Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[NH:13][N:14]=[C:10]3[CH2:9][CH2:8][CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.BrBr>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[NH:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)CC2
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Reaction time: 2 h

Procedure:
A suspension of 660 mg of 8-chloro-6-(2-fluorophenyl)-2,4,5,6-tetrahydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one in 150 ml of carbon tetrachloride is treated with 0.11 ml of bromine and heated to boiling while stirring for 2 hours while irradiating with a 500 W incandescent lamp. The solution is evaporated in vacuo. The residue is dissolved in chloroform and the solution is washed twice with saturated sodium hydrogen carbonate solution, dried and evaporated in vacuo. The residue is chromatographed on 35 g of silica gel. By elution with toluene/ethyl acetate (4:1) and crystallization from ethyl acetate/ether there is obtained 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 221°-224°.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]4[CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.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]>[CH:30]1([C@H:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]5([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]5)=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:34])=[O:33])[CH2:32][CH2:31]1
Reactant: C=CC1(C(=O)O)COCCOC1
Reactant: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (244 mg, 0.459 mmol), 6-vinyl-[1,4]dioxepane-6-carboxylic acid 57d (79 mg, 0.459 mmol), triethylamine (140 mg, 192 μL, 1.38 mmol) and tri(o-tolyl)phosphine (28 mg, 0.092 mmol) in 1,4-dioxane (9 mL) was degassed with nitrogen for 5 min and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.046 mmol) was added and the mixture was heated to 80° C. for 45 min and then allowed to cool. The suspension was filtered and evaporated to give crude title compound which was used in the next stage without further purification. LCMS (m/z) 624.2 [M+H], Tr=1.58 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1

Procedure:
Prepared according to Step D1 in General Procedure D using 2,4-difluoronitro-benzene (2.068 mL, 18.86 mmol) and 4-fluoroaniline (1.811 mL, 18.86 mmol) to give 5-fluoro-N-(4-fluorophenyl)-2-nitroaniline as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (1H, s), 8.24 (1H, dd, J=9.5, 6.2 Hz), 7.36-7.44 (2H, m), 7.25-7.33 (2H, m), 6.67-6.74 (1H, m), 6.64 (1H, dd, J=11.8, 2.6 Hz); LC-MS (ESI) m/z 251.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH:17]([CH2:51][O:52]CC1C=CC=CC=1)[CH2:18][N:19]([CH2:47][C:48]([OH:50])=[O:49])[CH2:20][CH:21]([CH2:38][O:39]CC1C=CC=CC=1)[N:22]([CH2:34][C:35]([OH:37])=[O:36])[CH2:23][CH2:24][CH2:25][O:26]CC1C=CC=CC=1)[CH2:6][CH2:7][CH2:8][O:9]CC1C=CC=CC=1)([OH:3])=[O:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:35]([CH2:34][N:22]([CH:21]([CH2:38][OH:39])[CH2:20][N:19]([CH2:47][C:48]([OH:50])=[O:49])[CH2:18][CH:17]([CH2:51][OH:52])[N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:6][CH2:7][CH2:8][OH:9])[CH2:23][CH2:24][CH2:25][OH:26])([OH:37])=[O:36]
Reactant: O=C(O)CN(CC(COCc1ccccc1)N(CCCOCc1ccccc1)CC(=O)O)CC(COCc1ccccc1)N(CCCOCc1ccccc1)CC(=O)O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(O)CN(CC(CO)N(CCCO)CC(=O)O)CC(CO)N(CCCO)CC(=O)O
Reaction time: 16 h

Procedure:
N4,N7,N10 -Triscarboxymethyl-1,13-bisbenzyloxy-5,9-bisbenzyloxymethyl-4,7,10-triazatridecane (0.30 g, 0.4 mmol) was dissolved in methanol (15 ml), 10% Palladium on carbon (0.3 g) and ammonium formate (0.1 g) were added and the mixture was kept at 50° C. for 16 hours. The catalyst was filtered off and washed with methanol (5 ml). The filtrate was evaporated and the title compound was isolated as a white powder. Yield 0.14 g (95%). M.p. 173°-177° C. The structure was confirmed by 1H NMR and 13CNMR.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11](O)[CH2:10]2)=[C:4]([F:15])[CH:3]=1.S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([Cl:18])[CH2:10]2)=[CH:6][C:7]=1[F:8]
Reactant: O=S(Cl)Cl
Reactant: OC1CCC(c2cc(F)c(Br)cc2F)C1
Product: Fc1cc(C2CCC(Cl)C2)c(F)cc1Br

Procedure:
A solution of 27.7 g (0.1 mol) of 3-(4-bromo-2,5-difluorophenyl)cyclopentanol in 150 ml of thionyl chloride was heated at reflux until gas evolution ceased (4 hours). The solvent was removed in vacuo and the residue was triturated with toluene (2×200 ml) which was also removed in vacuo. The residue was dissolved in ether, washed with water (3×100 ml), dried (MgSO4), filtered, and evaporated in vacuo to give 26.2 g of the title compound which was used without further purification.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([N:20]1[C:28]2[CH:27]=[C:26]([C:29]([OH:31])=O)[N:25]=[C:24]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]=2[NH:22][C:21]1=[O:40])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH:41][NH:42][C:43](=[NH:45])[CH3:44].[Al]>CN(C=O)C>[OH:41][N:42]=[C:43]([NH:45][C:29]([C:26]1[N:25]=[C:24]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:23]2[NH:22][C:21](=[O:40])[N:20]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:28]=2[CH:27]=1)=[O:31])[CH3:44]
Reactant: O=C(O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Al]
Solvent: CN(C)C=O
Product: CC(=NO)NC(=O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 132.7 %

Procedure:
CDI (52 mg, 0.32 mmol) was added to a solution of 1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (80 mg, 0.21 mmol) and Hunnigs base (83 μl, 0.64 mmol) in dry DMF in a ReactiVial. The vial was sealed and the mixture was stirred at room temperature for 15 minutes. N-Hydroxyacetamidine (24 mg, 0.32 mmol) was added and mixture heated to 60° C. in an aluminium block. The mixture was left to stir at this temperature for 3 hrs then allowed to cool and concentrated in vacuo. The residue was partitioned between EtOAc (15 ml) and water (5 ml). The layers were separated and the organic phase was washed with brine (5 ml). At this point, some solid precipitated and was left inside the separating funnel. This was washed into the organic phase with MeOH then the organics were dried (MgSO4) and evaporated to yield the final product as a white solid (120 mg, 130%). Material probably contains inorganic material, but taken on with a view to purification after next step.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:26][C:27]1[N:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])[CH2:24][CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:26][C:27]1[N:35]=[CH:34][C:33]([I:1])=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])[CH2:24][CH3:25]
Reactant: CCCOc1ncccc1C(=O)O
Reactant: NC(=O)CCC(=O)NI
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCOc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 ml) and trifluoroacetic anhydride (25 ml) were added to 2-propoxynicotinic acid (0.054 mol). The mixture was refluxed for 2.5h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a solid; 1H NMR (300 MHz, CDCl3): δ=1.05 (t, 3H), 1.85-2.0 (m, 2H), 4.5 (t, 2H), 8.5 (s, 1H), 8.6 (s, 1H), Analysis: found C, 35.16; H, 3.19; N, 4.46. Calcd for C9H10INO3: C, 35.19; H, 3.28; N, 4.56%; LRMS (TSP): 529.5 (MH+).
Reaction SMILES: [C:1]([OH:8])(=O)[C:2]#[C:3][CH2:4][CH2:5][CH3:6].[CH:9]1([NH2:12])[CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl>ClCCl>[CH:9]1([NH:12][C:1](=[O:8])[C:2]#[C:3][CH2:4][CH2:5][CH3:6])[CH2:11][CH2:10]1
Reactant: NC1CC1
Reactant: CCCC#CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCC#CC(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of 2-hexynoic acid (5.03 g) and cyclopropylamine (2.70 g) in dichloromethane (75 ml), and a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.00 g) and 1-hydroxybenzotriazole hydrate (7.19 g) in dichloromethane (75 ml) were mixed, and the mixture was stirred at room temperature for 18 hr. 1N Hydrochloric acid (200 ml) was added, and the mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and purified by silica gel column to give the title compound (6.04 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:11][CH:10]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13](=[N:24][OH:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ccccc1Nc1ccc(C(=NO)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-aminophenylamino)benzophenone (compound 101, 0.58 g, 2 mmol) and hydroxylamine hydrochloride (0.42 g, 6 mmol) in ethanol (30 ml) was added sodium acetate (0.49 g, 6 mmol). The reaction mixture was refluxed for 30 hours, cooled to room temperature, filtered, and evaporated in vacuo. The residue was treated with water (10 ml) and diluted ammonium hydroxide (5 ml). The precipitate that forms was filtered off, washed with water and dried to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][C:31]#[N:32])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].[NH4+].[Cl-].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:36])=[CH:27][C:28]([O:29][CH2:30][C:31]4[NH:43][N:42]=[N:41][N:32]=4)=[CH:33][C:34]=3[F:35])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCC#N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCc4nnn[nH]4)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)acetonitrile (129 mg, 0.23 mmol), NH4Cl (124 mg, 2.3 mmol) and NaN3 (16.60 mg, 0.25 mmol) in DMF (1.5 mL) was heated 17 h at 90° C. The reaction mixture was partitioned in EtOAc and H2O. The organic layer was washed with H2O and brine, dried over Na2SO4 and purified by flash chromatography (20% MeOH/DCM) to give the title compound (93 mg, 67%). 1HNMR (400 MHz, DMSO-d6) δ7.23 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 6.96 (m, 2H), 6.82 (m, 2H), 6.57-6.45 (m, 4H), 5.30 (s, 2H), 3.95 (s, 2H), 3.68 (s, 3H), 1.46 (s, 6H); MS (EI) m/z 601.3 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH3:16])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Cl:19][C:20]1[CH:37]=[C:36]([CH2:38]Br)[CH:35]=[CH:34][C:21]=1[O:22][CH:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25]>CN(C=O)C>[CH2:1]([C:5]1[N:14]([CH2:38][C:36]2[CH:35]=[CH:34][C:21]([O:22][CH:23]([C:24]([O:26][CH3:27])=[O:25])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([Cl:19])[CH:37]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:16])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C)ccc2[nH]1
Reactant: COC(=O)C(Oc1ccc(CBr)cc1Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(Cl)c1
Yield: 52.4 %

Procedure:
To a half suspension of 62 mg (0.287 mmol) of the product of Step A of Example 1 in 1.0 mL of anhydrous DMF was added 12 mg (1.05 eq) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under an N2 atmosphere. After stirring 10 minutes at room temperature, a solution of 0.127 g (1.2 eq) of the product of Step B dissolved in 1.0 mL DMF was added to the solution of the anion. The reaction mixture was then stirred overnight, then partitioned between water and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 76 mg (52%) of the title compound.
Reaction SMILES: [Cl:1][C:2]([Cl:14])([F:13])[S:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[O:15]1CCC[CH2:16]1.C=O>O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:14][C:2]([Cl:1])([F:13])[S:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][OH:15])[CH:5]=1
Reactant: FC(Cl)(Cl)Sc1c[nH]c2ccccc12
Reactant: C1CCOC1
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: OCn1cc(SC(F)(Cl)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 g of 3-{[dichlorofluoromethyl]thio}-1H-indole was dissolved to 10 ml of tetrahydrofuran. 10 ml of formaldehyde 36% in water and 0.4 ml of tetrabutylammonium hydroxide 10% in water were added to the solution, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, and extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 0.54 g of 3-{[dichlorofluoromethyl]thio}-1H-indole-1-ylmethanol.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:32])[CH2:28][CH2:29][CH2:30][CH3:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:7]=1
Reactant: CCCCCO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CCCCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and pentan-1-ol (87 μl; 0.773 mmol), example 45 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12](O)=[O:13])=[CH:4][CH:3]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>O>[C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:15])[CH:10]=[CH:11][C:12]2=[O:13])=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: O=C(O)/C=C\C(=O)Nc1ccc(O)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(N2C(=O)C=CC2=O)cc1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a three-neck 1 liter reaction vessel equipped with a condenser, a teflon stirring rod and a thermometer, 97 g (0.49 moles) of N-(4-hydroxyphenyl)maleamic acid, 27.7 g (0.38 moles) of sodium acetate and 400 g of acetic anhydride are added and then heated by using silicone oil. When the reaction solution reaches 70° C. for 2 hours with stirring, the solution is poured into a large amount of distilled water and a great amount of precipitates are formed. The precipitate is taken by filtration and washed several times with distilled water to remove acetic acid, followed by recrystallization from ethanol to give the titled compound. Yield 53%. B.P. 155°-158° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31]CC)=[O:30].[OH-].[K+]>C1COCC1.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([OH:31])=[O:30]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate (1.85 g, 3.09 mmol) was hydrolyzed with potassium hydroxide (0.523 g, 9.32 mmol) in THF (20 mL) and water (20 mL). Crystallization from methylene chloride/hexane and drying at 78° C for 12 hours yielded 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid a bright yellow solid (1.35 g), mp 115-117° C. Mass spectrum (+ESI, [M+H]+) m/z 573; 1HNMR (500 MHz, DMSO-d6): δ13.2-13.5 (br s, 1H), 8.45 (d, 1H, J=1.5 Hz), 8.2 (d, 1H, J=8.9 Hz), 8.1 (d, 1H, J=9.2 Hz), 8.05 (dd, 1H, J=7.7 Hz and 0.7 Hz), 8.0 (dd, 1H, J=8.9 Hz and 1.7 Hz), 7.75 (d, 1H, J=7.8 Hz), 7.4-7.45 (m, 6H), 7.3 (t, 2H, J=7.6 Hz), 7.25 (t, 1H, J=7.4 Hz), 5.35-5.4 (m, 1H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C32H27BrO5.0.10H2O: Calculated: C, 67.05; H, 4.78; N, 0.00. Found: C, 66.69; H, 4.38; N, 0.02.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1)[CH3:2].[OH-].[Na+].Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[N:16]=[C:15]([NH:29][CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:14]=1>C1C=CC=CC=1>[Cl:28][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[C:15]([NH:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[N:14]=[C:13]([O:9][CH:5]3[CH2:6][CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4]3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: CCN1CCCC(O)C1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCN1CCCC(Oc2nc(Nc3ccc(OC)c(Cl)c3)nc(NC3CCCCCC3)n2)C1
Temperature: 25 °C

Procedure:
A mixture of N-ethyl-3-hydroxypiperidine (0.3 g, 2.3 mmol) and NaOH (94 mg, 2.3 mmol) in benzene (10 ml) was heated to reflux for 2 hr with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 12 hrs., concentrated under vacuum and diluted with water (10 ml). The solid precipitated was filtered off and washed with petroleum ether to afford the title compound as a off white solid (0.3 g, 81%). mp 62-64° C.; HPLC: HICHROM RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 6.0); solvent B=CH3CN], Gradient elution program: T/% B=0/40, 5/40, 25/80, 35/80, 40/40, 45/40; 270 nm, Rt 26.83 min, 93.65% purity; MS (CI): m/z 447 (M+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[C:29]([OH:32])(=[S:31])[CH3:30]>>[C:26]([C:24]1[N:25]=[C:21]([C:19]([NH:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([S:31][C:29](=[O:32])[CH3:30])([CH3:15])[CH3:16])=[CH:13][C:8]=2[C:5]2[CH2:6][CH2:7][C:2]([CH3:28])([CH3:1])[CH2:3][CH:4]=2)=[O:20])[NH:22][CH:23]=1)#[N:27]
Reactant: CC(O)=S
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC(=O)SC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d)) and thioacetic acid using the conditions described in Example 70. 1H-NMR (CDCl3; 400 MHz): δ 9.73 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 7.74 (s, 1H), 7.49-7.47 (m, 1H), 7.35 (d, 1H, J=2.2 Hz), 5.79 (m, 1H), 2.32-2.28 (m, 2H), 2.20 (s, 3H), 2.11 (m, 2H), 1.86 (s, 6H), 1.59 (t, 2H, J=6.2 Hz), 1.11 (s, 6H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=1.Br[CH2:26][C:27]([CH3:29])=[CH2:28].Cl>C1COCC1.C(OCC)(=O)C>[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:28][C:27]([CH3:29])=[CH2:26])[C:16]([OH:18])=[O:17])[CH:10]=1
Reactant: O=C(O)Cc1cccc(-c2ccccc2)c1
Reactant: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 93 %

Procedure:
A solution of LDA (2.2 mL, 2.0 M in THF) in THF (20 mL) was cooled to 0° C. and then treated with biphenyl-3-ylacetic acid (0.212 g, 1.0 mmol). The mixture was stirred for 40 minutes, cooled to −78° C. and then treated with 3-bromo-2-methylpropene (135 μL, 1.3 mmol). The mixture was stirred for 1 hour, treated with 1 M hydrochloric acid (5 mL) and then diluted with ethyl acetate (50 mL). The organic layer was separated washed with water, brine, dried (MgSO4) and concentrated. Product was purified from the residue by flash column on silica gel (60° A) with 33% ethyl acetate in hexane to provide 2-biphenyl-3-yl-4-methylpent-4-enoic acid (250 mg, 0.93 mmol). 1H NMR (DMSO-d6): 1.71 (s, 3H), 2.52 (m, 2H), 3.68 (dd, 1H), 4.75 (m, 2H), 7.08 (d, 1H), 7.28-7.37 (m, 8H). LCMS: 267.1 (M+H+).