Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:29]#[N:30])([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:29]#[N:30])([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1Cl
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 56b (2.4 g, 7.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.7 g, 100%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([CH2:24]OS(C)(=O)=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.[C:30]([C:37]([O:39][CH2:40][CH3:41])=[O:38])#[C:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N.C1COCC1.CCO>[CH2:40]([O:39][C:37]([C:30]1[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:24]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[N:11]2[C:12]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:8][C:9]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N:10]2)=[O:38])[CH3:41]
Reactant: c1ccc(-c2cnnc(N3CCOCC3)c2)cc1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CS(=O)(=O)OCC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCO
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1C1CCCC1

Procedure:
A solution of 4-(5-phenylpyridazin-3-yl)morpholine (150 mg, 0.622 mmol) and methanesulfonic acid cyclopentylmethyl ester (Newcomb et al. (1980) J. Org. Chem. 45:1707-1708) (890 mg, 4.99 mmol) in CH3CN (30 mL) was heated at reflux for 48 h. The solvent was removed in vacuo to provide a brown oil. Diethyl acetylenedicarboxylate (150 μL, 0.933 mmol) and a 1M solution of TBAF in THF (684 μL, 0.684 mmol) were added to a solution of this oil in THF (30 mL) and EtOH (5 mL). The reaction mixture was heated at reflux for 20 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 15% EtOAc/hexane). The resulting residue was triturated in 1:1 Et2O/hexane to provide the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 0.86 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.66 (m, 2H), 1.76 (m, 2H), 1.87 (m, 2H), 2.23 (m, 2H), 3.48 (m, 6H), 3.72 (m, 4H), 4.06 (m, 1H), 4.15 (q, J=7.1 Hz, 2H), 6.77 (s, 1H), 7.39 (m, 2H), 7.45 (m, 3H). Mass Spectrum (ESI+) m/e=492.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](Cl)=[O:13]>C(Cl)Cl.N1C=CC=CC=1>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9])=[O:13]
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cc(Cl)ccc1O
Reaction time: 18 h
Yield: 55 %

Procedure:
To a cooled (0° C.) solution of 2-amino-4-chlorophenol (30 g, 209 mmol) in DCM (200 mL) and pyridine (17 mL) was added a solution of chloroacetyl chloride in DCM (23.6 g, 230 mmol in 75 mL). The mixture was allowed to reach rt slowly and was subsequently stirred for 18 h. The precipitate was filtered, washed with DCM, and dried overnight at 50° C. to give crude 2-chloro-N-(5-chloro-2-hydroxyphenyl)acetamide (intermediate 56) (26 g, 55%), as a brown solid which was used in the next step without any further purification.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)[Cl:8].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[C:20]([CH3:26])([CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[CH2:11]([N:18]1[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([Cl:8])=[C:22]([CH:4]=[O:5])[CH2:23]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CN(Cc2ccccc2)CC(C=O)=C1Cl
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of anhydrous DMF (142 mL, 1.85 mol) in anhydrous DCM (670 mL) was cooled to 0° C. A solution of POCl3 (121 mL, 1.3 mol) in anhydrous DCM (87 mL) was added dropwise. Upon complete addition, the solution was warmed to room temperature and further to reflux for 30 minutes. A solution of 1-benzyl-3,3-dimethylpiperidin-4-one (75 g, 0.35 mol) in anhydrous DCM (133 mL) was added all at once to the boiling solution and the mixture was further refluxed overnight. The reaction was cooled to room temperature and added dropwise to a biphasic mixture of 4.0 M aqueous sodium acetate (1000 mL) and DCM (300 mL). Upon separation of the layers, the organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated to dryness to afford 1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde (75 g, 82% crude yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Al](Cl)(C)C.[CH3:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[C:17]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:18]=[C:19]([C:24](OC)=[O:25])[CH:20]=2)[CH2:15]1>ClCCCl.C(Cl)Cl>[CH3:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[C:17]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=3)[CH:18]=[C:19]([C:24]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)=[O:25])[CH:20]=2)[CH2:15]1
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(C)C2
Agent: C[Al](C)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)C(=O)N(C)C3)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 5-methyl-2-aminopyridine (144 mg, 1.33 mmol) in DCE at 0° C. was added Al(CH3)2Cl drop-wise. The reaction was stirred at room temperature for 20 minutes followed by the addition of methyl 2-methyl-7-(4-(methylsulfonyl)phenoxy)-3-oxoisoindoline-5-carboxylate. After stirring the reaction at room temperature for 14 hours, it was diluted with CH2Cl2 and quench with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL) slowly. The solution was washed with brine, dried over Na2SO4, and concentrated. The crude sample was introduced into a silica gel column and eluted with 5-10% MeOH/CHCl3 to provide the product (40 mg, 85% yield) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3 H) 3.10 (s, 3 H) 3.19-3.33 (m, 3 H) 4.40 (s, 2 H) 7.19 (d, J=8.67 Hz, 2 H) 7.53-7.66 (m, 1 H) 7.82 (s, 1 H) 7.97 (d, J=8.67 Hz, 2 H) 8.10-8.17 (m, 1 H) 8.19 (s, 2 H) 8.81 (s, 1H); LC-MS (ESI)+ m/z=452.00 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH3:36].C(=O)([O-])[O-]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]=3[CH3:36])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: C[C@@H]1Nc2cc(C#N)ccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a rt solution of tert-butyl(3S,4S)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (308 mg, 974 μmol) in DMF (2.43 ml) was added 1-(chloromethyl)-2-methylnaphthalene (223 mg, 1.17 mmol) and cesiuim carbonate (952 mg, 2.92 mmol). The reaction was stirred at rt for 2 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (364 mg, 80% yield) as an off-white oil. MS m/z 493 (MNa)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([OH:6])=[O:5].S(Cl)([Cl:9])=O.[CH2:11](O)[CH2:12][CH2:13][CH3:14]>>[Cl-:9].[CH2:11]([O:5][C:4](=[O:6])[CH2:3][NH3+:2])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCO
Reactant: O=S(Cl)Cl
Reactant: NCC(=O)O
Agent: Cl
Product: CCCCOC(=O)C[NH3+]
Product: [Cl-]
Temperature: 70 °C

Procedure:
To a suspension of glycine hydrochloride (400 g, 3.58 mol) in n-butanol (8 L), thionyl chloride (1.37 L, 18.84 mol) was added slowly dropwise. After addition was complete, the reaction was heated at 70° C. overnight. The product mixture was concentrated under vacuum and the residue was triturated with a mixture of heptane/ethyl acetate. The white solid precipitated was filtered and dried under a stream of dry nitrogen to provide the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1([C:18]2[CH:27]=[CH:26][C:25]3[N+:24]4[CH:28]=[C:29]5[CH:38]=[CH:37][C:36]6[CH:35]=[C:34]([N:39]7[CH2:44][CH2:43]C[CH2:41][CH2:40]7)[CH:33]=[CH:32][C:31]=6[N:30]5[C:23]=4[CH:22]=[CH:21][C:20]=3[CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:45](O)[CH3:46]>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:1][CH:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:27]=[CH:26][C:25]3[N+:24]4[CH:28]=[C:29]5[CH:38]=[CH:37][C:36]6[CH:35]=[C:34]([N:39]7[CH2:40][CH2:41][CH:45]([CH3:46])[CH2:43][CH2:44]7)[CH:33]=[CH:32][C:31]=6[N:30]5[C:23]=4[CH:22]=[CH:21][C:20]=3[CH:19]=2)[CH2:17][CH2:16]1
Reactant: CCO
Reactant: c1cc2c(ccc3c[n+]4c5ccc(N6CCCCC6)cc5ccc4n32)cc1N1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC1CCN(c2ccc3c(ccc4c[n+]5c6ccc(N7CCC(C)CC7)cc6ccc5n43)c2)CC1

Procedure:
3,10-Di-(1-piperidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium p-Toluenesulfonate; m.p. 250°-260° C. (dec.), from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][N:6]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:9][N:8]=[C:7]1[SH:19].[CH3:24]I.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][N:6]1[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)=[CH:9][N:8]=[CH:7]1.[CH3:24][S:19][C:7]1[NH:8][CH:9]=[CH:10][N:6]=1
Reactant: CI
Reactant: CN1CCN(Cc2cnc(S)n2Cc2cc(F)cc(F)c2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2cncn2Cc2cc(F)cc(F)c2)CC1
Product: CSc1ncc[nH]1

Procedure:
Reaction of 1-(3,5-difluorobenzyl)-5-[(4-methyl-1-piperazinyl)methyl]imidazole-2-thiol prepared as in Example 1 with methyl iodide and sodium methoxide in methanol by known techniques yields 1-(3,5-difluorobenzyl)-5-[(4-methyl-1-piperazinyl)methyl]imidazole-2-methylthioimidazole.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:20](/[CH:21]=[CH:22]/[CH:23]=O)=[CH:19][CH:18]=1.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1.Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[CH:22][CH:23]=[C:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:25][CH:26]=1
Reactant: Cc1cccc(-c2nc(CCOc3ccc(/C=C/C=O)cc3)c(C)o2)c1
Reactant: O=C1COC(=O)N1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cccc(-c2nc(CCOc3ccc(C=CC=C4OC(=O)NC4=O)cc3)c(C)o2)c1
Yield: 34.3 %

Procedure:
A mixture of (E)-4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamaldehyde (1.20 g), 2,4-oxazolidinedione (0.525 g), piperidine (0.09 g) and ethanol (20 ml) was heated for 5 hours under reflux. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and, then, concentrated. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (50:1) was obtained 5-[4-[2-[5-methyl-2-(3-methylphenyl)-4-oxazolyl]ethoxy]cinnamylidene]-2,4-oxazolidinedione (0.51 g, 34%). Recrystallization from dichloromethane-methanol gave pale yellow prisms, m.p.213-214° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.O1CCCC1.O.[CH3:27][S:28]([N:31]1[CH2:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32]1)(=[O:30])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:34]3[CH2:35][CH2:36][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32][CH:33]=3)[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (1.9 g, 4.53 mmol) in 6:1 tetrahydrofuran/water (60 mL) was added 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.56 g, 5.43 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.37 g, 0.453 mmol) and cesium carbonate (3.54 g, 10.87 mmol). The mixture was heated at 50° C. overnight, cooled and diluted with 50 mL ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica (Analogix 280) eluting with a gradient of 10% to 60% ethyl acetate/hexanes gave the title compound. MS (ESI+) m/z 452.5 (M)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14][OH:15])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](O)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])=[O:10])[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CO)CC1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@H]1C(=O)N[C@H]1CC[C@H](C)CC1
Temperature: 0 °C

Procedure:
Add, dropwise, to a stirring suspension at −20° C. of trans-2-hydroxymethyl-cyclopropanecarboxylic acid trans-(4-methylcyclohexyl)-amide (Example 11c) (2.85 g, 13.5 mmol), triethylamine (3.74 mL, 27.0 mmol) and 4-(dimethylamino)pyridine (0.1 g, 0.82 mmol) in dichloromethane (100 ml) a solution of methanesulfonic acid (1.59 mL, 20.3 mmol) in DCM (10 mL). When the reaction is complete, pour the mixture into ice water and extract the mixture with DCM. Combine the extracts, wash with 0.1N KHSO4, brine, dry over MgSO4 and concentrate under vacuum. Treat the residue with a mixture of isopropanol/heptane and collect the precipitate by filtration to obtain 2.91 g (74%) of solid, MS m/z=290 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[N:11]=[C:10]([CH:12]=O)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.NC1C2C=C(C=O)SC=2N=CN=1.NC1CCNC1.[CH:32]1([CH2:38][N:39]2C(C3C=CC=CC=3)=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:41]=[CH:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:50]1([CH2:42][N:41]2[C:12]([C:10]3[S:9][C:5]4[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=4[N:11]=3)=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:39]=[CH:40]2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: c1ccc(-c2ncn(CC3CCCCC3)c2-c2ccccc2)cc1
Reactant: CSc1ncnc2sc(C=O)nc12
Agent: NC1CCNC1
Agent: Nc1ncnc2sc(C=O)cc12
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCCCC3)nc12

Procedure:
The title compound was prepared by a similar process to that described for Example 65 but using 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carbaldehyde (Intermediate 77) in place of 4-aminothieno[2,3-d]pyrimidine-6-carbaldehyde (Intermediate 73) and using cyclohexamethylamine in place of 3-aminopyrrolidine. Yellow solid (542 mg) (the product contained 33% of 1-(cyclohexylmethyl)-4,5-diphenyl-1H-imidazole but was used in subsequent steps without further purification);
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:38][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCC4)ncnc32)[C@]1(C)F
Yield: 76 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.50 g, 1.08 mmol) in ethanol (about 5 ml) was added cyclopentylamine (about 1.28 ml, 12.9 mmol) and refluxed for about 30 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 6% methanol in dichloromethane as eluent furnished title compound (0.42 g) as a colorless solid. Yield: 76%; 1H-NMR: 1H NMR (300 MHz, CDCl3): δ 8.39 (s, 1H), 8.06-7.96 (m, 3H), 7.57-7.42 (m, 3H), 6.54 (d, 1H, J=23.1 Hz), 5.92 (d, 1H, J=7.5 Hz), 4.83-4.77 (m, 2H), 4.48-4.44 (m, 1H), 2.15 (s, 3H), 2.08-1.91 (m, 1H), 1.89-1.88 (d, 3H, J=2.1 Hz), 1.78-1.58 (m, 8H), 1.44 (d, 3H, J=23.1 Hz); ES Mass: [M+1]+ 526 (20%), [M+Na] 548 (100%); IR cm−: 3437, 2925, 2855, 1733, 1612, 1232, 1059, 951, 711; HPLC: 98%.
Reaction SMILES: [OH-:1].[Na+].[NH2:3]O.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]([C:35]([F:38])([F:37])[F:36])=[CH:14][C:15]([C:17]2[CH:33]=[CH:32][C:20]([C:21]([NH:23][C@@H:24]3[CH2:28][O:27][N:26]([CH2:29][CH3:30])[C:25]3=[O:31])=[O:22])=[C:19]([CH3:34])[CH:18]=2)=O)[CH:9]=[C:10]([Cl:12])[CH:11]=1>ClC(Cl)C.ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:35]([F:38])([F:37])[F:36])[O:1][N:3]=[C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH:24]4[CH2:28][O:27][N:26]([CH2:29][CH3:30])[C:25]4=[O:31])=[O:22])=[C:19]([CH3:34])[CH:18]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: CCN1OC[C@@H](NC(=O)c2ccc(C(=O)C=C(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2C)C1=O
Reactant: [OH-]
Reactant: NO
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCN1OCC(NC(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C)C1=O
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A pre-cooled solution of 5M sodium hydroxide (0.09 ml) was added to a solution of hydroxylamine (50% in water, 0.024 ml) at 5° C. (ice bath). The solution was stirred for 15 min at 5° C. then added to a vigorously stirred solution of 4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-N-((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide (100 mg) and anthracenyl-methyl quininium bromide (20 mg) (Step A) in dichloroethane (1 ml) cooled in an ice-acetone bath. The mixture was stirred rapidly at 0° C. for 4 hours. The reaction mixture was diluted with dichloromethane, passed through an isolute phase separating cartridge and concentrated in vacuo to leave yellow oil. This residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 5%) to give the title compound (9 mg). The product was analysed by chiral HPLC (method H): 18.7 min (42.5%), 19.6 min (24.2%), 21.4 min (8.5%), 22.8 min (24.8%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32]([SH:35])[NH:33][CH:34]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32]([S:35][C:2]2[S:6][C:5]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[O:9])=[N:4][CH:3]=2)[NH:33][CH:34]=1)=[O:29])[CH3:26]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)s2)n1
Yield: 38 %

Procedure:
2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-1H-imidazole-4-carboxylic acid ethyl ester (190 mg, 38%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercapto-1H-imidazole-4-carboxylic acid ethyl ester (340 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[CH2:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)[CH3:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:45](=[O:46])[C:44]4[CH:48]=[CH:49][C:41]([CH2:39][CH3:40])=[CH:42][CH:43]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccc(CC)cc3)cc1)n2C)c1ccccn1
Yield: 64 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 4-ethylbenzoylchloride. Yield: 64% of theory, C36H37N7O4 (631.7) Rf value: 0.78 (silica gel; dichloromethane/methanol=9:1) ##EQU130##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]([Cl:36])([Cl:35])[C:32](Cl)=[O:33]>O1CCCC1>[Cl:30][C:31]([Cl:36])([Cl:35])[C:32]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:4]1[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=[C:2]([Cl:1])[CH:3]=1)=[O:33]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1OCc1cc(Cl)cc2c1OCOC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1OCc1cc(Cl)cc2c1OCOC2)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(6-chloro-2H,4H-benzo[e]1,3-dioxin-8-yl)methoxy]phenylamine (75 mg, 0.257 mmol) in anhydrous tetrahydrofuran (2 mL) was added N,N-diisopropylethylamine (0.090 mL, 0.514 mmol), followed by trichloroacetyl chloride (0.058 mL, 0.514 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to give 2,2,2-trichloro-N-{2-[(6-chloro(2H,4H-benzo[e]1,3-dioxin-8-yl))methoxy]phenyl}acetamide, M+1=438.1.