Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:7]1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1

Procedure:
Stir a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (200 mg, 0.82 mmol), 6-chloronicotinonitrile (75 mg, 0.54 mmol) and diisopropylethylamine (140 μl, 0.82 mmol) in DMF (5 mL) at room temperature overnight. Concentrate and chromatograph on silica gel to give the title compound. Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (300 MHz, MeOH-d4) δ 8.44 (1H, d, J=1.51 Hz), 7.95 (1H, dd, J=9.23, 2.07 Hz), 7.56-7.68 (2H, m), 7.40 (1H, dd, J=8.38, 2.17 Hz), 6.97 (1H, d, J=9.42 Hz), 4.42 (2H, d, J=3.01 Hz), 4.16-4.25 (1H, m), 4.04-4.13 (1H, m), 3.82-3.96 (2H, m), 3.63-3.77 (1H, m), 2.56-2.69 (1H, m), 2.43 (1H, m), MS (ES): 347 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)[C:5]2=[O:33].[CH2:34](I)[CH2:35][CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:34][CH2:35][CH3:36])[C:7](=[O:12])[N:6]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:17][CH2:18]1)[C:5]2=[O:33]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(Cl)cc5c4=O)CC3)c2cc1OC
Reactant: CCCI
Product: CCCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc(Cl)ccc21
Yield: 63 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.64 mmol) of Compound h was used in place of Compound 24 and propyl iodide was used in place of methyl iodide. As a result, 200.9 mg (yield: 63%) of Compound 42 was obtained as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[C@H:4]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:5][C:6](=[O:45])[C@@H:7]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH2:17].[CH2:51]([O:58][C:59]([NH:61][C@H:62]([C:78](O)=[O:79])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)=[CH:66][CH:65]=1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:50])[C@H:4]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:5][C:6](=[O:45])[C@@H:7]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:8][C:9](=[O:40])[C@H:10]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)[NH:11][C:12](=[O:31])[C@H:13]([CH2:29][OH:30])[NH:14][C:15](=[O:28])[C@H:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH:17][C:78](=[O:79])[C@H:62]([CH2:63][C:64]1[CH:65]=[CH:66][C:67]([O:70][CH2:71][C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)=[CH:68][CH:69]=1)[NH:61][C:59]([O:58][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:60]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1

Procedure:
The above product, 2.0 g. of L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucine methyl ester, is dissolved in 70 ml. of dimethylformamide and cooled in an ice bath. Nα -Benzyloxycarbonyl-O-benzyl-L-tyrosine, 970 mg., 355 mg. of 1-hydroxybenztriazole and 545 mg. of dicyclohexylcarbodiimide are added. The reaction is stirred at ice bath temperature for several hours, then to room temperature and finally at room temperature for twenty-four hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The residue is dissolved in 400 ml. of ethyl acetate, 20 ml. of water and 20 ml. of 0.5N hydrochloric acid. The ethyl acetate is separated, washed with saturated salt solution, with 0.5N sodium bicarbonate solution, again with saturated salt solution and is evaporated to a solid residue; 2.81 g.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([N+:18]([O-])=O)=[CH:10][C:9]=1[N+:21]([O-])=O)C(=O)C)(=O)[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH3:2][C:1]1[NH:4][C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([NH2:18])=[CH:10][C:9]=2[N:21]=1
Reactant: CC(=O)N(C(C)=O)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1nc2cc(N)cc(C(F)(F)F)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.63 g I.11 (N-acetyl-N-(2,4-dinitro-6-trifluoromethyl-phenyl)-acetamide) and 0.2 g Pd/C 10% in 20 ml glacial acetic acid was stirred for 5 h at 80° C. under a pressure of hydrogen of 50 psi. The catalyst was filtered and the solvent was evaporated. To the residue, 30 ml glacial acetic acid were added and the mixture was stirred for 2 h at reflux. The solvent was removed. The residue was treated with 50 ml 4 N aqueous hydrochloric acid and stirred for 1 h at reflux. The reaction mixture was cooled down to ambient temperature and the pH was adjusted to ˜7 with potassium carbonate. The resulting precipitate was filtered, washed with 30 ml water and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@:8]([CH2:22][OH:23])([CH3:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-])=O)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C@:8]([CH2:22][OH:23])([CH3:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)c(N)c1
Reaction time: 2 h

Procedure:
An argon purged solution of [(R)-1-Hydroxymethyl-3-(4-hydroxy-3-nitro-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (3.02 g, 8.87 mmol) in ethanol (40 ml) was treated with 10% Pd on activated charcoal (0.5 g). Argon was replaced by hydrogen and the reaction was allowed to proceed under atmospheric pressure for 2 hours. The reaction suspension was filtered and the filtrate evaporated to dryness in vacuum. Silica gel chromatography (eluent: DCM/methanol 20/1 to 10/1) followed by crystallization from diethyl ether provided the title compound as colorless crystals. mp 122.1/123.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C(N(CC)C(C)C)(C)C>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(OCCC#N)cc1

Procedure:
That is, 4-methoxyphenol (a) is reacted with acrylonitrile (b) in the presence of a base such as Triton B, triethylamine, N,N-diisopropylethylamine or the like, at 25 to 120° C. for 1 to 72 hours to obtain 3-(4-methoxyphenoxy)propionitrile (c), and the resultant is either reduced in a solvent such as tetrahydrofuran, dioxane or the like at 25 to 100° C. using a borane-tetrahydrofuran complex, a borane-dimethylsulfide complex, lithium aluminum hydride or the like, or reduced in a hydrogen atmosphere or in the presence of ammonia, using a catalyst such as Raney nickel or the like, thus to obtain 3-(4-methoxyphenoxy)propylamine (d). Subsequently, the resultant is reacted with 3-hydroxybenzaldehyde (e) in a solvent such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran, toluene, acetonitrile or the like, and then the resultant is reduced using a reducing agent such as sodium borohydride, sodium triacetoxy borohydride or the like to obtain N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzylamine (f). This is reacted with 2-chlorobenzoxazole (g) in a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate or the like, in the presence of an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate or the like, or an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine or the like, thus to obtain N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydrox ybenzylamine (compound (2)).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]3=[O:27])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].Br[CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:28][N:2]([CH3:1])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][C:21]3=[O:27])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: BrCc1cccs1
Reactant: CN(C)C(=O)C1CCN(Cc2ccc(CCn3ccc(O)cc3=O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCN(Cc2ccc(CCn3ccc(OCc4cccs4)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 50 mg (0.13 mmol) 1-{4-[2-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-ethyl]-benzyl}-piperidine-4-carboxylic acid dimethylamide (example 17.1a) in 2.0 mL DMF is added 130 μL (1 M solution in 1,4-dioxane, 0.13 mmol) 2-bromomethyl-thiophene and 45 mg (0.33 mmol) potassium carbonate at 0° C. The reaction mixture is stirred overnight at RT, filtered and the solvent is evaporated. The residue is dissolved in 2.5 mL of DMF and is purified via reverse HPLC chromatography (Waters symmetry, C18, 7 μm; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:18][C:17]2[C:12](=[N:13][CH:14]=[N:15][CH:16]=2)[N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ncncc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncncc2[nH]1

Procedure:
Prepared analogously to Example 1 from 8-(2'-methoxy-4'-hydroxy-phenyl)-purine and methanesulfonic acid chloride.
Reaction SMILES: Cl.Cl.[NH:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[NH2:4].O=[C:19]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21][CH:20]1[C:33](OCC)=[O:34].C(N(CC)CC)C>C(O)(C)(C)C>[O:34]=[C:33]1[CH:20]2[C:19]([CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[N:4][N:3]1[CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: NNC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC2=NN(C3CCN(Cc4ccccc4)CC3)C(=O)C2CC1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 4-hydrazino-1-(phenylmethyl)piperidine dihydrochloride (commercially available from e.g. Aurora Screening Library) (2.68 g, 9.63 mmol) and tert-butanol (60 ml) was added to 1-(1,1-dimethylethyl) 4-ethyl 5-oxohexahydro-1H-azepine-1,4-dicarboxylate (may be prepared as described in Synthetic Communications (1992), 22(9), 1249-58) (2.50 g, 8.76 mmol) followed by triethylamine (7.33 ml, 52.59 mmol) and the resulting suspension warmed to reflux over ˜10 min under Argon. The resulting clear yellow solution was then kept at this temperature for 65 h. The mixture was then allowed to cool to room temperature over ˜2 h and the mixture reduced under vacuum to give a cream coloured solid residue. Purification by chromatography on silica gel eluting with dichloromethane:methanol 50:1→25:1→10:1 afforded a product which as partitioned between water and dichloromethane (100 ml each) the layers separated and the organic layer washed with more water (100 ml), followed by brine (100 ml) and then dried (Na2SO4), filtered and reduced to give the title compound (D47). MS (ES+) m/e 427 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-fluorophenol (5.0 g) was dissolved in DMF (50 ml), ethyl 2-bromo-2-methylpropanoate (13.3 ml) and potassium carbonate (9.25 g) were added thereto, followed by stirring at 100° C. for 2 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain ethyl 2-(4-fluorophenoxy)-2-methylpropanoate (5.13 g) as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9](=O)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[S:20]([O:27]S(C(F)(F)F)(=O)=O)([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([O:27][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cccc2c1OC(=O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(OS(=O)(=O)C(F)(F)F)coc12
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a cold solution (−20° C.) of 3.3 g (20 mmol) 7-methoxy-benzofuranone in 30 mL methylene chloride was added 8.3 mL (6.0 mmol) of triethylamine. To the cold mixture, a solution of 8.5 g (30 mmol) of triflic anhydride in 20 ml of methylene chloride was added dropwise. The temperature was kept at −20° C. or 1 hour. The reaction was then quenched with 100 mL of saturated aqueous sodium bicarbonate aand extracted with methylene chloride (2×150 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuum to give 5.6 g of the desired product. MS (ES) m/z (relative intensity): 265 (M+H,100);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([Cl:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:24](=[CH:25][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Nc1ccc(Cl)cc1N
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(Cl)cc5N)cccc4c3)c2cc1OC
Yield: 85.6 %

Procedure:
The title compound (42.9 mg, 83% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-chloro-o-phenylenediamine (17.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 5.31 (s, 2H, benzene-NH2), 6.65 (d, J=8.3 Hz, 1H, Ar—H), 6.86 (d, J=1.9 Hz, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.58-7.67 (m, 4H, Ar—H), 7.89 (d, J=6.8 Hz, 1H, Ar—H), 8.01 (s, 1H, Ar—H), 8.09 (d, J=8.1 Hz, 1H, Ar—H), 8.37 (d, J=9.2 Hz, 1H, Ar—H), 8.55 (s, 1H, Ar—H), 9.84 (s, 1H, benzene-NH). LC-MS (m/z) 501 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].O[C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=3[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(-c3cccc(C(F)(F)F)c3)nc2c1

Procedure:
3-Trifluoromethylbenzoyl chloride (9.03 g, 0.043 mol) and 2-hydroxy-5-nitroaniline (6.58 g, 0.041 mol) in toluene (200 ml) are refluxed for 48 hours. POCl3 (20 ml) is added, the mixture is refluxed for a further 2 hours and concentrated, and the solid is recrystallized from NaOH (pH=10). The product is filtered off and recrystallized from water and finally from isopropyl ether. Yield: 10.3 g (78%); Rf (8/2 petroleum ether/ethyl acetate): 0.58; IR (KBr): 3085, 1620, 1531, 1425, 1340 cm−1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>CN(C)C=O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoronitrobenzene (25 g; ~0.18 mol) in 250 ml N,N-dimethylformamide was added imidazole (50 g; ~0.74 mol). The reaction mixture was stirred at 140° C. for 2 h, and then poured into ice-water to give the title compound as a precipitate. Yield: 32 g (~94%). M.p. 199°-202° C.
Reaction SMILES: [CH:1]1([C:4]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)([CH3:6])[CH3:5])[CH2:3][CH2:2]1.[OH:18]O.[OH-].[Na+].O>CS(C)=O>[CH:1]1([C:4]([NH:7][C:8]2[C:13]([C:14]([NH2:15])=[O:18])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)([CH3:6])[CH3:5])[CH2:3][CH2:2]1
Reactant: CSc1ncc(C#N)c(NC(C)(C)C2CC2)n1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ncc(C(N)=O)c(NC(C)(C)C2CC2)n1
Temperature: 50 °C
Reaction time: 0.2 h
Yield: 55 %

Procedure:
To a stirring solution of 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (665 mg, 2.68 mmol) in DMSO (4 mL) was added aqueous hydrogen peroxide solution (0.162 mL, 30%) and aqueous sodium hydroxide (2.2 mL, 6 mol/L) solution. The resulting mixture was stirred at 50° C. for 12 min, and then water was added. The desired product was filtered and dried in vacuo to give the crude product (392 mg, 1.47 mmol, 55% yield) as a white solid. MS (ESI) m/z 267.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[OH-].[Li+]>>[CH3:29][S:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)(=[O:27])=[O:28]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCN(S(C)(=O)=O)CC2)CC1
Yield: 74.6 %

Procedure:
A solution of 3-[(1-Methanesulfonyl-piperidin-4-yl)-(4-methylcyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (40 mg, 0.077 mmol) was hydrolysed as described before with lithium hydroxide (2M, 114 μL, 5.5 mg, 0.23 mmol)to give after acidic work-up 3-[(1-Methanesulfonyl-piperidin-4-yl)-(4-methylcyclohexane-carbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (29 mg, 74%) as a colourless powder; 1H (300 MHz, MeOD) 0.56-0.72 (m,1H), 0.79 (d, J=4.8 Hz, 3H), 1.23-1.44 (m, 5H), 1.51-1.79 (m, 6H), 1.92-1.98 (m, 1H), 2.04-2.14 (m, 2H), 2.78-2.90 (m, 2H), 2.80 (s, 3H), 3.66-3.74 (m, 1H), 3.75-3.81 (m, 1H), 4.52-4.62 (m, 1H), 7.39 (s, 1H), 7.40-7.90 (m, 3H), 7.73-7.77 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.[C:14](N1C=CN=C1)([N:16]1C=CN=[CH:17]1)=O>O1CCCC1>[CH3:14][N:16]([CH3:17])[C:8]([C:6]1[S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]=2[C:2](=[O:1])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1cc(=O)c2ccsc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(=O)c2ccsc2s1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
Under a nitrogen atmosphere, to a stirred solution of 4-oxo-4H-thieno[2,3-b]thiopyran-6-carboxylic acid (10.7 g, 0.05 mol) in tetrahydrofuran (50 ml) was added carbonyldiimidazole (8.9 g., 0.055 mol). The mixture was stirred at ambient temperature for 3/4 hour. Anhydrous dimethylamine was bubbled into the thick suspension at 0° C. until an excess was present. The resulting solution was stirred at 0° C. for 3/4 hour and the solvent was removed in vacuo. The residual oil was diluted with H2O (50 ml) and the solid which separated was filtered and dried to give 7.14 g of product, m.p. 126.5-128 of 97% purity by HPLC. The aqueous filtrate was concentrated in vacuo and the residual gum was chromatographed on silica gel (200 g) using 10% methanol in chloroform. An additional 3.15 g of impure product was recovered. Yield was about 80%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15](O)[CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:11][CH:10]=1
Reactant: OC(CCn1ccnc1)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Product: Brc1ccc(C(CCn2ccnc2)Oc2ccccc2)cc1

Procedure:
Phenol was reacted with 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol* following the procedure set out in Example 48B to give the title compound. LC/MS: (PS-A2) Rt 2.30 [M+H]+357.26, 359.27. *This starting material can be made by the method described in Example 47A.
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:15]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[N:14]=[C:13]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[CH:12]=2)[CH:6]=1)(=O)=O.[C-:32]#[N:33].[K+]>CN(C)C=O>[C:32]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:15]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[N:14]=[C:13]([C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])[CH:12]=2)[CH:6]=1)#[N:33]
Reactant: [C-]#N
Reactant: COc1ccc(-n2nc(C(=O)N3CCCCC3)cc2-c2cc(S(C)(=O)=O)ccn2)cn1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N3CCCCC3)cc2-c2cc(C#N)ccn2)cn1
Temperature: 120 °C
Reaction time: 37 h
Yield: 83.5 %

Procedure:
To a solution of 1-[5-(4-methanesulfonyl-2-pyridyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carbonyl]piperidine (0.60 g) obtained in Example 97 in N,N-dimethylformamide (12 mL), potassium cyanide (97.3 mg) was added at room temperature. The mixture was stirred at 120° C. for 37 hours, and then potassium cyanide (97.3 mg) was further added thereto. The mixture was further stirred at 120° C. for 4 hours, and then cooled in air. The reaction mixture was partitioned between saturated brine and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-ethyl acetate), to thereby give the title compound as a solid (0.441 g, 84%).