Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:6].[NH:24]1C=CN=[CH:25]1>>[N:2]1([CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH3:16])[C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:6])[CH:1]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: CN(C)CCC(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Product: Cn1c(-c2ccccc2)c(C(=O)CCn2ccnc2)c2ccccc21

Procedure:
3-(Dimethylamino)-1-(1-methyl-2-phenyl-1H-indol-3-yl)-1-propanone was converted to the methiodide (5.50 g) which was then reacted with imidazole (5.50 g) to give a solid which was crystallised from ethyl acetate to give the title compound (2.91 g), m.p. 159°-162°; λmax (EtOH) 251 nm (ε19,470), λmax 307 nm (ε13,800).
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:16]1OCCOCCOCCOCCOCCO[CH2:17]1.[OH-].[K+].BrCCBr>C(Cl)Cl>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:17][CH2:16]2)=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: BrCCBr
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1(n2cncn2)CC1
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 2-(1H-1,2,4-triazol-1-yl)-4'-fluoroacetophenone (10.24 g, 50 mMole) in methylene chloride (70 ml) was added 18-Crown-6 ether (1 g) (trade mark for 1,4,7,10,13,16-hexaoxacyclooctadecane) and potassium hydroxide (6.1 g, 109 mMole) with stirring. Ten minutes later 1,2-dibromoethane was added (10.3 g, 55 mMole in one batch. Stirring was continued for 18 hours. The mixture was poured into saturated saline solution (100 ml) and the organic phase was separated, washed with water (3×30 ml) and dried over anhydrous magnesium sulphate. Evaporation gave an oil, weight 13.7 g. Purification was carried out by flash column chromatography under slight pressure (2 p.s.i.) on a Merck "Kieselgel 60" (trade mark) 230-400 mesh fractions after collection and evaporation gave a solid, the pure title compound, 2.9 g, m.p. 73°-75° (25% yield).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:14]=[C:15]([P:25](=[O:52])([C:36]2[CH:41]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39]([O:46][CH3:47])=[C:38]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:37]=2)[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]=1[O:19][CH3:20])([CH3:12])([CH3:11])[CH3:10].CCCCCC>C(Cl)Cl>[Br:8][C:27]1[C:28]([O:34][CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=1[P:25](=[O:52])([C:36]1[CH:37]=[C:38]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:39]([O:46][CH3:47])=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:41]=1)[C:15]1[CH:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([O:19][CH3:20])=[C:13]([C:9]([CH3:10])([CH3:11])[CH3:12])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OC)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cc(OC)c(Br)c(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
NBS (206 g, 115.7 mmol) was added to a solution of bis(3,5-di-tert-butyl-4-methoxyphenyl)(3,5-dimethoxyphenyl)phosphine oxide (70 g, 112.4 mmol) in CH2Cl2 (350 mL) at 0° C. The resulting suspension was stirred at 0° C. for 1 h then was warmed to RT and stirred for 4 h. The reaction was monitored by TLC until no starting material remained. The solution was washed with conc. Na2CO3 (300 mL×2) at RT. The organic layer was separated and dried over MgSO4. It was filtered and the solvent was removed to give the crude product. Hexane (400 mL) was added and the solution concentrated to 300 mL. It became cloudy and a white solid precipitated. Another 100 mL of hexane was added. The suspension was stirred at RT for 2 h. It was filtered and the solid dried under vacuum to give the product as a colourless solid (64.4 g). A second crop (7.2 g) was obtained from the mother liquor. Overall yield=90.9%. 1H NMR (400 MHz, CDCl3) δ: 7.55 (d, J=13.2 Hz, 4H), 7.04 (dd, J1=13.2 Hz, J2=2.8 Hz, 1H), 6.65 (d, J=2.8 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.68 (s, 6H), 1.36 (s, 36H). 31P NMR (162.0 MHz, CDCl3) δ: 32.4.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([O:30][CH3:31])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24]>CO.O1CCCC1>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:3][C:2]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]([O:30][CH3:31])=[O:29])=[O:1])=[CH:12][CH:13]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(S(N)(=O)=O)cc1
Yield: 92.7 %

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzene sulfonamide in a mixture of 15 mL of methanol and 15 mL of tetrahydrofuran, and 0.27 g (1.6 mmol) of methyl thiosalicylate. The product was triturated with ether, filtered, washed with ether and dried in vacuo to give 0.66 g of the title compound, mp 288°-290° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14].I[CH2:16][CH3:17].O>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:16][CH3:17]
Reactant: Sc1ccccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add potassium carbonate (2.20 g, 15.92 mmol) to 2-bromobenzenethiol (2.00 g, 10.58 mmol) in acetone and stir at room temperature. After 10 minutes, add iodoethane (1.82 g, 11.67 mmol) with stirring. After 18 hours, add water and extract with ethyl acetate. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[Ca+2].[C:30](Cl)(Cl)=[S:31]>O>[N:13]([C@H:12]([C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[C:30]=[S:31]
Reactant: S=C(Cl)Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-(2-phenylthiazol-4-yl)ethanamine hydrobromide salt, 38, (2.03 g, 5 mmol) and CaCO3 (1 g, 10 mmol) in CC4/water (10:7.5 mL) is added thiophosgene (0.46 mL, 6 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2C2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue that is purified over silica (CH2Cl2) to afford 1.71 g (93% yield) of the desired product. ESI+ MS 368 (M+1).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[C:47]([CH3:49])([CH3:48])[S:46][C@H:45]2[CH2:50][CH2:51][CH2:52][CH2:53][N:44]2[C:43]1=[O:54]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[C:47]([CH3:48])([CH3:49])[S:46][C@H:45]2[CH2:50][CH2:51][CH2:52][CH2:53][N:44]2[C:43]1=[O:54])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC1(C)S[C@H]2CCCCN2C(=O)[C@H]1N
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3C(=O)N4CCCC[C@@H]4SC3(C)C)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((3R,9aS)-2,2-dimethyl-4-oxooctahydropyrido[2,1-b][1,3]thiazin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (15 mg, 0.026 mmol) and Intermediate 30 (8.7 mg, 0.026 mmol) to give a white solid (12 mg, 56% yield). Anal. Calcd. for C41H54N4O6S2 m/z 762.4. found: 763.4 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.09 (d, J=7.70 Hz, 1H), 7.94 (d, J=9.35 Hz, 1H), 7.28-7.06 (m, 10H), 5.54 (dd, J=6.32, 3.02 Hz, 1H), 5.13-5.07 (m, 1H), 5.03 (dd, J=10.17, 3.57 Hz, 1H), 4.82-4.78 (m, 1H), 4.76 (d, J=9.35 Hz, 1H), 4.20 (d, J=13.20 Hz, 1H), 3.63 (s, 3H), 3.14-3.04 (m, 1H), 3.00-2.91 (m, 1H), 2.91-2.76 (m, 4H), 2.77-2.66 (m, 3H), 2.41-2.28 (m, 1H), 2.14-2.03 (m, 1H), 2.02-1.87 (m, 2H), 1.84-1.51 (m, 14H), 0.99 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:10][C:3]=12.[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCCC1>O.C(OCC)(=O)C>[CH:11]1([C:9]2[NH:8][C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:20]4[CH:19]=[C:18]([F:17])[CH:23]=[CH:22][C:21]=4[O:27][CH3:28])=[C:3]3[CH:10]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Clc1ccnc2[nH]c(C3CCCCC3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCCC3)cc12
Temperature: 60 °C

Procedure:
A solution of Example 98B (200 mg, 0.852 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (188 mg, 1.108 mmol), phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (50 mg, 0.077 mmol) and potassium phosphate (543 mg, 2.56 mmol) in 8 mL 3:1 tetrahydrofuran:water was purged with nitrogen and heated under nitrogen at 60° C. for 4 hours. The cooled mixture was diluted with water and ethyl acetate and filtered through diatomaceous earth. The mixture was extracted into ethyl acetate (twice) and the combined extracts were rinsed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (1:1 ethyl acetate:hexanes) provided only a small amount of material. The column was washed with 10% methanol/dichloromethane and the remainder of the material eluted. The combined residue was suspended in diethyl ether and the solids were collected and rinsed with diethyl ether to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.48 (m, 5H) 1.64-1.76 (m, 3H) 1.99-2.02 (m, 2H) 2.70-2.73 (m, 1H) 3.72 (s, 3H) 5.92 (s, 1H) 6.99 (d, J=5.08 Hz, 1H) 7.15-7.27 (m, 3H) 8.12 (d, J=4.75 Hz, 1H) 11.50 (s, 1H). MS (DCI) m/e 325 (M+H)+.
Reaction SMILES: C(OC(=O)[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[C:8]([O:10]C(C)(C)C)=O)(C)(C)C.[CH:24]1[CH:29]=[C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([CH:34]=O)[C:27]2=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>[Br:21][C:18]1[CH:17]=[C:16]2[C:15]([CH2:7][C:8](=[O:10])[N:22]2[CH2:34][C:33]2[C:27]3[C:28](=[CH:29][CH:24]=[CH:25][CH:26]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1N
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2ccc(Br)cc2N1Cc1cccc2ccccc12
Reaction time: 0.75 h
Yield: 91.3 %

Procedure:
2-(2-Amino-4-bromo-phenyl)-malonic acid di-tert-butyl ester (7.73 g, 20.0 mmol) and 1-napthylaldehyde (3.0 ml, 22.0 mmol) were dissolved in 80 ml of acetic acid (AcOH) under an atmosphere of dry N2. To this solution was added 95% sodium triacetoxyborohydride (NaHB(OAc)3) (5.8 g, 26 mmol) and the solution was stirred for 45 minutes. The reaction mixture was concentrated under vacuum and then stirred in 100 ml of a 1:1 solution of DCM/water. To this mixture was slowly added NaHCO3 until the pH˜8. The DCM layer was then washed with saturated aqueous NaHCO3 and dried over MgSO4, filtered and concentrated under vacuum to give a foam which was subsequently dissolved in a solution of 80 ml of TFA and 10 ml of triethylsilane under an atmosphere of dry N2. The mixture was stirred overnight after which time the precipitate was collected, washed with hexanes and dried under vacuum to give 6.43 g of the titled compound as a white solid in 90% yield.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[CH2:11])=[CH:6][CH:5]=1.N1C=CC=CC=1>ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH2:11][Br:1])[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16][CH3:17])[O:18]2)=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: C=C(CCC(O)CCC)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A solution of bromine (1.28 g) in dichloromethane (25 ml) was added dropwise over 15 minutes to a stirred solution of 2-(4-chlorophenyl)-5-hydroxyoct-1-ene (1.9 g) and pyridine (0.63 g) in dichloromethane (25 ml) at 0° to 5° C. (decolourisation of bromine and mild exotherm). The cooling bath was removed and the mixture was stirred for a further 30 minutes, then washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate, and water, then dried over magnesium sulphate and concentrated under reduced pressure to give 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran (2.6 g) as a red oil, 1H nmr (CDCl3): δ3.9 (2H, singlet, CH2Br).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[N:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH3:25])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:28][N:29]([CH3:31])[CH3:30])[S:10][C:9]1=[N:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH3:25])[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=CN(C)C)C(=O)N1Cc1ccccc1
Temperature: 125 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
To a solution of 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylamino-benzonitrile (84 mg, 0.24 mmol) in toluene (1.0 mL, anhyd) was added N,N-dimethylformamide dimethyl acetal (1.0 mL, 7.5 mmol). The reaction mixture was heated at 125° C. After 20 h, the mixture was cooled and chromatographed (silica gel, DCM) to afford the title product (60 mg, 62%) as a pale yellow solid. 1H-NMR (CDCl3): δ 7.60 (1H, s), 7.24-7.40 (6H, m), 7.15 (1H, d), 6.46 (1H, d), 5.09 (2H, s), 4.14 (1H, br t), 3.12 (6H, s), 2.98 (2H, m), 0.99 (3H, t); MS (ESI): 406 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([NH:13][C@@H:14]3[CH2:16][C@H:15]3[C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[CH:19][CH:18]=3)[CH2:10][CH2:9][N:8]2C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:43].COC1CCCC1>C1COCC1>[ClH:43].[ClH:43].[C:1]1([CH:7]2[CH2:12][CH:11]([NH:13][C@@H:14]3[CH2:16][C@H:15]3[C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)=[CH:19][CH:18]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N[C@@H]2C[C@H]2c2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2)CC1c1ccccc1
Agent: Cl
Solvent: COC1CCCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NC2CCNC(c3ccccc3)C2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-phenyl-4-{[trans-2-(4-{[3-(trifluoromethyl)benzoyl]amino}phenyl)cyclopropyl]amino}-piperidine-1-carboxylate (62 mg) was dissolved in THF (0.5 mL), and the mixture was ice-cooled to 0° C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (5.0 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (24 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([F:31])[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)(=[O:3])[CH3:2].C(Cl)(=O)C1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>>[F:31][C:9]1[N:10]([C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[C:2]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[N:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Product: O=C(NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)c1ccncc1

Procedure:
Use of the same technique as for the starting material of Example 29, but replacing acetyl chloride with isonicotinoyl chloride gave 2-fluoro-4-(2-isonicotinoylaminoethyl)-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 2.7 (t, 2H); 3.71 (q, 2H); 6.35 (s, 1H); 7.0-7.5 (m, 15H); 7.65 (q, 2H); 8.72 (q, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1.Br[CH2:18][CH2:19][O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH2:19][O:20][CH3:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: COCCBr
Reactant: N#Cc1nc(N)nc(Nc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCN(c1ccccc1)c1nc(N)nc(C#N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-amino-6-phenylamino-[1,3,5]triazine-2-carbonitrile (prepared in an analogous manner to Intermediate 5, 100 mg, 470 μmol), 1-bromo-2-methoxyethane (50 μl, 0.52 mmol) and potassium carbonate 130 mg, 0.94 mmol) in DMF (5 ml) was heated to 100 C and stirred 3 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated under vacuum to give the crude product which was used without further purification (400 mg, >100%, contains DMF). Method C HPLC-MS: MH+ requires m/z=271. Found: m/z=271, Rt=1.23 min (52%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN1CCCC1=O>[C:18]1([N:1]2[C:5](=[O:6])[CH2:4][N:3]3[C:7](=[O:10])[CH2:8][CH2:9][CH:2]23)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CN2C(=O)CCC2N1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C1CCC2N1CC(=O)N2c1ccccc1
Yield: 11.7 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1 g, 7.14 mmol; prepared as described in J. Med. Chem. 36, 4214-4220, 1994,) in N-methylpyrrolidone (NMP, 12 cc), Cul (0.2 g, 1.05 mmol), K2CO3 (1 g, 7.14 mmol) and iodobenzene (5 g, 24.5 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 45 min. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with isopropyl ether. The solid was filtered, triturated with water and filtered to yield 0.18 g of the title compound, mp=185-188° C.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C@@H:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:10])=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.C(Cl)Cl.O>[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C@@H:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:13]2[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:10])=[CH:5][N:4]=1
Reactant: COc1ncc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2C(F)(F)F)cn1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F)c1cnc(O)nc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
A 25 mL round-bottomed flask containing a suspension of (S)-2-methoxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)pyrimidine-5-carboxamide (Example 44) (0.094 g, 0.206 mmol) and sodium iodide, anhydrous (0.129 g, 0.861 mmol) in anhydrous MeCN (3.5 mL) was treated with chlorotrimethylsilane, redistilled (0.130 mL, 1.028 mmol). The resulting suspension was stirred at rt for 17.5 h. The reaction was concentrated on the rotary evaporator resulting in a gummy residue which was taken up in DCM (55 mL), H2O (25 mL), and 10% aqueous sodium thiosulfate (20 mL). The resulting mixture was transferred to a separatory funnel and after vigorous extraction the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to yield the product. The product thus obtained was dissolved in DMSO/MeOH(1/1) (3.5 mL) and loaded on a Gibson HPLC system for purification using a MeCN/H2O/0.1% TFA gradient and Phenomenex™ Gemini Axia-5μ C-18 column (150×30 mm). The solvent was removed from the pure fractions in the Genevac™ and the resulting product was dissolved in MeOH (3 mL), concentrated in the Genevac™, and dried under high vacuum to yield (S)-2-hydroxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methyl)pyrimidine-5-carboxamide as an amorphous white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (d, J=7.6 Hz, 1H), 8.93 (d, J=3.9 Hz, 1H), 8.80 (s, 2H), 8.27 (dd, J=8.0, 1.2 Hz, 1H), 7.75-7.70 (m, 2H), 7.64 (dd, J=7.9, 5.0 Hz, 1H), 7.56-7.50 (m, 2H), 6.76 (d, J=7.6 Hz, 1H). MS (ESI pos. ion) m/z: 443.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:29](I)[CH3:30].CN(C)C=O>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:29][CH3:30])=[O:22])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
A mixture of 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid (54.8 g), sodium bicarbonate (29 g), ethyl iodide (21 ml) and N,N-dimethylformamide (150 ml) is stirred for 3 hours at 70°-80° C. After further addition of ethyl iodide (10 ml), the stirring is continued for further 3 hours at 90°-100° C. After cooling, the mixture is diluted with water and extracted with ethyl acetate (1 l). The extract is washed successively with water, 1N hydrochloric acid and sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)valerate (58 g) as a pale yellow oil.