Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:23])=[CH:3][CH2:4][O:5][C:6]1[CH:20]=[C:19]([Cl:21])[C:9]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:8]([Cl:22])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:23][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:22])[C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:19]([Cl:21])[CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 0 °C

Procedure:
A mixture of 0.3 gram (0.0008 mole) of tert-butyl 2-(4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy)acetate in 3.0 mL of methylene chloride was stirred and cooled to 0° C. Trifluoroacetic acid (3.0 mL, 0.04 mole) was added and the reaction mixture was allowed to warm to ambient temperature where it stirred for two hours. The reaction mixture was concentrated under reduced pressure leaving a residue. The residue was dissolved in methylene chloride and the solution concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride again. The solution was concentrated under reduced pressure to yield a quantitative amount of the subject compound as a white powder.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]1>>[Br:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:40][CH2:39][CH2:38][CH2:37][N:34]3[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]3)=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)Oc1ccccc1
Reactant: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNC(=O)Nc2snc(OCc3c(F)cc(Br)cc3F)c2C(N)=O)CC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,6-difluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 547 and 549 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][CH2:2][C:3]2[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=2)=[CH:19][CH:18]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Product: CC(C)(C)C(=O)Nc1cccc(COCc2ccc(Cl)cc2)n1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(6-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.73 g) and 4-chlorobenzyl bromide as a yellow oil (0.868 g). MS (ESI): 332.2 (MH+).
Reaction SMILES: [CH:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>CC(C)=O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: NS(=O)(=O)C1CCCC1
Reactant: O=C=Nc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Br)cc1)NS(=O)(=O)C1CCCC1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
The general method of procedure A was followed with cyclopentanesulfonamide (3 g), acetone (100 ml), 1N sodium hydroxide (21 ml), and 4-bromophenyl isocyanate (3.7 g) dissolved in acetone (50 ml). After two hours, 1N HCl (21 ml) was added. The resulting precipitate was collected, washed with water and dried at 60° C. under vacuum to provide 5.4 g of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][NH:28][C:19]([C@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH2:14]1)=[O:20]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 24f), by condensing (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent there is obtained (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=343 (M+H)+; [α]589=+28.17° (c=0.831, CH2Cl2).
Reaction SMILES: [Si]([O:18][C:19]1[CH:48]=[CH:47][C:22]([O:23][CH2:24][C@@H:25]([OH:46])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]3[C:42]([N+:43]([O-])=O)=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[H][H].[F-].C([NH3+])(C)(C)C>C(O)C.[Pd]>[NH2:43][C:42]1[C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]([OH:46])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:48][CH:47]=3)=[CH:31][CH:32]=2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: [H][H]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(Nc3ncccc3[N+](=O)[O-])cc2)cc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: CCO
Product: Nc1cccnc1Nc1ccc(CCNC[C@@H](O)COc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.4 %

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-({4-[(3-nitro-2-pyridinyl)amino]phenethyl}amino)-2-propanol (0.36 g, 0.543 mmol) was dissolved in ethanol, catalytic 10% palladium on carbon added, and shaken on a Parr apparatus under 50 psi hydrogen for 2 hours. The catalyst was removed by filtration through Celite and the filtrate taken to dryness in vacuo. The residue was dissolved in anhydrous tetrahydrofuran and treated with tert-butylammonium fluoride (0.7 mL, 1M solution in tetrahydrofuran, 0.7 mmol). The reaction was stirred at ambient temperature for 5 minutes, the solvent removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60 (eluant: 20:1 going to 5:1 chloroform-methanol containing 2% triethylamine). The solvent was removed in vacuo to furnish the title compound (0.05 g, 0.127 mmol).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:33][N:34]([CH:43]=[O:44])[O:35]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[NH:19][CH:20]=[CH:21][N:22]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:33][N:34]([CH:43]=[O:44])[OH:35])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[NH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ncc[nH]2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ncc[nH]1
Reaction time: 0.67 h
Yield: 93.5 %

Procedure:
To a 50 mL round-bottomed flask was added phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(1H-imidazol-2-ylamino)carbonyl]-1-pyrazolidinecarboxylate (39 mg, 0.065 mmol) in methanol (3 ml), followed by Pearlman's catalyst (9 mg). The mixture was stirred under a balloon of H2 for 40 min, the catalyst was filtered off. Removal of the solvent provided (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-1H-imidazol-2-yl-3-pyrazolidinecarboxamide as a off-white solid (23 mg, 92%). LCMS: (M+H)+: 379.4.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C(Cl)Cl>[C:19](=[O:20])([O:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)[O:10][C@@H:2]1[CH2:1][O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@H:3]12
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,4:3,6-dianhydro-D-mannitol (3.00 g, 20.5 mmol) and triethylamine (3.15 ml, 22.6 mmol) in DCM (100 ml), 4-nitrophenyl chloroformate (4.55 g, 22.6 g) was added and the mixture was stirred at room temperature for 18 hrs. Then the mixture was washed with a 5% solution of sodium dihydrogen phosphate (2×50 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 20 to 80%), affording the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)CC2C=CC(OC)=CC=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH2:74][C:75]1[C:76]([Cl:93])=[CH:77][C:78]([CH2:83][CH2:84][CH2:85][CH2:86][N:87]2[CH2:92][CH2:91][O:90][CH2:89][CH2:88]2)=[C:79]([CH:82]=1)[C:80]#[N:81]>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:93][C:76]1[CH:77]=[C:78]([CH2:83][CH2:84][CH2:85][CH2:86][N:87]2[CH2:88][CH2:89][O:90][CH2:91][CH2:92]2)[C:79]([C:80]#[N:81])=[CH:82][C:75]=1[NH:74][C:2]1[N:7]=[C:6]([NH:8][CH:18]2[CH2:19][CH2:20]2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: N#Cc1cc(N)c(Cl)cc1CCCCN1CCOCC1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)cc1CCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (53.2 mg, 0.15 mmol), cesium carbonate (98 mg, 0.300 mmol), palladium(II) acetate (10.10 mg, 0.045 mmol), DPPF (8.32 mg, 0.015 mmol) and Xantphos (8.68 mg, 0.015 mmol) was added a solution of 5-amino-4-chloro-2-(4-morpholinobutyl)benzonitrile (48.5 mg, 0.165 mmol) in dioxane (1 mL). The reaction was heated at 100° C. for 1.5 h at which point LCMS showed full conversation. The reaction was cooled to room temperature and diluted with EtOAc, filtered through a pad of celite, concentrated and purified by flash column chromatography. The intermediate was then treated with TFA/DCManisole (0.25 mL, 0.25 mL, 0.25 mL) and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and then diluted with MeOH (3 ml), loaded onto an SCX column, washed with MeOH (3×4 mL), and then 7N NH3/MeOH (4 mL). The ammonia filtrate was collected, concentrated in vacuo, and purified by preparative HPLC to give 2-((2-chloro-5-cyano-4-(4-morpholinobutyl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.5 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC1CCC(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
96 g (0.448 mol) of 4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylic acid (mixture of cis and trans isomers) was dissolved in CH2Cl2 (1 L). To this solution, oxalyl chloride (76 mL, 0.885 mol) was added dropwise. The reaction was stirred at room temperature for 2 hours and then concentrated. CH2Cl2 (1 L) was added to the residue and the solvent was stripped off. The process was repeated. Next, the residue was dissolved in CH2Cl2 (1 L) and Et3N (94 mL, 0.672 mol) was added. The solution was cooled to 10° C. and benzyl alcohol (56 mL, 0.537 mol) was added dropwise. The reaction was allowed to warm to room temperature and stir at room temperature for 12 hours. Next, the solvent was removed and toluene (1 L) was added. The volume of solvent was reduced to 500 mL and the solids were removed by filtration. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (0 to 20% EtOAc/heptanes) to afford benzyl trans-4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][NH:17][CH3:18])=[CH:14][CH:13]=1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:17]([CH2:16][C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)[CH3:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNCc1ccc(F)cc1
Reactant: CC(=O)N1CCC(=O)CC1
Product: CC(=O)N1CCC(N(C)Cc2ccc(F)cc2)CC1
Yield: 67.8 %

Procedure:
17.1 g (0.14 mol) of N-acetyl-4-piperidone and 16.9 g (0.14 mol) of N-(4-fluorobenzyl)-N-methylamine were reacted in a similar manner to Preparation 6. 25.1 g of 1-acetyl-4-(N-(4-fluorobenzyl)-N-methylamino)piperidine were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[N:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[CH:3][CH:4]=4)=[N:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1)c1cccc(C(F)(F)F)c1
Yield: 24.5 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol), 3-(trifluoromethyl)benzoic acid (110 mg, 0.581 mmol), oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as starting materials and in the same manner as in Example 412, the title compound (57 mg, 24%) was obtained as a white powder.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH2:49][CH3:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N1C(C(OCC)=O)=C(C(OCC)=O)NC1(C)Br)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:27]([N:34]1[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:37]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:36]=[C:35]1[CH:49]([Br:1])[CH3:50])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1nc(CC)n(Cc2ccccc2)c1C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: CCOC(=O)C1=C(C(=O)OCC)N(Cc2ccccc2)C(C)(Br)N1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(C(C)Br)n(Cc2ccccc2)c1C(=O)OCC
Yield: 97.8 %

Procedure:
3.08 g of N-bromosuccinimide and 0.51 g of benzoyl peroxide were added to a solution of 5.19 g of diethyl 1-benzyl-2-ethylimidazole-4,5-dicarboxylate [prepared as described in step (i) above] in 100 ml of carbon tetrachloride, and the resulting mixture was heated under reflux for 1 hour. Following a procedure similar to that described in Preparation 42(ii), 6.29 g of the title compound were obtained as a syrup from the resulting reaction solution.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O.O>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[C:9]([CH3:36])=[N:8][C:7]([N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:12][CH:11]=4)[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:24]=1
Reactant: C1CCNC1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCCC2)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 87980.8 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (123.7 mg, 0.208 mmol) in N,N-dimethylformamide (2.5 mL) was added pyrrolidine (86.8 μL, 1.04 mmol). The reaction mixture was stirred at 80° C. for 2.5 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (94.6 mg, 0.183 mol, 88%).
Reaction SMILES: [CH2:1](N(CC)CC)C.[C:8]([C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])(=O)[NH2:9].ClC(OC)=O>ClCCl>[C:8]([C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:12]=1[C:13]([O:15][CH3:1])=[O:14])#[N:9]
Reactant: NC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(Cl)cc1C#N
Temperature: 25 °C
Yield: 97.9 %

Procedure:
Triethylamine (25.4 mL, 0.182 mol) was added dropwise over a 20 minute period to a cold (0°-5° C.), stirred suspension of 2-carbamoyl-4,5-dichlorobenzoic acid (21.3 g, 91.0 mmol) in dichloromethane (110 mL). Methyl chloroformate (15.5 mL, 0.2 mol) was then added dropwise over a 30 minute period. The reaction mixture was then warmed to room temperature and stirred overnight. The solvents were removed and water (200 mL) was added. The water phase was filtered and the precipitate was washed with water and dried in vacuo to provide the product (20.5 g, 97%) as a tan solid, m.p. 120°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.[CH:21]([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH:10]([CH3:21])[C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: COc1cc(OC)c2c(c1)OC1(CCCCC1)CC2=O
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(OC)c2c(c1)OC1(CCCCC1)C(C)C2=O
Reaction time: 2 h
Yield: 69.6 %

Procedure:
A solution of 5,7-dimethoxyspiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 8) (1.38 g, 5 mmol) in dry tetrahydrofuran (10 ml) is added dropwise at -78° C. to a solution of lithium diisopropylamide (prepared from diisopropylamine (0.77 ml, 7.6 mmol) and 1.3N butyl lithium solution in hexane (3.85 ml, 5.0 mmol)) in tetrahydrofuran. To the mixture is added hexamethyl phosphoric triamide (1.05 ml) and then a solution of methyl iodide (0.78 g, 5.5 mmol) in tetrahydrofuran (1 ml) at -70° C. After the mixture is reacted at -78° to 0° C. for 2.5 hours and then at 0° to 3° C. for 2 hours, an aqueous solution of ammonium chloride is added thereto. The mixture is then extracted with diethyl ether and the organic layer is separated, washed twice with saturated brine, dried and the solvent is removed by distillation. The residue is loaded onto a Lober column and eluted with a mixture of acetonitrile and dichloromethane (1:9) to obtain the title compound as an oil (1.01 g, yield 69.6%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)=[O:11].[C:28]1([Li])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C>O1CCCC1.C1CCCCC1.C(OCC)C.C(Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:12]([C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[OH:11])[CH2:13][CH2:14]2)=[CH:25][CH:24]=1
Reactant: [Li]c1ccccc1
Reactant: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(CCN2CCC(C(O)(c3ccccc3)c3nc4ccccc4s3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve [2-benzothiazolyl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone (2.0 g, 5.26 mmol) in anhydrous tetrahydrofuran (50 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, phenyllithium (3.16 mL of a 2.0M solution in cyclohexane/ethyl ether, 6.31 mmol). Stir at -78° C. for 30 minutes, quench with saturated ammonium chloride (100 mL), separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (75% ethyl acetate/hexane) to give a yellow oil. Dissolve the oil in methylene chloride and treat with activated charcoal. Filter and evaporate the solvent in vacuo to give the title compound as a white electrostatic powder; mp 67°-70° C.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH3:14][C:15]([N:18]1[C:22]([NH2:23])=[CH:21][C:20]([CH3:24])=[N:19]1)([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:21]3[C:20]([CH3:24])=[N:19][N:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:22]=3[N:23]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)(C)C
Reaction time: 3 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 33 using ethyl 4-cyclopropyl-2,4-dioxobutanoate (481 mg, 2.61 mmol), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (400 mg, 2.61 mmol), and toluene (20 mL), wherein the reaction time was 3 h. The crude product was purified via silica gel chromatography (eluent: 0 to 10% EtOAc:Hex). The final product was collected as 0.24 g (30%). LCMS E-S (M+H)=302.5. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.23 (m, 4 H) 1.47 (t, J=7.20 Hz, 3 H) 1.79 (s, 9 H) 2.19 (s, 1 H) 2.66 (s, 3 H) 4.49 (q, J=7.07 Hz, 2 H) 7.44 (s, 1 H).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:12].C[O-].[Na+].[C:26](OC)(=[O:29])[C:27]#[CH:28]>>[F:22][C:19]([F:20])([F:21])[C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:11]([C:10]1[CH:28]=[CH:27][C:26](=[O:29])[N:1]2[C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=3[NH:3][C:2]=12)=[O:12]
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1cccc(C(F)(F)F)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 25 with 500 mg (1.62 mmol) of 2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-1-[3-(trifluoromethyl)phenyl]ethanone (example LII), 175 mg (3.25 mmol) of sodium methylate and 136 mg (1.62 mmol) methyl propiolate.