Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[CH3:28][C:29]1([CH3:38])[CH2:34][NH:33][C@H:32]([C:35]([OH:37])=[O:36])[CH2:31][O:30]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:33]2[CH2:34][C:29]([CH3:28])([CH3:38])[O:30][CH2:31][C@H:32]2[C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: CC1(C)CN[C@H](C(=O)O)CO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CC(C)(C)OC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 67.3 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.24 g, 0.51 mmol) was reacted with (S)-6,6-dimethyl morpholine-3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.19 g, 68%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[C:17]([C:19]1[N:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:25]([C:22]3[CH:23]=[N:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)(=[O:26])=[O:27])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)Nc2cc(OC(F)(F)F)cc3cccnc23)cn1
Yield: 35.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-(trifluoromethoxy)quinolin-8-ylamine (Intermediate 46) (125 mg, 0.54 mmol), 6-cyano-pyridine-3-sulfonyl chloride (Intermediate 19) (132 mg, 0.65 mmol), pyridine (0.09 ml, 1.09 mmol), DMAP (cat.) and DCM (10 ml) gave the title compound (75 mg, 35%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11](=[O:14])[CH2:12][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Product: CCOC(=O)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclohexylamine (45 g, 0.45 mol) in dichloromethane (100 mL) was slowly added bromo-acetic acid ethyl ester (15 g, 0.09 mol) in dichloromethane (150 mL) at 0° C. After the addition, the mixture was stirred at room temperature for 1 h and then washed with water (3×200 mL). The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was purified with chromatography (DCM: MeOH=30:1) to give cyclohexylamino-acetic acid ethyl ester as an oil. MS: 186 (M+H)+.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:16]1([S:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([S:1][C:9]3[CH:14]=[CH:13][C:12]([O:15][S:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:24])=[O:23])=[CH:11][CH:10]=3)=[CH:3][CH:4]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(Sc2ccc(OS(=O)(=O)c3ccccc3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A 100 ml 3-necked oven-dried flask is equipped with a magnetic stirring bar and a CaCl2 -Drierite drying tube and is charged with 4,4'-thiodiphenol (5.3 grams, 24.3 mmol), benzenesulfonyl chloride (6.5 ml, 50.9 mmol), 4-dimethylaminopyridine (0.59 grams, 4.8 mmol), and anhydrous pyridine (40 ml). The mixture is stirred at ambient temperature for 18 hours, and at reflux for 4 hours, then is poured into ice-cold water (100 ml) with vigorous stirring, and the yellow oil that separates is extracted into CH2Cl2 (100 ml), and washed with water (100 ml). Drying (MgSO4), filtration and concentration affords a yellow oil. Purification by filtration through a column packed with flash-grade silica gel (5"×2" i.d.), eluting with CH2Cl2 (ca. 0.5 1), gives after solvent removal under vacuum 11.8 grams (98 percent yield) of the title compound as a faintly yellowish, thick glass material.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](I)([CH3:24])([CH3:23])[CH3:22].C([SnH](CCCC)CCCC)CCC>ClC1C=CC=CC=1>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(C)I
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Clc1ccccc1
Product: CC(C)(C)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Yield: 44.5 %

Procedure:
A solution of 56.0 g (203 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 125 ml of chlorobenzene, and 58.9 g of t-butyl iodide is cooled to 5° C. Tri-n-butyltin hydride (29 g, 100 mmol) is added dropwise over 110 minutes while the temperature is maintained below 20° C. The reaction mixture is concentrated at reduced pressure and then purified by silica gel chromatography (200:1, then 100:3 heptane:ethyl acetate) to afford 30.1 g of a white solid, m.p. 80°-82.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:12][C:13]3[NH:17][CH:16]=[C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]=3[CH3:23])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:35][O:34][C:32]1[CH:31]=[C:28]([CH:27]=[C:26]([O:25][CH3:24])[CH:33]=1)[CH2:29][O:21][C:20](=[O:22])[CH2:19][CH2:18][C:15]1[C:14]([CH3:23])=[C:13]([CH:12]=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[NH:17][CH:16]=1
Reactant: COc1cc(CCl)cc(OC)c1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COC(=O)CCc2c[nH]c(C=C3C(=O)Nc4cc(O)ccc43)c2C)cc(OC)c1
Yield: 28.1 %

Procedure:
3-[5-(6-Hydroxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid (100 mg), 56 mg 3,5-dimethoxy-benzylchloride and 207 mg potassium carbonate in 2 mL anhydrous dimethylformamide were heated at 90° C. overnight. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 39 mg of the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9](=O)[CH2:10][CH3:11]>CC(C)=O>[CH2:10]([C:9]1[S:3][C:2]2=[N:6][CH:5]=[CH:4][N:1]2[CH:8]=1)[CH3:11]
Reactant: Nc1nccs1
Reactant: CCC(=O)CBr
Solvent: CC(C)=O
Product: CCc1cn2ccnc2s1
Yield: 66.1 %

Procedure:
A solution of 3.0 g of 2-aminothiazole and 4.5 g of 1-bromo-2-butanone in 50 ml of acetone is heated under reflux for an hour and the precipitated crystals are collected by filtration. The crystals in 30 ml of aqueous HBr solution (1N) is heated at 80°-90° C. for an hour. After cooling, the reaction mixture is neutralized with 10% aqueous sodium hydroxide solution and extracted with dichloromethane. The extract is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 3.0 g of the title compound as an oil.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[Cl:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C:22]2[CH:23]=[C:24]([CH2:27]Cl)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH3:29].O>CN(C)C=O>[C:1]1([S:7]([NH:10][CH2:27][C:24]2[CH:25]=[CH:26][C:21]3[N:20]=[C:19]([CH3:29])[N:18]([CH2:17][C:16]4[CH:30]=[CH:31][CH:32]=[CH:33][C:15]=4[Cl:14])[C:22]=3[CH:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 0.667 g of benzenesulfonic acid amide in 5 ml of N,N-dimethylformamide were added 0.127 g of 60% sodium hydride at room temperature, and the mixture was stirred for 1 hour. Further, 0.648 g of 1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloride were added thereto, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution to stop the reaction, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate and with water. The organic layer was concentrated, and was purified through silica-gel column chromatography (eluent: ethyl acetate) to give 0.240 g of 6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methylbenzimidazole (264).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.[NH2:20][CH:21]1[CH2:27][CH:26]2[N:28]([CH3:29])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1>>[CH3:29][N:28]1[CH:23]2[CH2:24][CH2:25][CH:26]1[CH2:27][CH:21]([NH:20][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:22]2
Reactant: CN1C2CCC1CC(N)C2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Product: CN1C2CCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4ccccc4)nc13)C2
Yield: 20 %

Procedure:
N-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide was prepared from 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid and 3-amino-8-methyl-8-azabicyclo[3.2.1]octane using the method outlined in Step C of Example 7. This compound was obtained in 20% yield as a white solid: mp 187-190° C.; 1H NMR (500 MHz, CDCl3) δ 9.44 (d, J=7.5 Hz, 1H), 8.26 (d, J=7.1 Hz, 2H), 8.21 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.65-7.47 (m, 3H), 4.46 (q, J=7.2 Hz, 1H), 3.25 (br s, 1H), 2.38 (m, 5H), 2.26 (m, 4H), 1.84 (d, J=14.3 Hz, 2H), 2.15 (m, 1H), 2.04 (m, 1H), 1.78-1.60 (m, 3H); MS (APCI) m/z 397 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[C:8]([OH:10])=[O:9].[CH2:11](OS(OCC)(=O)=O)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:7][C:4]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([Cl:1])[S:6][N:5]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)c1c(Cl)nsc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(Cl)nsc1Cl
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Into a 500-mL round-bottom flask, was placed dichloro-1,2-thiazole-4-carboxylic acid (10 g, 50.50 mmol, 1.00 equiv), acetone (100 mL). This was followed by the addition of EtOSO3Et (19.54 g) dropwise with stirring at 0° C. in 3 min. To this was added potassium carbonate (28.02 g, 202.73 mmol, 4.01 equiv). The resulting solution was stirred for 30 min at 58° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of H2O. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (12:88). This resulted in 1.353 g (12%) of ethyl 3,5-dichloro-1,2-thiazole-4-carboxylate as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)[CH:5]=[CH:6][CH:7]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>N1C=CC=CC=1.CCOC(C)=O>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:4]1[CH:3]=[C:2]([NH:1][C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH:7]=[CH:6][CH:5]=1)#[N:20]
Reactant: CCn1c(C#Cc2cccc(N)c2)c(C#N)c2ccc(OC)cc21
Reactant: CCN=C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cccc(C#Cc2c(C#N)c3ccc(OC)cc3n2CC)c1
Temperature: 100 °C
Yield: 35.6 %

Procedure:
2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is dissolved in pyridine (670 μL). Ethyl isocyanate (62 μL, 0.75 mmol) is added. The reaction mixture is then heated at 100° C. for 2 h. The mixture is then diluted in EtOAc, and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica chromatography (4/1, CH2Cl2/EtOAc), followed by trituration with hexanes/acetone (1/1), yields 1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-3-ethyl urea (44 mg, 36%) as a white solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:21]3[CH2:20][CH2:19][CH:18]([NH2:22])[CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].Cl>C(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:21]3[CH2:20][CH2:19][CH:18]([NH:22][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1
Yield: 52.1 %

Procedure:
Dissolve 9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine (Preparation 47) (580 mg, 1.53 mmol) and triethylamine (201 mg, 277 μL, 1.99 mmol) in CH2Cl2 (20 ML). Slowly add isobutyryl chloride (212 mg, 208 μL, 1.99 mmol) and stir at room temperature for 18 h. Dilute the reaction with dilute HCl (10 mL), then load the reaction onto a Varian ChemElut CE1020 solid-phase extraction cartridge (Varian part number 12198008). Elute, collect, and concentrate 125 mL CH2Cl2 to give the crude product (794 mg) as a brown oil. Purify the crude product on silica gel (40 g), eluting with 35-65% EtOAc/hexanes to afford 358 mg (52%) of the title compound as a yellow foam. MS (ES): m/z 450 (M+1), 448 (M−1); HPLC (Method B): Rt=8.21 min (100%).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:43])[CH2:6][NH:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH2:24][C:23]([C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=2)=[CH:12][CH:11]=1)=[O:9]>O1CCCC1.O>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:34]=[C:29]([C:23]2([C:25]([F:26])([F:27])[F:28])[O:22][N:21]=[C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]([C:8]([NH:7][CH2:6][C:5]([OH:43])=[O:4])=[O:9])=[CH:11][CH:12]=3)[CH2:24]2)[CH:30]=[C:31]([C:39]([F:40])([F:42])[F:41])[CH:32]=1
Reactant: COC(=O)CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An aqueous solution of LiOH (300 mg, in 10 mL of H2O) was added to a stirred solution of N-[[4-[5-[3,5-bis(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine methyl ester (i.e. the product of Step B, 850 mg) in tetrahydrofuran (10 mL). After stirring at room temperature for 1 h, the reaction mixture was diluted with water and extracted with hexane. The aqueous layer was acidified with 6.0 N HCl to pH 2, and a white precipitate formed. The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound (800 mg) as a white solid. 1H NMR (CDCl3): δ 8.63 (d, 1H), 8.12 (d, 1H), 8.10 (s, 2H), 7.99 (s, 1H), 7.23-7.48 (m, 4H), 7.09 (br t, 1H), 4.20 (d, 1H), 4.19 (s, 2H), 3.83 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:16][CH:15]=2)=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3Cl)cc2)cc1
Temperature: 55 °C

Procedure:
The product from Example 24A (75.0 mg, 0.321 mmol), 4tert-butylaniline (61 μL, 0.383 mmol), PS-DCC (1.35 mmol/g, 0.7132 g, 0.963 mmol), HOBT (44.0 mg, 0.326 mmol), and triethylamine (0.13 mL, 0.93 mmol) in DMF (3 mL) were combined and heated at 55° C. for 16 hours. The mixture was allowed to cool to room temperature, filtered, and the filtrate was diluted with diethyl ether (20 mL). The diethyl ether was washed with 1N HCl (15 mL), brine (15 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 8.63 (dd, 1H), 7.98 (d, 2H), 7.88 (d, 2H), 7.88 (d, 1H), 7.81 (br s, 1H), 7.59 (d, 2H), 7.41 (d, 2H), 7.29 (dd, 1H), 1.33 (s, 9H); MS (m/z) 365.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:34]=[C:35]1[NH:39][CH:38]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>ClCCl.CN(C)C1C=CN=CC=1>[O:43]=[C:42]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH2:8][S:9][CH3:10])[CH2:41][CH2:40][CH:38]1[CH2:37][CH2:36][C:35](=[O:34])[NH:39]1
Reactant: O=C(O)CCC1CCC(=O)N1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.025 mol) L-methionine methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.42 ml (0.028 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes, filtered, and a mixture of the following is added in a single addition: 6.32 g (0.03 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 3.85 g (0.025 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 19:1 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields crystalline analytically pure N-[1-oxo- 3-(5-oxo-2-pyrrolidinyl)propyl]-L-methionine, methyl ester with a melting point of 98°-100° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@:17]2([CH2:23][O:24][P:25](=[O:36])([O:31]C(C)(C)C)[O:26]C(C)(C)C)[CH2:21][O:20]C(C)=[N:18]2)=[CH:11][CH:10]=1.Cl>C(O)C>[NH2:18][C@:17]([CH2:21][OH:20])([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][F:1])=[CH:10][CH:11]=1)[CH2:23][O:24][P:25](=[O:26])([OH:31])[OH:36]
Reactant: CC1=N[C@](CCc2ccc(OCCCCCCF)cc2)(COP(=O)(OC(C)(C)C)OC(C)(C)C)CO1
Agent: Cl
Solvent: CCO
Product: N[C@](CO)(CCc1ccc(OCCCCCCF)cc1)COP(=O)(O)O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of phosphoric acid di-tert-butyl ester (S)-4-{2-[4-(6-fluoro-hexyloxy)-phenyl]-ethyl}-2-methyl-4,5-dihydro-oxazol-4-ylmethyl ester (33 mg, 0.050 mmol) in ethanol (2 ml) is added conc. HCl (2 ml). The reaction mixture is stirred at 85° C. for 2 hours, then concentrated to dryness. The residue is re-dissolved in ethyl acetate and precipitated with hexanes. The solid is filtered off, washed with dry ether and dried under vacuum to afford phosphoric acid mono-{(S)-2-amino-4-[4-(6-fluoro-hexyloxy)-phenyl]-2-hydroxymethyl-butyl}ester as a colorless powder.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([OH:16])=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[O:10])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[S:1]1[C:5]([C:6]2[C:7]([O:16][CH3:21])=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[O:10])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: COc1ccc(C=O)c(O)c1-c1cc2ccccc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C=O)c(OC)c1-c1cc2ccccc2s1
Yield: 97.1 %

Procedure:
Ex-44B: 3-Benzo[b]thiophen-2-yl-2-hydroxy-4-methoxy-benzaldehyde (Ex-44A, 57.4 mg, 0.202 mmol) was dissolved in acetone (5 mL) and potassium carbonate (31 mg, 0.22 mmol) was added. Methyl iodide (25 uL, 0.40 mmol) was added and the solution was heated to reflux for 3.5 h. After cooling, the crude reaction mix was concentrated on the rotavap. The resulting residue was taken up in 10 mL of a 1:9 mix of saturated, aqueous NH4Cl to water and extracted with EtOAc (2×15 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to provide 58.5 mg of 3-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde as an orange, oily residue which was used without further purification, 97% yield. 1H-NMR (CDCl3) δ 10.31 (s, 1H), 7.92 (d, J=9 Hz, 1H), 7.81–7.88 (m, 2H), 7.56 (d, 1H), 7.33–7.39 (m, 2H), 6.88 (d, J=9 Hz, 1H), 3.91 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:32]2[N:31]=[C:30]3[N:33]([C:37]4[C:38]([CH3:46])=[N:39][C:40]([N:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=4)[CH2:34][CH2:35][CH2:36][N:29]3[C:28]=2[C:27]([CH2:47][OH:48])=[CH:26][CH:25]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH:47]=[O:48])=[C:28]2[C:32]=1[N:31]=[C:30]1[N:33]([C:37]3[C:38]([CH3:46])=[N:39][C:40]([N:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=3)[CH2:34][CH2:35][CH2:36][N:29]21
Reactant: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 0 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
Dess-Martin reagent (410 mg, 0.967 mmol) was added to a stirred solution of {9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}methanol (327 mg, 0.879 mmol) in dimethyl sulfoxide (1.0 mL) and acetonitrile (6.0 mL) at 0° C., and the mixture was stirred at 0° C. for 4 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (243 mg, 0.657 mmol, 75%).