Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1>C(O)C>[CH3:1][S:2][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Na+]
Solvent: CCO
Product: CSCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
Sodium methanethiolate (13.5 g; 192 mmol) was added in two portions to a stirred solution of 1-(chloromethyl)-3-nitrobenzene (30.0 g; 175 mmol) in ethanol (360 ml) at −15° C. The cold bath was removed and the batch was stirred at room temperature for 3 hours. The batch was diluted with brine and extracted with ethyl acetate (2×). The combined organic phases were washed with water, dried (sodium sulfate), filtered and concentrated to give the desired product (32.2 g) that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1

Procedure:
N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in the same manner as described in Example 32C, from 4-methoxyphenylboronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Recrystallization using hexane/ethyl acetate gave a solid in quantative yield.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH2:22]CC)=[O:21])[CH2:4][CH:5](O)[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].P1(O)(OC2C=CC=CC=2C2C=CC=CC=2O1)=[O:26]>>[OH:26][CH2:2][CH2:1][N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH3:22])=[O:21])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: CCCS(=O)CCCN(CC)CC(O)COc1ccc(C#N)cc1
Reactant: O=P1(O)Oc2ccccc2-c2ccccc2O1
Product: CS(=O)CCCN(CCO)CCCOc1ccc(C#N)cc1

Procedure:
4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2-hydroxypropoxy]-benzonitrile, addition salt with biphenyl-2,2'-diyl hydrogen phosphate
Reaction SMILES: C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O.O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].[C:22]([O:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([CH2:34][CH2:33]2)[C:31](=[O:37])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>C1N(CCS(O)(=O)=O)CCOC1.CCCCCCC>[C:22]([O:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([CH2:34][CH2:33]2)[C@H:31]([OH:37])[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C(=O)C1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)CCN1CCOCC1
Solvent: O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@H](O)C1
Temperature: 35 °C
Yield: 93 %

Procedure:
D(+)-glucose monoydrate (300 g) and magnesium chloride hexahydrate (1.0 g) were dissolved in 10 mM MES buffer pH 6.5 (2.4 L; Sigma M3671). After addition of 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (300 g; 1.33 mmol) and □-NAD (3.0 g; free acid; Roche Diagnostics Cat. No. 10 004 626) the pH was re-adjusted and the suspension heated to 35° C. The reaction was started by adding ketoreductase KRED-NADH-117 (3.0 g; former Biocatalytics, now Codexis) and glucose dehydrogenase GDH-102 (300 mg; Biocatalytics). The suspension was vigorously stirred at 35° C. keeping the pH constant at 6.5 by the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution. After a consumption of 1.307 L (corresponding to 98% conversion; after 17 h) the reaction mixture was extracted with EtOAc (10 L). The organic phase was dried over sodium sulfate and concentrated in vacuo (200 mbar/45° C.) until evaporation fell off. Upon cooling the oily residue (411 g) started to crystallize and was stirred with heptane (1 L) for 2 h. The crystals were filtered off and the filtrate evaporated to dryness, redissolved in EtOAc (150 ml) and concentrated in vacuo as described above. The crystal suspension formed again upon cooling was stirred with heptane (200 ml; 2 h) and the crystals filtered off. Both crops of crystals were washed with heptane and dried under high vacuum to yield the title compound in 93% yield (250.77 g and 34.60 g white crystals), each having a purity of >98.5% GC and 99.8% ee. [α]D=−44.97° (c=1.00, CHCl3).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([CH2:18][N:19]1[C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:22][C:21]([C:42]([NH2:44])=O)=[N:20]1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16](=[O:17])[CH2:18][N:19]1[C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=2)=[CH:22][C:21]([C:42]#[N:44])=[N:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(OCc2ccccc2-c2ccc(C(F)(F)F)cc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cc(OCc2ccccc2-c2ccc(C(F)(F)F)cc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 36.6 %

Procedure:
To an ice cold solution of 310 mg (0.33 mmol max) of 1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-5-(4′-trifluoromethyl-biphenyl-2-ylmethoxy)-1H-pyrazole-3-carboxylic acid amide in 3 mL of pyridine was added 0.071 mL (0.76 mmol) of phosphorus oxychloride, and the resulting mixture was stirred at 0° C. for 2.5 h. The mixture was then diluted with ethyl acetate, washed with 1 N HCl solution, dried over sodium sulfate and concentrated. Since analysis by LC-MS indicated that some starting material was still present, the reaction was repeated under the same experimental conditions, and after complete consumption of starting material, it was worked up and purified via chromatography on silica gel (Biotage) with 3:1 hexane:ethyl acetate to give 71 mg (37% yield) of N-(2-benzyloxy-cyclohexyl)-2-[3-cyano-5-(4′-trifluoromethyl-biphenyl-2-ylmethoxy)-pyrazol-1-yl]-acetamide. LC-MS—calcd for C33H31F3N4O3 [M+H]+ 589.23, found 589.2.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C([O:9][C:10](=O)[CH:11]([Cl:15])[C:12](=O)[CH3:13])C.C(O)(=O)C>CCO>[Cl:15][C:11]1[C:12]([CH3:13])=[N:1][C:2]2[N:3]([N:4]=[CH:5][CH:6]=2)[C:10]=1[OH:9]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccnn2c(O)c1Cl
Temperature: 120 °C
Yield: 93.7 %

Procedure:
A mixture of 3-aminopyrazole (10.0 g, 120.3 mmol), 2-chloro-3-oxo-butyric acid ethyl ester (16.7 mL, 120.3 mmol), and glacial acetic acid (103 mL) was heated to 120° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOH and concentrated. Trituration with Et2O gave 20.7 g (94%) desired product. MS APCI (+) m/z 184, 186 (M+, Cl pattern) detected; 1H NMR (400 mHz, CD3OD) δ 7.90 (d, 1H), 6.17 (d, 1H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:11][CH:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][C:23]=1[CH3:33].[CH:34](O)=O.C=O.O>C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:11][CH:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH3:34])[CH2:29][CH2:28]2)=[N:24][C:23]=1[CH3:33]
Reactant: O=CO
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCNCC2)nc1C
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCN(C)CC2)nc1C

Procedure:
To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 mL CH2Cl2, was added trifluoroacetic acid (4 mL). The reaction stirred for 1.5 hours and concentrated under reduced pressure, neutralized with 10 mL Na2CO3 (1M) and lyophilized to afford 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (135 mg, 0.31 mmol), formic acid (300 μL, 6.76 mmol), formaldehyde (37% in water, 300 μL, 3.41 mmol) and water (1.5 mL) was heated to reflux for 10 hours. The reaction was diluted with saturated NaHCO3 until pH 9 and extracted with CH2Cl2 (3×20 mL). The residue was purified by preparative TLC with 10% methanol and 1% ammonium hydroxide in dichloromethane and lyophilized to give 43 mg (30% two steps) of the title compound as a white solid. m/z (ES+) 540 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10]>Cl.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH3:10]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CCc1cc(Cl)ccc1Cl
Temperature: 25 °C

Procedure:
A suspension of mossy zinc (10 g) and mercuric chloride (0.5 g) in concd HCl (0.5 mL) and water (5 mL) was shaken for ~5 min. The aqueous layer was then decanted. To the residue was added coned HCl (7.5 mL) and water (7.5 mL) followed by 2',5'-dichloroacetophenone (3.106 g, 16.43 mmol) and the suspension was refluxed for 4 h during which time, hourly addition of concd HCl (90.5 mL) was carried out. The resulting suspension was cooled to room temperature and the aqueous layer was decanted. The residual solid was washed with ether (3×30 mL). The aqueous layer was extracted with ether (3×50 mL). The combined ether layer was washed with brine, dried over anhydrous Na2SO4, and removed under vacuum. The residue was dried further under vacuum to obtain 2.664 g crude product, which was purified on silica gel (hexane) to obtain 0.813 g (28%) pure (1H NMR) title compound as a colorless liquid; 1H NMR (DMSO-d6) δ 1.23 (t, 3H, J=7.5 Hz), 2.73 (q, 2H, J=7.5 Hz), 7.09-7.27 (m, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]1(=O)[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=C1CCC1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1NC1CCC1

Procedure:
The title compound, off-white solid, MS: m/e=439.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and cyclobutanone.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Br:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Br:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1Br
Reactant: BrCc1ccccc1
Product: C=CCOc1cc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Br

Procedure:
The product from example 63D and benzylbromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1)=[O:14].O.[OH-].[Li+]>O.C1COCC1.CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1)=[O:14]
Reactant: COC(=O)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 4-fluoro-3-(imidazo[1,2-a]pyridine-3-carboxamido)benzoate (step 1) (7.2 g, 22.98 mmol) in water (30 ml), THF (45.0 ml) and MeOH (15.00 ml) was treated with lithium hydroxide monohydrate (4.82 g, 115 mmol). The reaction mixture was stirred at RT overnight and concentrated in vacuo to remove THF and MeOH. The resulting mixture was acidified with 2M HCl to yield a solid that was collected by filtration and washed with ether (3×). The white solid was dried in the vacuum oven at 50° C. to afford the title compound as a hydrochloride salt;
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:28]([N:33]([CH3:41])[C:34](=[O:40])[C@H:35]([CH:37]([CH3:39])[CH3:38])[NH2:36])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:26][CH3:27])[C@@H:13]([CH3:25])[C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[CH:42]1[C:54]2[CH:53]([CH2:55][O:56][C:57]([NH:59][CH2:60][C:61]([CH3:66])([CH3:65])[C:62](O)=[O:63])=[O:58])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[CH:51]1[C:52]2[CH:53]([CH2:55][O:56][C:57]([NH:59][CH2:60][C:61]([CH3:66])([CH3:65])[C:62]([NH:36][C@H:35]([C:34]([N:33]([C@@H:28]([C@@H:29]([CH3:32])[CH2:30][CH3:31])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:12]([O:26][CH3:27])[C@@H:13]([CH3:25])[C:14](=[O:24])[NH:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:6])[CH3:41])=[O:40])[CH:37]([CH3:39])[CH3:38])=[O:63])=[O:58])[C:54]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]=2[CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To #73 (100 mg, 0.174 mmol, 1 eq.) in dichloromethane (4 mL, 0.04 M) and N,N-dimethylformamide (0.5 mL) was added #93 (59.1 mg, 0.174 mmol, 1 eq.), followed by diisopropylethylamine (92 μL, 0.52 mmol, 3 eq.) and HATU (102 mg, 0.260 mmol, 1.5 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (6 mL) and was washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) provided #96 (102 mg, 65%) as a white solid. LC-MS: m/z 896.7 [M+H+], 918.8 [M+Na+], retention time=1.14 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic product signals: δ 7.88 (d, J=7.4 Hz, 2H), [7.83 (br dd, J=6, 5 Hz) and 8.03 (br dd, J=6, 5 Hz), total 1H], 7.67-7.73 (m, 2H), 7.36-7.48 (m, 3H), 7.22-7.35 (m, 4H), 7.13-7.21 (m, 3H), 6.86-6.96 (m, 1H), [4.44 (dd, J=8.6, 8.6 Hz) and 4.50 (dd, J=8.6, 8.6 Hz), total 1H], 3.18, 3.19, 3.26 and 3.29 (4 s, total 6H), 2.96 and 3.11 (2 br s, total 3H), 0.70-0.77 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:26])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[CH2:21][C:22](C)([CH3:24])[CH3:23].O=[C:28]1N(CC2C=CC=CC=2)[C@H](C(O)=O)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:26])[C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[CH2:21][C:22]1[CH:23]=[CH:30][CH:29]=[CH:28][CH:24]=1
Reactant: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Product: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(phenylmethyl)-D-prolinamide was prepared in an analogous manner to that described for the synthesis of N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-(2,2-dimethylpropyl)-5-oxoprolinamide (example 100) above but using 5-oxo-1-(phenylmethyl)proline in the place of 1-(2,2-dimethylpropyl)-5-oxoproline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30](I)=[CH:31][N:32]=4)[CH:29]=3)=[CH:22][N:21]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([C:7]5[CH:8]=[C:3]([CH:4]=[CH:5][CH:6]=5)[C:1]#[N:2])=[CH:31][N:32]=4)[CH:29]=3)=[CH:22][N:21]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:20]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(I)n3c2)cc1
Product: N#Cc1cccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)c1
Yield: 87.8 %

Procedure:
46 mg 3-cyanophenylboronic acid and 161 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 39) were reacted in the same manner as in Example 3, to give 136 mg 3-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl} benzonitrile as colorless crystals. This product was subjected to deprotection of the trityl group and converted into the corresponding hydrochloride by the same method as in Example 68, to give 90 mg of the title compound as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)Nc1ccc(N)cc1
Reaction time: 12 h
Yield: 94.6 %

Procedure:
A mixture of N-(4-nitrophenyl)propanamide (10 g, 51.5 mmol), 10% palladium on carbon (1 g), methanol (500 ml) and tetrahydrofuran (100 ml) was stirred under hydrogen atmosphere for 12 hours, insoluble substances were removed by filtration, and the filtrate was concentrated to give 8.00 g (94.8%) of the desired product as an oil.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:17]1[CH:21]2[CH2:22][NH:23][CH2:24][CH:20]2[CH2:19][N:18]1[C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:23]1[CH2:22][CH:21]2[CH2:17][N:18]([C:25]3[CH:34]=[N:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH2:19][CH:20]2[CH2:24]1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: O=S(=O)(c1ccccc1-c1ccccc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title prophetic compound may be synthesized using biphenylsulfonylchloride and Intermediate 35. MS (ESI) mass calcd. for C26H24N4O2S, 456.16.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Product: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(-c4ccnc(Cl)c4)nc3s2)cc1
Yield: 43 %

Procedure:
The titled compound (yield=43%, yellow solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 5.24 (s, 1H) 7.67 (d, J=8.34 Hz, 2H) 8.12 (d, J=8.34 Hz, 2H) 8.18 (d, J=5.56 Hz, 1H) 8.25 (s, 1H) 8.28-8.37 (m, 2H) 8.55 (d, J=5.31 Hz, 1H) 13.12 (s, 1H); ESI-MS: m/z 425.0 (M+H)+.
Reaction SMILES: N1C=CN=C1.[NH:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:7]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([NH2:18])=O)=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:16]([C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:7]([C@H:8]([CH2:10][CH3:11])[CH3:9])[NH:6][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])#[N:18]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C#N
Reaction time: 1 h
Yield: 94 %

Procedure:
Imidazole (84 mg, 1.24 mmol) was added to a solution of BocIleProNH2 in dry pyridine (10 cm3), under a nitrogen atmosphere. The solution was cooled to −35° C., before the dropwise addition of POCl3 (0.25 cm3, 2.48 mmol). The reaction was stirred at −30° C. to −20° C. for 60 min. The solution was then evaporated and the crude residue subjected to column chromatography (silica gel) to yield 180 mg (94%) of 2-(S)-cyano-1-[N-(t-butoxycarbonyl) isoleucyl]pyrrolidine as a colourless oil.