Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:18]([CH:39]([OH:57])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O(O)O.[BH4-].[Na+]>CO.C(O)(C)C>[CH2:1]([CH:18]([CH:19]([OH:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:39]([OH:57])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)C(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Agent: OOO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)C(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A solution of the keto-alcohol (6Z,9Z,29Z,32Z)-20-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-21-hydroxyoctatriaconta-6,9,29,32-tetraen-19-one (10) (920 mg, 1.16 mmol) in CH3OH (5 mL) and isopropanol (12 mL) was treated with NaBH4 (88 mg, 2.3 mmol). After stirring (1 h) a second portion of NaBH4 (88 mg, 23 mmol) was added and the mixture stirred (3 h). The reaction mixture was carefully quenched by the addition of cold HCl (5% aq.), extracted with CH2Cl2, washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was subjected to chromatography (1%→10% EtOAc-hexanes) to yield (6Z,9Z,29Z,32Z)-19-((8Z,11Z)-heptadeca-8,11-dien-1-yl)octatriaconta-6,9,29,32-tetraene-18,20-diol (11) (832 mg, 90%) as a colorless oil. Rf 0.23 (10% EtOAc-hexanes), FW 793.39, C55H100O2.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: NC(=O)CCl
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.8 %

Procedure:
A mixture of 2-chloroacetamide (5.6 g), 3-bromophenol (10 g), potassium carbonate (8.3 g) and potassium iodide (1 g) in acetonitrile was stirred at room temperature for 72 hours. The resulting mixture was filtered, and the solids washed with ethyl acetate, and then water. The dried solids were recrystallised from boiling ethanol: water(8:2) to give the sub-title compound as a solid (13.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.C([Li])CCC.[CH:17](=[O:19])[CH3:18]>O1CCCC1.O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([CH:17]([OH:19])[CH3:18])[O:9][C:8]=12
Reactant: COc1nccc2ccoc12
Reactant: CC=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nccc2cc(C(C)O)oc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 7-methoxyfuro[2,3-c]pyridine (1.5 g) in dry tetrahydrofuran (50 ml) was stirred at −78° C. under dry nitrogen. n-Butyllithium (1.6N solution in hexanes, 6.9 ml) was added dropwise and the resulting solution stirred at −78° C. for 60 minutes. Acetaldehyde (5.7 ml) was added and stirring continued at −78° C. for 90 minutes before warming to room temperature. The mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (1.8 g) as a brown oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3[F:20])[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH3-])(=O)C.[Na+]>>[F:21][C:16]1[CH:15]=[C:14]2[C:19](=[C:18]([F:20])[CH:17]=1)[N:10]([CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]1)[C:11](=[O:22])[CH:12]=[N:13]2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)cnc3cc(F)cc(F)c32)CC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5cc(F)cc(F)c54)CC3)nc2N1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,8-difluoroquinoxalin-2(1H)-one (Intermediate 196, 52 mg) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium acetoxyborohydride as described for Example 107 yielding 29 mg of the title compound.
Reaction SMILES: [NH2:1]N.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14]CN=O)[CH2:11][N+:10]([O-:18])=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1.O1CCCC1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:1])[CH2:11][N+:10]([O-:18])=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1
Reactant: NN
Reactant: O=NCNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Solvent: CO
Solvent: C1CCOC1
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Reaction time: 1 h

Procedure:
10 ml. of anhydrous hydrazine was added to a solution of 10 g. of 7-chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxide in 100 ml. of tetrahydrofuran and 50 ml. of methanol. After sitting at room temperature for 1 hour, the reaction mixture was evaporated under reduced pressure. The crystalline residue was partitioned between methylene chloride and water. The methylene chloride solution was dried and evaporated. Crystallization from methylene chloride/ether yielded 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 4-oxide with a melting point of 290°-292° dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Br)c1

Procedure:
3-Bromophenylacetic acid (0.31 mmol) was treated with concentrated sulfuric acid in ethanol at reflux for 2 hours to give (3-bromo-phenyl)-acetic acid ethyl ester.
Reaction SMILES: S(=O)(=O)(O)O.O[C:7]1([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C-]#[N:22].[K+].[ClH:24]>FC(F)(F)C(O)=O.CO.C(OCC)C>[ClH:24].[NH2:22][C:7]1([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [C-]#N
Reactant: Cn1cc(C2(O)CCCCC2)ccc1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CO
Product: Cn1cc(C2(N)CCCCC2)ccc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Concentrated sulfuric acid (67 ml) was added dropwise over 45 minutes to a suspension of 5-(1-hydroxycyclohexyl)-1-methyl-2(1H)-pyridinone (17.2 g) and potassium cyanide (16.3 g) in 334 ml of trifluoroacetic acid at 0° C. The resulting suspension was stirred at room temperature for 18 hours, and then it was cooled to 0° C., and diethyl ether was added slowly. The solvent was decanted, and the solids were washed with diethyl ether. The product was then dissolved in methanol and neutralized with poly-4-vinylpyridine. The polymer was removed by filtration, and the filtrate concentrated to yield a foam. The foam was dissolved in methanol, acidified with ethereal hydrochloric acid and concentrated, affording 17.1 g of foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([O:12][CH2:13][CH2:14][C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][C:18](B(O)O)=[CH:17][C:16]=2[CH2:26][CH3:27])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH2:34])=[O:33].O.[C:39]([OH:43])(=[O:42])[CH:40]=O>>[C:32]([C:31]1[CH:30]=[C:29]([NH:28][CH:40]([C:18]2[CH:19]=[C:20]([CH2:21][CH3:22])[C:15]([CH2:14][CH2:13][O:12][C:10](=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[C:16]([CH2:26][CH3:27])[CH:17]=2)[C:39]([OH:43])=[O:42])[CH:37]=[CH:36][CH:35]=1)(=[O:33])[NH2:34]
Reactant: NC(=O)c1cccc(N)c1
Reactant: CCc1cc(B(O)O)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Reactant: O=CC(=O)O
Solvent: O
Product: CCc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Yield: 70 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 37E (80 mg, 0.22 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 37F (81 mg, 70%) as a yellow oil. MS (ESI) m/z 515.21 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[N:5]1[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]1
Reactant: Clc1ncccn1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2ncccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
NaH (0.594 g, 14.84 mmol) was suspended in THF (10 mL), and 3,5-dimethylpyrazole (1.091 g, 11.35 mmol) was slowly added and stirred for one hour at room temperature. 2-Chloropyrimidine (1 g, 8.73 mmol) was slowly added to the mixture and refluxed for three hours. Completion of the reaction was confirmed by TLC, and then water (5 mL) was added to the mixture. The solvent was distilled off and the residue was extracted with ethyl acetate twice. The organic phase was washed with saturated brine and dried over magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→ethyl acetate) to give 1.05 g of the title compound (yield 69%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=3)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 40.6 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(ethylamino)piperidine-1-carboxylate obtained in Example (207a) (25.0 mg, 0.063 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (19 mg, 0.075 mmol) and sodium carbonate (66 mg, 0.625 mmol), to obtain 12 mg of the title compound (41%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](=O)[C:12]([C:15]#[N:16])=[CH:11][NH:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([Cl:21])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2[nH]cc(C#N)c(=O)c2c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Temperature: 75 °C

Procedure:
A 15 mL round bottom flask containing the compound 1C (370 mg, 1.51 mmol) was charged with POCl3 (1 mL) and heated to 75° C. for 2 h. The reaction mixture was concentrated in vacuo and the resulting yellow residue was dissolved in dichloromethane (10 mL) and added, via pipette, to a saturated aqueous solution of NaHCO3 with stirring at 0° C. The heterogeneous mixture was stirred for 10 min at 0° C. then warmed to room temperature and stirred for an additional 1 h. The mixture was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with dichloromethane (2×20 mL) and the combined organic extracts were washed with NaHCO3 (sat. aq., 1×20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was dissolved in EtOAc (20 mL) and filtered through a pad of silica using EtOAc (100 mL) to wash the silica pad. The filtrate was concentrated in vacuo to afford compound 1D as a yellow solid which was used without further purification. HPLC: 100% at 4.160 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[C:24]([Cl:29])[N:23]=1.O>C(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:11][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][N:7]=2)[CH3:10])[CH:25]=[C:24]([Cl:29])[N:23]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(Cl)nc(Cl)n1)c1ccc(F)cn1
Temperature: 80 °C
Yield: 56.2 %

Procedure:
(S)-1-(5-Fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 1.05 g, 4.91 mmol) and N,N′-diisopropylethylamine (2.80 mL, 16.36 mmol) were added to a solution of 2,4,6-trichloropyrimidine (0.75 g, 4.09 mmol) in ethanol (15 mL) and the resulting mixture was stirred and heated to 80° C. in a sealed tube for 1 hour. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes to 1:1 hexanes/ethyl acetate) to give the title compound (0.66 g, 57%) as a white solid.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:20]>>[CH2:1]([S:5]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCS(=O)(=O)Nc1ccc(C(=O)O)cc1
Product: CCCCS(=O)(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
In a manner similar to Preparation 10 react 4-[(1-butylsulfonyl)amino]benzoic acid with SOCl2 to obtain the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)(=[NH:4])=[O:3].[OH-].[Na+].C(OCC)(=O)C>C1COCC1.Cl>[NH2:11][C:7]1[CH:6]=[C:5]([S:2]([CH3:1])(=[NH:4])=[O:3])[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=N)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=N)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 200 mg (1.00 mmol) of (RS)-S-methyl-S-(3-nitrophenyl)sulfoximide in 20 ml of THF is mixed at room temperature with 8 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 3 hours, another 2 ml of the approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid is added and stirred overnight at room temperature. The batch is made basic with 1N NaOH solution and mixed with ethyl acetate. It is filtered, and the filter cakes are washed with ethyl acetate/MeoH (3:2). The organic solvent is drawn off in a rotary evaporator, and the residue is extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 0.82 mg (0.48 mmol, corresponding to 48% of theory) of the product is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[C:31](Cl)=[N:30][CH:29]=[CH:28][N:27]=1.CC(OC)(C)C.C(Cl)Cl>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:31]2[C:26]([Cl:25])=[N:27][CH:28]=[CH:29][N:30]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of compound (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (100 g, 0.42 mol) in anhydrous DMF (1.1 L) was added K2CO3 (145 g, 1.05 mol, 2.5 eq.) and 2,3-dichloropyrazine (75.08 g, 0.50 mol, 1.2 eq.). The reaction was stirred at 90° C. for 18 h. LCMS analysis of the reaction mixture showed that the reaction was complete. The reaction mixture was cooled to ambient temperature and ice-water (3 L) was added, stirred for 30 minutes. The resulting solid was filtered and washed with water (3 L) followed by MTBE (2×500 mL) and dried under vacuum. The solid was treated with 50% MTBE/DCM at 50° C. for 1 h and filtered hot, washed with 50% MTBE/DCM and dried under vacuum overnight to obtain product. Mother liquor was refluxed with 50% MTBE/DCM for 2 h and filtered hot and washed with 50% MTBE/DCM to get another batch of product. MS (ESI, pos. ion) m/z: 351.0 (M+1). IC50 (uM) +.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Brc1ccc(Nc2ncccn2)cc1
Reaction time: 3 h
Yield: 51.6 %

Procedure:
Under an argon atmosphere, 2-chloropyrimidine (2.68 g) and acetic acid (1.97 ml) were added to a solution of 4-bromoaniline (4.03 g) in dioxane (200 ml), and the resulting mixture was stirred for 3 hours while heating the mixture to reflux. Saturated aqueous sodium hydrogen carbonate solution was added in small portions to the reaction solution to neutralize it, and the resulting mixture was concentrated. Ethyl acetate (500 ml) was added to the residue and the resulting mixture was stirred at room temperature for 10 minutes, followed by removing insoluble matter by filtration. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from ethyl acetate to obtain N-(4-bromophenyl)pyrimidin-2-amine (3.02 g).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5][C:4]=2[CH:3]=1.[CH3:26][C:27]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29](C(OC(C)(C)C)=O)[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:26][C:27]1[NH:28][N:29]=[CH:30][C:31]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4CC[C@H](C4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
tert-Butyl (1R,3S,4S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.03 g) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.49 g), sodium carbonate (768 mg), 1,2-dimethoxyethane (8.0 mL) and water (4.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (197 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (690 mg) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:30])[C:9]2[C:10]([CH3:29])=[C:11]([CH:25]=[C:26]([Br:28])[CH:27]=2)[C:12]([NH:14][CH2:15][C:16]2[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:60](O)(=[O:62])[CH3:61]>CN(C=O)C.O>[C:60]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]([CH3:30])[C:9]2[C:10]([CH3:29])=[C:11]([CH:25]=[C:26]([Br:28])[CH:27]=2)[C:12]([NH:14][CH2:15][C:16]2[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])[CH2:6][CH2:7]1)(=[O:62])[CH3:61]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@@H](N)CC3)c2C)c(=O)[nH]1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CC[C@H](N(C)c2cc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c2C)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of trans-3-((4-aminocyclohexyl)(methyl)amino)-5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.225, 0.474 mmol) in DMF (3 mL), EDCI.HCl (0.138 g, 0.718 mmol), HOBt (0.064 g, 0.47 mmol), triethyl amine (0.1 g, 0.99 mmol) and acetic acid (0.057 g, 0.949 mmol) were added at room temperature and stirred at same temperature for 18 h. On completion, water was added and extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated giving crude material; which then purified by column chromatography to afford desired compound (0.13 g, 53%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:19]([NH:18][CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:33])=[CH:23][CH:24]=1)=[O:30]
Reactant: COC(=O)Cc1ccc(OC[C@H](C)N)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](C=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@H](C)NC[C@@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Preparation 29, but using 1.5 g of (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared as described in Preparation 26), 1.1 g of methyl 4-[2(S)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 28), 10 ml of absolute methanol and 950 mg of sodium cyanoborohydride, the title compound was obtained. [α]D23 +38.30° (c=1.116, chloroform)