Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][CH:18]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:19][CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N3CCCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 17 h

Procedure:
200 mg (1.170 mmol) 4-fluoro-2-methoxy-1-nitro-benzene are dissolvedjin 1 ml NMP, combined with 198 mg (1.284 mmol) 4-pyrrolidin-1-yl-piperidine and 300 μl diisopropylethylamine and stirred for 17 h at 80° C. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the finishing point.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:35])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:15][C:16](OC)=[O:17].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:35])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:15][C:16]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:17]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: COC(=O)C=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.55 g (3.1 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (14 mL). After addition of 1.0 g (3.1 mmol) of methyl 3,7,11,15-tetramethylhexadec-2-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[CH:25][NH:26]3)=[CH:22][CH:21]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([C:3]3[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)=[CH:10][CH:9]=[C:8]4[C:4]=3/[C:5](=[CH:12]/[C:13]3[NH:14][CH:15]=[CH:16][C:17]=3[O:18][CH3:19])/[C:6](=[O:11])[NH:7]4)[CH:28]=2)[CH:24]=[CH:25]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc4cc[nH]c4c3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccc4cc[nH]c4c3)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (Z)-5-amino-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (22 mg, 0.059 mmol) (from Step B above) in 2 mL tetrahydrofuran was added 2-thiopheneacetyl chloride (20 mg, 0.12 mmol) (Aldrich) and a saturated aqueous solution of sodium bicarbonate (0.15 mL). The reaction was stirred at room temperature for 16 hours at which time the reaction was diluted with water (10 mL), and the THF was evaporated in vacuo. The product was then extracted with EtOAc, and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting powder was recrystallized from EtOAc/Hex to give product as yellow crystals. (Yield 19 mg, 66%).
Reaction SMILES: C([C:3]1[CH2:4][S:5](=[O:30])[C@@H:6]2[CH:17]([NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=O.[C:31]([CH:36]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:33][CH2:34][CH3:35])=[O:32].[C:56]1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:34]([O:33][C:31]([CH:36]=[CH:56][C:3]1[CH2:4][S:5](=[O:30])[C@@H:6]2[CH:17]([NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[O:32])[CH3:35]
Reactant: CC(C)(C)OC(=O)C1=C(C=O)CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C=CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)C1
Reaction time: 264 h

Procedure:
To a solution of 0.5 millimole of tert-butyl 3-formyl-7-phenoxyacetamido-3-cephem-4-carboxylate-1-oxide in 10 cc. of dry benzene was added 175 mg. (1 equivalent) of (carbethoxymethylene)-triphenylphosphorane. After allowing the reaction mixture to stand at room temperature for 11 days, the solvent was removed under reduced pressure, the residue taken up in hot ethyl acetate, and cooled to yield 140 mg. of crystalline triphenylphosphine oxide (m.p., 155°-157° C.) as by-product.
Reaction SMILES: C(=O)([O-])O.[Na+].CS(C)=O.Cl.[NH2:11][OH:12].[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32](=[N:11][OH:12])[NH2:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)nc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Process 2: Sodium hydrogen carbonate (2.02 mg, 24.0 mmol) was added to dimethyl sulfoxide solution (20 mL) of hydroxylamine hydrochloride (1.42 g, 20.4 mmol) and stirred for 1 hour at 40° C. Dimethyl sulfoxide solution (3 mL) of 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}benzonitrile (430 mg, 0.987 mmol) was added to the reaction mixture and stirred for 19 hours at 90° C. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (ethyl acetate) to give 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (430 mg, 93%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][N:27]=[C:28]=[O:29].CCN(CC)CC.Cl>C1COCC1>[O:29]1[CH2:25][CH2:26][N:27]=[C:28]1[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]=[CH:10]2)[CH3:23]
Reactant: CNCCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: O=C=NCCCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1)C1=NCCO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 16.4 %

Procedure:
300 mg (0.96 mmol) {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methylamine in 10 ml THF were treated with 150 mg (1.4 mmol) 2-chloroethylisocyanate and the mixture stirred at room temperature during 10 hours. After addition of 0.2 ml NEt3 the mixture was stirred for an additional hour and treated with 0.1 M aqueous HCl. Extraction with Et2O, drying of the combined organic layers with Na2SO4, Evaporation of the solvent, and column chromatography on silica gel with CH2Cl2/MeOH/NEt3 10:1:0.1 gave 60 mg (16%) (4,5-Dihydro-oxazol-2-yl)-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine, MS: 382 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-:46].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:21][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:46])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CCN3CCOCC3)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CCN3CCOCC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A mixture of 6-ethyl-3-(2-morpholin-4-ylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.42 g), potassium carbonate (0.13 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.06 g, 13%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C@@H:17]([NH2:24])[C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[CH:6]=[CH:7][C:8]=1[F:9].C(OC(N[C@@](C1C=CC=CC=1C1C=CC(F)=C(Cl)C=1)(C)C(O)=O)=O)(C)(C)C.[CH3:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=2)=[CH:56][C:55]=1[C:70](O)=[O:71]>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C@@H:17]([NH:24][C:70]([C:55]2[CH:56]=[C:57]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([F:67])([F:69])[F:68])=[CH:62][CH:61]=3)[CH:58]=[CH:59][C:54]=2[O:53][CH3:52])=[O:71])[C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Cc1noc([C@H](N)Cc2ccccc2-c2ccc(F)c(Cl)c2)n1
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@](C)(C(=O)O)c1ccccc1-c1ccc(F)c(Cl)c1
Agent: Cl
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccccc1-c1ccc(F)c(Cl)c1)c1nc(C)no1
Yield: 66.4 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.081 g) was prepared from 2-(3′-Chloro-4′-fluoro-biphenyl-2-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride salt (0.075 g, 0.2 mmol) which was prepared from 2-(R)-tert-Butoxycarbonylamino-2-(3′-chloro-4′-fluoro-biphenyl-2-yl)-propionic acid following general procedure N and 4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.06 g, 0.2 mmol) following general procedure A.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[NH2:20][OH:21].[OH-].[Na+]>CO>[C:1](=[N:20][OH:21])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(c1ccccc1)c1ccccc1
Temperature: 5 °C

Procedure:
Benzophenone (182 g; 1.0 mol) mixed with absolute methanol (400 mL) was placed in a 2-liter 3-neck flask (baffled) fitted with over-head stirrer. To the solution was added hydroxylamine sulfate (120 g; 0.73 m) and maintained vigorously stirred with cooling in ice bath (5° C.). A solution of sodium hydroxide pellets (60 g; 1.50 mol) in absolute methanol (400 mL) was then added slowly with continued agitation. After stirring for 6 hours with cooling, it was heated under reflux (67° C.). pH of the mixture was 11.2. Heating at reflux continued for a total of 12 hours and the solution filtered while still hot.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:28].[C:30](O)(=[O:33])[CH2:31][OH:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:33][CH2:30][C:31]([NH:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:28])=[O:32]
Reactant: O=C(O)CO
Reactant: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC(O)CNC(=O)CO
Yield: 20.1 %

Procedure:
A solution of 1-amino-3-{4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (277 mg, 0.698 mmol), glycolic acid (80 mg, 1.05 mmol), DIPEA (362 mg, 2.80 mmol) and TBTU (382 mg, 1.19 mmol) in DMF (10 mL) is stirred at rt for 16 h before it is diluted with EA, washed with water, and concentrated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 10% of methanol to give 2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propyl)-acetamide (64 mg) as a pale yellow solid, LC-MS: tR=0.94 min, [M+1]+=456.18, 1H NMR (D6-DMSO): δ 1.30 (d, J=5.9 Hz, 6H), 2.31 (s, 6H), 3.16-3.25 (m, 2H), 3.63-3.79 (m, 2H), 3.81 (d, J=5.6 Hz, 2H), 3.86-3.97 (m, 1H), 4.72-4.83 (m, 1H), 5.28 (d, J=5.3 Hz, 1H), 5.54 (t, J=5.9 Hz, 1H), 7.14 (d, J=9.1 Hz, 2H), 7.68 (t, J=5.6 Hz, 1H), 7.73 (s, 2H), 8.08 (d, J=9.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:36].[H][H]>CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:36]
Reactant: [H][H]
Reactant: O=C(NCC/C=C\c1ccccc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Agent: O=[Pt]=O
Agent: [Na+]
Solvent: CO
Product: O=C(NCCCCc1ccccc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of sodium (Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylate (0.16 g, 0.31 mmol) in methanol (2 mL) was added platinum(IV) oxide (0.018 g, 0.079 mmol), and to the resulting stirred mixture at ambient temperature was fitted a balloon of hydrogen. The flask was purged and refilled five times with hydrogen, and the resulting mixture was stirred at ambient temperature under a balloon of hydrogen for 30 minutes, by which time the catalyst had clumped up. The methanol supernatant was decanted away from the catalyst with a pipet and concentrated, and the residue concentrated from diethyl ether to afford sodium 6-chloro-7-(4-(4-(2-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylate as a white glass (142 mg, 87% yield). MS (apci) m/z=514.1 (M+2H—Na).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[OH:20][CH:21]([CH3:29])[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([CH:22]([CH2:28][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:29]
Reactant: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: C=C(C(=O)OCC)C(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl)C(C)=O
Yield: 111 %

Procedure:
This compound was prepared in the manner of Example 6, with 18.28 grams (0.0415 mole—1.0 equiv.) of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 6.28 grams (0.0436 mole—1.05 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 15.4 grams (0.083 mole—2.0 equiv.) of tributylamine, and 0.233 gram (0.0010 mole—0.025 equiv.) of palladium(II) acetate as reagents. A yield of 20.3 grams of 75.6% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1yl]4-fluorobenzenepropanoate (87.9% yield) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:34][O:35][C:36](=[O:69])[NH:37][CH:38]([C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH:45]1[C:49]1[NH:50][CH:51]=[C:52]([C:54]2[CH:59]=[CH:58][C:57](B3OC(C)(C)C(C)(C)O3)=[CH:56][CH:55]=2)[N:53]=1)=[O:43])[CH:39]([CH3:41])[CH3:40].C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=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.O.COCCOC>[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:57]4[CH:58]=[CH:59][C:54]([C:52]5[NH:53][C:49]([CH:45]6[CH2:46][CH2:47][CH2:48][N:44]6[C:42](=[O:43])[CH:38]([NH:37][C:36]([O:35][CH3:34])=[O:69])[CH:39]([CH3:41])[CH3:40])=[N:50][CH:51]=5)=[CH:55][CH:56]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
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: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(CC(F)(F)F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 24.6 %

Procedure:
{1-[4-(4-Bromo-phenyl)-1′-(2,2,2-trifluoro-ethyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (13.0 mg, 0.0244 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (12.1 mg, 0.0244 mmol) under an argon atmosphere. Potassium carbonate (6.7 mg, 0.048 mmol) and Pd(PPh3)4 (2.7 mg, 0.0024 mmol) were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′-(2,2,2-trifluoro-ethyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (6.1 mg, 0.006 mmol) as the TFA salt: LCMS-ESI+: calc'd for C41H50F3N9O6: 821.8 (M+). Found: 823.4 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.89-7.82 (m, 10H), 5.39 (dd, J=6.3, 6.3 Hz, 1H), 5.25 (m, 1H), 4.78 (d, J=6.9 Hz, 1H), 4.24 (d, J=7.5 Hz, 1H), 4.10 (m, 1H), 4.00 (d, J=7.5 Hz, 1H), 3.88 (m, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.65-3.43 (m, 4H), 2.58 (m, 1H), 2.29-2.01 (m, 5H), 1.03-0.89 (m, 12H).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([O:18]C)=[O:17])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2>ClCCl.O1CCCC1>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([OH:18])=[O:17])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH:13]1[CH:12]=[CH:11][C:10]([C:9]2[CH:16]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1c2ccccc2N(C)c2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1c2ccccc2C(C(=O)O)c2ccccc21
Product: c1ccc(-c2ccccc2)cc1

Procedure:
A solution of 0.24 parts of 10-methylacridan-9-carboxylic acid chloride(78) in 10 mL dichloromethane and 0.145 parts of 4-phenylphenol (76) in 5 mL of dichloromethane and 1 mL of tetrahydrofuran is treated as described in example I, to give 0.21 parts of 4,4′-biphenyl 10-methylacridan-9-carboxylate. This compound has the following structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[H+].[N:20](OCCCCC)=O>C(O)C.C(OCC)C>[F:14][B-:15]([F:18])([F:17])[F:16].[N+:1](=[C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[C:4]([CH3:13])[CH2:3]1)=[N-:20]
Reactant: Cc1cc(N)cnc1CCCCN
Reactant: CCCCCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CCO
Product: CC1=C(CCCCN)N=CC(=[N+]=[N-])C1
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) mixture of 5-amino-2-[4-aminobutyl]-3-methylpyridine (0.86 g) and fluoroboric acid (5 ml) in ethanol (30 ml) was reacted with amyl nitrite (3 ml) over 15 minutes and then stirred for a further 15 minutes, diluted with diethyl ether at 0° C. to give 5-diazo-2-(4-aminobutyl)-3-methylpyridine fluoroborate (1.88 g) m.p. 80°-120° C. (dec).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[H-].[Na+]>CN(C)C=O>[N:30]1([CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:10][CH2:9]2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](COC/C=C/Cn2ccnc2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 25.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide (example 19.1) was reacted with imidazole in N,N-dimethylformamide in the presence of sodium hydride to yield trans-N-[4-(4-imidazol-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as yellowish solid, MS: 486 (MH+).