Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=S)[CH2:11][CH2:10]3)[CH:2]=1.[CH:18]([NH:20][NH2:21])=O.C1(O)CCCCC1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>CS(C)=O>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]2[CH:18]=[N:20][N:21]=[C:12]2[CH2:11][CH2:10]3)[CH:2]=1
Reactant: S=C1CCc2cc(-c3cccnc3)ccc2N1
Reactant: NNC=O
Solvent: OC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: c1cncc(-c2ccc3c(c2)CCc2nncn2-3)c1
Temperature: 25 °C

Procedure:
A flask containing the title compound from Example 1 Step B (20 mg, 0.08 mmol), formic hydrazide (6.0 mg, 0.10 mmol) and cyclohexanol (0.50 ml, 0.08 mmol) was heated to reflux for 6 hours. The reaction was cooled to room temperature, diluted with dimethylsulfoxide, acidified with trifluoroacetic acid and passed through a syringe filter. Purification by reverse phase HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid) provided the title compound: LCMS m/z 249.16 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 9.90 (s, 1H), 9.30 (d, J=2.0 Hz, 1H), 9.01 (ddd, J=1.5, 1.9, 8.2 Hz, 1H), 8.93 (d, J=5.6 Hz, 1H), 8.23 (dd, J=5.8, 8.2 Hz, 1H), 8.10-8.07 (m, 2H), 8.02 (dd, J=1.9, 8.4 Hz, 1H), 3.46-3.43 (m, 2H), 3.38-3.35 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:18])[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([F:30])([F:29])[CH2:27]I.O>CN(C=O)C>[F:25][C:26]([F:30])([F:29])[CH2:27][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH2:9][C:10]1=[O:18]
Reactant: FC(F)(F)CI
Reactant: O=c1cnc(-c2ccccc2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 5-phenyl-1,4-benzodiazepine-2-one (50 g, 0.211 mole) in DMF (100 mL) was treated with cesium carbonate (103.5 g, 0.317 mole) and trifluoroethyl iodide (109.7 g, 0.525 mole). The mixture was stirred at 50° C.-60° C. overnight. The reaction mixture was then poured into water (2 L) and extracted with ethyl acetate (3×1 L). The combined ethyl acetate fractions were dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The material was chromatographed on silica gel (1.5 Kg) eluting with 1:1 ethyl acetate/heaxane. The combined pure fractions were concentrated at reduced pressure. The residue was swished with warm ethyl ether, cooled and filtered to give the product. MP=130°-131° C.; 1H NMR CDCl3, δ7.65-7.60 (m, 2H), 7.60-7.45 (m, 5H), 7.40-7.20(m, 2H), 5.25 (dq, J=14, 8.6 Hz, 1H), 4.82(d, J=10.5 Hz, 1H), 4.15 (app sextet, J=8.6 Hz, 1H), 3.81 (d, J=10.5 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:26][C:27]2[N:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23].COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[CH:29][C:28]2[C:27]([NH:26][C:18]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=3)=[N:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COc1cc(Nc2ncccc2C=O)cc(OC)c1OC
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cccnc2Nc2cc(OC)c(OC)c(OC)c2)cc1OC
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
To a solution of 3,4-dimethoxyacetophenone (124 mg, 0.692 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then 2-(3,4,5-trimethoxyphenylamino)nicotinaldehyde (200 mg, 0.692 mmol) added and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h then reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6w) (254.7 mg, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Clc1nccc(-c2ccccc2)n1
Temperature: 125 °C
Yield: 83.2 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (1.47 g, 9.8 mmol), benzene boronic acid (1 g, 8.2 mmol), Na2CO3 (2.61 g, 24.61=01) in a mixture of DME (15 ml), EtOH (2 ml) and water (3 ml) was added Pd(PPh3)4 (190 mg, 0.16 mmol) and the resulting mixture heated in a microwave at 125° C. for 30 min. The reaction was repeated on same scale. The reaction mixtures were combined and diluted with water and extracted with EtOAc (×2). The EtOAc layers were combined and washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 40+M) eluent: 100% Hexanes (180 ml), gradient rising from 100% Hexanes to 10% EtOAc in Hexanes (900 ml), then 10% EtOAc in Hexanes (500 ml) to give 1.3 g of the title compound (41%) as a white solid. 1H NMR (CDCl3): 7.54 (m, 3H), 7.76 (s, 1H), 8.08 (m, 2H), 9.04 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](Cl)[CH2:14][OH:15].[OH-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][CH2:13][CH2:14][OH:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: OCCCl
Reactant: Nc1cc([N+](=O)[O-])c(N)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)c(NCCO)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
18.7 g (0.1 mole) of 1,4-diamino-2-nitro-5-chlorobenzene were dissolved in 20 ml methylglycol and 12 g ethylenechlorohydrin (1.5 mole) and the solution then heated on a bath having a temperature of 120°C. 6.6 g of sodium hydroxide dissolved in 60 ml water were then slowly added dropwise over a period of 3 hours. Heating was then continued for 1 hour whereupon a chromatographic check wss made to ascertain whether most or all of the starting compound had been reacted. After cooling the mass was diluted with water and the precipitated hydroxyethylated compound was removed by suction. Recrystallation was effected from water and thereafter from a 20% acetic acid. Yield: 4.5 g; m.p.: 130°-131°C. Analysis: C8H10ClO3N3
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].C(N(CC)CC)C.[C:21]([O:25][CH2:26][C@H:27]([C:36](O)=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH3:24])([CH3:23])[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[C:32]([O:31][C:29]([NH:28][C@H:27]([CH2:26][O:25][C:21]([CH3:24])([CH3:23])[CH3:22])[C:36]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:37])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 200 mg (1.13 mmol) of 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step B) in 8 mL of dry methylene chloride was added 0.206 mL (1.48 mmol) of triethylamine, 553 mg (1.25 mmol) of BOC-D-serine t-butyl ether followed by 602 mg (1.36 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. The reaction mixture was stirred at room temperature for 2 hours then diluted with 100 mL of ethyl acetate, washed with 25 mL of 5% aqueous citric acid, 25 mL of saturated sodium bicarbonate and 25 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvents removed under vacuum. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexane (55:45) to afford 480 mg (200%) of the product as a white foam. 1H NMR (200 MHz,CDCl3): 1.20 (s,9H), 1.47 (s,9H), 1.92 (m,1H), 2.55-3.02 (m,3H), 3.38 (t,8 Hz,1H), 3.78 (m,1H), 4.15 (m,1H), 4.52 (m,1H), 5.45 (s,1H), 7.00 (m,1H), 7.10-7.35 (m,3H), 7.68 (d,4 Hz,1H), 8.05 (s,1H). FAB-MS: calculated for C22H33N3O5 419; found 420 (M+H,205), 426 (M+Li,40%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:26](Cl)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(#N)C>[C:26]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCC(=O)Cl
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.5 part of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide and 19.6 parts of acetonitrile is added 0.298 part of sodium bicarbonate followed by 0.562 part of octanoyl chloride. The solution is stirred for 48 hours at room temperature, after which time the solvent is removed under reduced pressure and the resulting oil crystallized by trituration with cyclohexane. Recrystallization from cyclohexane yields 1-octanoyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl) hydrazine, melting at about 127°-129° and represented by the following structural formula ##SPC2##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](OCC)=[O:27])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.NC1C=CC(CCO)=CC=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cc(F)cc(Cl)c3)nc3c2CCC3)cc1
Agent: Nc1ccc(CCO)cc1
Product: Cl
Product: OCCc1ccc(Nc2cc(-c3cc(F)cc(Cl)c3)nc3c2CCC3)cc1
Yield: 30 %

Procedure:
Following General Procedure B2, ethyl 2-(4-((2-(3-chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate (0.075 g, 0.27 mmol) was reacted with 4-aminophenethyl alcohol (0.055 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.017 g, 23%) as a yellow solid. MW=419.32. 1H NMR (DMSO-d6, 300 MHz) δ 14.06 (s, 1H), 9.77 (s, 1H), 7.79-7.76 (m, 1H), 7.75-7.72 (m, 1H), 7.71-7.68 (m, 1H), 7.33 (s, 4H), 7.05 (s, 1H), 3.64 (t, J=6.9 Hz, 3H), 3.15 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.30-2.17 (m, 2H); APCI MS m/z 383 [M+H]+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]([O:48][CH3:49])=[C:15]([C:17]([CH3:47])([CH3:46])[CH2:18][C:19]([OH:45])([C:41]([F:44])([F:43])[F:42])[CH2:20][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35](O)=[O:36])[CH:16]=1.CN(C(O[N:58]1N=[N:65][C:60]2C=CC=N[C:59]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC(O)=[O:78]>CN(C=O)C>[NH2:58][C:59](=[O:78])[CH2:60][NH:65][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][CH:40]=[C:32]([N:26]2[C:27]3[C:23](=[C:22]([NH:21][CH2:20][C:19]([OH:45])([C:41]([F:44])([F:43])[F:42])[CH2:18][C:17]([C:15]4[CH:16]=[C:11]([F:10])[CH:12]=[CH:13][C:14]=4[O:48][CH3:49])([CH3:46])[CH3:47])[CH:30]=[C:29]([CH3:31])[CH:28]=3)[CH:24]=[N:25]2)[CH:33]=1
Reactant: NCC(=O)O
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)NCC(N)=O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
N,N-Diisopropylethylamine (0.109 mL, 0.625 mmol) was added to a solution of 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid (70 mg, 0.125 mmol) and HATU (47.5 mg, 0.125 mmol) in DMF (2.5 mL) and the solution stirred at room temperature for 5 min. Glycine hydrochloride (34.6 mg, 0.313 mmol) was added and the mixture stirred at room temperature overnight and then partitioned between 2M HCl (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with aqueous sodium bicarbonate (50 ml), dried over anhydrous sodium sulphate and evaporated to give crude product which was purified by mass directed autopreparation (System B) to give the title compound (62.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].Cl[C:12](OC1C=CC([N+]([O-])=O)=CC=1)=[O:13].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)=[CH:39][C:40]([NH2:44])=[N:41]2)=[CH:36][CH:35]=1>>[NH2:44][C:40]1[CH:39]=[C:38]([N:45]2[CH2:50][CH2:49][N:48]([C:12]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[C:3]([O:9][CH3:10])[CH:4]=3)=[O:13])[CH2:47][CH2:46]2)[C:37]2[C:42](=[CH:43][C:34]([Cl:33])=[CH:35][CH:36]=2)[N:41]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: COc1cc(N)ccc1F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)ccc1F

Procedure:
As described for example 78, 4-fluoro-3-methoxy-aniline, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 430 (M++1). 1H NMR (CD3OD) δ 8.25 (m, 2H), 7.82 (m, 1H), 7.45 (s, 1H), 7.40 (d, 2H), 7.20 (d, 1H), 6.40 (s, 1H), 3.95 (s, 3H), 3.80 (m, 4H), 3.25 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:21].[CH2:22](OC(OCC)OCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]2[C:18]3[CH:17]=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:21]=[CH:22]1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc2ncc(N)c(Nc3ccccc3Cl)c2c1
Product: COc1ccc2ncc3ncn(-c4ccccc4Cl)c3c2c1

Procedure:
0.2 g (0.66 mmol) of N4-(2-chloro-phenyl)-6-methoxy-quinoline-3,4-diamine (Example 44i) in 6 ml triethylorthoformate are heated under reflux for 4 h. The solvent is evaporated almost to dryness, the dark residue is dissolved in ca. 1 ml ethyl acetate and the compound is precipitated by adding ca. 30 ml of hexane. The desired title compound is filtered off, and is dried for 16 h at 60° C. (high-vacuum). mp: 202-205° C.; MS: 310 (M++1); HPLC: tret=70.56 min (Grad 1).
Reaction SMILES: [O:1]=[C:2]1[O:7][C:6](=[O:8])[CH2:5][N:4]([CH2:9][CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][C:22](=[O:24])[O:21][C:20](=[O:25])[CH2:19]2)[CH2:12][C:13]([OH:15])=[O:14])[CH2:3]1.Cl.[NH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].CC[N:55]([CH2:58][CH3:59])CC>CN(C=O)C>[C:13]([CH2:12][N:11]([CH2:10][CH2:9][N:4]([CH2:3][C:2]([OH:7])=[O:1])[CH2:5][C:6](=[O:8])[NH:55][CH2:58][CH2:59][O:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][N:18]([CH2:19][C:20]([NH:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:25])[CH2:23][C:22]([OH:21])=[O:24])([OH:15])=[O:14]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCOCCN
Reactant: O=C(O)CN(CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)NCCOCCOC(=O)CCCCCCCCCCCCCCCCC)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.3 %

Procedure:
N,N-Bis(2-(2,6-dioxo-4-morpholinyl)ethyl]glycine (1.9 g; 5.5 mmol) (commercial product) was added to a solution of octadecanoic acid 2-(2-aminoethoxy)ethyl ester hydrochloride (4.5 g; 11 mmol) and Et3N (1.5 g; 14 mmol) in DMF (150 mL) at 60° C. After 5 min the temperature was decreased to 45° C. After 2.5 h the mixture was cooled to room temperature to give a precipitate that was filtered, washed with acetone/H2O 15/5, then with acetone. The crude was dissolved in acetone and 0.1 N HCl and the solution heated at 50° C. After 10 min the solution was cooled to room temperature to afford a precipitate which was filtered, washed with acetone/H2O 15/5 then with acetone and dried under reduced pressure to give the desired compound (1.7 g; 1.5 mmol). Yield 27%. HPLC: 100% (area %). HPCE: 100% (area). K.F.: 3.11%. Weight loss (120 ° C.): 4.49%. The 1H-NMR, 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[CH:22]1[CH:23]=[CH:24][C:25]2N(O)N=N[C:26]=2[CH:27]=1.O1C=CC=C1[CH2:37][NH2:38].N=C=N>CN(C=O)C>[C:37]([C:25]1[CH:24]=[CH:23][C:22]([O:11][CH2:9][C:8]2([O:7][C:6]3[CH:16]=[CH:17][C:3]([C:1]#[N:2])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=3)[CH2:12][C:13]2([CH3:15])[CH3:14])=[CH:27][C:26]=1[C:18]([F:21])([F:20])[F:19])#[N:38]
Reactant: On1nnc2ccccc21
Reactant: NCc1ccco1
Reactant: CC(C)CC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1(C)CC1(COc1ccc(C#N)c(C(F)(F)F)c1)Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
To 1 mL of 0.1M(molar) solutions of the 2-(4-Cyano-3-trifluoromethyl-phenoxy)-4-methyl-pentanoic acid in DMF(dimethylformamide) (0.1 mmol) were added 0.5 mL of a 0.376M solution of HOBT, 1-hydroxybenztriaole, (0.2 mmol) in DMF, 0.1 mL of a 0.1M solution of the C-furan-2-yl-methylamine (0.1 mmol) in DMF, and approximately 183 mg of silica bound carbodiimide (loading: 1.09 g/mmol, 0.2 mmol). The resultant mixtures were shaken and heated at 70° C. for approximately 18 h. The reactions were filtered and the resin thoroughly rinsed with DMF. The solvent was removed in-vacuo to obtain oils that were then purified by HPLC(high performance liquid chromatography).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 48 h
Yield: 83.8 %

Procedure:
10% Pd/C (Aldrich cat no 205699, 0.30 g) was added to a stirred solution of 2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoic acid methyl ester (2.71 g, 5.96 mmol) in MeOH (75 mL) at room temperature. Stirring was continued for 2 days under H2 (1 atm.). Then the mixture was filtered through Celite, concentrated in vacuo to give the compound (1.83 g, 84%) as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[NH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[ClH:44].CCOCC>C(#N)C>[ClH:44].[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[NH:13][N:12]=[C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[CH2:4][NH2:1])[N:15]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2nc(-c3cccc(CN=[N+]=[N-])c3)n[nH]2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2nc(-c3cccc(CN)c3)n[nH]2)cc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of 3-(3-azidomethyl-phenyl)-5-(4-methoxy-phenyl)-1H-[1,2,4]triazole (980 mg, 3.2 mmol) in acetonitrile (40 ml) was treated with triphenyl phosphine (839 mg, 3.2 mmol) and water (288 mg, 16 mmol) at 20° C. for 20 min, then for 30 min. at 60° C. Upon cooling the product mixture was filtered, the solvent was evaporated and the residue chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 97:3 affording a solid after evaporation of the solvent. This material was dissolved in ethanol at r.t. and an excess 2N HCl/ether solution (2.0 ml, 4 mmol) was added. After 30 min. the precipitate was filtered off, washed with ether and dried under high vacuum at 60° C. overnight affording the title compound (700 mg, 69% yield) as a white solid. MS: m/e=281.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]([I:11])=[C:6]2[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([NH:28][C:29]1([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:27]>C(O)C.C(Cl)Cl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:10]([I:11])=[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([N:32]3[CH2:31][CH2:30][C:29]([NH:28][CH2:26][CH3:27])([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33]3)[N:7]2[N:8]=1
Reactant: CCNC1(C(N)=O)CCNCC1
Reactant: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC1(C(N)=O)CCN(c2ccnc3c(I)c(-c4ccccc4Cl)nn23)CC1
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 7-chloro-2-(2-chlorophenyl)-3-iodopyrazolo[1,5-a]pyrimidine (I-1A-1d; 80 mg, 0.21 mmol) and triethylamine (44 μl, 0.32 mmol) in 1:1 ethanol/methylene chloride (2 ml) was added 4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1g; 40 mg, 0.23 mmol). A colorless precipitate formed after several minutes and the mixture was stirred overnight. The solid precipitate was isolated by vacuum filtration, washed with ethanol and ether, and then dried, in vacuo, to afford product I-1A-1h as an off-white solid (95 mg, 86%): +APcI MS (M+1) 525.4; 1H NMR (400 MHz, CD3OD) δ 8.27 (d, J=5.4 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.48–7.39 (m, 3H), 6.45 (d, J=5.6 Hz, 1H), 4.14–3.96 (m, 2H), 3.92–3.84 (m, 2H), 2.50 (q, J=7.1 Hz, 2H), 2.23–2.15 (m, 2H), 1.85–1.77 (m, 2H), 1.16 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34]O)[C:24]=1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34][O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[C:24]=1[OH:25]
Reactant: Oc1ccc2ccccc2n1
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Product: O=C1OC(CCOc2ccc3ccccc3n2)C(O)=C1O
Yield: 17.4 %

Procedure:
Mitsunoble coupling of 0.17 g (1.2 mmol) of 2-hydroxyquinoline with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 50 mg (17% yield) of 3,4-dihydroxy-5-[2-(quinoline-2-oxy)ethyl]-2(5H)-furanone as a fluffy white solid after recrystallization from ether and hexanes: 1H NMR (acetone-d6) δ 8.25-8.17 (m, 1H); 7.88-7.38 (m, 4H), 7.01-6.93 (m, 1H); 4.97 (dd, J=4.9, 8.7 H, 1H), 4.81-4.55 (m, 2H); 2.62-2.45 (m, 1H), 2.20-1.95 (m, 1H). Anal Calcd for C15H13NO5 +0.5H2O: C, 60.81; H, 5.10; N, 4.72. Found: C, 61.04; H 5.04: N, 4.32.