Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.[C:16](=[O:19])([O-])[O-].[K+].[K+].[CH4:22]>CO.CC(C)=O>[C:22]1([C:16](=[O:19])[CH2:6][CH2:7][CH2:14][O:15][C:6]2[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]3[O:3][CH:2]=[CH:1][C:5]=23)[CH:1]=[CH:5][CH:4]=[CH:9][CH:8]=1
Reactant: C
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: O=C(CCCOc1c2ccoc2cc2oc(=O)ccc12)c1ccccc1
Reaction time: 0.29 h

Procedure:
497 mg (2.720 mmol) of 4-chlorobutyrophenone and 445 mg (2.968 mmol) of sodium iodide were refluxed in 30 ml acetone for 1.5 hours to obtain the iodo derivative. The reaction was monitored by TLC and also visually by the precipitation of sodium chloride. To this slurry was added 500 mg (2.473 mmol) of 5-hydroxypsoralen, an excess (2 g) of anhydrous potassium carbonate and it was refluxed for 140 hours. The progress of the reaction was monitored by thin layer chromatography. After 140 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min, filtered and washed with water and dried under vacuum. The solids were suspended in 50 ml ethyl acetate and refluxed to separate the un-reacted 5-hydroxypsoralen. The ethyl acetate layer was concentrated, the resulting residue dissolved in 100 ml dichloromethane and extracted with 25 ml of 1% sodium hydroxide to separate the remaining trace amounts of un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid solution, dried over anhydrous sodium sulfate and concentrated. The solid residue obtained was dissolved in a methanol-acetone mixture, treated with charcoal and re-crystallized from a petroleum ether-acetone (90:10) mixture.
Reaction SMILES: [CH2:1]([N:6](CCCCC)CCCCC)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-:17].[Na+]>>[CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [OH-]
Reactant: CCCCCN(CCCCC)CCCCC
Agent: [Na+]
Product: CCCCCN
Product: CCCCCO

Procedure:
To synthesize tri-n-pentylamine, a solution of 1 mol of n-pentylamine in 4 mol of n-pentanol was prepared. This solution was treated with 0.25% by weight of 50% strength by weight sodium hydroxide solution.
Reaction SMILES: CN(N=[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[O:23])[C:12]2=[O:32])=[CH:7][CH2:6]1)C.[CH3:33][NH:34][CH2:35][CH2:36][NH2:37].[CH3:38]C(O)=O>>[CH3:33][N:34]1[CH2:35][CH2:36][N:37]=[C:38]1[C:17]1[CH:18]=[CH:19][C:20]([N:11]2[C:8]3[C:7](=[CH:6][CH:5]=[CH:10][CH:9]=3)[CH2:14][CH:13]([NH:21][C:22]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[O:23])[C:12]2=[O:32])=[CH:15][CH:16]=1
Reactant: CC(=O)O
Reactant: CNCCN
Reactant: CN(C)N=C1C=CC(N2C(=O)C(NC(=O)Nc3ccc(Cl)cc3)Cc3ccccc32)=CC1
Product: CN1CCN=C1c1ccc(N2C(=O)C(NC(=O)Nc3ccc(Cl)cc3)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.063 mmol) from Example 134, a pre-mixed N-methylethylenediamine (0.039 mL, 0.44 mmol) and HOAc (0.080 mL, 1.4 mmol) were added. The mixture was heated to reflux for 1 h, then was stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (15 mg). MS 474.3 and 476.3 (M+H, Cl pattern).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C[C@@H]1O[C@@H]([O:19][C@H:20]2[C@H:25]([O:26][C:27]3[CH:28]=[C:29]([OH:45])[C:30]4[C:36](=[O:37])[CH2:35][C@@H:34]([C:38]5[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=5)[O:33][C:31]=4[CH:32]=3)[O:24][C@H:23]([CH2:46][OH:47])[C@@H:22]([OH:48])[C@@H:21]2[OH:49])[C@H](O)[C@H](O)[C@H]1O.S(=O)(=O)(O)O>>[O:26]=[CH:25][C@@H:20]([C@H:21]([C@@H:22]([C@@H:23]([CH2:46][OH:47])[OH:24])[OH:48])[OH:49])[OH:19].[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[CH:43]1[C:38]([C@H:34]2[O:33][C:31]3[CH:32]=[C:27]([OH:26])[CH:28]=[C:29]([OH:45])[C:30]=3[C:36](=[O:37])[CH2:35]2)=[CH:39][CH:40]=[C:41]([OH:44])[CH:42]=1
Reactant: C[C@@H]1O[C@@H](O[C@H]2[C@H](Oc3cc(O)c4c(c3)O[C@H](c3ccc(O)cc3)CC4=O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Agent: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: O=S(=O)(O)O
Product: O=C1C[C@@H](c2ccc(O)cc2)Oc2cc(O)cc(O)c21
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Illustrative of a process for obtaining L-rhamnose from naringin is described by G. N. Pulley, et al., "Preparation of Rhamnose from Naringin", J. Amer. Chem. Soc., 61, p. 175 (1939), in which naringin is hydrolyzed by refluxing it with sulphuric acid (~3.7%). Glucose, L-rhamnose, naringenin and other reaction products are formed by the reaction. The reaction medium is cooled and naringenin, which is semi-solid, is separated from the cooled reaction medium. The remaining filtrate then is neutralized and heated to boiling in the presence of charcoal. The charcoal treated product is concentrated in vacuo and then is inoculated with yeast to ferment glucose. L-rhamnose is isolated from the fermented liquor by several steps of concentration in vacuo and washing.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2C(OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]([CH:25]=[O:26])C.[H-].[Na+].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>O.C1COCC1>[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:10]2[N:23]([C:22]2[CH:12]=[N:11][CH:10]=[CH:9][CH:17]=2)[CH:25]=[O:26])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1[nH]c2ccccc2c1OCc1ccccc1
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Cn2c(N(C=O)c3cccnc3)c(OCc3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round bottom flask was placed methyl 3-(phenylmethoxy)indole-2-carboxylate (50 mg) along with DMF (1.0 mL), THF (1.0 mL) and 10 mg of a NaH suspension (60% in oil). To this stirred mixture was added 4-tert-butylbenzyl bromide and allowed to stir at room temperature overnight. At this time, the reaction mixture was diluted with H2O, poured into a teflon fritted cartridge and extracted with CH2Cl2. The filtrate was concentrated and then treated with THF/H2O (5.0 mL, 1:1), MeOH (2.0 mL), NaOH (1 mL of a 1N aq. solution) and allowed to stir at room temperature overnight. At this time, the reaction mixture was acidified to pH 4 with an aqueous 1N HCl solution, diluted with 2 mL H2O, extracted with CH2Cl2 through a teflon fritted cartridge as above and the filtrate was concentrated. The resulting crude carboxylic acid was taken up in THF (2.0 mL) and treated with i-Pr2NEt (0.1 mL), MsCl (10 μL) followed by 3-aminopyridine (50 mg) as described previously for the preparation of example 166. After work-up and purification by flash chromatography 10.6 mg of the title amide was isolated.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]2[CH2:34][CH2:35][CH2:36]2)[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C1CCC1
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (153 mg) and 37% formalin (0.10 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and triethylamine (0.34 mL) and 3-cyano-5-cyclobutyl-4-methoxybenzoyl chloride (204 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (j).
Reaction SMILES: C(C1C(C)=NC(C)=C(C=1)C#N)(=[O:3])C.S1C=CN=C1C(=O)C.[CH3:22][C:23]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][C@H:45]4[CH3:49])[CH:38]=3)[N:33]=2)=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:22][C:23]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][C@H:45]4[CH3:49])[CH:38]=3)[N:33]=2)=[CH:27][C:24]=1[C:25]([NH2:26])=[O:3]
Reactant: CC(=O)c1cc(C#N)c(C)nc1C
Reactant: Cc1nc(C)c(-c2ccc3cc(CCN4CCC[C@H]4C)ccc3n2)cc1C#N
Agent: CC(=O)c1nccs1
Product: Cc1nc(C)c(-c2ccc3cc(CCN4CCC[C@H]4C)ccc3n2)cc1C(N)=O

Procedure:
The title compound was prepared using the procedure described in Example 57 using 5-acetyl-2,6-dimethylnicotinonitrile for 1-(1,3-thiazol-2-yl)ethanone providing the product from Example 67 which eluted first and the title compound which eluted second. 1H NMR (CDCl3) δ ppm 1.18 (d, J=5.43 Hz, 3 H), 1.53 (m, 1 H), 1.80 (m, 2 H), 1.98 (m, 1 H), 2.2-2.6 (m, 3 H), 2.65 (s, 3 H), 2.78 (s, 3 H), 3.09 (m, 2 H), 3.19 (m, 1 H), 3.33 (m, 1 H), 5.75 (s, 1 H), 5.90 (s, 1H), 7.52 (d, J=8.48 Hz, 1 H), 7.66 (dd, J=8.65, 1.87 Hz, 1 H), 7.71 (s, 1 H), 7.94 (s, 1 H), 8.06 (d, J=8.82 Hz, 1 H), 8.19 (d, J=8.14 Hz, 1 H). MS (DCl—NH3) [M+H]+ at 389.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][C:18]2[C:13]([CH3:12])=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1ncccc1N
Solvent: c1ccncc1
Product: Cc1ncccc1NS(=O)(=O)c1ccc(Br)cc1
Yield: 62.7 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (4.73 g, 18.5 mmol) and 2-methyl-3-aminopyridine (2.04 g, 18.9 mmol) in pyridine (36 ml) according to the method of intermediate 1, to give the title compound as a white solid (3.81 g, 11.6 mmol, 63%). δH (CDCl3, 300K) 8.36 (1H, dd J 4.8 Hz 1.5 Hz), 7.70 (1H, dd J 8.1 Hz 1.5 Hz), 7.63 (2H, dd J 6.6 Hz 2.3 Hz), 7.60 (2H, dd J 6.6 Hz 2.3 Hz), 7.17 (1H, dd J 8.1 Hz 4.8 Hz), 6.89 (1H, s), 2.25 (3H, s). m/z (ES+, 70V) 329.0 (MH+).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:27]([N+:35]([O-:37])=[O:36])=[CH:26][CH:25]=1.[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[C:46]1[C:51]([C:52]2[NH:53][CH:54]=[CH:55][N:56]=2)=[CH:50][N:49]=[C:48]([NH:57][CH2:58][CH2:59][NH:60]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:47]=1>>[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[C:46]1[C:51]([C:52]2[NH:56][CH:55]=[CH:54][N:53]=2)=[CH:50][N:49]=[C:48]([NH:57][CH2:58][CH2:59][NH:60][C:24]2[N:29]=[C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:27]([N+:35]([O-:37])=[O:36])=[CH:26][CH:25]=2)[N:47]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CS(=O)(=O)Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)-amino]-3-nitro(2-pyridyl)}(methylsulfonyl)amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and (6-chloro-3-nitro(2-pyridyl))(methylsulfonyl)amine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].CN(C)C=O.[H-].[Na+].I[CH2:24][CH3:25]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:15][O:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH2:24][CH3:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine methyl 3,5-dimethoxy-4-hydroxy-benzoate (2.12 g, 10 mmol) and dimethylformamide (50 mL). Cool in an ice bath. Add portionwise, sodium hydride (0.4 g, 16.7 mmol). after 2 hours, add iodoethane (4 mL, 50 mmol). Warm to ambient temperature. After 18 hours, dilute the reaction mixture with ethyl acetate and extract with water, 1M hydrochloric acid solution, a saturated sodium bicarbonate solution, and then brine. Dry the organic layer over MgSO4, filtered and evaporated in vacuo to give a residue. chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give methyl 3,5-dimethoxy-4-ethoxy-benzoate.
Reaction SMILES: [NH2:1][C:2]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2OC(=O)[C:14](=[C:18]=[O:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:3].O.[NH2:21][NH2:22].[CH2:23]([OH:25])C>>[NH2:1][C:2]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]([CH2:23][OH:25])[CH2:14][C:18](=[O:19])[NH:21][N:22]=2)=[CH:10][CH:11]=1)=[O:3]
Reactant: NC(=O)COc1ccc(C2CC(=C=O)C(=O)O2)cc1
Reactant: NN
Reactant: CCO
Solvent: O
Product: NC(=O)COc1ccc(C2=NNC(=O)CC2CO)cc1

Procedure:
11.3 g (0.043 mol) of 4-(4-(aminocarbonylmethoxy)-phenyl)-carbonyl-γ-butyrolactone and 2.4 g (0.048 mol) of hydrazine hydrate are reacted in 70 ml of ethanol, as described above.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1ccc2ccccc2n1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc2ccc(F)nc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-fluoroquinoline (1.3 g, 8.9 mmol) in chlorosulfonic acid (15 mL) was stirred at −5-0° C. for 15 minutes and at 130° C. overnight. The resulting reaction mixture was poured into an ice-water mixture (300 mL), stirred at room temperature for 20 min, and extracted with EtOAc. The organic layer was then washed with brine, dried over Na2SO4 and solvent was removed. The residue was purified by column chromatography using a gradient elution from 100% PE to PE/EtOAc (100:6) to afford 1.1 g of title compound. 1H NMR (CHLOROFORM-d) δ: 8.56 (d, J=7.5 Hz, 1H), 8.43 (t, J=8.3 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.32 (dd, J=8.9, 3.0 Hz, 1H). LC-MS: m/z 246.3 (M+H)+
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][N:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Brc1ccncn1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1cc(-c2ccncn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 120 °C
Yield: 50.9 %

Procedure:
Into an appropriate sized reaction vessel, a mixture of (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.24 mmol), 4-bromopyrimidine (77.3 mg, 0.49 mmol), sodium carbonate (77.3 mg, 0.73 mmol) and Pd(PPh3)4 (14.04 mg, 0.01 mmol) was added Dioxane (8 ml), water (1 ml). The reaction mixture was stirred and heated at 120° C. for 3 h. Then, it was filtered through a pad of Celite and partitioned between EtOAc (2×30 mL) and brine (2×10 mL). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH in EtOAc) to give 45.0 mg (50.9%) of (R)-4-((R)-1-((1-cyclopropyl-5-(pyrimidin-4-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 9.211 (d, J=1.2 Hz, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.19 (dd, J=2.4, 0.9 Hz, 2H), 8.11 (s, 1H), 7.719 (s, 1H). 7.603 (s, 1H), 4.91-4.83 (m, 1H), 3.77-3.70 (m, 1H), 3.41 (t, J=9.2 Hz, 1H), 3.21 (dd, J=6.6, 6.9 Hz, 1H), 2.87-2.82 (m, 1H), 2.41-2.24 (m, 2H), 1.34 (d, J=6 Hz, 3H), 1.20-1.01 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C20H21N5O2: 363.17; found 364.04.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[BrH:16]>O>[Br:16][CH2:12][CH2:11][CH2:10][N:6]1[C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: Br
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCBr

Procedure:
A mixture of 9.3 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one and 83 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 6 hours. The reaction mixture was cooled and allowed to crystallize overnight at room temperature. The precipitated product was filtered off and stirred a few times in 100 parts of water till the pH of the filtrate was greater than 2. The product was stirred and refluxed for 1 hour in 55 parts of chlorobenzene with 1.3 parts of activated charcoal. The latter was filtered off and the filtrate was allowed to crystallize overnight in an ice-box. The product was filtered off and recrystallized twice: first from chlorobenzene (activated charcoal) and then from methylbenzene (activated charcoal), yielding 4.9 parts of 1-(3-bromopropyl)-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 161.5° C. (intermediate 29).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1ccco1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccco1
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3 g, 7.6 mmol) in DCM (50 mL) was added pyridine (10 mL). The mixture was cooled to 0° C. Furan-2-sulfonyl chloride (1.4 g, 8.4 mmol) in DCM (5 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (100 mL), and extracted with DCM (2×100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc 4:1) to afford the title compound of Step A (2.5 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=5.5 Hz, 1H), 7.59-7.66 (m, 1H), 7.42-7.75 (br, 1H), 7.13-7.20 (m, 2H), 7.02 (d, J=5.5 Hz, 1H), 6.93-6.98 (m, 1H), 6.37-6.42 (m, 2H), 3.50-3.57 (m, 4H), 3.72-3.78 (m, 4H). MS (ES+): 522 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][OH:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]([CH3:16])=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14]([CH3:16])([CH3:13])[O:12][NH:11][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NO)Nc1cccc(Cl)c1
Reactant: CC(C)=O
Solvent: O
Product: CC1(C)ONC(=O)N1c1cccc(Cl)c1

Procedure:
18.6 g. (0.1 moles) of N-(3-chlorophenyl)-N'-hydroxy-urea are added to 130 g. of acetone. The mixture is stirred for 15 minutes at the temperature of the water bath under reflux. The reaction mixture is then evaporated to dryness and the residue is recrystallized from the mixture of acetone and water.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1.N[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.[N:22]#[C:23][Br:24]>CO>[BrH:24].[C:9]([CH2:8][CH2:7]/[C:3](/[CH:2]=[N:22]/[C:23]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)=[CH:4]\[CH:5]=[CH:6]\[NH:1][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)([OH:11])=[O:10]
Reactant: O=C(O)CCc1cccnc1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#CBr
Solvent: CO
Product: Br
Product: O=C(O)CCC(/C=N/c1ccc(C(=O)O)cc1)=C\C=C\Nc1ccc(C(=O)O)cc1
Reaction time: 2 h

Procedure:
3-Pyridinepropionic acid (10 mmol, 1.52 g) and 4-aminobenzoic acid (20 mmol, 2.74 g) were dissolved in 75 mL methanol on an ice water bath. Cyanogen bromide (10 mmol, 1.07 g) in 5 mL methanol was then added to the reaction solution over 5 min. The product, (1.02 g, 21%), was collected by filtration after stirring for 2 hours and was washed with dichloromethane. 1H NMR (500 MHz, DMSO-d6): δ 12.40 (s, 3H), 7.95-7.83 (m, 5H), 7.67-7.65 (m, 1H), 7.17 (d, 2H, J=8.0 Hz), 7.09 (d, 2H, J=8.5 Hz), 6.95 (d, 1H, J=10.5 Hz), 6.17 (t, 1H, J=12.3 Hz), 2.71 (t, 2H, J=7.5 Hz), 2.40 (t, 2H, J=7.8 Hz). ESI [M+H]+ m/z calcd. for [C22H2iN2O6]+ 409.4, found 409.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=1.[CH2:16]([N:18]([CH2:39][CH3:40])[C:19](=[O:38])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCCl.O>[CH2:39]([N:18]([CH2:16][CH3:17])[C:19](=[O:38])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=3)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:40]
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Reactant: CCN(CC)C(=O)COc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCC(=O)N(CC)CC)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of ethyl 3-(4-amino-2-fluorophenyl)propanoate (0.496 g, 2.35 mmol) and N,N-diethyl-2-[(3′-formyl-2,6-dimethylbiphenyl-4-yl)oxy]acetamide (0.725 g, 2.14 mmol) in 1,2-dichloroethane (10 mL) was added acetic acid (0.245 mL, 4.28 mmol), and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (0.907 q, 4.28 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. Water and 10% aqueous citric acid solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-70% ethyl acetate/hexane) to give the title compound (0.978 g, yield 86%) as a yellow oil.