogen atoms of hydroxyl groups in polyhydroxystyrene were replaced by tert-butoxycarbonyl groups, and the carboxyl group moieties which had been introduced in an amount of 2.0 mol % formed ester bonds with alcoholic hydroxyl groups of diethylene glycol di(1-hydroxyethyl) ether to provide crosslinking.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][NH2:4].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][N:9]=1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C1COCC1>[Cl:7][C:8]1[N:13]=[C:12]([NH:4][CH2:3][C:2]([NH:6][S:23]([CH3:26])(=[O:25])=[O:24])([CH3:5])[CH3:1])[C:11]([Cl:15])=[CH:10][N:9]=1
Reactant: CC(C)(N)CN
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
2-Methyl-propane-1,2-diamine (2.38 g, 27.03 mmol, 2.83 mL, 1.5 eq.) in THF (100 mL) was cooled to 0 C and 2,4,5-trichloropyrimidine (3.30 g, 18.02 mmol, 2.06 mL, 1.0 eq.) was added. The reaction was stirred for 5 minutes before NEt3 (6.5 mL) and mesyl chloride (3.08 g, 27.03 mmol, 2.08 mL, 1.5 eq.) were added simultaneously via two syringes. After 5 minutes, external cooling was removed and the reaction was stirred under a nitrogen atmosphere for 45 minutes. The reaction was then partitioned between CH2Cl2 (100 mL) and sat. NaHCO3 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure onto basic alumina. Purification by basic alumina chromatography (dry loaded) using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1,1-dimethyl-ethyl]-methanesulfonamide as a pale yellow solid (3.60 g, 64%). m.p.=143-145° C.; LCMS (m/e) 313 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 6.43-6.32 (m, 1H), 4.82 (s, 1H), 3.74 (d, 2H, J=6.2 Hz), 3.10 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([OH:19])[C:15]1=[O:20].[C:22](N1C=CN=C1)(=[O:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[N:3]1[CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([O:19][C:22](=[O:24])[CH3:23])[C:15]1=[O:20]
Reactant: CC(=O)n1ccnc1
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Solvent: Cc1ccccc1
Product: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O

Procedure:
0.594 g of (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide is boiled at reflux for 4 hours with 0.222 g of N-acetylimidazole in 10 ml of toluene. The mixture is chromatographed over 21 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride has a melting point of 120°-121° after crystallization from diethyl ether.
Reaction SMILES: Cl.C(OC([N:9]1[C:13]2=[C:14]([NH:29][S:30]([C:33]3([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[CH2:35][CH2:34]3)(=[O:32])=[O:31])[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[F:28])=[C:16]([CH3:19])[C:17](=[O:18])[N:12]2[CH2:11][CH2:10]1)=O)(C)(C)C.CO>C1COCC1.C(Cl)(Cl)Cl>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]2[C:14]([NH:29][S:30]([C:33]3([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[CH2:34][CH2:35]3)(=[O:32])=[O:31])=[C:13]3[NH:9][CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]=2[CH3:19])=[C:22]([F:28])[CH:23]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCN2
Temperature: 45 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
Concentrated HCl (3 mL) was added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-8-[1-(2,3-dihydroxy-propyl)-cyclopropanesulfonylamino]-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (75 mg) in THF (10 mL). The resulting mixture was stirred at 45° C. for 1 hour. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford 25 mg of the product (39.58% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:44]=[CH:43][N:42]=[C:41]([C:45]([OH:47])=O)[CH:40]=2)[CH2:35][CH2:34]1.[N+:48]([C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][CH2:55][CH2:54]2)([O-:50])=[O:49].C(N(CC)CC)C>CN(C=O)C.O>[N+:48]([C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([C:45]([C:41]1[N:42]=[CH:43][N:44]=[C:39]([N:36]3[CH2:37][CH2:38][CH:33]([N:25]4[C:26]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:32][C:24]4=[O:23])[CH2:34][CH2:35]3)[CH:40]=1)=[O:47])[CH2:55][CH2:54]2)([O-:50])=[O:49]
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.47 mmol) TBTU were added to 150 mg (0.44 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 75 mg (0.46 mmol) 5-nitro-2,3-dihydro-1H-indole, 100 μL and (0.712 mmol) triethylamine in 1.5 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was poured onto 30 mL water. The precipitated product was suction filtered and dried at 50° C. in the CAD.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3C(C#N)[C:6]=2[CH:18]=1.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[Br:1][C:2]1[CH:18]=[CH:6][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:21]([C:20]([OH:23])=[O:22])[C:4]=2[CH:3]=1
Reactant: N#CC1c2cc(Br)ccc2COc2ccccc21
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C1c2cc(Br)ccc2COc2ccccc21

Procedure:
A mixture of 5.48 g of 9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carbonitrile, 80 ml of conc. hydrochloric acid and 80 ml of acetic acid was heated under reflux for 15 hours. The reaction mixture was allowed to stand at room temperature. The crystals precipitated were collected by filtration and dissolved in dichloromethane. The solution was washed with water, dried and concentrated to dryness under reduced pressure. The crude crystals were recrystallized from toluene to obtain 1.83 g of Compound R.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:17])=O.[CH2:19]([N:21]([CH2:28][CH3:29])[CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24]O)[CH3:20]>C1C=CC=CC=1>[ClH:17].[CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])=[O:9])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(Cl)Cl
Reactant: CCN(CC)CC(C)(C)CO
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: CCN(CC)CC(C)(C)COC(=O)C=Cc1ccc2c(c1)OCO2
Product: Cl
Reaction time: 8 h

Procedure:
3,4-METHYLENEDIOXYCINNAMIC ACID (15 G, 0.08 MOLE) WAS ADDED TO THIONYL CHLORIDE (30 ML) WITH RAPID STIRRING AND THEN REFLUXED FOR 3 HOURS. The mixture was stripped of excess thionyl chloride, benzene (100 ml) was added, and the mixture was again stripped of solvent. The residue was treated with a solution of 3-diethylamino-2,2-dimethylpropanol (12.8 g, 0.08 mole) in benzene (400 ml), refluxed for 3 hours, cooled, diluted with petroleum ether (500 ml) and stored overnight at room temperature. The benzene-petroleum ether solution was decanted, the residue dissolved in H2O (500 ml), adjusted to pH 10 with saturated aqueous K2CO3, and the product was extracted with CHCl3 (600 ml). The CHCl3 extract was dried overnight over MgSO4 and Darco, filtered, and the filtrate was stripped of solvent under reduced pressure. The product was dissolved in ether (800 ml) and the solution was adjusted to pH 2 with a solution of dry HCl in ether. The product crystallized with scratching and was collected by filtration. Yield: 18 g (61%). A sample was recrystallized from ethyl acetate, m.p. 152°-154°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Cl[C:18]1[C:19]([N+:47]([O-:49])=[O:48])=[C:20]([CH:30]=[CH:31][C:32]2[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:35]([N+:41]([O-:43])=[O:42])=[CH:34][C:33]=2[N+:44]([O-:46])=[O:45])[C:21]([N+:27]([O-:29])=[O:28])=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].C(#N)C>CO>[N+:8]([C:7]1[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[CH2:1][C:22]1[C:21]([N+:27]([O-:29])=[O:28])=[C:20]([CH:30]=[CH:31][C:32]2[C:33]([N+:44]([O-:46])=[O:45])=[CH:34][C:35]([N+:41]([O-:43])=[O:42])=[CH:36][C:37]=2[N+:38]([O-:40])=[O:39])[C:19]([N+:47]([O-:49])=[O:48])=[CH:18][C:23]=1[N+:24]([O-:26])=[O:25])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(C=Cc2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c2[N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Solvent: CC#N
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(C=Cc2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cc3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])c2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
The reaction of 4.5 g (0.02 mole) of TNT with 4.6 g (0.01 mole) of 3-chloro-2,2',4,4',6,6'-hexanitrostilbene was carried out as in the above reactions. The crude reaction product, after extraction with methanol was a brittle mass which was dissolved in 50 mol of acetonitrile, diluted with an equal volume of methanol and heated on a hot plate with magnetic stirring. Light yellow crystals separated and were filtered off, washed well with methanol and dried. This material weighed 4.8 g, 71% of the theoretical yield, melted at 168°-170° (dec), and elemental analysis showed that it contained a mole of acetonitrile. Calcd for C23H12N10O18 : N, 19.6. Found: N, 19.7, 19.4. Recrystallized from 50 ml of THF with 50 ml of methanol added to the hot THF solution after filtering, the product separated in very fine, almost colorless crystals, mp 210°-211°C. Anal. Calcd for C21H9N9O18 : C, 37.2; H, 1.3; N, 18.8. Found: C, 37.5, 37.7; H, 1.6, 1.5; N, 19.0, 18.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([N+:19]([O-])=O)[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>[Ni].CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:12]=[C:11]([NH2:19])[C:10]=1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1c(N)cc(C(C)(C)C)cc1OCc1ccccc1

Procedure:
This is obtained, by reducing 2-methyl-3-nitro-5-tert.-butylphenyl benzyl ether with hydrazine hydrate and Raney nickel in methanol, in the form of a pale brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:29]=1.CCO.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:28]([O:24][C:21]1[CH:22]=[CH:23][C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]4[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3][C:4]([CH3:26])([CH3:25])[CH2:5]4)[N:14]=3)[S:19][C:18]=2[CH:20]=1)[CH3:29]
Reactant: CC1(C)CC(Nc2nccc(-c3cc4ccc(O)cc4s3)n2)CC(C)(C)N1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1
Temperature: 25 °C

Procedure:
Compound of Example 153 (76 mg, 0.2 mmol), triphenylphosphine (80 mg, 0.3 mmol) and EtOH (30 mg, 0.65 mmol) were suspended in 8 ml of THF, then diethylazodicarboxylate (52 mg, 0.3 mmol) dissolved in 4 ml THF was added dropwise. This mixture was stirred at room temperature over night and afterwards evaporated. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 33 mg (40%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[C:12]2[N:13]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[N:18][C:16]=3[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.O>[CH3:1][C:2]([C:7]1[C:12]2[N:13]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH2:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[N:18][C:16]=3[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH2:41])=[O:4]
Reactant: CC(C)(C(=O)O)c1cccc2c1N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1cccc2c1N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the product of Example 435 (217 mg, 0.4 mmol) in DMF (10 mL) was added HATU (169 mg, 0.4 mmol), Hunig's base (0.1 ml, 0.4 mmol) and NH3 (0.5 M in dioxane) (2.2 mL, 0.7 mmol). The resulting solution was stirred at rt overnight, diluted with H2O, and extracted with EtOAc(3×50 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give an oil which was purified by flash chromatography (0-7% MeOH/CH2Cl2) to give the title compound as a racemic mixture. The racemic mixture was separated by HPLC on a chiralcel OD column with 20% MeOH/CO2 as the mobile phase. The faster eluting enantiomer (E1) has a retention time of 4.0 minutes, while the slower enantiomer (E2) has a retention time of 4.6 minutes. E1: 1H NMR (500 MHz, (CD3)2CO): δ 8.11 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.31-7.35 (m, 3H), 7.28 (dd, J=1.5, 7.5 Hz, 1H), 7.18 (dd, J=1.5, 7.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 2H), 6.55 (s, 1H), 6.31 (s, 1H), 5.11 (d, J=17.5 Hz, 1H), 4.81 (d, J=17.5 Hz, 1H), 1.85 (s, 3H), 1.74 (s, 3H). LCMS: m/e 587.08 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:26]=[C:27]=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:27](=[O:28])[NH:26][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCN=C=O
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
Mixture of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol), heptyl isocyanate (0.169 g., 1.2 mmol) and pyridine (1 ml) in dry tetrahydrofuran (10 ml), was heated with stirring at 65° C. for 48 hours. Reaction mixture was quenched with water (1 ml) and concentrated under vaccum. The separated solid was washed with water (2×5 ml) and crystallised with ether to give (2 g) as oil; yield: 0.200 g. (52.6%), C24H32N2O2; 1H NMR δ ppm (CDCl3): 0.86 (bs, 3H), 1.20-1.29 (m, 6H), 1.55-1.58 (m, 4H), 1.96-2.06 (m, 2H), 2.79 (t, 2H), 3.17-3.36 (m, 4H), 4.44 (st, 2H), 4.87 (bs, 1H), 6.39-6.44 (m, 1H4), 6.71-6.75 (m, 2M), 7.25-7.34 (m, 5H); IR vmax (Neat) (cm−1): 757, 902, 1.70, 1160, 1199, 1228, 1348, 1458, 1502, 1618, 1718, 2362, 2857, 2928, 3028, 3342, 3854; MS: m/z=380 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[C:27]([O:29][CH3:30])=[O:28].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.C(Cl)Cl.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:15]([NH:14][S:11]([C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[C:19]=2[C:27]([O:29][CH3:30])=[O:28])(=[O:13])=[O:12])=[O:16])[N:3]=1
Reactant: COC(=O)c1cc2ccccc2n1C
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc(C)nc(N)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1c(S(=O)(=O)NC(=O)Nc2nc(C)cc(C)n2)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a stirred suspension of 2.59 g (0.021 mole) of 2-amino-4,6-dimethylpyrimidine in 75 ml dry nitromethane at -10° was added dropwise under nitrogen via syringe 2.0 ml (0.023 mole) of chlorosulfonyl isocyanate at such a rate as to maintain the temperature below 0°. The resulting clear solution was stirred for 0.5 hour at -5° to -10° and then contacted dropwise with a solution of 3.97 g (0.021 mole) of methyl 1-methyl-1H-indole-2-carboxylate dissolved in 40 ml of dry nitromethane. Upon completion of the addition, 2.95 g (0.022 mole) of aluminum (III) chloride was added in one portion. The reaction mixture was stirred at reflux for 3 hours, then cooled to room temperature and poured into 300 ml H2O. Methylene chloride was added and the layers separated. The aqueous solution was extracted with two additional portions of CH2Cl2 and the combined organic solutions were washed with H2O, dried over MgSO4 and evaporated in vacuo. Trituration of the residue with minimal CH2Cl2 afforded 2.02 g of the desired product as a white solid, m.p. 212°-215° (d). The infrared spectrum of the product included absorptions at 3215 and 3150 (NH), 1730 (C=O), 1710 (C=O), 1345 and 1150 (SO2) cm-1, 'H NMR (CDCl3 /DMSO-d6)δ 2.43 (s, 6H, pyrimidine CH3), 3.88 (s, 6H, ester CH3 and N--CH3), 6.90 (s, 1H, pyrimidine CH), 7.23-7.75 (m, 3H, indole CH), 8.16-8.47 (m, 1H, indole CH), 10.30 (s, 1H, NH), 13.26 (br s, 1H, NH). Mass spectral analysis showed m/e 123, ##STR30##
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[C:13]=1[NH2:20].C>[OH-].[Na+]>[Cl:19][C:14]1[CH:15]=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:11]2
Reactant: Nc1cc(F)cc(Cl)c1N
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(F)cc(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
5-Chloro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.64 g, 18.1 mmol) and 1,2-diamino-3-chloro-5-fluorobenzene (290 mg, 1.81 mmol) was heated to reflux under N2 for 10 h. The reaction was allowed to cool to room temperature and the shiny yellow-brown crystals collected by vacuum filtration and rinsed with EtOH (10 mL) and air dried to give 164.1 mg (42%). A portion of this solid was taken and dissolved in 10 mL 1N NaOH. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 1N HCl (pH=6). Pale yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 20 mL of H2O and further dried under vacuum (0.1 torr, 78° C.) to yield 67.8 of powdery pale yellow crystals. mp 306°-308° C. (dec), 1H NMR (d6 -DMSO) δ7.28 (s, 1H, ArH), 7.56 (s, 1H, ArH), 11.7 (br s, 2H, NH), EIMS m/z 216 (M+2,34, 214 (M+, bp), 188 (21), 186 (68), 123 (61), 131 (62). EIHRMS calc. for C8H4ClFN2O2 213.9945, found 213.9961.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:35]=[O:36]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH:35]=[O:36])[N:7]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C=O)n3)c2)cc1

Procedure:
A solution of 6-bromo-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine (15.1 mmol) in 100 mL of dry THF is added dropwise to a solution of n-butyl lithium (15.5 mmol) in 20 mL of tetrahydrofuran (THF) at -78° C. under H2 over 12 minutes. After 10 minutes the reaction mixture is treated with dimethylformamide (7.5 mL) in THF (15 mL), and quenched after 15 minutes with aqueous 10% HCl. The product is extracted into cold chloroform which is washed with saturated sodium chloride solution, filtered, and the solvent is evaporated. The residue is triturated with CH3CN, filtered, and recrystallized from ethyl acetate to provide the desired compound.