Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([O:18][CH3:19])[N:17]=[C:13]3[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([O:18][CH3:19])[N:17]=[C:13]3[N:12]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=3)[C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc(OC)nn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(OC)nn2C1c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
(rac)-Ethyl 7-(4-cyanophenyl)-2-methoxy-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (185 mg, 0.55 mmol), 3-(trifluoromethyl)phenylboronic acid (207 mg, 1.09 mmol, 2 eq.), anhydrous copper(II) acetate (198 mg, 1.09 mmol, 2 eq.) and molecular sieve (80 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (12 ml), pyridine (176 μl, 2.18 mmol, 4 eq.) and triethylamine (152 μl, 1.09 mmol, 2 eq.) were added. After 24 h of stirring, the mixture was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.05% TFA). After lyophilization, the product was obtained as a solid (103 mg, 39% of theory).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH:15]=[O:16].OC1C=CC2C(=CC=CC=2)C=1C=O.[BH4-].[Na+]>C(O)C.O>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH2:15][OH:16]
Reactant: O=Cc1c(OCCF)ccc2ccccc12
Agent: O=Cc1c(O)ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1c(OCCF)ccc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.4 %

Procedure:
A solution of 2.5 grams (0.012 mole) of 2-(2-fluoroethoxy)-1-naphthaldehyde (prepared by the method of Example 1 from 2-hydroxy-1-naphthaldehyde) and 0.6 gram (0.015 mole) of sodium borohydride in 35 ml of ethanol was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.2 gram of 2-(2-fluoroethoxy)-1-hydroxymethylnaphthalene as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:15]O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1.N1C=CC=CC=1>C1C=CC=CC=1>[CH:5]1([CH2:15][Cl:3])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: O=S(Cl)Cl
Reactant: OCC1OCCc2ccccc21
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: ClCC1OCCc2ccccc21
Yield: 97.8 %

Procedure:
8.4 g (70.6 mmol) of thionyl chloride was dropwise added to a solution of 10 g (61 mmol) of (isochroman-1-yl)methanol [J. Med. Chem., 28, 1026 (1985)] and 5 g (63 mmol) of anhydrous pyridine in dried benzene, and the resulting mixture was heated under reflux for 2 hours. Excessive amounts of thionyl chloride and benzene were evaporated, and the residue was dissolved in ether. The ethereal solution was washed with water and dried, and the solvent was then evaporated. The residue was distilled under reduced pressure (140° C./20 mmHg) to give 10.9 g (98%) of the desired compound as an oily.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[N:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[N:1]1([C:7]2[N:12]=[C:11]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cncc(N2CCOCC2)n1
Reactant: Nc1nnn[nH]1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCOCC2)n1

Procedure:
To a suspension of 2.50 g of 6-(4-morpholinyl) pyrazine-2-carboxylic acid in 50 ml of tetrahydrofuran, 3.60 ml of triethylamine and 1.60 ml of pivaloyl chloride were added dropwise successively at 0° C. under stirring. After stirring for 1 hour at 0° C., 1.12 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 1 hour at room temperature, and then refluxed for 12 hours. The reaction mixture was evaporated, and water was added to the residue. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.74 g of the desired compound as yellow needles. The obtained crystal was consistent with that of (a).
Reaction SMILES: [NH2:1][C:2]1([C:5]([NH:7][C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:12][CH:13]=2)=[O:6])[CH2:4][CH2:3]1.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[N:10]=[CH:9][C:8]([N:7]3[C:5](=[O:6])[C:2]4([CH2:4][CH2:3]4)[NH:1][C:25]3=[O:27])=[CH:13][CH:12]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccc(NC(=O)C3(N)CC3)cn2)ccc1C
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)NC4(CC4)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 1-amino-N-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)cyclopropanecarboxamide (Intermediate 105, 58 mg) in dry dichloromethane (2 mL) TEA (0.129 mL, 0.925 mmol) was added. The reaction mixture was cooled in an ice-bath, then a solution of triphosgene (24.72 mg, 0.083 mmol) in dry dichloromethane (0.500 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then the solution of triphosgene (24.72 mg, 0.083 mmol) in dry dichloromethane (0.500 mL) was added again. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was maintained in the ice-bath and quenched with water (10 mL). The organic layer was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column 25 g SNAP column and cyclohexane/ethylacetate as eluents from 100:0 to 50:50. This afforded the title compound as a white solid (20 mg).
Reaction SMILES: CC(C1CC1)C(Cl)=O.[C:9]([NH:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:30])[CH:25]([CH3:29])[CH:26]2[CH2:28][CH2:27]2)=[C:19]([O:31][C:32](=[O:38])[CH:33]([CH3:37])[CH:34]2[CH2:36][CH2:35]2)[CH:18]=1)=[O:16])([CH3:12])([CH3:11])[CH3:10]>>[CH3:37][CH:33]([CH:34]1[CH2:35][CH2:36]1)[C:32]([O:31][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[O:23][C:24](=[O:30])[CH:25]([CH3:29])[CH:26]1[CH2:27][CH2:28]1)[CH:15]([OH:16])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:38]
Reactant: CC(C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C(C)C1CC1)C1CC1
Agent: CC(C(=O)Cl)C1CC1
Product: CC(C(=O)Oc1ccc(C(O)CNC(C)(C)C)cc1OC(=O)C(C)C1CC1)C1CC1

Procedure:
Following the procedure described above in Example 15A but using alpha-methylcyclopropaneacetyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(alpha-methylcyclopropaneacetoxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated, using the procedure described above in Example 15B, there is obtained 3,4-bis(alphamethylcyclopropaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CS(C)=O>[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NNC(=O)c1ccc(C(=O)NN2CCCCC2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NN2CCCCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 87.4 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (29 mg, 0.1 mmol) in dimethyl sulfoxide (4.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid piperidin-1-ylamide (27 mg, 0.1 mmol) prepared in Reference Synthetic Example 9 at 100° C. for 20 hours and allowed to cool to room temperature. 2 mL of water was added, and the precipitated solid was collected by filtration, washed with 1 mL of chloroform and dried to give 47 mg of the desired product (yield 87%).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[C:8]([C:12]#[N:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].N>CO.[Ni]>[NH2:13][CH2:12][C:8]1[C:9](=[O:11])[NH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(C#N)c(=O)[nH]1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCCCc1ccc(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
intermediate (24a) (180 mg, 1 mmol) was dissolved in MeOH (10 mL). Aqueous ammonia (1 mL) was added, followed by wet Raney Nickel (100 mg). The mixture was stirred at room temperature under hydrogen for 3 hours. The mixture was then filtered and the filtrate evaporated to yield intermediate (24b) (157 mg, 870 μmol, which was used without further purification. MS m/z: [M+H+] calcd for C10H17N2O, 181.3. found 181.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-:13].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)[CH:23]=[C:5]2[C:6]([OH:11])=[O:13]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)O)c3cc(Cl)ccc3n2)cc1

Procedure:
To a suspension of 18.15 g of 5-chloroisatin in 200 ml of ethanol was added 30 ml of 10N sodium hydroxide. To this mixture was added 16 ml (0.12 mol) of p-methylacetophenone, and it was stirred and heated under reflux for 3.2 hr. It was then concentrated in vacuo, and the residue was diluted to 250 ml with water. The above named acid was precipitated by the addition of acetic acid as a tan solid. Recrystallization from acetonitrile gave 31.6 g of the above-named acid as a tan solid.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O.[Cu]>[Cl:8][C:7]1[C:2]([C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Clc1cnc(Br)c(Cl)c1
Agent: [Cu]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ncc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 56 g (0.246 mol) of 2-bromo-3,5-dichloropyridine in 500 mL of dry dimethylsulfoxide, were added 53 g (0.261 mol) of ethyl bromodifluoroacetate followed by 94 g (0.518 mol) of copper bronze (200 mesh). The beige suspension was heated at 50° C. for 5 hours. After cooling of the reaction mixture, a solution of 44 g (0.328 mol) of potassium monophosphate in 280 mL of water was added and stirred for 1 hour. The black mixture was then filtered over a cake of Supercel™, and the cake was washed three times by 200 mL of ethyl acetate. The organic phases were collected, washed with brine and dried over magnesium sulfate. Evaporation of the solvent under vacuum gave 57.6 g of brown oil. After purification by column chromatography on silica gel (heptane/ethyl acetate 9/1) 40 g (57%) of ethyl (3,5-dichloropyridin-2-yl)(difluoro)acetate (Int-7) were obtained as a yellow oil, (M+1)=270, 19F-NMR (235 MHz, CDCl3) δ (ppm): −104.21 (CF2).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18]C=[N:16][C:15]=2C(OCC)=O)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.[BrH:24]>>[BrH:24].[NH2:16][CH2:15][C:14]([C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([OH:9])=[C:3]([OH:2])[CH:4]=1)=[O:18]
Reactant: CCOC(=O)c1ncoc1-c1cc(OC)c(OC)c([N+](=O)[O-])c1
Agent: Br
Product: NCC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
1.0 g of ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolecarboxylate is treated with 10 ml of constant-boiling hydrobromic acid and stirred at 140° for 2 hours. After distillation of the excess hydrobromic acid, the yellow residue is recrystallized from ethanol/acetone. There is obtained 2-amino-3',4'-dihydroxy-5'-nitroacetophenone hydrobromide in the form of yellow crystals of m.p.>250° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Cc1ccc(Br)cc1
Yield: 88 %

Procedure:
A solution of 4-bromobenzylsulfonyl acetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 88% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5][O:6][CH2:7][CH2:8][CH3:9])=[O:4].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>C(Cl)(Cl)Cl>[Cl-:1].[O:4]=[C:3]([CH2:5][O:6][CH2:7][CH2:8][CH3:9])[CH2:2][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCOCC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCOCC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 63.9 %

Procedure:
A solution of 1-chloro-3-propoxyacetone (8.5 g.) and triphenylphosphine (15.6 g.) in chloroform (20 ml.) was saturated with nitrogen and heated at reflux under nitrogen overnight. An excess of dry diethyl ether was added, and then the solvents were decanted from the gum that separated. The remaining solvent was removed in vacuo to give crude 2-oxo-3-propoxypropyltriphenylphosphonium chloride (14.9 g.). This was stirred vigorously with a solution of sodium carbonate (14.6 g.) in water (146 ml.) for 24 hours. The solution was extracted with diethyl ether and the ethereal extracts dried over sodium sulphate. The solvent was removed by evaporation, and the residue was triturated with petroleum to give propoxyacetylmethylenetriphenylphosphorane (6.3 g.), a sticky solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:21])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: O=Cc1ccccc1
Product: COc1ccc2cc(C(O)c3ccccc3)ccc2c1

Procedure:
Using general procedure B, 2-bromo-6-methoxy-naphthalene was reacted with benzaldehyde to give (6-methoxy-naphthalen-2-yl)-phenyl-methanol as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccccc1C(=O)NCCc1ncc[nH]1)c1ccc(-c2ccccc2)cc1
Yield: 65.1 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 1.50 g (0.00651 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)ethyl]benzamide, prepared as in Example 6A, and 3.76 g (0.01738 mol) of p-phenylbenzoyl chloride, with the exception that after removing ethyl acetate the final product was recrystallized from an ethyl acetate/methanol solution to provide 1.74 g of the desired titled compound (m.p. 197°-201° C.).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:30](=[O:31])/[CH:29]=[CH:28]/[C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:26])([F:25])[F:27])[C:18]=3[F:17])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1F
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C(F)(F)F)c3F)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-fluoro-3-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.16 min; [M+H]+=443.98.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1([CH3:13])[CH3:12].C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:12][C:4]1([CH3:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[N:2]([CH3:1])[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:46])([F:47])[F:45])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: CNC1c2ccccc2CC1(C)C
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3c4ccccc4CC3(C)C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a solution of 2,3-dihydro-N,2,2-trimethyl-1H-inden-1-amine (193 mg, 1.1 mmol) and triethylamine (0.19 mL, 1.38 mmol) in 5 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (386 mg, 0.92 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo to give 300 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13](I)=[CH:12]2.[Cu]C#N.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([C:13]2[CH:14]=[N:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:6])=[O:26])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Clc1cccc2cc(I)cnc12
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1cccc(Cl)c1)c1cnc2c(Cl)cccc2c1
Temperature: -40 °C
Reaction time: 0.3 h
Yield: 59.6 %

Procedure:
iso-Propyl magnesium chloride (2M solution in tetrahydrofuran) (2.85 ml, 5.7 mmol) was added dropwise over 5 mins to a stirred solution of 8-chloro-3-iodoquinoline (D1)(1.5 g, 5.2 mmol) in tetrahydrofuran (15 ml) at −40° C. under argon. After stirring the solution at this temperature for 0.3 h, copper (I) cyanide (0.47 g, 5.2 mmol) was added in portions over 5 mins. The whole mixture was left to stir at −40° C. for a further 10 mins and then 3-chlorobenzoyl chloride (1.0 g, 5.7 mmol) was added dropwise over 10 mins. The temperature was maintained at −40° C. for 0.5 h and then the reaction was warmed to 0° C. at which temperature it was quenched by the addition of a saturated solution of sodium chloride (100 ml). The mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to a solid. The solid was purified by chromatography over silica gel eluting with a gradient of acetone/toluene to give the title compound (D5) as a white solid (0.95 g, 3.1 mmol, 60%).
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC([N+]([O-])=O)=CC=3)=CC=2)C1=O)C(OC)=O.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[CH:32][C:31]=1[C:45]([O:47]C)=O.Cl.[NH2:50][C@@H:51]1[CH2:55][CH2:54][CH2:53][C@@H:52]1[C:56]([O:58][CH3:59])=[O:57]>>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([C:33]2[CH:32]=[C:31]3[C:30]([CH2:29][N:50]([C@@H:51]4[CH2:55][CH2:54][CH2:53][C@@H:52]4[C:56]([O:58][CH3:59])=[O:57])[C:45]3=[O:47])=[CH:35][CH:34]=2)=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: COC(=O)[C@H]1CCC[C@H]1N
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: Cl
Product: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Yield: 75 %

Procedure:
The compound of example 591 was prepared analogous to compound of example 5 by reaction of compound of example 4 with (1S,2R)-methyl 2-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: S(=O)(=O)(O)N.[CH2:6]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl([O-])=[O:30].[Na+]>O.CC(C)=O>[CH2:6]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:30])=[O:24])=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
Sulphamic acid (0.526 g, 5.43 mmol) in 2 mL water was added at 0° C. to 4-(4-benzyloxy-phenoxy)-benzaldehyde (0.55 g, 1.81 mmol) in acetone (8 mL). After 5 minutes, sodium chlorite (0.654 g, 7.24 mmol) was added and the mixture was stirred at 0° C. for three hours. Water was added and the resulting solid was isolated by filtration to afford 495 mg (85% yield) of 4-(4-benzyloxy-phenoxy)-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[Na].BrCCCCC[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O1CCCC1.C(OCC)C.O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: CC(C)(C)[Si](C)(C)CCCCCBr
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CCCCCO[Si](C)(C)C(C)(C)C)c1ccc(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 111.9 %

Procedure:
To a solution, -78° C. under argon, of 2.38 g of 3,4-dimethoxyphenyl acetic acid methyl ester in 30 ml of tetrahydrofuran is added 12.45 ml of 1.0M sodium hexamethylsidilazide. The solution is stirred at -78° C. for 5 minutes and then warmed to 0° C. for 1 hour. To this solution is added 3.5 g of (5-bromopentyl)(1,1-dimethylethyl)dimethyl silane. The reaction mixture is allowed to warm to room temperature and stirred for 12 hours. The mixture is diluted with diethyl ether and water, the layers are separated and the organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: hexane/ethyl acetate,5/1) to give 2.6 g of the desired product as a clear oil. MS(Hi res): calcd 410.2488 found 410.2492