Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].N1C=CN=C1.[F:11][C:12]([F:48])([F:47])[C:13]1[CH:14]=[C:15]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:16][N:17]([CH3:39])[C:18](=[O:38])[C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][C:22]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:21][CH:20]=1>>[F:48][C:12]([F:47])([F:11])[C:13]1[CH:14]=[C:15]([CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1)[CH2:16][N:17]([CH3:39])[C:18](=[O:38])[C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][C:22]([N:32]2[CH2:33][CH2:34][N:35]([CH:3]=[O:4])[CH2:36][CH2:37]2)=[N:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1c[nH]cn1
Product: Cc1ccccc1-c1cc(N2CCN(C=O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 75.5 %

Procedure:
To a mixture of 0.089 ml (1.1 mmol) N,N-dimethylformamide and 38 mg (0.56 mmol) imidazole 0.071 ml (0.56 mmol) trimethylchlorosilane were added dropwise at room temperature. The reaction mixture was cooled to 0° C., and 0.10 g (0.19 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide (Example 53) were added. The ice-water bath was removed and the mixture stirred over night. The reaction was quenched with a mixture of 2 ml 1 N aqueous hydrochloric acid solution and 4 ml water, and the mixture was extracted with ethyl acetate. The combined extracts were dried with sodium sulfate and concentrated. Flash column chromatography afforded 81 mg (82%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:18]([CH:20]2[CH2:25][CH2:24][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 1 h
Yield: 37 %

Procedure:
The compound obtained in Example 2 (252 mg, 0.60 mmol) and triethylamine (0.201 ml) were dissolved in THF (5 ml), and under ice cooling, to the solution was added methanesulfonyl chloride (0.093 ml). The mixture was stirred at the same temperature for 1 hour. The compound obtained in Example 2 (252 mg, 0.60 mmol) and triethylamine (0.201 ml) were dissolved in THF (5 ml). To the solution was added methanesulfonyl chloride (0.093 ml) under ice cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added diisopropyl ether (100 ml), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether, and dried under reduced pressure to give the titled compound (110 mg, 0.22 mmol, Yield 37%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[C:13](Cl)(=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:7][CH2:6]2
Reactant: CCCCCCCC(=O)Cl
Reactant: COc1ccc2c(c1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)N1CCc2cc(OC)ccc2C1

Procedure:
4.0 g of 6-methoxy-1,2,3,4-tetrahydroisoquinoline and 3.5 ml of triethylamine in 50 ml of methylene chloride are initially introduced, and a solution of 4.0 g of octanoyl chloride in 10 ml of methylene chloride is added dropwise with stirring and cooling. The mixture is stirred at room temperature for 1 hour, then shaken with 1N hydrochloric acid, sodium carbonate solution and water, and the organic phase is dried over magnesium sulfate and evaporated in a rotary evaporator. The crude product (6.7 g of colorless oil) is reacted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16](O)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:44]1(=[O:53])[CH:52]2[CH:47]([CH2:48][NH:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1>CN(C=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:49]2[CH2:50][CH2:51][CH:52]3[C:44](=[O:53])[NH:45][CH2:46][CH:47]3[CH2:48]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Reactant: O=C1NCC2CNCCC12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCC2CN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CCC12
Reaction time: 12 h

Procedure:
The following was added sequentially to DMF (10 mL): 1-(4-chlorobenzyl)-1H-indole-2-carboxylic acid (250 mg, 0.875 mmol), DIPEA (0.46 mL, 2.64 mmol), EDC (202 mg, 1.050 mmol), and HOBT (162 mg, 1.050 mmol). This solution was allowed to stir at rt for 1 h, at which time crude octahydro-1H-pyrrolo[3,4-c]pyridin-1-one (˜123 mg, 0.875 mmol) was added. Stirring continued for 12 h at rt, at which time the solution was partitioned between water and 1:1 solution of ethyl acetate:diethyl ether. The organic extract was then washed with water (1×) and saturated aq. sodium carbonate (1×), dried with magnesium sulfate, and concentrated in vacuo. Purification was accomplished via silica gel flash chromatography (100 g silica, 100% EtOAc.) Resulting residue was crystallized from the in vacuo removal of DCM to give the title compound as a slightly pink solid. (Yield: 200 mg, 0.49 mmol, 56%) 1H NMR (400 MHz, CDCl3) 7.72, 7.40-7.24, 7.20, 7.17-7.11, 6.94, 6.31, 5.51, 4.57, 4.30-4.08, 3.59-3.46, 3.39, 3.17-3.02, 2.63, 2.51, 2.02-1.77
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([NH:36][CH3:37])[N:35]=1)[C:30](O)=[O:31])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([NH:36][CH3:37])[N:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:31])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CNc1cc(C(=O)O)cc(C(C)(C)C)n1
Product: CNc1cc(C(=O)Nc2ccc(C)c(-n3ccn4nc(-c5cccnc5)cc34)c2)cc(C(C)(C)C)n1
Reaction time: 16 h

Procedure:
60 mg (0.21 mmol) of the compound of Example 6A and 43 mg (0.21 mmol) of the compound of Example 44A were reacted analogously to the procedure of Example 33, except that in this case the reaction time was 16 h. This gave 31 mg (31% of theory) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]([C:20]([O:22]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)[CH:2]=1.[C:28]1([C:34]2[N:38]=[C:37]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[S:36][N:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:28]1([C:34]2[N:38]=[C:37]([N:39]3[CH2:44][CH2:43][N:42]([C:20]([NH:11][C:3]4[CH:2]=[N:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:22])[CH2:41][CH2:40]3)[S:36][N:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1cnc2ccccc2c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cnc2ccccc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixed solution of bis(2,2,2-trichloroethyl) quinolin-3-ylimidodicarbonate (301.4 mg, 0.610 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.106 ml, 0.610 mmol) in dimethyl sulfoxide (2 ml) was stirred at 70° C. for 5 hours and then stirred at 80° C. for 1 hour and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was poured to the residue, and 110 mg (43.2%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]([C:31]1[N:32]=[C:33]([NH:36][C:37](=[O:48])[C@@H:38]([NH2:47])[C@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[S:34][CH:35]=1)=[O:30].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:27][O:28][C:29]([C:31]1[N:32]=[C:33]([NH:36][C:37](=[O:48])[C@@H:38]([NH:47][C:10](=[O:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[CH:17][CH:18]=2)[C@H:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40])[S:34][CH:35]=1)=[O:30]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(=O)OC(C)(C)C)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of (R)-tert-butoxycarbonylamino-(4-tert-butoxycarbonylamino-phenyl)-acetic acid (420 mg, 1.13 mmol) and (2S,3S)-2-(2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (300 mg, 0.94 mmol) (prepared as described in Example 7) in dichloromethane (50 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (220 mg, 1.13 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature slowly, stirred overnight and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by chromatography over silica gel gradient eluted between 0 and 60% ethyl acetate in hexanes followed by a precipitation of the product from dichloromethane with excess hexanes gave 2-{(2S,3S)-2-[(R)-2-tert-butoxycarbonylamino-2-(4-tert-butoxycarbonylamino-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester as a white solid (520 mg, 82%).
Reaction SMILES: I[C:2]1[C:3]([S:12][C:13]2[NH:14][C:15]3[C:20]([N:21]=2)=[C:19]([NH2:22])[N:18]=[CH:17][N:16]=3)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[N:24]([O-])=O.[Na+].NC(N)=O>O>[NH2:24][C:2]1[C:3]([S:12][C:13]2[NH:14][C:15]3[C:20]([N:21]=2)=[C:19]([NH2:22])[N:18]=[CH:17][N:16]=3)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=N[O-]
Reactant: Nc1ncnc2[nH]c(Sc3cc4ccccc4cc3I)nc12
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: Nc1cc2ccccc2cc1Sc1nc2c(N)ncnc2[nH]1
Reaction time: 0.17 h

Procedure:
8-(3-iodonaphthalen-2-ylthio)-9H-purin-6-amine (S13-5). To a suspension of S13-4 (14 mg, 0.0454 mmol) in water (150 μL) at 5° C. was added 6 M HCl (140 μL) over 5 min. Then a solution of NaNO2 (6.3 mg, 0.0908 mmol) in water (70 μL) was added dropwise over 30 min. at below 5° C. The mixture was stirred for an additional 10 min., then urea (1.9 mg, 0.0317 mmol) was added slowly. After 10 minutes, a solution of KI (22.6 mg, 0.136 mmol) in water (70 μL) was added dropwise over 5 min. and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 8:1) to give 8 mg (42%) of S13-5 as a solid. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.51 (s, 1H), 8.17 (s, 2H), 7.75-7.80 (m, 2H), 7.52-7.60 (m, 2H); MS (ESI) m/z 420.01 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[K+]>CN(C)C=O>[C:26]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:6][CH2:7]1)#[N:27]
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C#N)CC3)c(F)c2)C(=O)O1
Yield: 42 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-oxopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (12.0 mmol) and potassium cyanide (18.0 mmol) in dimethylformamide (25 ml) at a temperature 25° C. for four hours and by purifying the compound by silica gel column chromatography in 42% yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[C:9]([CH3:23])([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[CH3:23][C:9]1([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[O:11][CH2:10]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)Cc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(Cc2cccc3ccccc23)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-Methyl-3-naphthalen-1-ylmethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (150 mg, 0.45 mmol), sodium hydroxide (150 mg, 3.75 mmol), ethanol (5 ml) and water (1 ml) in tetrahydrofuran (5 ml), was stirred for 12 h at room temperature. The reaction medium was acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product was obtained as a brown oil (M: 128 mg, 89%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dichloromethane (3 mL) at room temperature was added isonicotinoyl chloride (0.4 g, 2.79 mmol) and triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane (2×). Combined organic layers were washed with 10% KHSO4, sat. NaHCO3, and brine before drying (MgSO4), and concentration under reduced pressure to provide (4-methyl-1-(pyridine-4-carbonyl)-piperidin-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 354 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.69 (d, 2H), 7.40-7.31(m, 7H), 5.06 (s, 2H), 4.15 (m, 1H), 4.62 (m, 4H), 2.12 (m, 2H), 1.77-1.45 (m, 2H), 1.42 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:23]1(O)[CH2:27][CH2:26][O:25][CH2:24]1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[O:25]1[CH2:26][CH2:27][CH:23]([C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH2:24]1
Reactant: OC1(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CCOC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(C2CCOC2)c(O)c1
Yield: 38.2 %

Procedure:
A mixture of 1.56 g of 3-(2,4-bis(benzyloxy)-phenyl)tetrahydrofuran-3-ol in 25 ml of ethyl acetate, in the presence of 780 mg of palladium-on-charcoal at 10%, is stirred at ambient temperature under a hydrogen pressure of 5 bar for 7 hours. The reaction medium is filtered and then the filtrate is evaporated. The residue is chromatographed on silica gel, elution being carried out with 50/50 heptane/ethyl acetate. The solid obtained is crystallized from dichloromethane/heptane. 285 mg of 4-(tetrahydrofuran-3-yl)benzene-1,3-diol are obtained in the form of a white powder. Yield=36%.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[C:4]=1[CH2:5][NH2:6].[BrH:13]>>[BrH:13].[OH:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:4]=1[CH2:5][NH2:6]
Reactant: COc1cccc(OC)c1CN
Agent: Br
Product: NCc1c(O)cccc1O

Procedure:
2,6-Dimethoxybenzylamine was treated with 48% hydrobromic acid to obtain 2,6-dihydroxybenzylamine hydrobromide. F: 140.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C@@H:14]2[C@@:25]3([C:33]4[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[C:17]3([CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]3)[NH:16][C@H:15]2[C:36](=[O:45])[NH:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]2)[CH:13]=1)[C:7](OC)=[O:8].Cl.Cl.CN.[CH2:50]([N:52](CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>CO>[Cl:34][C:30]1[CH:29]=[C:28]2[C:33]([C@@:25]3([C@@H:14]([C:12]4[CH:11]=[C:6]([C:7](=[O:8])[NH:52][CH3:50])[CH:5]=[C:4]([Cl:3])[CH:13]=4)[C@H:15]([C:36]([NH:37][C@H:38]4[CH2:39][CH2:40][C@H:41]([OH:44])[CH2:42][CH2:43]4)=[O:45])[NH:16][C:17]43[CH2:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22]4)[C:26](=[O:35])[NH:27]2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1cc(Cl)cc([C@H]2[C@H](C(=O)N[C@H]3CC[C@H](O)CC3)NC3(CCC(C)(C)CC3)[C@@]23C(=O)Nc2cc(Cl)ccc23)c1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CO
Product: CNC(=O)c1cc(Cl)cc([C@H]2[C@H](C(=O)N[C@H]3CC[C@H](O)CC3)NC3(CCC(C)(C)CC3)[C@@]23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1N sodium hydroxide solution (0.19 ml, 0.19 mmol) was added to a methanol (4 ml) solution of the compound (81 mg, 0.13 mmol) obtained in Step 4 above and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was neutralized by addition of 1N hydrochloric acid and then the resulting mixture was concentrated under reduced pressure. Dichloromethane (4 ml) was added to the residue, then methylamine hydrochloride (26 mg, 0.39 mmol), triethylamine (0.11 ml, 0.77 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74 mg, 0.39 mmol) were added and the resulting mixture was stirred at room temperature for 24 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by NH-silica gel column chromatography [methanol:ethyl acetate=5:95 (v/v)] to give 42 mg (52%) of the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.Cl[C:19]1[C:24](C2C=CC(Cl)=CC=2)=[N:23][CH:22]=[CH:21][N:20]=1.N1CCNCC1.O>C(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:19]3)=[N:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2nccnc2Cl)cc1
Reactant: FC(F)(F)c1ccc(-c2nccnc2Cl)cc1
Agent: C1CNCCN1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(-c2nccnc2N2CCNCC2)cc1

Procedure:
Prepare 2-chloro-3-(4-trifluoromethylphenyl)-pyrazine in 30% according to the procedure used to make 2-chloro-3-(4-chlorophenyl)-pyrazine. Couple 2-chloro-3-(4-trifluoromethylphenyl)-pyrazine (0.570 g, 2.20 mmol) and piperazine (4.31 g, 50.0 mmol), at 125° C. for 111 min. Cool the reaction to about 70° C., add water (50 mL), stir until the reaction temperature is below 35° C. and dilute with DCM (70 mL). Separate the layers, extract the aqueous layer with DCM (2×70 mL), wash the combined organic layers with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 1:1 ethyl acetate:hexanes), to give the title preparation (0.384 g, 57%). MS (ES): m/z=309 [M+H]+.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[C:6]([S:10]([NH2:12])=[O:11])([CH3:9])([CH3:8])[CH3:7].[Cl-].[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:7][C:6]([S:10]([N:12]=[C:3]1[CH2:4][O:1][CH2:2]1)=[O:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1COC1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1COC1
Temperature: 25 °C
Yield: 18.8 %

Procedure:
3-Oxetanone (3 g, 41.63 mmol), tert-butyl sulfinamide (5.55 g, 45.8 mmol) and titanium (IV) ethoxide (13.5 mL, 62.4 mmol) were stirred in THF (200 mL) at 40° C. for 72 hours. The mixture was cooled to room temperature and poured into a rapidly stirred aqueous solution of saturated sodium chloride (200 mL). The resulting suspension was filtered through Celite© and the filter cake washed with ethyl acetate. The organic layer was separated and washed with brine, then dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (1.37 g, 19% yield).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:35]([F:38])([F:37])[F:36])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:38][C:35]([F:36])([F:37])[C:21]1[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:12]3[S:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][N:11]=3)[N:15]=[CH:16]2)[CH:24]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[CH:22]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 23 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To 2-{1-[6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonic acid tert-butylamide (example 302) (0.150 g, 0.260 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between TBME and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.120 g, 88%). MS (ISP) 520.2 [(M+H)+]; mp>250° C.